Angina Research: 2002-2006
   
Ann Thorac Surg. 2006 Nov;82(5):1704-8.
Spinal cord stimulation for patients with refractory angina and previous coronary surgery.
Lapenna E, Rapati D, Cardano P, De Bonis M, Lullo F, Zangrillo A, Alfieri O.
Department of Cardiac Surgery, San Raffaele University Hospital, Milan, Italy. lapenna.elisabetta@hsr.it

BACKGROUND: Refractory angina pectoris is an exceptionally debilitating condition affecting patients who have typically failed multiple percutaneous and surgical revascularizations and optimal medical therapy and who are not amenable for further revascularization procedures. Spinal cord stimulation (SCS) has been adopted in this context at our institution and midterm mortality, anginal status, and quality of life have been evaluated. METHODS: From 1998 to 2004, 51 patients with refractory class III-IV angina, who were not considered candidates for revascularization procedures, underwent SCS. All patients had already undergone previous surgical revascularization and a median of two percutaneous procedures. Transmyocardial laser revascularization had been previously performed in 8 cases (15.6%). Most of the patients (70.5%) had experienced a myocardial infarction. Mean ejection fraction was 0.42 +/- 0.121, Canadian Cardiovascular Society class 3.5 +/- 0.5, quality of life (Spitzer index) 4.5 +/- 1.2, and the median frequency of weekly angina episodes was 10. RESULTS: There were no SCS implantation-related complications. At follow-up (100% complete, mean 24 +/- 18 months), a significant improvement of anginal symptoms (>50% reduction of weekly anginal episodes) occurred in 45 patients (88.2%). In those patients (Responders), the quality of life improved significantly (6.8 +/- 1.5; p < 0.0001), CCS class decreased to 2 +/- 0.7 (p < 0.0001), and the median frequency of weekly angina episodes to 3 (p < 0.0001). At 3 years, Responders' survival was 91.8 +/- 4.6% and the freedom from cardiac events 72.6 +/- 8.42%. CONCLUSIONS: Spinal cord stimulation is a safe and effective procedure in truly no-option patients affected by refractory angina. A midterm sustained improvement of symptoms and quality of life have been documented with a satisfactory 3-year survival rate.

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Am J Cardiol. 2006 Nov 1;98(9):1214-7. Epub 2006 Sep 7.
Acute and Long-Term Results of Bifurcation Stenting (from the COroflex Registry).
Rux S, Sonntag S, Schulze R, Rau M, Weber F, Muhling H, Cioppa A, Kleber FX; BISCOR Investigators.
ukb Academic Teaching Hospital, Berlin, Germany.

Angioplasty of bifurcation lesions represents a continuing challenge. A total of 421 consecutive patients were prospectively followed in a registry on bifurcation stenting with a high-end bare metal stent (Coroflex, BBraun, Berlin, Germany), allowing side branch percutaneous transluminal coronary angioplasty through the stent struts without distraction of the main vessel stent from the vessel wall or other distortions. This approach obviated the 2-wire technique and kissing balloons. Detailed data, including lesion location, stenosis morphology, procedural success, and hospital and follow-up major adverse cardiac events (MACEs; acute myocardial infarction, death, revascularization, hospitalization due to angina), were collected from 6 European centers. Of the patients, 60% had stable angina, 23% had unstable angina pectoris/non-ST-elevation myocardial infarction, and 17% had ST-elevation myocardial infarction. In 17% of patients, the main vessel alone was stented; in 71%, stenting of the main vessel was complemented by side branch percutaneous transluminal coronary angioplasty. Technical success (residual stenosis <50%) in the 2 branches was achieved in 90% (main vessel in 99%). The rate of MACEs at discharge was 2%. After 6 months, 17% of patients had undergone target lesion revascularization or coronary artery bypass grafting. The total 6-month MACE rate was 22%. In conclusion, successful bifurcation stenting with a low MACE rate is possible in most patients using a simplified approach with a dedicated high-end bare metal stent.

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Internist (Berl). 2006 Oct 25; [Epub ahead of print]
[Therapy of chronic coronary artery disease : Medical treatment vs. bypass surgery vs. coronary intervention.]
[Article in German]
Elsner D.
III. Medizinische Klinik, Klinikum Passau, Innstr. 76, 94032, Passau, Deutschland, dietmar.elsner@klinikum-passau.de.

The management of coronary artery disease should always include life style modification, control of cardiovascular risk factors and drugs with proven prognostic efficacy, i.e. antiplatelet drugs, statins, ss-blockers and, in most cases, ACE-inhibitors. Nitrates, sometimes also calcium antagonists, are used to control the symptoms of angina pectoris. Revascularisation by percutaneous treatment (stent implantation) or bypass surgery is indicated in patients with large areas of ischemia during stress testing or with high risk coronary anatomy during angiography, especially with reduced ventricular function, or when the angina cannot be adequately controlled by medicinal management. Single vessel and uncomplicated two vessel involvement are usually treated using a stent. Main stem stenosis, three vessel and severe two vessel involvement, particularly with reduced ventricular function, remain the domain of bypass surgery. Controlled studies show identical prognoses for patients with multiple vessel involvement for whom both treatment strategies are possible, although there is a higher reintervention rate for the stent patients. Coronary anatomy, ventricular function, as well as various patient-related factors have to be taken into account when deciding on the form of revascularisation therapy.

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J Am Coll Cardiol. 2006 Oct 3;48(7):1319-25. Epub 2006 Sep 12.
Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials.
Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT.
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA.

OBJECTIVES: This study sought to systematically determine whether early invasive therapy improves survival and reduces adverse cardiovascular events in the management of non-ST-segment elevation acute coronary syndromes. BACKGROUND: Although early invasive therapy reduces recurrent unstable angina, the magnitude of benefit on other important adverse outcomes is unknown. METHODS: Clinical trials that randomized non-ST-segment elevation acute coronary syndrome patients to early invasive therapy versus a more conservative approach were included for analysis. RESULTS: In all there were 7 trials with 8,375 patients available for analysis. At a mean follow-up of 2 years, the incidence of all-cause mortality was 4.9% in the early invasive group, compared with 6.5% in the conservative group (risk ratio [RR] = 0.75, 95% confidence interval [CI] 0.63 to 0.90, p = 0.001), and at 1 month (RR = 0.82, 95% CI 0.50 to 1.34, p = 0.43). At 2 years of follow-up, the incidence of nonfatal myocardial infarction was 7.6% in the invasive group, versus 9.1% in the conservative group (RR = 0.83, 95% CI 0.72 to 0.96, p = 0.012), and at 1 month (RR = 0.93, 95% CI 0.73 to 1.19, p = 0.57). At a mean of 13 months of follow-up, there was a reduction in rehospitalization for unstable angina (RR = 0.69, 95% CI 0.65 to 0.74, p < 0.0001). CONCLUSIONS: Managing non-ST-segment elevation acute coronary syndromes by early invasive therapy improves long-term survival and reduces late myocardial infarction and rehospitalization for unstable angina.

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J Cardiovasc Pharmacol. 2006 Sep;48(3):110-6.
Effects of long-term oral dipyridamole treatment on coronary microcirculatory function in patients with chronic stable angina: a substudy of the persantine in stable angina (PISA) study.
Jagathesan R, Rosen SD, Foale RA, Camici PG, Picano E.
MRC Clinical Sciences Centre and National Heart and Lung Institute, Imperial College, London, UK.

AIMS: A meta-analysis of 13 randomized placebo-controlled trials demonstrated a benefit for dipyridamole therapy, particularly with longer duration of treatment. Although the mechanism of this effect is not well understood, dipyridamole increases endogenous tissue adenosine, which may have a beneficial effect on myocardial perfusion. Therefore, we measured the effects of dipyridamole on myocardial blood flow (MBF) and coronary flow reserve (CFR) by using positron emission tomography and H2O in patients with coronary artery disease. METHODS: Forty-four patients with angiographically documented coronary artery disease were double-blind randomized to either oral dipyridamole [200 milligrams (mg) twice daily (bd)] or placebo as add-on to conventional antianginal treatment for 24 weeks. MBF was measured at rest and during dobutamine stress at baseline and study completion for the region subtended by the most severe coronary artery stenosis (Isc) and remote myocardium subtended by arteries with minimal or no disease (Rem). CFR was calculated as MBF-peak/MBF-rest. RESULTS: Thirty-five patients completed the study. Isc MBF-rest decreased in patients receiving dipyridamole (0.10 mL/minute/g; P = 0.03) and increased in the placebo group (0.16 mL/minute/g; P = 0.01) during the 24-week study. No significant change in MBF-peak was demonstrated in either group. Consequently, Isc-CFR increased significantly in patients receiving dipyridamole (1.65 +/- 0.47 vs 1.83 +/- 0.67; P < 0.05). By contrast, Isc-CFR decreased significantly in those receiving placebo (1.74 +/- 0.44 versus 1.38 +/- 0.46; P < 0.03). No change was seen in Rem-CFR territories. CONCLUSIONS: At the end of treatment, a reduction in baseline MBF but no significant changes in hyperemic MBF were observed in ischemic myocardial territories, and therefore the significance of the observed improvement in CFR remains unclear.

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Am J Cardiol. 2006 Sep 4;98(5A):8J-13J. Epub 2006 Jul 24.
Clinical benefits of a metabolic approach with trimetazidine in revascularized patients with angina.
Danchin N.
Division of Cardiology and Coronary Artery Disease, Hopital Europeen Georges Pompidou, Paris, France. nicolas.danchin@egp.ap-hop-paris.fr

As patients with coronary artery disease live longer and more often reach the stage where further myocardial revascularization procedures can no longer be performed, efficacious and well-tolerated antianginal medications are needed. Metabolic agents offer the advantage of controlling symptoms without untoward hemodynamic effects. This article reviews the epidemiology of stable angina and the use of antianginal medications in patients who have undergone myocardial revascularization. It also describes the clinical data on the anti-ischemic effects of metabolic agents in patients undergoing coronary artery bypass surgery or angioplasty, the latter in the setting of acute myocardial infarction and elective procedures. Lastly, the effects of trimetazidine on exercise tests in previously revascularized patients treated with beta-blockers, such as documented in the subgroup analysis of the Second Trimetazidine in Poland (TRIMPOL II) trial, are reported. In all, metabolic agents are likely to be beneficial in revascularized patients, with a documented anti-ischemic effect during myocardial revascularization procedures and the ability to improve exercise tolerance and symptoms in patients with chronic stable angina, despite myocardial revascularization.

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Curr Opin Cardiol. 2006 Sep;21(5):492-502.
Current strategies for the prevention of angina in patients with stable coronary artery disease.
Bhatt AB, Stone PH.
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

PURPOSE OF REVIEW: Angina pectoris affects at least 6.6 million people in the US and approximately 400,000 new cases of stable angina occur each year. Angina may be one of the first signs of ischemic heart disease, although it is likely not causally related to the likelihood of plaque rupture leading to an acute coronary syndrome. Modalities for treatment of angina should be used maximally to improve quality of life and decrease cardiovascular morbidity and mortality. The current recommended pharmacologic and invasive approaches, as well as novel therapies, are reviewed. RECENT FINDINGS: Antiischemic agents, including beta-blockers, nitrates and calcium channel blockers, remain the mainstay in the prevention of angina. Revascularization via percutaneous interventions or coronary bypass surgery are appropriate in specific cases or when medical treatment fails. Noninvasive treatment options for refractory angina, metabolic agents, and vasodilator therapies are adding to the armamentarium to prevent and treat angina. SUMMARY: A multifaceted approach is optimal to address the prevention of angina. Once angina is recognized, there are many modalities that lessen the incidence of daily life-induced and exercise-induced angina and ischemia. Angina management is best addressed by pharmacologic and lifestyle interventions.

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Adv Ther. 2006 Jul-Aug;23(4):601-14.
Tolerability to 1-year treatment with once-daily molsidomine in patients with stable angina.
Messin R, Bruhwyler J, Dubois C, Famaey JP, Geczy J.
Therabel Pharma S.A./N.V., Brussels, Belgium.

Prolonged-release molsidomine 16 mg once daily )QD( has proved effective in the short-term treatment of patients with stable angina. The purpose of this multicenter study was to assess its long-term tolerability and clinical effectiveness. A total of 320 patients with stable angina were treated for 1 year with molsidomine 16 mg QD administered open label as monotherapy or add-on therapy, when beta blockers and/or calcium antagonists were prescribed concomitantly )in 128 patients, ie, 40% of cases), depending on the severity of disease and/or local therapeutic policies. In all, 293 patients (91.6%) completed the study. The proportion of patients who reported drug-related adverse events (AEs) was 9.1%, which is not significantly different (P=.13) from the 5.9% observed during previous short-term (2-4 wk) treatment. Headache accounted for 80.6% of all drug-related AEs and required discontinuation of the drug in one quarter of patients who reported the symptom (ie, 1.9% of the 320 patients involved in the study). No serious drugrelated AEs occurred during the study. Tolerability to molsidomine, evaluated with use of a visual analog scale (VAS), improved by 20% from beginning to end of 1-year follow-up. Two-by-two Bonferroni's comparisons were significant at the .05 level between the 2-month assessment and assessments performed at 8, 10, and 12 months. No age-time interaction was noted (P=.82). Heart rate, blood pressure, electrocardiogram, and blood parameters showed no statistically significant or clinically relevant changes during the study. Compliance with treatment was satisfactory throughout the follow-up period. There was no significant change in the weekly frequency of anginal attacks and consumption of short-acting nitroderivatives during the 1-year study (P=.07 and P=.12,respectively), but their frequency was significantly (ie, ~50%) lower than during a preceding short-term treatment period (P<.0001 and P=.014, respectively). Subjective clinical status, evaluated through an appropriate VAS, improved by 38% from start to end of 1-year follow-up. Bonferroni's comparisons between baseline and subsequent 2-month evaluations were all significant at the .05 level. No age-time interaction could be seen for frequency of anginal attacks and consumption of short-acting nitroderivatives, nor for clinical status )P=.10, P=.11, and P=.51, respectively). Neither tolerability to molsidomine nor effectiveness of the drug was biased by concomitant antianginal therapies, insofar as none of these parameters showed a significant treatment type (ie, molsidomine administered as monotherapy or add-on therapy)-time interaction (VAS for tolerability: P=.44; angina: P=.39; nitroderivatives: P=.72; VAS for clinical status: P=.62). Molsidomine 16 mg QD administered for 1 y to patients with stable angina was well tolerated and remained effective during the entire treatment period, independent of age and concomitant antianginal therapy.

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Cochrane Database Syst Rev. 2006 Jul 19;3:CD004815.
Early invasive versus conservative strategies for unstable angina & non-ST-elevation myocardial infarction in the stent era.
Hoenig M, Doust J, Aroney C, Scott Ia.

BACKGROUND: In patients with unstable angina and non-ST-elevation myocardial infarction (UA/NSTEMI) two strategies are possible: a routine invasive strategy where all patients undergo coronary angiography shortly after admission and, if indicated, coronary revascularization; or a conservative strategy where medical therapy alone is used initially with selection of patients for angiography based on clinical symptoms or investigational evidence of persistent myocardial ischemia. OBJECTIVES: To determine the benefits of an invasive compared to a conservative strategy for treating UA/NSTEMI in the stent era. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (Issue 3 2005), MEDLINE and EMBASE were searched from 1996 to September 2005 with no language restrictions. SELECTION CRITERIA: Included studies were prospective trials comparing invasive with conservative strategies in UA/NSTEMI. DATA COLLECTION AND ANALYSIS: We identified 5 studies (7818 participants). Using intention-to-treat analysis with random effects models, summary estimates of relative risk (95% confidence interval [CI]) were determined for primary end-points of all-cause death, fatal and non-fatal myocardial infarction; all-cause death or non-fatal myocardial infarction; and refractory angina. Further analysis of included studies was undertaken based on whether glycoprotein IIb/IIIa receptor antagonists were used routinely. Heterogeneity was assessed using chi-square and variance (I(2)) methods. MAIN RESULTS: In the all-study analysis, mortality during initial hospitalization showed a trend to hazard with an invasive strategy; relative risk 1.59 (95% CI 0.96 to 2.64). Mortality and myocardial infarction assessed at 2-5 years in two trials were significantly decreased by an invasive strategy with relative risk of 0.75 (95% CI 0.62 to 0.92) and 0.75 (95% CI 0.61 to 0.91) respectively. The composite end-point of death or non-fatal myocardial infarction was significantly decreased by an invasive strategy at several time points after initial hospitalization. The incidence of early (<4 months) and intermediate (6-12 months) refractory angina were both significantly decreased by an invasive strategy; relative risk 0.47 (95% CI 0.32 to 0.68) and 0.67 (95% CI 0.55 to 0.83) respectively, as were early and intermediate rehospitalization rates with relative risk 0.60 (95% CI 0.41 to 0.88) and 0.67 (95% CI 0.61 to 0.74) respectively. The invasive strategy was associated with a two-fold increase in the relative risk of peri-procedural myocardial infarction (as variably defined) and a 1.7-fold increase in the relative risk of bleeding. AUTHORS' CONCLUSIONS: An early invasive strategy is preferable to a conservative strategy in the treatment of UA/NSTEMI.

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Cochrane Database Syst Rev. 2006 Jul 19;3:CD004196.
Puerarin injection for unstable angina pectoris.
Wang Q, Wu T, Chen X, Ni J, Duan X, Zheng J, Qiao J, Zhou L, Wei J.

BACKGROUND: Puerarin is extracted from the Chinese herb puerariae lobata. Many users of Chinese herbal medicine believe that puerarin has positive effects in the treatment of coronary heart disease (CHD). In recent years puerarin injection has been widely used to treat CHD and angina pectoris. OBJECTIVES: To assess the benefits and harms of puerarin injection for unstable angina. SEARCH STRATEGY: The following electronic databases were searched: The Cochrane Controlled Trials Register on The Cochrane Library (Issue 3, 2004), MEDLINE (1995 to 2004), EMBASE (1995 to 2004), CBM (1995 to 2004), Chinese Cochrane Centre Controlled Trials Register (to 2004), Current Controlled Trials (www.controlled-trials.com) and The National Research Register. We also hand searched 60 Chinese traditional medicine journals. SELECTION CRITERIA: Randomised controlled trials undertaken on adults with unstable angina evaluating the following types of interventions: Puerarin injection compared to western drugs or placebo, or puerarin injection used with western drugs compared to western drugs alone. DATA COLLECTION AND ANALYSIS: Data were extracted and analysed independently by two reviewers. Differences in data extraction and analysis were resolved by consensus, referring back to the original article. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: 20 trials involving 1240 people were included. All trials identified were classified as having a high risk of bias because of poor reported methodology. The duration of treatment was 7-20 days and no information supplied suggested longer follow-ups were conducted for any trials. This limited the observation to participants who were not undertaking normal activities of daily living.The primary outcome (death) was not report in any trial. For all the secondary outcome measures, frequency of acute angina attacks, improvements in ECG, doses and incidence of nitroglycerine needed and levels of plasma endothelin, there was no evidence that puerarin had better or worse effects to other conventional treatments. There was strong evidence to suggest that puerarin injection plus western drugs was a better treatment option than western drugs alone. AUTHORS' CONCLUSIONS: Puerarin injection may be effective in unstable angina when used in addition to conventional treatments. However, these finding should be interpreted with care because of the very low methodological quality of studies and potential publication bias. In the light of the findings, a more rigorously designed, randomised double-blind placebo-controlled trial is needed.

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Circulation. 2006 Jul 4;114(1 Suppl):I486-91.
Long-term results after systematic off-pump coronary artery bypass graft surgery in 1000 consecutive patients.
El-Hamamsy I, Cartier R, Demers P, Bouchard D, Pellerin M.
Department of Cardiovascular Surgery, Montreal Heart Institute, 5000 Belanger St, Montreal, Quebec H1T 1C8, Canada.

BACKGROUND: Off-pump coronary artery bypass surgery (OPCAB) is currently used as an alternative to conventional "on-pump" surgery, but there are very little data available on long-term follow-up. The aim of this study was to review our long-term experience with the use of systematic OPCAB. METHODS AND RESULTS: 1000 consecutive OPCAB surgeries were systematically performed between 1996 and 2004, representing 95% of all coronary revascularization during that same time frame, with a 97% complete follow-up. Average age of the patients was 64+/-10 years (778 men and 222 women). Seventy-three percent had triple-vessel disease. Operative 30-day mortality was 1.6%. Overall survival at 96 months was 74+/-3.5% and cardiac survival was 94+/-1.3%. By Cox regression analysis, age (odds ratio [OR], 1.07), congestive heart failure (CHF) (OR, 1.90), peripheral vascular disease (OR, 1.74), chronic renal insufficiency (OR, 2.04), previous myocardial infarction (MI) (OR, 1.60), and New York Heart Association functional class (OR, 1.60) were risk factors for long- term mortality. Survival free of any cardiac events (cardiac death, MI, unstable angina, heart failure, or reintervention) was 80+/-3.4%. Survival free of any type of reintervention alone was 90+/-3%. By Cox regression analysis, mitral regurgitation (OR, 2.3), peripheral vascular disease (OR, 2.1), and diffuse coronary disease (OR, 2.3) were significant predictors of recurrent cardiac events. Conversion to "on-pump" (OR, 14.3) was predictor of long-term need for repeat revascularization. CONCLUSIONS: In this series, systematic OPCAB surgery was shown to be an acceptable alternative to conventional "on-pump" coronary artery bypass graft for the treatment of coronary artery disease.

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Ann Thorac Cardiovasc Surg. 2006 Jun;12(3):174-8.
Early angiographic results of multivessel off-pump coronary artery bypass grafting.
Tabata M, Niinami H, Suda Y, Sasaki A, Yamamoto M, Asano R, Ikeda M, Takeuchi Y.
Department of Cadiovascular Surgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.

OBJECTIVES: Recently off-pump coronary artery bypass grafting (CABG) is being widely used for coronary revascularization. However, there is some evidence that off-pump surgery increases the risk of recurrent angina and the need for reintervention, suggesting poor graft quality or incomplete revascularization. We describe our experience to demonstrate the feasibility of multiple coronary revascularization in off-pump CABG (OPCAB). PATIENTS AND METHODS: From January 2002 to March 2003, 168 patients underwent OPCAB at our institute. In 16 of them, 6 to 9 vessels were revascularized in each patient. There were 14 males and 2 females with a mean age of 66 years (47 to 74 years). All patients had triple-vessel disease. Ten patients received in situ arterial grafts only which were harvested with the skeletonization technique using an ultrasonic scalpel. We used the Starfish heart positioner to expose lateral, posterior, and inferior walls of the heart with minimal hemodynamic compromise. RESULTS: All patients were discharged from the hospital without any serious complications. Postoperative angiography was performed in 87.5% within 1 month after operation. The patency rate was 96.6%. CONCLUSION: These results indicate that complete revascularization can be achieved in OPCAB in patients with diffuse coronary arterial disease. Complete revascularization with in situ arterial conduits only is technically feasible and yields a high early graft patency, even in the off-pump situation.

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Curr Cardiol Rep. 2006 Jun;8(4):247-54.
Surgical, medical, and percutaneous therapies for patients with multivessel coronary artery disease.
Ali MJ, Davidoff R.
Section of Cardiology, Evans Department of Medicine,Boston Medical Center, Boston University School of Medicine,88 East Newton Street, Boston, MA 02118, USA. ravin.davidoff@bmc.org.

Patients with multivessel coronary artery disease (CAD) are now faced with a number of treatment choices, including coronary artery bypass graft surgery, medical therapy, and percutaneous coronary interventions (using bare-metal or drug-eluting stents). Each carries certain benefits and risks: bypass surgery is favored in the subset of patients with multivessel disease and diabetes or impaired left ventricular systolic function who are able to receive a left internal mammary artery graft; medical therapy consisting of beta-blockers, angiotensin-converting enzyme inhibitors, statins, aspirin, and nitrates is offered to patients with stable angina. Percutaneous procedures have previously been limited in their efficacy by restenosis and resulting morbidity, but contemporary stenting procedures appear to show equivalent mortality and morbidity outcomes (to bypass surgery) at 5 years. Drug-eluting stents are the newest percutaneous technique and show significant reduction in restenosis compared with older catheter-based therapies, but further investigation is needed to definitively define the role of drug-eluting stents in the treatment of multivessel CAD. This review summarizes the data comparing medical, surgical, and percutaneous treatment approaches for patients with multivessel CAD.

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BMC Cardiovasc Disord. 2006 Jun 15;6(1):28 [Epub ahead of print]
One year follow-up of patients with refractory angina pectoris treated with enhanced external counterpulsation.
Pettersson T, Bondesson S, Cojocaru D, Ohlsson O, Wackenfors A, Edvinsson L.

ABSTRACT: BACKGROUND: Enhanced external counterpulsation (EECP) is a non-invasive technique that has been shown to be effective in reducing both angina and myocardial ischemia in patients not responding to medical therapy and without revascularization alternatives. The aim of the present study was to assess the long-term outcome of EECP treatment at a Scandinavian centre, in relieving angina in patients with chronic refractory angina pectoris. METHODS: 55 patients were treated with EECP. Canadian cardiovascular society (CCS) class, antianginal medication and adverse clinical events were collected prior to EECP, at the end of the treatment, and at six and 12 months after EECP treatment. Clinical signs and symptoms were recorded. RESULTS: EECP treatment significantly improved the CCS class in 79 6 % of the patients with chronic angina pectoris (p < 0.001). The reduction in CCS angina class was seen in patients with CCS class III and IV and persisted 12 months after EECP treatment. There was no significant relief in angina in patients with CCS class II prior to EECP treatment. 73 7 % of the patients with a reduction in CCS class after EECP treatment improved one CCS class, and 22 7 % of the patients improved two CCS classes. The improvement of two CCS classes could progress over a six months period and tended to be more prominent in patients with CCS class IV. In accordance with the reduction in CCS classes there was a significant decrease in the weekly nitroglycerin usage (p < 0.05). CONCLUSIONS: The results from the present study show that EECP is a safe treatment for highly symptomatic patients with refractory angina. The beneficial effects were sustained during a 12-months follow-up period.

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Am J Ther. 2006 May-Jun;13(3):188-91.
Chronic nitrate therapy in patients with angina with comorbidity.
Jansen R, Cleophas TJ, Zwinderman AH, Niemeijer MG.
Martini Hospital, Groningen, The Netherlands.

In a retrospective study from the Dutch Mononitrate Quality of Life (DUMQOL) Study Group, the authors found that patients with angina with concomitant diabetes or hypercholesterolemia derived more benefit from changing over to a once-daily nitrate treatment regimen than did patients without angina. The aim of this study was to assess this issue prospectively. In an open-label study, patients with stable angina pectoris from facilities in Germany, Portugal, and me Czech Republic were treated for 3 months with multiple daily doses and subsequently for 3 more months with once-daily isosorbide mononitrate/dinitrate. After the first and second 3-month periods, they were assessed by a validated QOL battery including domains for mobility, side effects, life satisfaction, anginal pain, and psychological distress. In the 1045 patients who participated in the study, the mean summary domain scores varied from 5 to 16 points and score improvements from 1.6 to 4.3 points. In the patients without concomitant hypertension and smokers, domain scores improved less than they did in the patients without, with differences in domain score improvements up to 1.0 points (P<0.001), which is substantial considering the range of improvement was between 1.6 and 4.3 points. In the patients with diabetes mellitus or hypercholesterolemia, a reverse pattern was observed with differences in domain score improvements up to 0.4 points (P<0.05). Patients with angina with diabetes or hypercholesterolemia derived more benefit from an asymmetric regimen of isosorbide mononitrate/dinitrate than did patients without. Patients with angina with hypertension and smokers benefited less. Differences in endothelial function may be involved.

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Postgrad Med J. 2006 Mar;82(965):224-7.
Long term clinical outcome and bleeding complications among hospital survivors with acute coronary syndromes.
Wong P, Robinson A, Shaw S, Rodrigues E.
Aintree Cardiac Centre, University Hospital Aintree, Liverpool, UK. peter.wong@aht.nwest.nhs.uk

OBJECTIVE: To examine the 21 month clinical outcome and bleeding complications in hospital survivors with non-ST segment elevation acute coronary syndromes (NSTEACS) who were discharged with combined clopidogrel and aspirin anti-thrombotic therapy, and compare with those having ST segment elevation myocardial infarction (STEMI) who were discharged with aspirin alone. DESIGN: Observational study. SETTING: A large university hospital. PATIENTS: 224 patients were admitted to hospital with either NSTEACS or STEMI, and survived to discharge between 1 October 2001 and 31 December 2002. MAIN OUTCOME MEASURES: Cardiovascular death, total death, new myocardial infarction, unstable angina requiring hospitalisation, stroke or transient ischaemic attack, coronary revascularisation; and fatal, life threatening, major and minor bleeding over 21 months after discharge. RESULTS: Despite having no or small infarct (median maximum creatine kinase 155 v 1295 u/l; p<0.001) and taking more antianginal drugs, patients with NSTEACS had similar rates of cardiovascular death (9.5% v 8.3%; p = NS), new myocardial infarction (9.5% v 6.5%; p = NS) or unstable angina requiring hospitalisation (15.5% v 10.2%; p = NS) when compared with STEMI. Fatal, life threatening or major bleeding were <1% in both groups (p = NS); and minor bleeding occurred in 4.3% NSTEACS and 2.8% STEMI patients respectively (p = NS). CONCLUSIONS: Patients with NSTEACS had a similar and unfavourable long term outcome when compared with STEMI. There was no difference in serious bleeding complications between both groups.

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Am J Cardiol. 2006 Mar 15;97(6):823-9. Epub 2006 Jan 30.
Safety and feasibility of transendocardial autologous bone marrow cell transplantation in patients with advanced heart disease.
Fuchs S, Kornowski R, Weisz G, Satler LF, Smits PC, Okubagzi P, Baffour R, Aggarwal A, Weissman NJ, Cerqueira M, Waksman R, Serrruys P, Battler A, Moses JW, Leon MB, Epstein SE.
Rabin Medical Center, Petach-Tikva, Israel.

The present report contains the final results of a Phase I study that evaluated the feasibility, safety, and potential efficacy of intramyocardial injection of autologous bone marrow (BM) in "no-option" patients with refractory angina and myocardial ischemia. Twenty-seven patients underwent electromechanic mapping-guided transendomyocardial injections (n = 12, 0.2 ml each) of unfractionated autologous BM cells directed to ischemic, noninfarcted myocardial territory. Patients were injected with 28 +/- 27 x 10(6)/ml nucleated cells containing 2.2 +/- 1.4% CD34+ cells. The autologous BM injection procedure was successful in all patients and was associated with no adverse events. At 3 months, the Canadian Cardiovascular Society angina score (3.2 +/- 0.5 vs 2.0 +/- 0.91, p = 0.001) and treadmill exercise duration (418 +/- 136 vs 489 +/- 142 seconds, p = 0.017) had improved significantly. The stress-induced ischemia score within the injected territories (118 segments) had also improved (2.2 +/- 0.8 vs 1.7 +/- 1.1, p <0.001). At 1 year, the clinical improvement was sustained, although 5 patients had undergone revascularization procedures. The number of total injected nucleated cells (CD45+), progenitor cells (CD34+), and the magnitude of secreted vascular endothelial growth factor and macrophage chemoattractant protein-1 by cultured BM cells failed to predict the clinical response. In conclusion, the 3- and 12-month study results have indicated the safety of catheter-based transendocardial delivery of autologous BM cells in patients with advanced symptomatic ischemic heart disease and may suggest sustained potential efficacy. The cellular and humeral characteristics of autologous BM cells did not predict the clinical response, underscoring the advisability of additional mechanistic exploration.

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Am Heart J. 2006 Mar;151(3):674-80.
Direct intramyocardial percutaneous delivery of autologous bone marrow in patients with refractory myocardial angina.
Briguori C, Reimers B, Sarais C, Napodano M, Pascotto P, Azzarello G, Bregni M, Porcellini A, Vinante O, Zanco P, Peschle C, Condorelli G, Colombo A.
Vita-Salute University School of Medicine, San Raffaele Hospital, Milan, Italy.

BACKGROUND: Intramyocardial injection of autologous bone marrow (ABM) may induce angiogenesis. We tested the safety and feasibility of catheter-based direct percutaneous intramyocardial delivery of ABM in patients with refractory angina pectoris. METHODS: Ten patients (9 men, 67 +/- 8 years) with refractory angina (Canadian Cardiovascular Society class III-IV) and documented myocardial ischemia were enrolled. After left ventricular electromechanical mapping, freshly aspirated and filtered ABM was percutaneously injected into target myocardial ischemic areas. Clinical symptoms (as assessed according to the Canadian Cardiovascular Society class), quality of life, and myocardial perfusion were evaluated before the procedure and through the follow-up. RESULTS: In all patients, ABM was successfully injected into the target regions. No periprocedural complications occurred. At 12 months, no major cardiac events (death, acute myocardial infarction, stroke, and malignant ventricular arrhythmias) occurred. Severity of angina improved of > or = 2 classes in 3 patients. Quality of life showed a significant improvement in all patients. Myocardial perfusion in the target regions improved in 4 of 8 patients. CONCLUSIONS: Direct percutaneous intramyocardial delivery of ABM appears feasible and safe. Further evaluation is warranted to test its clinical efficacy.

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Expert Rev Med Devices. 2006 Mar;3(2):137-46.
Holmium:YAG laser system for transmyocardial revascularization.
Allen KB.
Heart Center of Indiana, Department of Cardiothoracic Surgery, 10590 N. Meridian St, Suite 105, Indianapolis, IN 46290, USA. kallen2340@aol.com.

Transmyocardial revascularization, using the US FDA-approved holmium: yttrium-aluminum-garnet (Ho:YAG) laser system, is a surgical option for patients with debilitating angina caused by diffuse coronary artery disease in areas of the heart not amenable to complete revascularization using conventional treatments. Increased utilization of this therapy is warranted, in parallel with continuing research into therapeutic or cell-based methods for enhancing the clinically relevant, positive outcomes. This article will review the clinical science surrounding Ho:YAG transmyocardial revascularization with an emphasis on the randomized controlled trials performed in these patient groups.

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Clin Cardiol. 2006 Feb;29(2):69-73.
Two-year outcomes in patients with mild refractory angina treated with enhanced external counterpulsation.
Lawson WE, Hui JC, Kennard ED, Kelsey SF, Michaels AD, Soran O; International Enhanced External Counterpulsation Patient Registry Investigators.
Cardiovascular Division, SUNY Stony Brook, Stony Brook, New York 11794, USA. William.lawson@stonybrook.edu

BACKGROUND: In the International Enhanced External Counterpulsation Patient Registry (IEPR), approximately 85% of the patients treated are in Canadian Cardiovascular Society (CCS) class III-IV with no option for further invasive coronary revascularization procedures. HYPOTHESIS: This study sought to determine whether it is clinically important to establish whether the observed durable reduction in disabling severe angina with enhanced external counterpulsation (EECP) treatment can be extended to those with less severe CCS class II angina, who also have no option for further revascularization. METHODS: This study evaluated the immediate response, durability and clinical events over a 2-year period after EECP treatment in 112 patients with Canadian Cardiovascular Society (CCS) class II angina versus 1346 patients with class III-IV angina using data from the International EECP Patient Registry (IEPR). RESULTS: Treatment with EECP significantly (by at least one CCS class) reduced angina frequency, nitroglycerin use, and improved quality of life in both groups. At 2-year follow-up, 74% of class II and 70% of class III-IV patients remained free of major adverse cardiovascular events (MACE) and continued to demonstrate a durable CCS class improvement over baseline. CONCLUSION: The robust effectiveness of EECP as a noninvasive device, together with its relatively low start-up and recurrent costs, makes it an attractive consideration for treating patients with milder refractory angina in addition to the patient with severely disabling angina treated in current practice.

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Herz. 2006 Feb;31(1):55-74.
[Selective I(f) Channel Inhibition: an Alternative for Treating Coronary Artery Disease?]
[Article in German]
Schipke JD, Buter I, Hohlfeld T, Schmitz-Spanke S, Gams E.
Forschungsgruppe Experimentelle Chirurgie, Universitatsklinikum Dusseldorf, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf.

Several clinical studies demonstrate the importance of the heart rate for the cardiovascular morbidity and mortality. Over the last 50 years, some thought has been given to those substances that selectively reduce the heart rate. It is now recognized that I(f) ion channels of the sinus node play a major role in the automatism and modulation of the heart rate. Substances that selectively reduce the heart rate should decrease myocardial oxygen consumption and increase oxygen delivery via the prolonged diastolic coronary perfusion. Direct inotropic effects, however, are unlikely. In principle, anti-anginal and anti-ischemic effects of specific bradycardic substances can be expected. The clinical experience with some of the former bradycardic substances has not been sufficiently convincing. The more recent ivabradine (Procoralan((R))) presents an exception to this, as it successfully completed a clinical program for the treatment of chronically stable angina pectoris.In this review article, specific bradycardic substances (= I(f) channel inhibitors) are presented together with the corresponding experimental and clinical studies. The studies were selected against the background of the efficacy of I(f) channel inhibitors in the therapy of cardiovascular disease. As only ivabradine has completed a study on 5,000 patients, the discussion on that particular I(f) channel inhibitor is somewhat extensive. In addition, prospective possibilities and limitations of bradycardic substances are presented.

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JAMA. 2006 Feb 22;295(8):895-904.
Sirolimus- vs paclitaxel-eluting stents in de novo coronary artery lesions: the REALITY trial: a randomized controlled trial.
Morice MC, Colombo A, Meier B, Serruys P, Tamburino C, Guagliumi G, Sousa E, Stoll HP; REALITY Trial Investigators.
Institut Cardiovasculaire Paris Sud, Massy, France. mc.morice@icps.com.fr

CONTEXT: Compared with bare metal stents, sirolimus-eluting and paclitaxel-eluting stents have been shown to markedly improve angiographic and clinical outcomes after percutaneous coronary revascularization, but their performance in the treatment of de novo coronary lesions has not been compared in a prospective multicenter study. OBJECTIVE: To compare the safety and efficacy of sirolimus-eluting vs paclitaxel-eluting coronary stents. DESIGN: Prospective, randomized comparative trial (the REALITY trial) conducted between August 2003 and February 2004, with angiographic follow-up at 8 months and clinical follow-up at 12 months. SETTING: Ninety hospitals in Europe, Latin America, and Asia. PATIENTS: A total of 1386 patients (mean age, 62.6 years; 73.1% men; 28.0% with diabetes) with angina pectoris and 1 or 2 de novo lesions (2.25-3.00 mm in diameter) in native coronary arteries. INTERVENTION: Patients were randomly assigned in a 1:1 ratio to receive a sirolimus-eluting stent (n = 701) or a paclitaxel-eluting stent (n = 685). MAIN OUTCOME MEASURES: The primary end point was in-lesion binary restenosis (presence of a more than 50% luminal-diameter stenosis) at 8 months. Secondary end points included 1-year rates of target lesion and vessel revascularization and a composite end point of cardiac death, Q-wave or non-Q-wave myocardial infarction, coronary artery bypass graft surgery, or repeat target lesion revascularization. RESULTS: In-lesion binary restenosis at 8 months occurred in 86 patients (9.6%) with a sirolimus-eluting stent vs 95 (11.1%) with a paclitaxel-eluting stent (relative risk [RR], 0.84; 95% confidence interval [CI], 0.61-1.17; P = .31). For sirolimus- vs paclitaxel-eluting stents, respectively, the mean (SD) in-stent late loss was 0.09 (0.43) mm vs 0.31 (0.44) mm (difference, -0.22 mm; 95% CI, -0.26 to -0.18 mm; P<.001), mean (SD) in-stent diameter stenosis was 23.1% (16.6%) vs 26.7% (15.8%) (difference, -3.60%; 95% CI, -5.12% to -2.08%; P<.001), and the number of major adverse cardiac events at 1 year was 73 (10.7%) vs 76 (11.4%) (RR, 0.94; 95% CI, 0.69-1.27; P = .73). CONCLUSION: In this trial comparing sirolimus- and paclitaxel-eluting coronary stents, there were no differences in the rates of binary restenosis or major adverse cardiac events. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00235092.

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Eur Heart J. 2006 Feb 23; [Epub ahead of print]
Treatment benefit by perindopril in patients with stable coronary artery disease at different levels of risk.
Deckers JW, Goedhart DM, Boersma E, Briggs A, Bertrand M, Ferrari R, Remme WJ, Fox K, Simoons ML.
Department of Cardiology, Thoraxcenter, Erasmus University Medical Center Rotterdam, Room Ba 350, Dr Molewaterplein 40, 3015GD Rotterdam, The Netherlands.

AIMS: Patients with stable coronary artery disease (CAD) are at increased risk. Estimation of individual risk is difficult. We developed a cardiovascular risk model based on the Europa study population and investigated whether benefit of long-term administration of the angiotensin-converting enzyme (ACE)-inhibitor perindopril was modified by risk level. METHODS AND RESULTS: A total of 12 218 patients with stable CAD were treated with 8 mg perindopril or placebo. Baseline patient characteristics were assessed for association with 1091 cardiovascular deaths or non-fatal myocardial infarction (MI). Risk factors were age over 65 years, male gender [hazard ratio (HR) 1.2], previous MI (HR 1.5), previous stroke and/or peripheral vascular disease (HR 1.7), diabetes, smoking, angina (all HR 1.5), and high serum cholesterol and systolic blood pressure. Treatment benefit by perindopril was consistent among high, intermediate, and low risk patients (HRs 0.88, 0.68, and 0.83, respectively). Risk reduction was thus not modified by absolute risk level. CONCLUSION: Risk factors such as age, male gender, smoking, total cholesterol, and blood pressure continue to play an important role once clinical sequellae of coronary heart disease have developed. Patients at moderate-to-high risk because of uncontrolled risk factors and those with other indications or ACE-inhibitors have the most to gain from ACE-inhibition.

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Pharmacotherapy. 2006 Jan;26(1):135-42.
Ranolazine, a novel agent for chronic stable angina.
Gaffney SM.
Department of Pharmacy, Greenville Hospital System University Medical Center, 701 Grove Road, Greenville, SC 29605, USA.

One of the first signs of ischemic heart disease may manifest as chronic stable angina, a mismatch between oxygen supply and demand. With more than approximately 16.5 million people each year having stable angina, development of new therapies to help control this disease state are warranted. Ranolazine, a novel agent exerting its effect through a partial fatty oxidase inhibitor, is one of the first new drugs in more than 20 years to be developed for chronic stable angina. Working through enzymatic modulation, instead of altering myocardial hemodynamics, ranolazine appears to be effective. An overview of chronic stable angina is provided, the American College of Cardiology-American Heart Association (ACC-AHA) current pharmacologic treatment guidelines are reviewed, and the mechanism of action of ranolazine is explored. Finally, the major clinical trials supporting its place in medical therapy are discussed. Additional clinical trials are under way to further elucidate ranolazine's exact role in the treatment of chronic stable angina. From results of the existing phase III clinical trials, however, the most beneficial potential role of ranolazine in the treatment algorithm of chronic stable angina appears to be as adjunctive therapy to the recommended ACC-AHA treatment modalities.

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Eur J Med Res. 2006 Jan 31;11(1):38-42.
Off pump coronary artery bypass grafting - midterm results.
Massoudy P, Thielmann M, Kienbaum P, Kuehl H, Aleksic I, Erbel R, Jakob H.
Department of Thoracic and Cardiovascular Surgery,University Duisburg-Essen, West German Heart Center Essen, Germany. parwis.massoudy@uni-essen.de

OBJECTIVE: Off pump coronary artery bypass (OPCAB) grafting is still discussed controversially in the cardiac surgical community. Early perioperative results are encouraging. Only few reports have focused on mid-term recurrence of angina and freedoms from death or re-intervention. - METHODS: 107 OPCAB patients (mean age 63 +/- 1 years, 77 male, log EuroScore 5.6 +/- 0.7, number of distal anastomoses 2.0 +/- 0.1), operated on between January 1999 and December 2003, were systematically followed up comparing pre- and post-op NYHA- and CCS-classifications and assessing freedom from death and re-intervention. 52 of 107 patients underwent postoperative angiography or multi-slice computed tomography (MSCT); 6 of the latter 52 patients were symptomatic, 3 with unstable angina, the others underwent follow-up studies having given their informed consent. - RESULTS: The 30 day mortality was 2%. Freedom from death or re-intervention at 5.5 years was 91% and 80%, respectively. Only three patients required re-intervention in an OPCAB-related vessel. CCS classification was 2.8 +/- 0.1 before surgery and 1.8 +/- 0.2 (p<0.01) at follow-up (3.3 +/- 0.3 years). NYHA classification was 2.7 +/- 0.1 and 2.2 +/- 0.1 (p<0.01), respectively. Out of 107 patients, 52 underwent coronary angiography or MSCT (6 for cardiac symptoms) at a mean follow-up of 2.2 +/- 0.3 years. Left internal thoracic artery was patent in 91%, venous graft patency rate was 83%. - CONCLUSIONS: In this small but consecutive OPCAB population with a considerable perioperative risk according to the EuroScore, freedom from death and re-intervention at 5.5 years is acceptable and graft patency rate at 2.2 +/- 0.3 years is in the expected range. Significant reduction in both CCS and NYHA classification indicate sustained clinical improvement at mid-term.

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Can J Cardiol. 2005 Nov;21(13):1175-81.
The Canadian off-pump coronary artery bypass graft registry: A one-year prospective comparison with on-pump coronary artery bypass grafting.
Lamy A, Farrokhyar F, Kent R, Wang X, Smith KM, Mullen JC, Carrier M, Cheung A, Baillot R.
McMaster University, Hamilton, Canada.

BACKGROUND: The authors sought to examine in-hospital and one-year outcomes of off-pump coronary artery bypass grafting (CABG) and to determine the subgroups of patients most likely to benefit from the off-pump procedure in a regular surgical practice. METHODS: From March 2001 to December 2002, 1657 consecutive patients were treated with off-pump CABG and 1693 consecutive patients were treated with on-pump CABG. Propensity score modelling was performed to control for treatment and selection bias. A propensity-matched analysis was performed to identify factors associated with survival benefit from the off-pump procedure. RESULTS: The mortality was similar postoperatively and at one year after surgery. The rate of stroke was decreased in the off-pump group postoperatively (OR=0.49, 95% CI 0.23 to 1.06) and significantly at one year after surgery (OR=0.49, 95% CI 0.27 to 0.90). A significant reduction in acute renal dialysis and a significant increase in myocardial infarction rates were seen in off-pump patients during the initial hospitalization but these differences disappeared during the follow-up period. The number of grafts completed was significantly lower in off-pump CABG than in on-pump CABG (2.62+/-1.00 versus 3.36+/-0.92, respectively; P<0.001). Hospital length of stay and the percentage of patients who required mechanical ventilation were significantly lower in the off-pump group than in the on-pump group. At one year after surgery, the adjusted rate of coronary angiogram and revascularization was similar between the two groups, and the adjusted rate of self-reported angina and memory status was significantly better in the off-pump CABG group. Almost all subgroups of patients had a neutral effect or a survival benefit with the off-pump technique. CONCLUSIONS: The results from a Canada-wide multicentre registry showed the safety and effectiveness of off-pump CABG in most subgroups of patients in a regular surgical practice.

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Am Heart J. 2005 Nov;150(5):1066-73.
The effects of enhanced external counterpulsation on myocardial perfusion in patients with stable angina: a multicenter radionuclide study.
Michaels AD, Raisinghani A, Soran O, de Lame PA, Lemaire ML, Kligfield P, Watson DD, Conti CR, Beller G.
Division of Cardiology, University of California, San Francisco Medical Center, San Francisco, California 94143-0124, USA. andrewm@itsa.ucsf.edu

BACKGROUND: Enhanced external counterpulsation (EECP) reduces angina and extends time to exercise-induced ischemia in patients with symptomatic coronary disease. One- and two-center studies and a retrospective case series reported that EECP improves myocardial perfusion in stable angina pectoris. We sought to critically evaluate and quantify the effect of EECP on myocardial perfusion. METHODS: In 6 US university hospitals, EECP was performed for 35 hours in patients with class II to IV angina who had exercise-induced myocardial ischemia. Symptom-limited quantitative gated technetium Tc 99m sestamibi single photon emission computed tomography exercise perfusion imaging was performed at baseline and 1 month post-EECP. Sestamibi was injected at the same heart rate in both stress tests. Single photon emission computed tomography images were read at a blinded core laboratory. RESULTS: Thirty-seven patients were enrolled, 34 of whom completed pre- and post-EECP stress testing. The mean age was 61 +/- 10 years, 81% were male, 78% had prior revascularization, and 68% had 3-vessel disease. The mean angina class decreased from 2.7 +/- 0.7 at baseline to 1.7 +/- 0.7 after EECP (P < .001). Exercise duration increased from 9.1 +/- 3.7 minutes at baseline to 10.2 +/- 3.6 minutes post-EECP (P = .03). The average percentage of tracer uptake, magnitude of reversibility, average thickening fraction, and the left ventricular ejection fraction remained unchanged after EECP. CONCLUSIONS: We confirm previous report that EECP reduces angina and improves exercise capacity. There were no significant changes in mean defect magnitude, amount of reversibility, thickening fraction, and ejection fraction measured using myocardial quantitative single photon emission computed tomography imaging when compared at identical pre- and post-EECP heart rates.

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Am J Cardiol. 2005 Oct 1;96(7):917-21.
Treating patients with acute coronary syndromes with aggressive antiplatelet therapy (from the Global Registry of Acute Coronary Events).
Lim MJ, Eagle KA, Gore JM, Anderson FA Jr, Dabbous OH, Mehta RH, Granger CB, Fox KA, Spencer FA, Goldberg RJ; Global Registry of Acute Coronary Events Investigators.
Saint Louis University, St. Louis, Missouri, USA. limmj@slu.edu

Few data exist on the use of aggressive combination therapy with thienopyridines and glycoprotein IIb/IIIa inhibitors in higher risk patients with an acute coronary syndrome (ACS). The aim of this study was to characterize the combined use of these agents and the associated hospital outcomes in patients with ACS enrolled in the multinational Global Registry of Acute Coronary Events. Data from 8,081 patients with non-ST-segment elevation myocardial infarction or unstable angina were analyzed. Of these patients, 5,070 (62.7%) received aspirin and a thienopyridine, and the remainder received aspirin, a thienopyridine, and a glycoprotein IIb/IIIa blocker. The presence of a non-ST-segment elevation myocardial infarction; a history of diabetes or coronary artery bypass surgery; performance of in-hospital catheterization, percutaneous coronary intervention, or coronary artery bypass grafting; and in-hospital use of heparin were independent predictors of the use of triple antiplatelet therapy with aspirin, thienopyridines, and glycoprotein IIb/IIIa blockers. Increased diastolic blood pressure and increased serum creatinine were associated with a failure to prescribe triple therapy. An increased risk of major bleeding during hospitalization was associated with the use of triple antiplatelet therapy (odds ratio 1.6, 95% confidence interval 1.2 to 2.2). Aggressive antiplatelet therapy was used in approximately 2 of every 5 patients presenting with an ACS. Triple therapy was associated with the performance of catheterization and/or percutaneous coronary intervention, as well as high-risk patient features. Although no differences in hospital death rates were evident in patients receiving triple therapy, this population was at significantly increased risk of major bleeding episodes during hospitalization.

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Heart. 2005 Oct;91(10):1319-23.
Effects of vitamin C on intracoronary L-arginine dependent coronary vasodilatation in patients with stable angina.
Tousoulis D, Xenakis C, Tentolouris C, Davies G, Antoniades C, Crake T, Stefanadis C.
Athens University Medical School, Athens, Greece. drtousoulis@hotmail.com

OBJECTIVE: To assess the effects of intravenous vitamin C administration on the vasomotor responses to intracoronary L-arginine infusion in epicardial coronary arteries. METHODS: 28 patients with coronary artery disease and stable angina were enrolled in the study. Eight patients received intracoronary infusions of 150 micromol/min L-arginine before and after intravenous infusion of vitamin C, 10 patients received intracoronary infusions of 150 micromol/min L-arginine before and after intravenous infusion of normal saline, and 10 patients received intracoronary normal saline before and after intravenous infusion of vitamin C. The diameter of proximal and distal coronary artery segments was measured by quantitative angiography. RESULTS: Infusion of L-arginine caused significant dilatation of both proximal (4.87 (0.96)%, p < 0.01 v normal saline) and distal (6.33 (1.38)%, p < 0.01 v normal saline) coronary segments. Co-infusion of vitamin C and L-arginine dilated proximal coronary segments by 8.68 (1.40)% (p < 0.01 v normal saline, p < 0.01 v L-arginine) and distal segments by 13.07 (2.15)% (p < 0.01 v normal saline, p < 0.01 v L-arginine). Intravenous infusion of vitamin C caused a borderline increase in proximal and distal coronary segment diameters (1.93 (0.76)% and 2.09 (1.28)%, respectively, not significant). CONCLUSIONS: L-arginine dependent coronary segment vasodilatation was augmented by the antioxidant vitamin C in patients with coronary artery disease. Thus, vitamin C may have beneficial effects on nitric oxide bioavailability induced by L-arginine.

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Expert Rev Cardiovasc Ther. 2005 Sep;3(5):821-9.
Ranolazine: new approach for the treatment of stable angina pectoris.
Stanley WC.
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4970, USA. wcs4@case.edu

Myocardial ischemia is a metabolic problem involving reduced delivery of oxygen to cardiac mitochondria, resulting in less ATP formation, acceleration of glycolysis and production of lactate and H+ by the cell. Traditional therapies for ischemia aim at restoring the balance between mitochondrial ATP production and breakdown by reducing the need for ATP via suppression of heart rate, blood pressure and cardiac contractility, or by increasing oxygen delivery via increased myocardial blood flow. Despite optimal treatment with traditional hemodynamically oriented drugs (beta-adrenergic receptor antagonist, Ca2+ channel antagonist and nitrates), many patients continue to suffer from angina. Thus, there is a need for anti-anginal drugs that act directly on cardiomyocytes to lessen the metabolic abnormalities induced by ischemia and reduce the symptoms (chest pain and exercise intolerance). Ranolazine has been demonstrated to improve exercise time to angina or 1 mm of ST-segment depression in a manner similar to currently approved drugs, but without any significant effects on heart rate or blood pressure at rest or during exercise. In two Phase III trials, ranolazine improved exercise tolerance and reduced the frequency of angina attacks in chronic severe angina patients when administered either as monotherapy or on a background of atenolol, amlodinine or diltiazem. At present, ranolazine is under review for US Food and Drug Administration approval and, if approved, it will represent the first drug of its class in the USA.

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Nippon Ronen Igakkai Zasshi. 2005 Sep;42(5):557-63.
["Can high fluid intake prevent cerebral and myocardial infarction?" Systematic review]
[Article in Japanese]
Okamura K, Washimi Y, Endo H, Tokuda H, Shiga Y, Miura H, Nojiri Y.
Department of Urology, National Center Hospital for Geriatrics and Gerontology.

OBJECTIVES: We performed a systematic review about whether high fluid intake can prevent cerebral and myocardial infarction. MATERIALS AND METHODS: Previously published papers were searched for in PubMed using the combined terms of dehydration, hydration, water intake, fluid intake, cerebral infarction, cerebrovascular disease, apoplexy, myocardial infarction, angina pectoris, ischemic heart disease, blood viscosity and hemorheology. RESULTS: Of 611 papers searched, twenty-two were selected. There was one prospective randomized study, four prospective non-randomized studies, eight epidemiologic (cohort or case-control) studies and nine retrospective descriptive studies, presenting the following points. Dehydration, which increases blood viscosity, is one of the causes of cerebral or myocardial infarction. Important factors other than dehydration can cause an increase in viscosity. Drinking water during the night can protect an increase in blood viscosity but there has been no evidence that drinking excessive amount of water prevents cerebral infarction. There was one report that the risk of myocardial infarction was lower in people drinking more than 5 glasses of water than those drinking less than 2. CONCLUSION: Since cerebral and myocardial infarction are primarily caused by atherosclerosis and atheroma plaque, it is essential to adjust life style for prophylaxis. There has been no direct evidence that decrease in viscosity due to high fluid intake can prevent cerebral infarction. Further studies regarding the relationship between fluid intake and ischemic diseases, and the appropriate fluid intake for the elderly to improve their QoL are needed.

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Zhongguo Zhong Xi Yi Jie He Za Zhi. 2005 Sep;25(9):787-9.
[Observation on effect of compound danshen droplet-pill combined with trimetazidine in treating senile unstable angina pectoris]
[Article in Chinese]
Qiu ZX, Ma HJ, Wang DF.
Clinical College of China Medical University, Shenyang. qiuzhongxia116600@vip.sina.com

OBJECTIVE: To investigate the effect of compound Danshen Droplet-pill (DS) combined with trimetazidine (TMZ) in treating senile unstable angina pectoris (SUAP). METHODS: One hundred and twenty patients with SUAP were eaually and randomly divided into 2 groups, the treated group and the control group. Changes of angina, occurrence of arrhythmia, myocardial infarction and sudden death, myocardial ischemia in ECG and partial indexes of heart function were observed. RESULTS: The total effective rate in the treated group was 78.3%, while that in the control group was 53.3%, comparison of the two groups showed significant difference (P < 0.05). The incidence rate of arrhythmia in the two groups was 18.2% and 30.0% respectively and that of acute myocardial infarction and sudden death was 0 and 5.0% respectively, also showed significant difference between them (P < 0.05). Condition of myocardial ischemia revealed in ECG and partial indexes of heart function in the treated group were all improved to certain extent. Conclusion DS combined with TMZ is superior in treating SUAP.

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N Engl J Med. 2005 Sep 15;353(11):1095-104.
Early invasive versus selectively invasive management for acute coronary syndromes.
de Winter RJ, Windhausen F, Cornel JH, Dunselman PH, Janus CL, Bendermacher PE, Michels HR, Sanders GT, Tijssen JG, Verheugt FW; Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators.
Academisch Medisch Centrum, Amsterdam, Netherlands. r.j.dewinter@amc.uva.nl

BACKGROUND: Current guidelines recommend an early invasive strategy for patients who have acute coronary syndromes without ST-segment elevation and with an elevated cardiac troponin T level. However, randomized trials have not shown an overall reduction in mortality, and the reduction in the rate of myocardial infarction in previous trials has varied depending on the definition of myocardial infarction. METHODS: We randomly assigned 1200 patients with acute coronary syndrome without ST-segment elevation who had chest pain, an elevated cardiac troponin T level (> or =0.03 mug per liter), and either electrocardiographic evidence of ischemia at admission or a documented history of coronary disease to an early invasive strategy or to a more conservative (selectively invasive) strategy. Patients received aspirin daily, enoxaparin for 48 hours, and abciximab at the time of percutaneous coronary intervention. The use of clopidogrel and intensive lipid-lowering therapy was recommended. The primary end point was a composite of death, nonfatal myocardial infarction, or rehospitalization for anginal symptoms within one year after randomization. RESULTS: The estimated cumulative rate of the primary end point was 22.7 percent in the group assigned to early invasive management and 21.2 percent in the group assigned to selectively invasive management (relative risk, 1.07; 95 percent confidence interval, 0.87 to 1.33; P=0.33). The mortality rate was the same in the two groups (2.5 percent). Myocardial infarction was significantly more frequent in the group assigned to early invasive management (15.0 percent vs. 10.0 percent, P=0.005), but rehospitalization was less frequent in that group (7.4 percent vs. 10.9 percent, P=0.04). CONCLUSIONS: We could not demonstrate that, given optimized medical therapy, an early invasive strategy was superior to a selectively invasive strategy in patients with acute coronary syndromes without ST-segment elevation and with an elevated cardiac troponin T level. Copyright 2005 Massachusetts Medical Society.

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Semin Vasc Med. 2005 Aug;5(3):293-300.
Prevention of cardiovascular events after acute coronary syndrome.
Wallentin L.
Department of Cardiology, Uppsala Clinical Research Centre, University Hospital, Uppsala, Sweden.

Given the pivotal role of thrombin in the pathogenesis of acute coronary syndromes (ACS) and its persistent activation at the site of arterial lesions, antithrombin agents are essential for the prevention of coronary events. Antiplatelet agents are used routinely in the prevention of ACS, but their inability to prevent thrombin generation might contribute to the remaining high rates of recurrent ischemic events after intense antithrombotic treatment in the acute phase. Combination treatment with antiplatelet agents and anticoagulants, such as low-molecular-weight heparins (LMWH) and vitamin K antagonists, provides improved efficacy in the secondary prevention of ACS but these agents have limitations that prevent widespread adoption of their use for long-term treatment. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors (DTIs) and has considerable therapeutic potential in ACS. The DTIs are able to inhibit free and fibrin-bound thrombin by directly binding to the thrombin catalytic site. Furthermore, the oral administration and predictable pharmacokinetics of ximelagatran mean that it can be used at a fixed dose without coagulation monitoring and is convenient for long-term therapy. The efficacy of ximelagatran in the prevention of coronary events has been investigated in patients with recent myocardial infarction (MI) in the phase II Efficacy and Safety of the Oral Direct Thrombin inhibitor Ximelagatran in Patients with Recent Myocardial Damage (ESTEEM) trial. Ximelagatran (24 to 60 mg twice daily) added to aspirin (160 mg once daily) reduced the risk of the composite end point of death, MI, and severe recurrent ischemia by 24% versus aspirin alone, with no significant increase in major bleeding. Elevated serum transaminase enzymes developed during the first 1 to 6 months of treatment in a proportion of patients given ximelagatran. These elevations usually abated without clinical sequelae whether or not treatment was continued. The ESTEEM results highlight the potential for ximelagatran as an efficacious and well-tolerated long-term treatment for the prevention of arterial thrombotic events.

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Am J Hypertens. 2005 Aug;18(8):1026-32.
Prevalence, treatment, and control of chest pain syndromes and associated risk factors in hypertensive patients.
Hendrix KH, Mayhan S, Lackland DT, Egan BM.
Department of General Internal Medicine, Hypertension Section, Medical University of South Carolina, Charleston, SC 29425, USA. hendrikh@musc.edu

BACKGROUND: Prevalence of chest pain syndromes (CPS)-chest pain, angina pectoris, chronic angina, and preinfarction angina/intermediate coronary syndrome (ICS)-among hypertensive patients and medical management of these disorders in primary care are not well defined. METHODS: The Hypertension Initiative primary care database with 72,508 hypertensives was analyzed to characterize prevalence and management of CPS. Patients with more than one CPS were categorized by the most severe diagnosis. RESULTS: Eleven percent of hypertensives had a CPS. Of these patients, 66% (5284) were diagnosed with chest pain only, 15% (1204) with angina, and 19% (1508) with ICS. More men than women were diagnosed with angina (18% v 4%) and ICS (21% v 10%). More women than men were diagnosed with chest pain only (86% v 61%). African Americans received more chest pain diagnoses (71% v 62%), similar angina diagnoses (14% v 16%), and slightly fewer ICS diagnoses (15% v 22%) than whites. Most striking, women and African Americans with CPS received fewer medications than men and whites, both overall and within diagnostic categories. Prescription rates differed more by gender (male/female) than by ethnic group (white/African American) for angiotensin-converting enzyme inhibitor, diuretics, aspirin, statins, and nitrates. Hypertensives with CPS received more medications and achieved better risk factor control than non-CPS hypertensives, but the majority remained above goal levels. CONCLUSIONS: Primary care physicians treat cardiovascular risk factors relatively aggressively in hypertensives with CPS. However, substantial numbers of these patients do not reach goal levels. Demographic differences in treatment represent opportunities to reduce disparities.

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Med Hypotheses. 2005 Aug 3; [Epub ahead of print]
High-dose zinc to terminate angina pectoris: A review and hypothesis for action by ICAM inhibition.
Eby GA, Halcomb WW.
George Eby Research, 14909-C Fitzhugh Road, Austin, TX 78704, United States.

We reviewed the literature related to the effects of high-dose zinc in arteriosclerosis-induced angina pectoris. Lipid peroxidation and LDL oxidation are believed to be critical for arteriosclerosis, and consequently angina pectoris. Administration of biologically available zinc was a beneficial treatment in a significant percentage of patients with severely symptomatic, inoperable atherosclerotic disease. In these patients, there was no difference in zinc concentration between patients with and without atherosclerosis in whole blood, erythocytes or hair, but there was a major difference between normal aorta and diseased aortas (40.6ppm zinc in normal aorta vs. 23.2ppm zinc in atherosclerotic aorta, 40.6ppm zinc in normal aorta vs. 19.4ppm zinc in atherosclerotic aneurysm aorta, and no difference between normal and aneurysm aorta), although copper was low in aneurysm aorta. Medication with high-dose zinc sulfate to raise zinc serum concentrations from 95 to 177mug/dl resulted in objective improvement in 12 of 16 of these patients, including a patient that also had Reynard's disease. Long term environmental exposure to zinc resulted in a 40% reduction in the incidence of angina of effort compared to people not exposed to environmental zinc (P<0.01) and a 40% reduction in the incidence of probable ischemia in exercise (P<0.001). Lead had no effect while cadmium exposure resulted in more than tripling the incidence of angina of effort (P<0.001). The antioxidative action of zinc prevents oxidation of LDL cholesterol and consequently stops the main mechanism of atherogenesis. Zinc blocks calcium and its several actions on atherogenesis. Increased amounts of cytotoxic cytokines such as TNF-alpha, IL-beta and IL-8, often produced in the elderly, are blocked by high-dose zinc. We hypothesize that higher serum concentrations of LDL cholesterol resulting from administration of 300mg of zinc per day is caused by a release of low density cholesterol from cardiovascular tissues, beneficially flushing it into the serum where it is readily observed, thus decreasing arteriosclerosis, increasing circulation, terminating angina pectoris and restoring more youthful cardiac function. Although prevention of cholesterol-induced arteriosclerosis by zinc is predicted from findings related to oxidative stress and lipid peroxidation, removal of LDL might be attributable to action of ionic zinc on ICAM inhibition. In stark contrast to current practice, high-dose zinc should be considered as basic in the strategy of prophylaxis and therapy of the atherosclerosis process to terminate angina pectoris and restore youthful cardiac function.

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Clin Cardiol. 2005 Jul;28(7):343-8.
Assessment of the efficacy, optimal dosage, and safety of diltiazem in early treatment of unstable angina pectoris.
Bai R; Diltiazem Clinical Trial Task Group of Wuhan.
Department of Internal Medicine/Cardiology, Tong-Ji Hospital, Tong-Ji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, PR China. bairong74@yahoo.com.cn

BACKGROUND: The anti-ischemic benefits of diltiazem are well recognized; however, there are fewer studies of the use of intravenous diltiazem for early treatment of unstable angina pectoris (UAP). HYPOTHESIS: The present study prospectively evaluated the efficacy, optimal dosage, and safety of continuous intravenous diltiazem for initial management of UAP. METHODS: In all, 102 patients with UAP were recruited in this multicenter trial. Diltiazem was administered as a continuous intravenous infusion with a fixed incremental dosage of 1,3, and 5 microg/kg/min, titrated according to the patients' symptoms of angina, and then was maintained for a further 48 h at the angina-free dose. Episodes of angina, hemodynamic stability, and complications were observed. RESULTS: Angina was adequately controlled with continuous intravenous infusion of diltiazem in 64 patients (63%) at a dosage of 1 microg/kg/min, in 26 patients (25%) at dosage of 3 microg/kg/ min, and in 6 patients (6%) at dosage of 5 microg/kg/min, leading to a cumulative effective ratio of 94% in all patients. Additional anti-ischemic medications were required in six patients (6%) who had refractory angina. Bradyarrhythmias noted in only six patients (6%) were reversible after decreasing the dosage of diltiazem. No acute myocardial infarction or other severe side effects occurred. CONCLUSION: Continuous intravenous infusion of diltiazem is well tolerated and relieves symptoms rapidly and effectively in up to 94% patients with UAP, with the majority (63%) treated at the low dosage of 1 microg/kg/min. Diltiazem can be used as a first-line anti-ischemic agent for early conservation treatment of UAP.

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Am J Cardiol. 2005 Jul 15;96(2):193-8.
Influence of revascularization on long-term outcome in patients > or =75 years of age with diabetes mellitus and angina pectoris.
Jeger RV, Bonetti PO, Zellweger MJ, Tobler D, Kaiser CA, Osswald S, Buser PT, Pfisterer ME.
Department of Cardiology, University Hospital, Basel, Switzerland.

Little is known about the effect of revascularization in patients > or =75 years of age with symptomatic coronary artery disease (CAD) and diabetes mellitus (DM) for whom periprocedural risk and overall mortality are increased. Therefore, we examined the 301 patients of the Trial of Invasive versus Medical therapy in the Elderly with symptomatic CAD (TIME) with special regard to diabetic status. Patients were randomized to an invasive versus optimized medical strategy. The median follow-up was 4.1 years (range 0.1 to 6.9). Patients with DM (n = 69) had a greater incidence of hypertension (73% vs 58%, p = 0.03), > or =2 risk factors (93% vs 46%, p <0.01), previous heart failure (22% vs 12%, p = 0.04), and previous myocardial infarction (59% vs 43%, p = 0.02), and a lower left ventricular ejection fraction (48% vs 54%, p = 0.02) than did patients without DM. Mortality was greater in patients with DM than in those without DM (41% vs 25%, p = 0.01; adjusted hazard ratio 1.86, p = 0.01). Revascularization improved the overall survival rate from 61% (no revascularization) to 79% (p <0.01; adjusted hazard ratio 1.68, p = 0.03), an effect similarly observed in patients with and without DM. The event-free survival rate was 11% in nonrevascularized patients with DM compared with 40% in nonrevascularized patients without DM and 41% and 53% in revascularized patients with and without DM, respectively (p <0.01). Angina severity and antianginal drug use were similar for patients with and without DM, but those with DM performed worse in daily activities and physical functioning. In conclusion, elderly diabetic patients with chronic angina have a worse outcome than those with DM but benefit similarly from revascularization regarding symptom relief and long-term outcome. However, physical functioning related to daily activities is reduced in those with DM and may need special attention.

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Heart. 2005 Jul 1; [Epub ahead of print]
Off-pump coronary artery bypass surgery for significant left ventricular dysfunction: safety, feasibility, and trends in methodology over time - an early experience.
Sharoni E, Song H, Peterson R, Guyton R, Puskas J.
Rabin Medical Center, Tel Aviv University,, Israel.

Objective: To examine the safety and applicability of off-pump coronary artery bypass in patients with significant left ventricular dysfunction, and to discuss the clinical implications for the surgical methodology. DESIGN: Retrospective study. Setting: Tertiary-care university-affiliated referral centre. Participants: Three hundred fifty-three consecutive patients with preoperative left ventricular ejection fraction </=35% who underwent cardiopulmonary bypass at our center over a 3-year period. Main outcome measures: Postoperative morbidity and mortality. Methods: One hundred forty-four patients operated by off-pump coronary artery bypass were compared to 209 patients operated by conventional coronary artery bypass. Multivariate and univariate analyses were performed on the pre- and post-operative variables to predict risk factors associated with hospital morbidity and mortality. Results: Patients in the off-pump coronary artery bypass group were more likely to be female, and to have congestive heart failure, chronic obstruction pulmonary disease, hypertension and diabetes; patients in the on-pump group were more likely to have had a recent myocardial infarction and to have more severe angina pectoris and an urgent/emergent status. There were no significant between-group differences in length of stay, major postoperative complication rates, or mortality. Comparison of the impact of the procedures on surgical methodologyover time showed an increase in the use of off-pump coronary artery bypass (13% to 67%), without any impact on morbidity or mortality. Conclusions: Off-pump coronary artery bypass is feasible and applicable for patients with depressed left ventricular function. This high-risk group can potentially benefit from the off-pump approach.

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JAMA. 2005 Jun 15;293(23):2908-17.
Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials.
Mehta SR, Cannon CP, Fox KA, Wallentin L, Boden WE, Spacek R, Widimsky P, McCullough PA, Hunt D, Braunwald E, Yusuf S.
Department of Medicine, McMaster University, and Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada L6K 1B8. smehta@mcmaster.ca

CONTEXT: Patients with unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI) can be cared for with a routine invasive strategy involving coronary angiography and revascularization or more conservatively with a selective invasive strategy in which only those with recurrent or inducible ischemia are referred for acute intervention. OBJECTIVE: To conduct a meta-analysis that compares benefits and risks of routine invasive vs selective invasive strategies. DATA SOURCES: Randomized controlled trials identified through search of MEDLINE and the Cochrane databases (1970 through June 2004) and hand searching of cross-references from original articles and reviews. STUDY SELECTION: Trials were included that involved patients with unstable angina or NSTEMI who received a routine invasive or a selective invasive strategy. DATA EXTRACTION: Major outcomes of death and myocardial infarction (MI) occurring from initial hospitalization to the end of follow-up were extracted from published results of eligible trials. DATA SYNTHESIS: A total of 7 trials (N = 9212 patients) were eligible. Overall, death or MI was reduced from 663 (14.4%) of 4604 patients in the selective invasive group to 561 (12.2%) of 4608 patients in the routine invasive group (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.72-0.93; P = .001). There was a nonsignificant trend toward fewer deaths (6.0% vs 5.5%; OR, 0.92; 95% CI, 0.77-1.09; P = .33) and a significant reduction in MI alone (9.4% vs 7.3%; OR, 0.75; 95% CI, 0.65-0.88; P<.001). Higher-risk patients with elevated cardiac biomarker levels at baseline benefited more from routine intervention, with no significant benefit observed in lower-risk patients with negative baseline marker levels. During the initial hospitalization, a routine invasive strategy was associated with a significantly higher early mortality (1.1% vs 1.8% for selective vs routine, respectively; OR, 1.60; 95% CI, 1.14-2.25; P = .007) and the composite of death or MI (3.8% vs 5.2%; OR, 1.36; 95% CI, 1.12-1.66; P = .002). But after discharge, the routine invasive strategy was associated with fewer subsequent deaths (4.9% vs 3.8%; OR, 0.76; 95% CI, 0.62-0.94; P = .01) and the composite of death or MI (11.0% vs 7.4%; OR, 0.64; 95% CI, 0.56-0.75; P<.001). At the end of follow-up, there was a 33% reduction in severe angina (14.0% vs 11.2%; OR, 0.77; 95% CI, 0.68-0.87; P<.001) and a 34% reduction in rehospitalization (41.3% vs 32.5%; OR, 0.66; 95% CI, 0.60-0.72; P<.001) with a routine invasive strategy. CONCLUSIONS: A routine invasive strategy exceeded a selective invasive strategy in reducing MI, severe angina, and rehospitalization over a mean follow-up of 17 months. But routine intervention was associated with a higher early mortality hazard and a trend toward a mortality reduction at follow-up. Future strategies should explore ways to minimize the early hazard and enhance later benefits by focusing on higher-risk patients and optimizing timing of intervention and use of proven therapies.

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Heart. 2005 Jun 10; [Epub ahead of print]
Favourable long-term prognosis in stable angina pectoris: an extended follow-up of the Angina Prognosis study In Stockholm (APSIS).
Hjemdahl P, Eriksson SV, Held C, Forslund L, Nasman P, Rehnqvist N.
Dept of Medicine, Clin Pharm Unit, Karolinska University Hospital (Solna), Sweden.

Objective: To evaluate the long term prognosis of patients with stable angina pectoris. Design: Registry based follow-up (median 9.1 years) of patients participating in the Angina Prognosis Study in Stockholm (APSIS), which was a double-blind, single centre trial of antianginal drug treatment. Patients: 809 patients (31% women) with stable angina pectoris <70 (59+/-7 years at inclusion), and an age- and sex-matched reference population from the same catchment area. Interventions: Double-blind treatment with metoprolol or verapamil during 3.4 years (median), followed by referral for usual care with open treatment. Main outcome measures: CV death and non-fatal myocardial infarction (MI) in the APSIS cohort, and total mortality in comparisons with reference subjects. Results: 123 patients died (41 MI, 36 other CV causes), and 72 suffered non-fatal MI. Mortality (19% vs. 6%; p<0.001) and fatal MI (6.6 vs. 1.6%; p<0.001) were increased among male compared to female patients. Diabetes, previous MI, hypertension, and male sex independently predicted CV mortality (p<0.001). Diabetes markedly increased the risk in a small subgruoup of female patients. Male patients hade higher mortality rates than males in the reference population during the first three years (cumulative absolute difference 3.8%), but apparently not thereafter. Female patients had similar mortality rates as females in the reference population throughout the 9.1 years of observation. Conclusions: Female patients with stable angina had similar mortality rates as matched female reference subjects, but male patients had an increased risk. Diabetes, previous MI, hypertension and male sex were strong risk factors for CV death or MI.

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Eur J Cardiovasc Prev Rehabil. 2005 Jun;12(3):193-202.
Relaxation therapy for rehabilitation and prevention in ischaemic heart disease: a systematic review and meta-analysis.
van Dixhoorn J, White A.
Kennemer Hospital, Haarlem, The Netherlands. vdixhoorn@euronet.nl

AIMS: To establish the effects of relaxation therapy on the recovery from a cardiac ischaemic event and secondary prevention. METHODS AND RESULTS: A search was conducted for controlled trials in which patients with myocardial ischaemia were taught relaxation therapy, and outcomes were measured with respect to physiological, psychological, cardiac effects, return to work and cardiac events. A total of 27 studies were located. Six studies used abbreviated relaxation therapy (3 h or less of instruction), 13 studies used full relaxation therapy (9 h of supervised instruction and discussion), and in eight studies full relaxation therapy was expanded with cognitive therapy (11 h on average). Physiological outcomes: reduction in resting heart rate, increased heart rate variability, improved exercise tolerance and increased high-density lipoprotein cholesterol were found. No effect was found on blood pressure or cholesterol. Psychological outcome: state anxiety was reduced, trait anxiety was not, depression was reduced. Cardiac effects: the frequency of occurrence of angina pectoris was reduced, the occurrence of arrhythmia and exercise induced ischaemia were reduced. Return to work was improved. Cardiac events occurred less frequently, as well as cardiac deaths. With the exception of resting heart rate, the effects were small, absent or not measured in studies in which abbreviated relaxation therapy was given. No difference was found between the effects of full or expanded relaxation therapy. CONCLUSION: Intensive supervised relaxation practice enhances recovery from an ischaemic cardiac event and contributes to secondary prevention. It is an important ingredient of cardiac rehabilitation, in addition to exercise and psycho-education.

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JAMA. 2005 Jun 1;293(21):2641-7.
Effects of antibiotic therapy on outcomes of patients with coronary artery disease: a meta-analysis of randomized controlled trials.
Andraws R, Berger JS, Brown DL.
Cardiovascular Medicine, Department of Medicine, Beth Israel Medical Center, New York, NY, USA.

CONTEXT: Although Chlamydia pneumoniae infection has been associated with the initiation and progression of atherosclerosis, results of clinical trials investigating antichlamydial antibiotics as adjuncts to standard therapy in patients with coronary artery disease (CAD) have been inconsistent. OBJECTIVE: To conduct a meta-analysis of clinical trials of antichlamydial antibiotic therapy in patients with CAD. DATA SOURCES: The MEDLINE and Cochrane Central Register of Controlled Trials databases were searched from 1966 to April 2005 for English-language trials of antibiotic therapy in patients with CAD. Bibliographies of retrieved articles were searched for further studies. Presentations at major scientific meetings (2003-2004) were also reviewed. Search terms included antibacterial agents, myocardial infarction, unstable angina, and coronary arteriosclerosis. STUDY SELECTION: Eligible studies were prospective, randomized, placebo-controlled trials of antichlamydial antibiotic therapy in patients with CAD that reported all-cause mortality, myocardial infarction, or unstable angina. Of the 110 potentially relevant articles identified, 11 reports enrolling 19,217 patients were included. DATA EXTRACTION: Included studies were reviewed to determine the number of patients randomized, mean duration of follow-up, and end points. End points of interest included all-cause mortality, myocardial infarction (MI), and a combined end point of MI and unstable angina. DATA SYNTHESIS: Event rates were combined using a random-effects model. Antibiotic therapy had no impact on all-cause mortality among treated vs untreated patients (4.7% vs 4.6%; odds ratio [OR], 1.02; 95% confidence interval [CI], 0.89-1.16; P = .83), on the rates of MI (5.0% vs 5.4%; OR, 0.92; 95% CI, 0.81-1.04; P = .19), or on the combined end point of MI and unstable angina (9.2% vs 9.6%; OR, 0.91; 95% CI, 0.76-1.07; P = .25). CONCLUSION: Evidence available to date does not demonstrate an overall benefit of antibiotic therapy in reducing mortality or cardiovascular events in patients with CAD.

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Int J Cardiol. 2005 May 11;101(1):1-7.
Treatment of refractory angina pectoris.
Gowda RM, Khan IA, Punukollu G, Vasavada BC, Nair CK.
Division of Cardiology, Long Island College Hospital, Brooklyn, NY, USA.

Refractory angina pectoris is defined as Canadian Cardiovascular Society class III or IV angina, where there is marked limitation of ordinary physical activity or inability to perform ordinary physical activity without discomfort, with an objective evidence of myocardial ischemia and persistence of symptoms despite optimal medical therapy, life style modification treatments, and revascularization therapies. The patients with refractory angina pectoris may have diffuse coronary artery disease, multiple distal coronary stenoses, and or small coronary arteries. In addition, a substantial portion of these patients cannot achieve complete revascularization and continue to experience residual anginal symptoms that may impair quality of their life and increase morbidity. This represents an end-stage coronary artery disease characterized by a severe myocardial insufficiency usually with impaired left ventricular function. As the life expectancy is increasing, patients with angina pectoris refractory to conventional antianginal therapeutics are a challenging problem. We review the nonconventional therapies to treat the refractory angina pectoris, including pharmacotherapy, therapeutic angiogenesis, transcutaneus electrical nerve and spinal cord stimulation, enhanced external counterpulsation, surgical transmyocardial laser revascularization, percutaneous transmyocardial laser revascularization, percutaneous in situ coronary venous arterializations, and percutaneous in situ coronary artery bypass. These therapies are not supported by a large body of data and have only a complementary role; therefore, the aggressive traditional and proven treatment of angina pectoris should be continued along with these therapies, used on an individual basis.

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Curr Vasc Pharmacol. 2005 Apr;3(2):195-205.
Dihydropyridines, nitric oxide and vascular protection.
Crespi F.
Biology, Psychiatry CEDD, GlaxoSmithKline, via Flemming 4, 37135 Verona, Italy. Francesco.M.Crespi@gsk.com

For more than decades calcium antagonists (CEBs) have been widely used for the treatment of myocardial ischaemia (angina pectoris). Among the classes of CEBs, the 1,4-dihidropyridine (DHPs) have been used for this indication because of their haemodynamic and electrophysiological properties. In particular, DHPs are compounds capable of vascular protection on both smooth muscle and endothelium. The main protective activity is related to their calcium antagonist activity. In addition, they present vascular dilatation function, which has been related to an anti-endothelin efficacy. The newer DHPs are endowed with slow onset and long duration of vasodilator activity and reduce coronary resistance with little or no effect on heart rate. The more lipophilic DHP, lacidipine, is also able to reduce the formation of atheroma plaque in animal models at therapeutic doses. It has potent and long-lasting antihypertensive properties and appears to protect the arterial wall against the development of atherosclerotic lesions in animal models or human subjects with severe and multiple risk factors. Additionally, it has been observed that: i) NO/cyclic GMP pathway facilitates the inhibitory effect of Ca(++) antagonists on KCl-evoked contraction in rat aorta; ii) Vasodilator effect of lacidipine was significantly attenuated in the presence of NO-synthase inhibitors; iii) DHPs stimulate an electrochemical activity related to the nitric oxide (NO) system within the aortic vessel tissue, in rats and mice. In particular, they implement endothelial NO at "useful" and not toxic nanomolar levels. These activities join the already described positive effects of these compounds upon vascular functions.

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J Am Coll Cardiol. 2005 Apr 19;45(8):1165-71.
Outcomes with the paclitaxel-eluting stent in patients with acute coronary syndromes: analysis from the TAXUS-IV trial.
Moses JW, Mehran R, Nikolsky E, Lasala JM, Corey W, Albin G, Hirsch C, Leon MB, Russell ME, Ellis SG, Stone GW.
Columbia University Medical Center, New York, New York, USA.

OBJECTIVES: We sought to investigate the outcomes of paclitaxel-eluting stent implantation in patients with unstable angina or non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). BACKGROUND: Whether the paclitaxel-eluting stent is safe and effective in patients with acute coronary syndromes (ACS) is unknown. METHODS: In the TAXUS-IV trial, 1,314 patients with stable or unstable ischemic syndromes undergoing PCI were randomized to treatment with either the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or a bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). The results were stratified by the acuity of the presenting clinical syndrome. RESULTS: Acute coronary syndromes were present in 450 patients (34.2%), 237 of whom were assigned to paclitaxel-eluting stents and 213 to bare-metal stents. The baseline and procedural characteristics were well matched between the groups. Clinical outcomes at 30 days were similar with both stents. At one-year follow-up, patients with ACS assigned to the paclitaxel-eluting stent compared to the control stent had strikingly lower rates of target lesion revascularization (TLR) (3.9% vs. 16.0%, p < 0.0001) and major adverse cardiac events (11.1 vs. 21.7%, p = 0.002). By multivariate analysis, ACS was an independent predictor of in-stent restenosis in the cohort treated with bare-metal stents (hazard ratio [HR] = 2.03 [95% confidence interval (CI) 1.05 to 3.92], p = 0.035), while among patients randomized to the paclitaxel-eluting stents, ACS was an independent predictor of freedom from restenosis (HR = 0.27 [95% CI 0.08 to 0.97], p = 0.04). CONCLUSIONS: The use of the paclitaxel-eluting TAXUS stent was safe in patients with unstable ischemic syndromes, and was associated with marked reduction of ischemia-driven TLR and adverse cardiac events at one year.

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Drugs. 2005;65(6):787-97.
Optimising the use of beta-adrenoceptor antagonists in coronary artery disease.
Ellison KE, Gandhi G.
Department of Medicine, Brown University, Rhode Island Hospital, Providence, 02905, USA. KEllison@Lifespan.org

beta-Adrenoceptor antagonists (beta-blockers) provide multiple benefits to patients with coronary artery disease. The 2001 American Heart Association and American College of Cardiology (AHA/ACC) guidelines for secondary prevention of myocardial infarction (MI) recommend initiating beta-adrenoceptor blockade in all post-MI patients and continuing therapy indefinitely. Atenolol and metoprolol have been shown to decrease vascular mortality in the acute-MI period. In the post-MI period timolol provided a 39% reduction in mortality in the Norwegian Multicenter Study group and propranolol was associated with a 26% reduction in mortality in BHAT (Beta-blocker Heart Attack Trial). beta-Adrenoceptor antagonist therapy results in reduction of myocardial oxygen demand and is therefore also effective for the treatment of angina pectoris. In CAST (Cardiac Arrhythmia Suppression Trial) beta-adrenoceptor antagonist therapy was associated with a significant reduction in arrhythmic death or cardiac arrest. In the post-MI amiodarone trials EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) there was a mortality benefit and decreased arrhythmic death in patients who received both amiodarone and beta-adrenoceptor antagonist therapy, compared with patients receiving amiodarone therapy alone. In the post-MI defibrillator (implantable cardioverter defibrillator [ICD]) trials, AVID (Antiarrhythmic Versus Implantable Defibrillator) and MUSTT (Multicenter Unsustained Tachycardia Trial), beta-adrenoceptor antagonist therapy was independently associated with improved overall survival. The exception was the ICD patients in MUSTT, and the benefit was attenuated in the amiodarone and ICD patients in AVID.AHA/ACC guidelines recommend the use of beta-adrenoceptor antagonists in all patients with symptomatic left ventricular dysfunction, based on several large, controlled heart failure trials. Extended-release metoprolol succinate reduced all-cause mortality by 34% in MERIT-HF (Metoprolol Controlled-Release/Extended-Release Randomized Intervention Trial in Heart Failure). Bisoprolol was associated with a 34% mortality benefit in CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and carvedilol was associated with a 35% mortality reduction in the COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival) trial. beta-Adrenoceptor antagonists reduce perioperative mortality in patients undergoing cardiac as well as non-cardiac surgery; however, they remain underutilised. Contraindications to beta-adrenoceptor antagonist therapy include severe bradycardia, high-grade atrioventricular block, marked sinus node dysfunction and acute exacerbations of heart failure. Many of the perceived adverse effects of beta-adrenoceptor antagonists have not been substantiated by large clinical trials.beta-Adrenoceptor antagonists differ with regard to receptor selectivity, receptor affinity, lipophilicity and intrinsic sympathomimetic activity. Beneficial properties of beta-adrenoceptor antagonists may not always be extrapolated as a class effect, and patient selection and drug preparations should follow trial guidelines. The beneficial effects of beta-adrenoceptor antagonists are clearly proven in cardiac patients and those at risk for cardiac disease. They are indicated for heart failure and proven beneficial in patients undergoing cardiac and non-cardiac surgery. These benefits appear to be consistent across most patient subgroups. beta-Adrenoceptor antagonists are generally well tolerated, yet significant morbidity and mortality result from their continued underutilisation.

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Am Heart J. 2005 Feb;149(2):e1-9.
Efficacy and safety of a once-daily graded-release diltiazem formulation dosed at bedtime compared to placebo and to morning dosing in chronic stable angina pectoris.
Glasser SP, Gana TJ, Pascual LG, Albert KS.
Department of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. glasser@epi.umn.edu

BACKGROUND: The efficacy and safety of a once-daily graded-release diltiazem hydrochloride (GRD) formulation dosed at 10 PM in doses of 180, 360, and 420 mg were compared with placebo and with GRD 360 mg dosed once daily at 8 AM in patients (n = 311) with chronic stable angina pectoris. METHODS: This was a 3-week multicenter, randomized, double-blind, double-dummy, parallel-group, placebo-controlled trial. Standard Bruce protocol treadmill stress test was performed at baseline and end point between 6 and 8 PM (trough for evening doses) and between 7 and 11 AM (trough for morning doses). RESULTS: All GRD evening doses showed a significant (P < or = .0201) increase in total duration of exercise at trough and a greater significant increase (P < or = .0002) at peak, compared with placebo. The GRD 360-mg evening dose showed the greatest increase at trough. In contrast, GRD 360-mg morning dose showed an increase in total duration of exercise at trough that was not significantly different (P = .0555) from placebo AM. GRD 360-mg evening dose showed a 4-fold placebo-adjusted improvement compared with GRD 360-mg morning dose between 7 and 11 AM. Significant increases (P < or = .0240) in time to onset of angina were obtained for all evening doses at trough and peak. All GRD doses were well tolerated, and incidence of adverse events for all GRD groups combined was less than that for placebo. CONCLUSIONS: Bedtime GRD significantly increases exercise tolerance in patients with angina pectoris over the 24-hour dosing interval. A greater 4-fold placebo-adjusted improvement occurred between 7 and 11 AM compared with the same morning dose, coinciding with the period of increased cardiovascular risk. GRD was safe and well tolerated.

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Am J Cardiol. 2005 Feb 1;95(3):311-6.
Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris.
Rousseau MF, Pouleur H, Cocco G, Wolff AA.
Division of Cardiology, University of Louvain, Brussels, Belgium.

We investigated whether ranolazine therapy improves exercise-induced angina pectoris and myocardial ischemia compared with placebo or with standard doses of atenolol in patients who had chronic angina and evaluated the effects on hemodynamics at rest and during exercise. In this trial, 158 patients who had symptom-limited exercise discontinued beta-blocker therapy and were randomized into a double-blind, 3-period, crossover study of 400 mg of immediate-release ranolazine 3 times daily, 100 mg/day of atenolol, or placebo, each administered for 1 week. Exercise tests were administered at the end of each treatment period. Therapy with ranolazine or atenolol produced statistically significant improvement in all 3 exercise end points compared with placebo. Compared with atenolol therapy, ranolazine therapy resulted in significantly longer total exercise duration and was statistically indistinguishable from atenolol for time to onset of angina and ST-segment depression. Except for a modest increase in systolic blood pressure at peak exercise during ranolazine therapy, hemodynamic measurements did not differ significantly during ranolazine and placebo therapies. In contrast, atenolol significantly decreased blood pressure, heart rate, and rate-pressure product at rest and during exercise compared with placebo or ranolazine. In conclusion, ranolazine therapy prolonged exercise duration and decreased exercise-induced ischemia and angina with quantitative effects equal to or greater than those with atenolol. Unlike atenolol, the anti-ischemic and antianginal effects of ranolazine occurred without decreases in blood pressure, heart rate, or rate-pressure product.

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Am J Cardiol. 2005 Feb 15;95(4):502-5.
Effect of dexamethasone-eluting stents on systemic inflammatory response in patients with unstable angina pectoris or recent myocardial infarction undergoing percutaneous coronary intervention.
Patti G, Pasceri V, Carminati P, D'Ambrosio A, Carcagni A, Di Sciascio G.
Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome, Rome, Italy.

The effect of treatment with steroid-eluting stents on systemic inflammatory response was investigated in patients with unstable angina pectoris or recent myocardial infarction who underwent percutaneous intervention. Compared with controls, dexamethasone-eluting stents significantly reduced C-reactive protein peak levels 48 hours after the procedure; this effect persisted for 7 days and was particularly evident in patients with elevated (>/=3 mg/L) preprocedural C-reactive protein values. Patients receiving a dexamethasone-eluting stent had lower adverse events during follow-up.

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Int J Cardiol. 2005 Feb;98(2):299-306.
Treatment of angina pectoris: associations with symptom severity.
Kirwan BA, Lubsen J, Poole-Wilson PA; on behalf of the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) investigators.
SOCAR Research SA, Nyon, Switzerland.

Objective: To evaluate whether the frequency of anginal attacks in medically treated patients with stable angina is related to the intensity of anti-anginal treatment, the clinical history and coronary anatomy. Methods: Analysis of baseline data from the A Coronary disease Trial Investigating Outcome with Nifedipine GITS (ACTION) study, an ongoing placebo-controlled trial in 7669 patients with stable angina pectoris who require anti-anginal treatment. Results: Prior to randomisation, 8% of 7669 patients had no anginal attacks, 63% had occasional, 22% had regular, 4% had frequent and 3% had daily attacks. Men (79% of all patients) and patients with a history of MI (51%) had less frequent anginal attacks (P<0.0001). The number of coronary angiograms ever performed (70% had at least one angiogram), the extent of angiographic coronary disease (32% of those who had angiography had more than two-vessel disease), a history of peripheral artery disease (12%), the number of anti-anginal drugs used (64% were prescribed two or more such medications) and a history of revascularisation (a history of coronary bypass surgery was present in 23% and of balloon dilatation in 26%) were each positively associated with anginal attack frequency. Conclusions: For the majority of patients with chronic stable angina not on a calcium-antagonist, medical treatment with other anti-anginal drugs is sufficient to control symptoms and only a minority of patients are refractory to medical treatment. Invasive treatments for chronic stable angina are only needed in a small proportion where symptoms persist.

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Pacing Clin Electrophysiol. 2005 Jan;28 Suppl 1:S8-S10.
Long-term follow-up of patients with refractory heart failure and myocardial ischemia treated with cardiac resynchronization therapy.
De Cock CC, Van Campen LM, Jessurun ER, Allaart CA, Vos DS, Visser CA.
Department of Cardiology, VU University Medical Centre, Amsterdam, The Netherlands. cc.dcock@vumc.nl

Studies in patients without coronary artery disease have shown the restoration of glucose metabolism by cardiac resynchronization therapy (CRT) without changes in myocardial perfusion. We report on the long-term outcome of CRT in 24 patients with severe heart failure (HF) and advanced coronary artery disease not amenable for revascularization. All patients had documented myocardial ischemia on stress (99)Tc-sestamibi single-photon emission computed tomography, and all underwent successful implantations of CRT systems. The mean left ventricular ejection fraction was 21%+/- 4%, 19 patients (79%) had anginal complaints and 20 (83%) had diffuse three-vessel disease. During a follow-up of 13 +/- 0.7 months, two patients died suddenly and one died of progressive HF. Among survivors, functional capacity decreased from New York Heart Association class 3.2 +/- 1.4 to 2.1 +/- 1.0 (P < 0.01), and the Minnesota questionnaire quality-of-life scores decreased from 43 +/- 15 to 28 +/- 13 (P < 0.01). Despite an increase from 264 +/- 104 to 385 +/- 121 m in distance walked in 6 minutes (P < 0.01), the number of anginal attacks/week remained unchanged (4.7 +/- 0.7 to 4.5 +/- 0.6). Patients with advanced HF, stable angina, and documented myocardial ischemia may undergo safe and successful implantations of CRT systems.

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Int J Cardiol. 2005 Jan;98(1):79-89.
Efficacy and safety of molsidomine once-a-day in patients with stable angina pectoris.
Messin R, Opolski G, Fenyvesi T, Carreer-Bruhwyler F, Dubois C, Famaey JP, Geczy J.
Therabel Pharma S.A./N.V., 108 rue Egide Van Ophem, B-1180 Brussels, Belgium.

Background: The objective of this study was to compare the efficacy and tolerability of molsidomine prolonged-release 16 mg once-a-day (o.a.d.) with 8 mg twice-a-day (b.i.d.) and placebo in patients with stable angina pectoris. Methods: After a run-in placebo period of 7 days, the two formulations were compared acutely and then chronically (2 weeks) using cycloergometric tests and a randomized, multicenter, double-blind, double-dummy, crossover design in 533 patients. The quality of life was assessed using the frequency of anginal crises and nitrate sublingual tablets consumption. Results: Both formulations significantly improved exercise test parameters compared with placebo, being it after acute drug intake or after a 2-week treatment period and independently of spontaneous diurnal variation in exercise tolerance. Noninferiority of molsidomine 16 mg compared with 8 mg was demonstrated with a statistically significant superiority of the 16-mg formulation from 14 to 24 h postintake. Both treatments reduced incidence of anginal attacks and use of sublingual isosorbide dinitrate tablets. Tolerability of active drugs was satisfactory, the incidence of drug-related headache being not significantly different from placebo. Only hypotension was significantly more frequent with molsidomine 16 mg than with placebo, pretrial diastolic blood pressure being significantly lower in these patients than in those who did not develop hypotension during the study. Conclusions: Both molsidomine formulations were effective in controlling patients' angina, did not induce any habituation and were well tolerated. However, the once-daily 16-mg formulation tended to provide better 24-h protection against myocardial ischemia than the 8-mg b.i.d. formulation.

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JAMA. 2005 Jan 26;293(4):427-35.
Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation.
Yusuf S, Mehta SR, Xie C, Ahmed RJ, Xavier D, Pais P, Zhu J, Liu L; CREATE Trial Group Investigators.
Population Health Research Institute, Hamilton Health Sciences, Hamilton General Hospital and McMaster University, Hamilton, Ontario, Canada. yusuf@mcmaster.ca

CONTEXT: Although reperfusion therapy, aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors reduce mortality when used early in patients with acute myocardial infarction (MI), mortality and morbidity remain high. No antithrombotic or newer antiplatelet drug has been shown to reduce mortality in acute MI. OBJECTIVE: To evaluate the effects of reviparin, a low-molecular-weight heparin, when initiated early and given for 7 days in addition to usual therapy on the primary composite outcome of death, myocardial reinfarction, or strokes at 7 and 30 days. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled trial (Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation [CREATE]) of 15,570 patients with ST-segment elevation or new left bundle-branch block, presenting within 12 hours of symptom onset at 341 hospitals in India and China from July 2001 through July 2004. INTERVENTION: Reviparin or placebo subcutaneously twice daily for 7 days. MAIN OUTCOME MEASURE: Primary composite outcome of death, myocardial reinfarction, or stroke at 7 and 30 days. RESULTS: The primary composite outcome was significantly reduced from 854 (11.0%) of 7790 patients in the placebo group to 745 (9.6%) of 7780 in the reviparin group (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96; P = .005). These benefits persisted at 30 days (1056 [13.6%] vs 921 [11.8%] patients; HR, 0.87; 95% CI, 0.79-0.95; P = .001) with significant reductions in 30-day mortality (877 [11.3%] vs 766 [9.8%]; HR, 0.87; 95% CI, 0.79-0.96; P = .005) and reinfarction (199 [2.6%] vs 154 [2.0%]; HR, 0.77; 95% CI, 0.62-0.95; P = .01), and no significant differences in strokes (64 [0.8%] vs 80 [1.0%]; P = .19). Reviparin treatment was significantly better when it was initiated very early after symptom onset at 7 days (<2 hours: HR, 0.70; 95% CI, 0.52-0.96; P = .03; 30/1000 events prevented; 2 to <4 hours: HR, 0.81; 95% CI, 0.67-0.98; P = .03; 21/1000 events prevented; 4 to <8 hours: HR, 0.85; 95% CI, 0.73-0.99; P = .05; 16/1000 events prevented; and > or =8 hours: HR, 1.06; 95% CI, 0.86-1.30; P = .58; P = .04 for trend). There was an increase in life-threatening bleeding at 7 days with reviparin and placebo (17 [0.2%] vs 7 [0.1%], respectively; P = .07), but the absolute excess was small (1 more per 1000) vs reductions in the primary outcome (18 fewer per 1000) or mortality (15 fewer per 1000). CONCLUSIONS: In patients with acute ST-segment elevation or new left bundle-branch block MI, reviparin reduces mortality and reinfarction, without a substantive increase in overall stroke rates. There is a small absolute excess of life-threatening bleeding but the benefits outweigh the risks.

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JAMA. 2005 Jan 19;293(3):349-57.
A simplified approach to the management of non-ST-segment elevation acute coronary syndromes.
Gluckman TJ, Sachdev M, Schulman SP, Blumenthal RS.
Division of Cardiology, the Johns Hopkins Hospital, Baltimore, Md, USA.

CONTEXT: While current practice guidelines provide an evidence-based approach to management of acute coronary syndromes (ACS), application of the evidence by individual physicians has been suboptimal. OBJECTIVE: To assess and synthesize the evidence regarding optimal management of non-ST-segment elevation ACS (NSTE-ACS). DATA SOURCES: Systematic searches of peer-reviewed publications were performed in MEDLINE and the Cochrane Database from January 1990 through November 2004, with consultation by content experts. Search terms included antiplatelet therapy, antithrombotic therapy, angiotensin-converting enzyme inhibition, angiotensin receptor blockade, beta-blockade, hypertension, hyperlipidemia, cigarette smoking, diet, diabetes mellitus, exercise, myocardial ischemia, and coronary artery disease. STUDY SELECTION AND DATA EXTRACTION: Criteria for selection of studies included controlled study design, English language, and clinical pertinence. Data quality was based on the publishing journal and relevance to clinical management of NSTE-ACS. DATA SYNTHESIS: While outcomes of controlled studies support a comprehensive approach in the management of patients with NSTE-ACS, many physicians perceive existing guidelines as lengthy and complex. After risk stratification to identify those patients most likely to benefit from an early invasive vs early conservative strategy, a comprehensive management plan can be assembled through an "ABCDE" approach. The elements of this include "A" for antiplatelet therapy, anticoagulation, angiotensin-converting enzyme inhibition, and angiotensin receptor blockade; "B" for beta-blockade and blood pressure control; "C" for cholesterol treatment and cigarette smoking cessation; "D" for diabetes management and diet; and "E" for exercise. CONCLUSION: An "ABCDE" approach for the management of NSTE-ACS provides a practical and systematic means to implement evidence-based medicine into clinical practice.

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Korean J Intern Med. 2004 Dec;19(4):230-6.
Effects of cilostazol on platelet activation in coronary stenting patients who already treated with aspirin and clopidogrel.
Ahn JC, Song WH, Kwon JA, Park CG, Seo HS, Oh DJ, Rho YM.
Department of Internal Medicine, Ansan Hospital, Korea University College of Medicine, Seoul, Korea.

BACKGROUND: A recent study has shown that triple anti-platelet therapy (cilostazol+clopidogrel+aspirin) resulted in a significantly lower restenosis rate after coronary stenting than did conventional therapy (clopidogrel+aspirin). However, the anti-platelet effects of cilostazol, when combined with clopidogrel and aspirin, have not been evaluated. METHODS: Low dose cilostazol (50 mg/BID) was given to 47 patients who had already been taking clopidogrel (75 mg/day) and aspirin (100 mg/day) for more than 1 month subsequent to coronary stenting due to AMI and unstable angina. Markers of platelet activation, P-selectin and activated GPIIb/IIIa on platelets, were measured at baseline and 2 weeks after cilostazol treatment. We empirically divided patients into tertiles (low, n =16; moderate, n = 14; high group, n = 17), according to the baseline P-selectin expression. We then performed a comparative assessment of the anti-platelet effects of cilostazol at baseline and after 2 weeks of cilosatzol administration. RESULTS: P-selectin was significantly decreased after 2 weeks of cilostazol treatment in total patients (n = 47, 3.2 +/- 2.4% to 2.0 +/- 1.9%, p = 0.03). This inhibition of P-selectin expression was mainly achieved in the moderate and high P-selectin groups (low group; 1.4 +/- 0.5 to 1.9 +/- 1.3%, p > 0.05, moderate group; 2.5 +/- 0.3 to 1.3 +/- 0.3%, p < 0.05, high group; 5.4 +/- 2.7 to 2.7 +/- 2.8%, p < 0.05). Activated GPIIb/IIIa was not significantly changed (13.5% to 17.6%, p > 0.05). Underying disease, cardiovascular risk factors, concomitant medication including statin, and hsCRP were not related to the degree of P-selectin expression. CONCLUSION: Our data demonstrated that cilostazol treatment in addition to conventional anti-platelet therapy provides more effective suppression of platelet P-selectin expression in patients with relatively high platelet activity.

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Ann Pharmacother. 2004 Dec;38(12):2094-104. Epub 2004 Nov 09.
Role of Low-Molecular-Weight Heparin in Invasive Management of Non-ST-Elevation Acute Coronary Syndromes.
Moser LR, Kalus JS.
Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University; Clinical Pharmacy Specialist, Department of Pharmacy Services, St. Johns Hospital and Medical Center, Detroit, MI.

OBJECTIVE: To review the available literature addressing the role of low-molecular-weight heparin (LMWH) as an alternative to unfractionated heparin (UFH) in percutaneous coronary intervention (PCI) for treatment of non-ST-elevation acute coronary syndromes (NSTEACS). DATA SOURCES: A MEDLINE search (1966-March 2004) identified pertinent articles using the key words acute coronary syndromes, unstable angina, non-ST-elevation myocardial infarction, low-molecular-weight heparin, enoxaparin, dalteparin, glycoprotein IIb/IIIa receptor antagonists, abciximab, tirofiban, eptifibatide, percutaneous transluminal coronary angioplasty, and percutaneous coronary intervention. The references of these articles were reviewed for additional pertinent references. STUDY SELECTION AND DATA EXTRACTION: All human trials of LMWH in PCI for treatment of NSTEACS were evaluated. All pertinent studies were included in the review. DATA SYNTHESIS: Administration of LMWH with or without a glycoprotein IIb/IIIa inhibitor during PCI appears to be similar to UFH in terms of efficacy. LMWH, especially in combination with a glycoprotein IIb/IIIa inhibitor, may increase risk of bleeding compared with UFH. CONCLUSIONS: Available clinical trials do not provide definitive evidence to suggest superiority of LMWH over UFH when managing NSTEACS during PCI; however, dosing strategies are available if an LMWH is to be used in this setting.

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Heart. 2004 Dec;90(12):1427-30.
Impact of nicorandil in angina: subgroup analyses.
IONA Study Group.

AIMS: IONA (impact of nicorandil in angina) is a randomised, double blind, placebo controlled trial of nicorandil, with a target dose of 20 mg twice daily. The consistency of benefits seen in subgroups is reported. METHODS: The primary composite end point of the study was coronary heart disease death, non-fatal myocardial infarction, or unplanned hospitalisation for cardiac chest pain. Subgroups were defined using baseline characteristics including, age, sex, histories of smoking, diabetes, hypertension, myocardial infarction, revascularisation, anginal status, anti-anginal treatment, other cardiovascular drugs, and an overall assessment of risk. RESULTS: A total of 5126 patients were randomised to receive nicorandil or identical placebo in addition to standard anti-anginal treatment. Overall, nicorandil reduced the incidence of the primary end point from 15.5% to 13.1% (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.72 to 0.97; p = 0.014). There was no evidence of significant heterogeneity of benefit across all subgroups studied. The absolute risk reduction was greatest and the numbers needed to treat to prevent one event was lowest in subjects at greatest risk. CONCLUSIONS: The IONA study demonstrates a significant improvement in outcome by nicorandil treatment across a broad range of patients with stable angina.

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Am J Ther. 2004 Nov-Dec;11(6):423-32.
A Randomized, Double-Blind Comparison of Lercanidipine 10 and 20 mg in Patients with Stable Effort Angina: Clinical Evaluation of Cardiac Function by Ambulatory Ventricular Scintigraphic Monitoring.
Acanfora D, Gheorghiade M, Trojano L, Furgi G, Papa A, Cacciatore F, Viati L, Mazzella F, Rengo F.
"Salvatore Maugeri" Foundation, Institute of Care and Scientific Research, Rehabilitation Institute of Telese, Benevento, Italy; Division of Cardiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois.

We evaluated the antiischemic action and the effects on left ventricular response to exercise of lercanidipine, a long-acting dihydropyridine calcium antagonist, in 23 patients with stable effort angina in a randomized, double-blind, parallel trial. Left ventricular function was assessed during upright bicycle exercise using an ambulatory radionuclide detector for continuous noninvasive monitoring of cardiac function. Exercise was performed under control conditions before (run-in placebo period) and after 2-week treatment with lercanidipine 10 or 20 mg once daily. During the placebo run-in period and at the study end, patients underwent clinical examination, ECG, exercise tests, ambulatory ventricular scintigraphic monitoring (VEST). Results showed that both drug doses increased time to onset of ST segment depression >/=1 mm and peak ST segment depression, with improvement of total exercise duration. Heart rate, blood pressure, and the rate-pressure product did not significantly change with respect to pretreatment value. The left ventricular ejection fraction, indicating contractility state of myocardium, was unchanged at rest and during exercise after both lercanidipine doses. In conclusion, lercanidipine is safe and effective in reducing ischemia in patients with stable effort angina without any deterioration of cardiac function.

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Clin Cardiol. 2004 Oct;27(10):547-51.
Should standard medical therapy for angina include a statin?
Corti R, Fuster V.
Zena and Michael A. Wiener Cardiovascular Institute, The Mount Sinai School of Medicine, New York, New York 10029, USA.

Although a wealth of evidence supports the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in patients with clinically evident coronary artery disease, these agents are still underutilized. Statins are the most effective agents in reducing low-density lipoprotein-cholesterol among lipid-lowering drugs, and studies have recently shown that they improve endothelial function and plaque stabilization, and induce regression of atherosclerotic lesions. This article reviews the most recent evidence and guideline recommendations supporting the use of statins in chronic stable angina pectoris and acute coronary syndromes.

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Eur J Heart Fail. 2004 Oct;6(6):787-91.
Clinical trials update from the European Society of Cardiology: SENIORS, ACES, PROVE-IT, ACTION, and the HF-ACTION trial.
Cleland JG, Huan Loh P, Freemantle N, Clark AL, Coletta AP.
Department of Cardiology, University of Hull, Castle Hill Hospital, Cottingham, Kingston-upon-Hull, HU16 5JQ, UK.

This article provides information and a commentary on landmark trials presented at the European Society of Cardiology Congress in August 2004, relevant to the pathophysiology, prevention or treatment of heart failure. The SENIORS trial suggests that nebivolol is well tolerated and effective in older patients with heart failure, even if left ventricular systolic function is not markedly depressed. However, patients aged >75 years appeared to gain less benefit. Further data on the effects of nebivolol on symptoms and quality of life are awaited. Two new trials of long-term antibiotic prophylaxis after myocardial infarction (ACES and PROVE-IT) showed no benefit. The ACTION trial showed no reduction in serious cardiovascular events with nifedipine GITS in patients with chronic stable angina, despite a substantial reduction in blood pressure. The HF-ACTION trial announced that the first 700 patients of a projected 3000 had been randomised to either an exercise program or encouragement to exercise but without a formal program. The primary outcome measure is death or hospitalisation for any reason.

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Am Heart Hosp J. 2004 Fall;2(4 Suppl 1):21-30.
Acute coronary syndromes: pathogenesis, acute diagnosis with risk stratification, and treatment.
Chesebro JH.
Division of Cardiovascular Diseases, Mayo Clinic-Jacksonville, 4500 San Pablo Road South, Jacksonville, FL 32224, USA. chesebro.james@mayo.edu.

Acute ischemic chest pain at rest consistent with unstable angina or non-ST-elevation myocardial infarction is a common problem that may cause death or recurrent myocardial infarction within 30 days unless identified and risk stratified acutely. The latter may be done within 15 minutes by the history, physical exam, and electrocardiogram, and is aided by the measurement of troponin T/I. According to the Agency for Health Care Policy and Research guidelines, low-risk patients can be discharged home and rechecked within 72 hours. Intermediate-risk patients with no ST-segment changes with continuous monitoring and no elevation of troponin should undergo exercise stress testing by electrocardiogram (or nuclear or echocardiographic evaluation if electrocardiogram is non-analyzable). Patients with a negative stress test are low risk (no death or myocardial infarction at 30 days or 6 months) and can be discharged home. Patients with a positive test or who are at high risk according to the Agency for Health Care Policy and Research guidelines should undergo acute invasive testing for possible revascularization. Aspirin and low molecular weight heparin or unfractionated heparin, along with anti-ischemia therapy, is indicated in intermediate- or high-risk patients. The addition of clopidogrel is indicated in these patients, except in those who are potential candidates for coronary artery bypass graft. Platelet glycoprotein IIb/IIIa inhibitors are indicated in high-risk patients likely to undergo percutaneous coronary intervention, should be started early if recurrent ischemia occurs, but are not indicated in lower-risk patients who do not require percutaneous coronary intervention. Intensive secondary prevention should be started before dismissal.

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Tex Heart Inst J. 2004;31(3):231-9.
Transmyocardial laser revascularization as an adjunct to coronary artery bypass grafting: a randomized, multicenter study with 4-year follow-up.
Frazier OH, Tuzun E, Eichstadt H, Boyce SW, Lansing AM, March RJ, Sartori M, Kadipasaoglu KA.
Cardiopulmonary Transplant Service and the Cullen Cardiovascular Research Laboratories of the Texas Heart Institute, Houston, Texas 77030, USA.

We evaluated transmyocardial laser revascularization (TMLR) with coronary artery bypass grafting (CABG) versus CABG alone for severe coronary artery disease involving 21 myocardial region unsuited for CABG. At 4 centers, 44 consecutive patients were randomized for CABG+TMLR (n = 23) or CABG alone (n = 21). Operative and in-hospital mortality and morbidity rates were monitored. Clinical status was evaluated at hospital discharge, 1 year, and 4 years. Success was characterized by relief of angina and freedom from repeat revascularization and death. Preoperatively, 20 patients (47%) were at high risk. The CABG technique, number of grafts, and target vessels were similar in both groups. Patients undergoing CABG+TMLR received 25 +/- 11 laser channels. Their < or = 30-day mortality was 13% (3/23) compared with 28% (6/21) after CABG alone (P = 0.21). There were no significant intergroup differences in the number of intraoperative or in-hospital adverse events. The follow-up period was 50.3 +/- 17.8 months for CABG alone and 48.1 +/- 16.8 months for CABG+TMLR. Both groups had substantially improved angina and functional status at 1 and 4 years, with no significant differences in cumulative 4-year mortality. The incidence of repeat revascularization was 24% after CABG alone versus none after CABG+TMLR (P < 0.05). The 4-year event-free survival rate was 14% versus 39%, respectively (P < 0.064). In conclusion, CABG+TMLR appears safe and poses no additional threat for high-risk patients. Improved overall success and repeat revascularization rates may be due to better perfusion of ischemic areas not amenable to bypass. Further studies are warranted to determine whether these trends are indeed significant.

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Am J Cardiovasc Drugs. 2004;4(6):379-84.
Clinical and experimental experience with factor xa inhibitors.
Viles-Gonzalez JF, Gaztanaga J, Zafar UM, Fuster V, Badimon JJ.
Cardiovascular Biology Research Laboratory, Mount Sinai School of Medicine, Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA.

Cardiovascular disease is the major cause of mortality in the industrial world today. We are constantly moving towards new and better ways of fighting this epidemic. Advances have been made in various fields such as patient education, imaging techniques, interventional cardiology, and novel therapeutic agents. In particular, antithrombotics are being studied with great interest and hope. Amid this class of agents, factor Xa inhibitors have already begun to show promising results in trials involving patients with acute coronary syndromes. Whereas DX-9065a is in late stage clinical trials, fondaparinux sodium is available for clinical use. Promising results have been obtained with fondaparinux sodium in patients with coronary artery disease in the PENTUA (Pentasaccharide in Unstable Angina) and PENTALYSE (Pentasaccharide as an Adjunct to Fibrinolysis in ST-Elevation Acute Myocardial Infarction) trials. Besides having a direct effect on the coagulation cascade, they have shown properties that indirectly influence the remodeling of plaques in the coronary circulation. Available evidence on factor Xa inhibitors does not ensure a remedy to acute coronary syndromes but it gives hope of improving current treatments and reducing the morbidity and mortality of cardiovascular disease.The efficacy and tolerability of fondaparinux sodium in the prevention and treatment of deep vein thrombosis (with or without pulmonary embolism) has been established in several large trials such as PENTATHLON (Pentasaccharide in Total Hip Replacement Surgery), PENTAMAKS (Pentasaccharide in Major Knee Surgery), EPHESUS (European Pentasaccharide Hip Elective Surgery), PENTHIFRA (Pentasaccharide in Hip-Fracture Surgery), and PENTHIFRA-Plus. Whereas fondaparinux sodium offers benefits over low molecular weight heparins and unfractionated heparin, the incidence of bleeding complications was greater with fondaparinux sodium than with unfractionated heparin. Treatment with factor VIIa can reverse the anticoagulant effect of fondaparinux sodium and this may be particularly important in patients who need to undergo emergency surgical procedures. Fondaparinux sodium has been recently approved for use, in conjunction with warfarin, in patients with symptomatic deep vein thrombosis or acute pulmonary embolism based on the results of two large trials conducted by the Matisse investigators. In conclusion, these observations strongly suggest the clinical potential of this class of agents in preventing arterial and venous thrombosis.

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Mol Cell Biochem. 2004 Sep;264(1-2):63-74.
Therapeutic myocardial angiogenesis with vascular endothelial growth factors.
Yoon YS, Johnson IA, Park JS, Diaz L, Losordo DW.
Division of Cardiovascular Research, Caritas St Elizabeth's Medical Center, Boston, MA 02135, USA. young.yoon@tufts.edu

Emerging evidence has shown that administration of angiogenic growth factors, either as recombinant protein or by gene transfer, can augment tissue perfusion through neovascularization in animal models of myocardial and hindlimb ischemia. Many cytokines have angiogenic activity; one of those that have been best studied in animal models and clinical trials is vascular endothelial growth factor (VEGF). VEGF has been known to be a key regulator of physiologic and pathologic angiogenesis associated with tumor. Recently the effect of VEGF is not restricted to the direct angiogenic effect in vivo but includes mobilization of bone-marrow-derived endothelial progenitor cells and augmentation of postnatal vasculogenesis in situ. Clinical trials of therapeutic angiogenesis with VEGF in patients with end-stage coronary artery disease have shown increases in exercise time and reductions in anginal symptoms and have provided objective evidence of improved perfusion and left ventricular function. Larger scale placebo-controlled trials with recombinant protein (rhVEGF165) have been limited to intracoronary and intravenous administration and have shown favorable trends in exercise time and angina frequency. Small-scale, placebo-controlled, randomized clinical trials of gene transfer (phVEGF-2) via thoracotomy or percutaneous intramyocardial delivery demonstrated significant improvement of both subjective symptoms and objective measures of myocardial ischemia. Both therapeutic modalities appear to be safe and well tolerated. Further studies are required to determine the optimal dose, formulation, route of administration, and combinations of growth factors and the utility of adjunctive endothelial progenitor cell or other stem cell supplementation, to provide safe and effective therapeutic myocardial neovascularization.

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Am Fam Physician. 2004 Aug 1;70(3):525-32.
Unstable angina and non-ST-segment elevation myocardial infarction: part I. Initial evaluation and management, and hospital care.
Wiviott SD, Braunwald E.
Thrombolysis in Myocardial Infarction Study Group, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA. swiviott@partners.org

Each year, more than 1 million patients are admitted to U.S. hospitals because of unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). To help standardize the assessment and treatment of these patients, the American College of Cardiology and the American Heart Association convened a task force to formulate a management guideline. This guideline, which was published in 2000 and updated in 2002, highlights recent medical advances and is a practical tool to help physicians provide medical care for patients with UA/NSTEMI. Management of suspected UA/NSTEMI has four components: initial evaluation and management; hospital care; coronary revascularization; and hospital discharge and post-hospital care. Part I of this two-part article discusses the first two components of management. During the initial evaluation, the history, physical examination, electrocardiogram, and cardiac biomarkers are used to determine the likelihood that the patient has UA/NSTEMI and to aid in risk assessment when the diagnosis is established. Hospital care consists of appropriate initial triage and monitoring. Medical treatment includes anti-ischemic therapy (oxygen, nitroglycerin, beta blocker), antiplatelet therapy (aspirin, clopidogrel, platelet glycoprotein IIb/IIIa inhibitor), and antithrombotic therapy (heparin, low-molecular-weight heparin).

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Am Fam Physician. 2004 Aug 1;70(3):535-8.
Unstable angina and non-ST-segment elevation myocardial infarction: part II. Coronary revascularization, hospital discharge, and post-hospital care.
Wiviott SD, Braunwald E.
Thrombolysis in Myocardial Infarction Study Group, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.

In the guideline developed by the American College of Cardiology and the American Heart Association, the management of suspected unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) has four components: initial evaluation and management; hospital care; coronary revascularization; and hospital discharge and post-hospital care. Part II of this two-part article discusses coronary revascularization, hospital discharge, and post-hospital care. Decisions must be made about the use of coronary angiography and coronary revascularization in patients hospitalized with UA/NSTEMI. With an early conservative strategy, medical management is employed. Coronary angiography and revascularization are reserved for use in patients with evidence of ischemia at rest (or with minimal activity) and patients with a strongly positive stress test. With an early invasive strategy, coronary angiography and revascularization are recommended within 48 hours in patients without contraindications. Hospital discharge planning involves coordination of medical care, preparation of the patient for resumption of normal activities, and evaluation of the need for long-term risk factor reduction. Discharge medications should be continued to control ongoing symptoms (anti-ischemic agents) and prevent recurrent events (aspirin, clopidogrel, beta blocker, and an angiotensin-converting enzyme inhibitor or statins in selected patients).

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Ann Thorac Surg. 2004 Aug;78(2):458-65.
Adjunctive transmyocardial revascularization: five-year follow-up of a prospective, randomized trial.
Allen KB, Dowling RD, Schuch DR, Pfeffer TA, Marra S, Lefrak EA, Fudge TL, Mostovych M, Szentpetery S, Saha SP, Murphy D, Dennis H.
Departments of Cardiothoracic Surgery, St. Vincent Hospital, Indiana Heart Institute, Indianapolis, Indiana, USA.

BACKGROUND: In a prospective, randomized trial involving 263 patients who would be incompletely revascularized by coronary artery bypass grafting (CABG) alone, CABG plus transmyocardial revascularization (CABG/TMR) provided an early mortality benefit with similar angina relief compared with CABG alone at 1 year. We evaluated the long-term outcome of patients randomized to CABG/TMR or CABG alone. METHODS: Thirteen centers that enrolled 83% (218/263) of the patients in the original trial participated in this longitudinal study. Between 1996 and 1998, these centers randomized 218 patients who would be incompletely revascularized by CABG alone because of diffusely diseased target vessels to either holmium:yttrium-aluminum-garnet (holmium:YAG) CABG/TMR (n = 110) or CABG alone (n = 108). Baseline demographics and operative characteristics were similar between groups. Follow-up (mean 5.0 +/- 1.7 years) included survival and blinded angina class assessment. RESULTS: At this 5-year follow-up both groups experienced significant angina improvement from baseline, however, the CABG/TMR group had a lower mean angina score (0.4 +/- 0.7 vs 0.7 +/- 1.1, p = 0.05), a significantly lower proportion of patients with severe angina (class III/IV: 0% [0/68] vs 10% [6/60], p = 0.009), and a trend towards greater number of angina-free patients (78% [53/68] vs 63% [38/60], p = 0.08), compared with CABG alone patients. Kaplan-Meier survival at 6 years was similar between CABG/TMR and CABG alone patients (76% vs 80%, p = 0.90). CONCLUSIONS: Five-year follow-up of prospectively randomized patients who would be incompletely revascularized because of diffuse coronary artery disease indicates that the addition of TMR to conventional CABG provides superior angina relief compared to CABG alone.

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Int J Clin Pract. 2004 Jul;58(7):669-74.
An investigation into the 'carry over' effect of neurostimulation in the treatment of angina pectoris.
Murray S, Collins PD, James MA.
Department of Cardiology, Taunton & Somerset Hospital, Taunton, Somerset, UK. drstevemurray@lycos.co.uk

Neurostimulation, by way of transcutaneous electrical nerve stimulation (TENS) and spinal cord stimulation, improves signs and symptoms of myocardial ischaemia, with evidence (from non-randomised studies) that this effect extends beyond the period of stimulation itself ('carry-over' effect). In this randomised controlled trial, 10 patients underwent baseline treadmill-exercise-testing (TET), followed by two further tests at fortnightly intervals. TENS was compared to placebo in a randomised fashion. TENS produced a significant increase in total exercise time (399.3 vs. 364.5 s, p < 0.05) and time to maximum ST depression (374 vs. 324 s, p = 0.01) without a significant difference in the maximum degree of ST depression (2.0 vs. 2.1 mm, p = NS). Rate-pressure product at peak exercise was not significantly different (197 vs. 193, p = NS). TENS produced a nonsignificant change in time to onset of angina (352 vs. 325 s, p = 0.07). Pre-treatment with TENS produces a significant improvement in exercise tolerance and measures of ischaemia but not significant improvement in symptoms.

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Am J Crit Care. 2004 Jul;13(4):350-4.
Prinzmetal's angina.
Keller KB, Lemberg L.
Florida Atlantic University Christine E. Lynn College of Nursing, Boca Raton, Florida, USA.

Prinzmetal's angina, often referred to as "variant" angina, is a temporary increase in coronary vascular tone (vasospasm) causing a marked, but transient reduction in luminal diameter. This coronary vasospastic state is usually focal at a single site and can occur in either a normal or diseased vessel. Patients are predominantly younger women who may not have the classical cardiovascular risk factors (except for cigarette use). PVA has been associated with vasospastic disorders such as Raynaud's phenomenon and migraine headaches. Arrhythmias are common and may be life threatening especially when the effects of vasospasm are seen in those ECG leads that reflect the potential variations of the epicardial surface of the left ventricle. Endothelial dysfunction has been considered as primarily responsible for PVA. The diagnosis is made by observing transient ST-segment elevation during the attack of angina. Since PVA is not a "demand"- induced symptom, but rather a supply (vasospastic) abnormality, exercise treadmill stress testing is of no value in the diagnosis of PVA. The most sensitive and specific test for PVA is the administration of ergonovine intravenously. Fifty micrograms at 5-minute intervals is given until a positive result or a maximum dose of 400 microg has been administered. When positive, the symptoms and associated ST-segment elevation should be present. Nitroglycerin rapidly reverses the effects of ergonovine if refractory spasm occurs. Medical therapy classically employs vasodilator drugs, which include nitrates and calcium channel blockers. The prognosis is good when there is no significant coronary artery stenosis. Treatment of associated coronary atherosclerosis in elderly patients with PVA is advised. When PVA is associated with coronary atherosclerosis, the prognosis is determined by the severity of the underlying disease. beta-Blockers and large doses of aspirin are contraindicated in PVA.

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Wien Med Wochenschr. 2004 Jun;154(11-12):266-81.
[Risk management of coronary artery disease--pharmacological therapy]
[Article in German]
Hofmann T.
Herzzentrum, Medizinische Klinik III, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Deutschland. thofmann@uke.uni-hamburg.de

Treatment of coronary artery disease primarily aims at reducing the severity and frequency of cardiac symptoms and improving prognosis. Both goals can be achieved by the administration of beta-receptor blockers, which are now used as first-line therapy in these patients. Calcium channel blockers or nitrates should be given in the event of contraindications or severe intolerance to beta-receptor blocking therapy. Only long-acting calcium channel blockers should be used in this setting. Another indication for additional treatment with calcium channel blockers and nitrates is given when the efficacy of beta-blocker therapy is not sufficient to relieve symptoms. Nitroglycerin and nitrates are the drugs of choice for the treatment of the acute angina pectoris attack. Calcium channel blockers are used as first-line treatment in patients with vasospastic angina. In patients with syndrome X, nitrates as well as calcium channel blockers or beta-receptor blockers can be administered. In the absence of contraindications, every patient with coronary artery disease should be given aspirin. A daily dosage of 75 to 150 mg is sufficient to reduce the rate of future cardiac events. Clopidogrel should be given in every patient with intolerance or contraindications for aspirin. Increased plasma homocystein levels seem to be a risk factor for coronary artery disease. Homocystein levels can be reduced by dietary means as well as supplementation of folic acid or vitamin B complex. There is no evidence from controlled randomised studies that a decrease of homocystein is beneficial for the prognosis of patients with coronary artery disease.

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Curr Med Chem Cardiovasc Hematol Agents. 2004 Apr;2(2):157-167.
Progress in the Field of GPIIb/IIIa Antagonists.
Hanson J, De Leval X, David JL, Supuran C, Pirotte B, Dogne JM.
Dogne Jean-Michel, Department of Medicinal Chemistry, University of Liege, 1, av. de l'hopital, B36, B-4000 Liege (Sart-Tilman), Belgium. Jean-Michel.Dogne@ulg.ac.be

Platelet aggregation plays an important role in pathological situations such as myocardial infarction, unstable angina, peripheral artery disease, and stroke. Thus, pharmacological agents that specifically inhibit platelet aggregation are of great interest in the treatment and prevention of these cardiovascular diseases. Since binding of activated glycoprotein IIb/IIIa complex, a platelet surface integrin, to fibrinogen is the final step leading to platelet aggregation regardless of the initial stimulus, many researches have focused on the development of drugs that could antagonize this integrin. Three intravenous glycoprotein IIb/IIIa antagonists are currently marketed for the prevention of myocardial infarction in patients undergoing percutaneous intervention: Abciximab, Eptifibatide and Tirofiban. To further test the clinical efficacy of these agents, oral glycoprotein IIb/IIIa antagonists have been developed but only led to disappointing clinical results. Nevertheless, due to recognized usefulness of oral agents for the prevention and treatment of cardiovascular diseases, a great number of new orally active compounds are under clinical or preclinical evaluation. The aim of this review is to describe the chemical, pharmacological and clinical properties of existing and forthcoming glycoprotein IIb/IIIa antagonists.

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Heart Surg Forum. 2004;7(3):E218-29.
Transmyocardial laser therapy: a strategic approach.
Samuels L, Emery R, Lattouf O, Grosso M, AlZeerah M, Schuch D, Wehberg K, Muehrcke D, Dowling R.
Lankenau Hospital, Wynnewood, Pennsylvania 19096, USA.

BACKGROUND: Coronary artery bypass and percutaneous intervention have become the established methods of coronary revascularization in treating angina pectoris. Subsets of angina patients, however, are not amenable to either of these procedures. Transmyocardial laser revascularization (TMR) has been developed as a potential treatment to address such patients, and clinical research to date illustrates the success of TMR for this patient group. STRATEGIC PLAN SUMMARY: Although the symptoms of ischemic heart disease manifest themselves in a variety of ways, the best results with TMR are seen in patients with severe angina rather than in patients with silent ischemia or congestive heart failure. Potential TMR patients receive diagnostic tests to determine if and where the therapy should be applied. A recent cardiac catheterization is required to document the status of and the coronary-system suitability for the planned intervention. It is not appropriate to assume that a patient with nonbypassable, noninterventional coronary artery disease has to be relegated to medical therapy only. Additionally, echocardiography demonstrates the status of cardiac valves and segmental wall motion activity. This knowledge allows the surgeon to determine the sequence of surgery and if abnormalities are present. Once the decision to use TMR use has been made, there are 2 approaches--sole therapy or adjunctive therapy. TMR is not to be substituted for a feasible bypass graft, but the best time to make this decision may well be during the surgery itself, because grafts that appear surgically feasible on an angiogram may be less feasible after the chest has been opened. The decision to perform sole-therapy TMR in the absence of bypassable vessels clearly must be made before opening the chest. Whether to use cardiopulmonary bypass (CPB) and the sequence in which to perform TMR and bypass grafts are based on surgeon preference. The advantage of performing TMR on CPB is that channels can quickly be lased without pause. A potential advantage of performing TMR before bypass grafts is that "channel leak" (bleeding) can be minimized by the conclusion of the surgery. Complete revascularization has become technically more difficult because of the increasing use of percutaneous approaches and because patients are being referred for coronary artery bypass grafting much later in the course of their coronary disease progression than before. TMR may well be a viable alternative to bypassing a heavily diseased, previously intervened, small-diameter coronary artery. Thus, a model in which myocardial perfusion is considered within the context of the natural circulation can be conceived as an alternative to a model in which circulation is altered by interventional, surgical, and/or transmyocardial methods. TMR has been shown to be effective in accomplishing a complete revascularization when the restoration of circulation to ischemic territories with interventional therapy, bypass surgery, or a combination of both has been ineffective. We recommend that interested users follow this "complete revascularization strategy" algorithm for all ischemic vessels being considered for interventional or surgical treatment. Running each diseased vessel through this thought process will ensure that available treatment options are considered in the optimization of a patient's outcome. CONCLUSION: The use of TMR for angina relief has evolved into a clinically proven technology that has enabled physicians to address difficult revascularization cases with a therapy that is safe and effective.

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JAMA. 2004 Jan 21;291(3):309-16.
Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial.
Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA; Combination Assessment of Ranolazine In Stable Angina (CARISA) Investigators.
Department of Medicine, Division of Cardiology, St Louis University School of Medicine, St Louis, Mo, USA. chaitman@slu.edu

CONTEXT: Many patients with chronic angina experience anginal episodes despite revascularization and antianginal medications. In a previous trial, antianginal monotherapy with ranolazine, a drug believed to partially inhibit fatty acid oxidation, increased treadmill exercise performance; however, its long-term efficacy and safety have not been studied in combination with beta-blockers or calcium antagonists in a large patient population with severe chronic angina. OBJECTIVES: To determine whether, at trough levels, ranolazine improves the total exercise time of patients who have symptoms of chronic angina and who experience angina and ischemia at low workloads despite taking standard doses of atenolol, amlodipine, or diltiazem and to determine times to angina onset and to electrocardiographic evidence of myocardial ischemia, effect on angina attacks and nitroglycerin use, and effect on long-term survival in an open-label observational study extension. DESIGN, SETTING, AND PATIENTS: A randomized, 3-group parallel, double-blind, placebo-controlled trial of 823 eligible adults with symptomatic chronic angina who were randomly assigned to receive placebo or 1 of 2 doses of ranolazine. Patients treated at the 118 participating ambulatory outpatient settings in several countries were enrolled in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial from July 1999 to August 2001 and followed up through October 31, 2002. INTERVENTION: Patients received twice-daily placebo or 750 mg or 1000 mg of ranolazine. Treadmill exercise 12 hours (trough) and 4 hours (peak) after dosing was assessed after 2, 6 (trough only), and 12 weeks of treatment. MAIN OUTCOME MEASURES: Change in exercise duration, time to onset of angina, time to onset of ischemia, nitroglycerin use, and number of angina attacks. RESULTS: Trough exercise duration increased by 115.6 seconds from baseline in both ranolazine groups (pooled) vs 91.7 seconds in the placebo group (P =.01). The times to angina and to electrocardiographic ischemia also increased in the ranolazine groups, at peak more than at trough. The increases did not depend on changes in blood pressure, heart rate, or background antianginal therapy and persisted throughout 12 weeks. Ranolazine reduced angina attacks and nitroglycerin use by about 1 per week vs placebo (P<.02). Survival of 750 patients taking ranolazine during the CARISA trial or its associated long-term open-label study was 98.4% in the first year and 95.9% in the second year. CONCLUSION: Twice-daily doses of ranolazine increased exercise capacity and provided additional antianginal relief to symptomatic patients with severe chronic angina taking standard doses of atenolol, amlodipine, or diltiazem, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.

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Am J Med. 2004 Jan 1;116(1):35-43.
Calcium channel blockers: an update.
Eisenberg MJ, Brox A, Bestawros AN.
Division of Cardiology, Jewish General Hospital, Montreal, Quebec, Canada. marke@epid.jgh.mcgill.ca

This paper reviews the current literature pertaining to calcium channel blockers, including their classification, properties, and therapeutic indications, in light of several recent trials that have addressed their safety. Calcium channel blockers are a structurally and functionally heterogeneous group of medications that are used widely to control blood pressure and manage symptoms of angina. They are classified as dihydropyridines or nondihydropyridines. As a class, they are well tolerated and are associated with few side effects. The question of whether they may precipitate cardiovascular events has been largely settled by recent trials, such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the International Verapamil Slow-Release/Trandolapril Study (INVEST), and the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) study, in which no such association was found. Even so, the use of these agents has been linked with an increased risk of heart failure. Thus, long-acting calcium channel blockers may be safely used in the management of hypertension and angina. However, as a class, they are not as protective as other antihypertensive agents against heart failure.

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Anesthesiol Clin North America. 2003 Dec;21(4):797-804.
Spinal cord stimulation for angina pectoris and peripheral vascular disease.
Erdek MA, Staats PS.
Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 550 N. Broadway, Suite 301, Baltimore, MD 21205, USA. merdek@jhmi.edu

SCS is a viable option for treating angina pectoris and inoperable PVD. Its mechanism of action remains controversial, but successful pain relief has been consistently reported in various studies. Many clinicians are foregoing a formal trial, choosing instead to obtain an adequate area of paresthesia and implant in one session. Long-term follow-up of SCS patients treated for angina pectoris shows continued pain relief, increase in activities, and decreased use of medications. Emerging literature supports the finding that SCS is cost-effective in this patient population relative to CABG. SCS does not mask the ischemic pain that signals impending further damage of the myocardium. In patients with inoperable PVD, SCS relieves pain and improves microcirculatory blood flow. Quality of life and mobility can be improved with SCS. The beneficial effects of SCS on ulcer healing are controversial, and evidence suggests that the best candidates for the procedure are those with ischemic rest pain without tissue loss. Patients with diabetes mellitus and hypertension may have the least favorable outcomes with regard to limb salvage. No convincing data have been published on the cost-effectiveness of SCS in this patient population. SCS is a safe procedure that is minimally invasive, reversible, and associated with only infrequent side effects, the most common of which include lead migration and infection. SCS is clearly an option for the improvement of pain and the quality of life in this carefully selected subset of patients.

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Atheroscler Suppl. 2003 Dec;4(5):3-9.
The next step in cardiovascular protection.
Cannon CP.
TIMI Study Group, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. cpcannon@partners.org

While aggressive interventional therapy and anti-thrombotic therapy have revolutionized the management of acute coronary syndromes (ACS), defined as acute myocardial infarction (MI) or unstable angina (UA), long-term event rates remain high. Elevated lipids, inflammation and infection have each been implicated as additional mechanisms contributing to instability of vulnerable plaques. The new frontier in ACS management has focussed on treatment of these components of vascular disease. Preliminary trials have shown that early treatment with statins after ACS reduces coronary events but additional studies are needed to confirm this benefit. Furthermore, it is not clear what degree of low-density lipoprotein cholesterol (LDL-C) lowering is needed to stabilize the ACS patient. Chlamydia pneumoniae has been implicated in the development of coronary heart disease (CHD) but the results of preliminary trials investigating anti-chlamydial antibiotics have been inconsistent. Therefore, the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT TIMI 22) trial has been designed specifically to determine whether standard LDL-C reduction (with pravastatin 40 mg) provides a similar clinical benefit to more aggressive LDL-C reduction (with atorvastatin 80 mg). In 4162 ACS patients over a 2-year period, this trial will also evaluate the long-term effect of the quinolone antibiotic, gatifloxacin, in reducing cardiovascular events.

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Asian Cardiovasc Thorac Ann. 2003 Dec;11(4):285-8.
Off-pump surgery: a choice in unstable angina.
Kohli V, Goel M, Sharma VK, Mishra Y, Malhotra R, Mehta Y, Trehan N.
Escorts Heart Institute and Research Centre, Okhla Road, New Delhi 110-025, India. vijay_K22@yahoo.com

The benefit and safety of off-pump coronary artery bypass surgery in patients with unstable angina was assessed retrospectively. From February 1996 to October 2001, 5,306 patients underwent multivessel off-pump coronary artery bypass, of whom 920 (17%) had unstable angina. In these 920 patients, ejection fractions ranged from 15% to 70%, 203 (22%) had an ejection fraction of 20%-35%, and 11 (1%) had an ejection fraction < 20%. Triple-vessel disease was present in 625 patients. Preoperative intraaortic balloon pump support was used in 28 patients. Operative approaches included mid sternotomy (86%), lower partial sternotomy (9%), and left anterior thoracotomy (2%). The number of grafts ranged from 1 to 5 with a mean of 2.43 +/- 0.86, and 92.3% of patients received a left internal mammary artery graft. Twenty-two patients need intraoperative intraaortic balloon pumping. Ten patients (1%) suffered perioperative myocardial infarction. The mean hospital stay was 7.8 +/- 4.3 days. Hospital mortality was 2/920 (0.22%). Intraaortic balloon pumping was helpful in these cases of unstable angina refractory to medical therapy. Off-pump coronary artery surgery was found to be safe and beneficial in these patients.

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J Am Coll Cardiol. 2003 Dec 17;42(12):2090-5.
External counterpulsation therapy improves endothelial function in patients with refractory
angina pectoris.
Shechter M, Matetzky S, Feinberg MS, Chouraqui P, Rotstein Z, Hod H.
Heart Institute, Chaim Sheba Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel. schectes@netvision.net.il

OBJECTIVES: The goal of this study was to investigate the influence of short-term external counterpulsation (ECP) therapy on flow-mediated dilation (FMD) in patients with coronary artery disease (CAD). BACKGROUND: In patients with CAD, the vascular endothelium is usually impaired and modification or reversal of endothelial dysfunction may significantly enhance treatment. Although ECP therapy reduces angina and improves exercise tolerance in patients with CAD, its short-term effects on FMD in patients with refractory angina pectoris have not yet been described. METHODS: We prospectively assessed endothelial function in 20 consecutive CAD patients (15 males), mean age 68 +/- 11 years, with refractory angina pectoris (Canadian Cardiovascular Society [CCS] angina class III to IV), unsuitable for coronary revascularization, before and after ECP, and compared them with 20 age- and gender-matched controls. Endothelium-dependent brachial artery FMD and endothelium-independent nitroglycerin (NTG)-mediated vasodilation were assessed before and after ECP therapy, using high-resolution ultrasound. RESULTS: External counterpulsation therapy resulted in significant improvement in post-intervention FMD (8.2 +/- 2.1%, p = 0.01), compared with controls (3.1 +/- 2.2%, p = 0.78). There was no significant effect of treatment on NTG-induced vasodilation between ECP and controls (10.7 +/- 2.8% vs. 10.2 +/- 2.4%, p = 0.85). External counterpulsation significantly improved anginal symptoms assessed by reduction in mean sublingual daily nitrate consumption, compared with controls (4.2 +/- 2.7 nitrate tablets vs. 0.4 +/- 0.5 nitrate tablets, p <0.001 and 4.5 +/- 2.3 nitrate tablets vs. 4.4 +/- 2.6 nitrate tablets, p = 0.87, respectively) and in mean CCS angina class compared with controls (3.5 +/- 0.5 vs. 1.9 +/- 0.3, p <0.0001 and 3.3 +/- 0.6 vs. 3.5 +/- 0.5, p = 0.89, respectively). CONCLUSIONS: External counterpulsation significantly improved vascular endothelial function in CAD patients with refractory angina pectoris, thereby suggesting that improved anginal symptoms may be the result of such a mechanism.

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J Am Coll Cardiol. 2003 Dec 17;42(12):2049-59.
Effects of angiotensin-converting enzyme inhibition on transient ischemia: the Quinapril Anti-Ischemia and Symptoms of Angina Reduction (QUASAR) trial.
Pepine CJ, Rouleau JL, Annis K, Ducharme A, Ma P, Lenis J, Davies R, Thadani U, Chaitman B, Haber HE, Freedman SB, Pressler ML, Pitt B; QUASAR Study Group.
University of Florida College of Medicine, Division of Cardiovascular Medicine, Gainesville, Florida 32610-0277, USA. pepincj@medicine.ufl.edu

OBJECTIVES: We sought to determine whether angiotensin-converting enzyme inhibition (ACE-I) (i.e., quinapril) prevents transient ischemia (exertional and spontaneous) in patients with coronary artery disease (CAD). BACKGROUND: It is known that ACE-I reduces the risk of death, myocardial infarction (MI), and other CAD-related outcomes in high-risk patients. Numerous studies have confirmed that ACE-I improves coronary flow and endothelial function. Whether ACE-I also decreases transient ischemia is unclear, because no studies have been adequately designed or sufficiently powered to evaluate this issue. METHODS: Using a randomized, double-blinded, placebo-controlled, multicenter design, we enrolled 336 CAD patients with stable angina. None had uncontrolled hypertension, left ventricular (LV) dysfunction, or recent MI, and all developed electrocardiographic (ECG) evidence of ischemia during exercise. They were randomly assigned to one of two groups: 40 mg/day quinapril (n = 177) or placebo (n = 159) for 8 weeks. Patients then entered an additional eight-week treatment phase to examine the full dose range. Those assigned to 40 mg quinapril continued that dose and those assigned to placebo were titrated to 80 mg/day. Treadmill testing, the Seattle Angina Questionnaire, and ambulatory ECG monitoring were used to assess responses at baseline and at 8 and 16 weeks. RESULTS: The groups did not differ significantly at entry or in terms of indexes assessing myocardial ischemia at 8 or 16 weeks of treatment. In this low-risk population, ACE-I was not associated with serious adverse events. CONCLUSIONS: Our findings suggest short-term ACE-I in CAD patients without hypertension, LV dysfunction, or acute MI is not associated with significant effects on transient ischemia.

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Kyobu Geka. 2003 Dec;56(13):1075-81; discussion 1081-4.
[Emergency coronary artery bypass grafting for acute coronary syndrome with preoperative intraaortic balloon pumping; comparative surgical outcome and long-term results]
[Article in Japanese]
Kamohara K, Yoshikai M, Yunoki J, Fumoto H, Itoh T, Murayama J, Hamada M.
Department of Cardiovascular Surgery, Tenjin-kai Shin-Koga Hospital, Kurume, Japan.

With recent technical improvements in catheter interventional therapy, percutaneous coronary intervention (PCI) has now become the treatment of first choice for acute coronary syndrome (ACS). The objective of the present study was to evaluate critically the timing of coronary artery bypass grafting (CABG) for severe ACS with preoperative intraaortic balloon pumping (IABP). Since 1994, a total of 70 patients have gone emergency or urgent CABG for ACS. Of 70 patients, 50 patients required preoperative IABP. There were 22 patients (17 men, 5 women) with acute myocardial infarction (AMI), with a mean age of 67.7 years, and 28 patients (19 men, 9 women) with unstable angina pectoris (UAP), with a mean age of 69.2 years. There was a significant difference, between AMI and UAP, in the prevalence of emergency operation (95.5% vs 25.0%), in preoperative cardiogenic shock (81.8% vs 17.9%), in the level of preoperative CPK-MB (196.7 IU/l vs 2.0 IU/l) and in preoperative ejection fraction (41.8% vs 47.3%). Two patients in AMI required percutaneous cardiopulmonary support (PCPS). Thirteen patients in AMI and 22 patients in UAP presented left main trunk (LMT) disease. Of the 13 LMT patients in AMI, 4 patients were AMI due to acute occlusion in the LMT. The AMI patients received 2.45 distal anastomoses on average, while the UAP patients 3.14 distal anastomoses (p = 0.019). Excluding the mean number of distal anastomoses, there was no difference in the intraoperative technical factors, such as aortic cross clamping duration, cardiopulmonary bypass duration, rate of complete revascularization, between AMI and UAP. There were postoperative significant differences in low cardiac output syndrome (LOS) [45.6% in AMI vs 3.6% in UAP] and in prolongation of mechanical ventilation (59.1% in AMI vs 14.3% in UAP). The hospital mortality was 9.1% (2/22) in AMI, and 3.6% (1/28) in UAP, with no significant difference. Of these 3 patients, 1 patient died from perioperative cerebrovascular accident (CVA), another from LOS, and the other from postoperative mesenteric ischemia, with an overall mortality of 6.0% (3/50). The overall patency rate of the grafts was 100% in AMI and 96.6% in UAP. The 5-year-survival rate excluding in-hospital death was 72.5% in AMI, and 89.6% in UAP. The 5-year-cardiac event-free rate was 77% in AMI and 89.4% in UAP. The overall survival rate, and cardiac event-free rate, at 5 years was 80.8%, and 83.8%, respectively. In conclusion, for ACS cases, especially UAP cases of LMT, in which symptoms, findings of ischemia and hemodynamics are stabilized by medical intervention including IABP; emergency surgery could be avoided immediately after coronary angiography. Recovery in the ischemic myocardium is intended by IABP, and urgent surgery should be performed after sufficient and precise preoperative examinations. An improvement not only in the perioperative but also long-term results can be expected by performing complete revascularizations.

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Chest. 2003 Dec;124(6):2074-8.
Did the widespread use of long-acting calcium antagonists decrease the occurrence of variant angina?
Sueda S, Kohno H, Fukuda H, Uraoka T.
Department of Cardiology, Saiseikai Saijo Hospital, Tsuitachi 269-1, Saijo City, Ehime Prefecture, Japan 793-0027. EZF03146@nifty.or.jp

BACKGROUND: We have not often encountered variant angina (VA) since the use of long-acting calcium antagonists (L-CAs) became widespread. OBJECTIVES: This study examined the frequency of VA retrospectively. METHODS: and results: We diagnosed angiographically confirmed coronary spastic angina (CSA) in 349 consecutive patients using selective spasm provocation tests from January 1991 to December 2002. During this period, 3,148 diagnostic cardiac catheterizations and 1,515 selective spasm provocation tests were performed. Seventy-four of these 349 patients (21.2%) had VA. Coronary spasms were defined as transient luminal narrowings of > 99%, and VA was defined as an ST elevation during spontaneous attacks or noninvasive stress tests. We classified the 12 years of the study into four periods of 3 years each. No tendency to decrease for the ratio of the number of patients with CSA and the number of selective spasm provocation tests was observed among the four time periods (18%, 24%, 32%, and 23%, respectively). However, the number of patients with VA (28, 33, 9, and 4) and the VA/CSA ratio (32%, 28%, 14%, and 5%, respectively) in the four group significantly decreased. The frequency of administration of calcium antagonists (CAs) before hospital admission (49% vs 33%, respectively; p < 0.05) was significantly higher in the last time period (from 2000 to 2002) than in the first period (from 1991 to 1993). L-CAs were administered in > 90% of CSA patients who had been medicated with CAs before hospital admission in the last period (from 2000 to 2002), while L-CAs were administered in only 20% in the former period (from 1991 to 1993). The administration of statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers before hospital admission gradually increased according to the period passed, but not significantly. CONCLUSION: The frequency of VA has decreased in Japan, possibly due to the widespread use of therapy with L-CAs.

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Circulation. 2003 Dec 9;108(23):2870-6. Epub 2003 Dec 01.
Randomized comparison between stenting and off-pump bypass surgery in patients referred for angioplasty.
Eefting F, Nathoe H, van Dijk D, Jansen E, Lahpor J, Stella P, Suyker W, Diephuis J, Suryapranata H, Ernst S, Borst C, Buskens E, Grobbee D, de Jaegere P.
Department of Cardiology, Heart Lung Center Utrecht, Utrecht, The Netherlands.

BACKGROUND: Stenting improves cardiac outcome in comparison with balloon angioplasty. Compared with conventional surgery, off-pump bypass surgery on the beating heart without cardiopulmonary bypass may reduce morbidity, hospital stay, and costs. The purpose, therefore, was to compare cardiac outcome, quality of life, and cost-effectiveness 1 year after stenting and after off-pump surgery. METHODS AND RESULTS: Patients referred for angioplasty (n=280) were randomly assigned to stenting (n=138) or off-pump bypass surgery. At 1 year, survival free from stroke, myocardial infarction, and repeat revascularization was 85.5% after stenting and 91.5% after off-pump surgery (relative risk, 0.93; 95% CI, 0.86 to 1.02). Freedom from angina was 78.3% after stenting and 87.0% after off-pump surgery (P=0.06). Quality-adjusted lifetime was 0.82 year after stenting and 0.79 year after off-pump surgery (P=0.09). Hospital stay after the initial procedure was 1.43 and 5.77 days, respectively (P<0.01). Stenting reduced overall costs by 2933 dollars (26.2%) per patient (8276 dollars versus 11 209 dollars; P<0.01). Stenting was more cost-effective in 95% of the bootstrap estimates. CONCLUSIONS: At 1 year, stenting was more cost-effective than off-pump surgery while maintaining comparable cardiac outcome and quality of life. Stenting rather than off-pump surgery, therefore, can be recommended as a first-choice revascularization strategy in selected patients.

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Am J Med. 2003 Dec 1;115(8):606-12.
Effects of an early invasive strategy on ischemia and exercise tolerance among patients with unstable coronary artery disease.
Diderholm E, Andren B, Frostfeldt G, Genberg M, Jernberg T, Lagerqvist B, Lindahl B, Wallentin L.
Department of Cardiology, University Hospital, Uppsala, Sweden. erik.diderholm@thorax.uas.lul.se

BACKGROUND: An early invasive approach after an episode of unstable coronary artery disease has beneficial effects on mortality and myocardial infarction, but its effects on exercise capacity and ischemia have not been investigated. METHODS: In the Fast Revascularisation during InStability in Coronary disease (FRISC) II trial, 2457 patients with unstable coronary artery disease were assigned randomly to an early invasive or noninvasive strategy. A symptom-limited bicycle exercise test was performed before discharge in the noninvasive group and after 3 months in both groups. RESULTS: At 3 months, 86% (1046/1222) of the patients in the invasive group and 81% (995/1235) in the noninvasive group performed the exercise test. Before the test, revascularization had been performed in 78% (n = 819) of these patients in the invasive group compared with 28% (n = 281) of those in the noninvasive group. The mean (+/- SD) exercise capacity was higher (6.4 +/- 1.9 vs. 6.2 +/- 1.9 metabolic equivalents [METS], P <0.01), and the occurrence of ischemia lower (23% [229/1004] vs. 36% [352/966], P <0.001) in the invasive group. In the noninvasive group, 882 patients performed an exercise test both predischarge and at 3 months. If a revascularization procedure was performed (n = 210), exercise tolerance increased from 5.1 +/- 1.4 to 6.0 +/- 1.8 METS (P <0.001) and the number of patients with ST depression decreased from 65% (131/203) to 31% (63/203) (P <0.001). Without revascularization (n = 670), exercise tolerance increased from 5.9 +/- 2.2 to 6.3 +/- 1.9 METS (P <0.001), and there were no differences in the occurrence of ischemia. CONCLUSION: In unstable coronary artery disease, an invasive strategy improves exercise tolerance and reduces exercise-induced ischemia.

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Drug Ther Bull. 2003 Nov;41(11):86-8.
Nicorandil for angina—an update.
[No authors listed]

Around 2 million people in the UK have angina pectoris and are therefore at high risk of severe coronary events such as myocardial infarction (MI) or sudden death. Conventional management of patients with stable angina includes glyceryl trinitrate, a beta-blocker, aspirin and a statin, with the aim of controlling symptoms and reducing the risk of a coronary event. For patients unable to tolerate a beta-blocker, the choice is less clear but calcium channel blockers and long-acting nitrates provide effective symptom control. Another option is nicorandil (Ikorel--Rhone-Poulenc Rorer), a potassium channel activator licensed for the "prevention and long term treatment of chronic stable angina pectoris". In our review of nicorandil 8 years ago, we concluded that it provided symptom control that was as good as, but no better than, other less expensive anti-anginal drugs. Since then, new data have suggested that nicorandil might reduce the frequency of coronary events in patients with stable angina. Here, we consider these findings and reassess the place of nicorandil for patients with angina.

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Jpn Heart J. 2003 Nov;44(6):899-906.
Effects of enoxaparin and nadroparin on major cardiac events in high-risk unstable angina treated with a glycoprotein IIb/IIIa inhibitor.
Okmen E, Ozen E, Uyarel H, Sanli A, Tartan Z, Cam N.
Department of Cardiology, Siyami Ersek Cardiovascular and Thoracic Surgery Center, Istanbul, Turkey.

Clinical trials have reported the beneficial effects of platelet glycoprotein (GP) IIb/IIIa receptor antagonists and low-molecular-weight heparins (LMWH) on major cardiac events (MACE) in patients presenting with unstable angina or non-ST elevation myocardial infarction. A number of studies have documented the significant superiority of low-molecular-weight heparins, especially enoxaparin, over unfractionated heparin in the treatment of acute coronary syndromes. The purpose of this study was to compare the effects of two different LMWHs, enoxaparin and nadroparin, accompanied by platelet GP IIb/IIIa inhibition on MACE in high-risk unstable angina. The study was designed as an open-label and observational study. Sixty-eight patients presenting with unstable angina associated with high-risk criteria were randomly assigned to treatment with enoxaparin plus tirofiban (36 patients, mean age 57 +/- 11) or nadroparin plus tirofiban (32 patients, mean age: 58 +/- 8). In-hospital MACE including acute myocardial infarction (AMI), recurrent refractory angina, death, stroke, and urgent revascularization were compared between the study groups. Patient characteristics and durations of LMWH and tirofiban treatments were not different between the study groups. Coronary artery risk factors, except family history (which was observed more frequently in the enoxaparin group, P = 0.02), were also similar. MACE between the enoxaparin and nadroparin groups including AMI (5.5%, 6%), recurrent refractory angina (19%, 12%), death (0%, 3%), stroke (was not observed in either group), urgent revascularization (14%, 12%) and total MACE (19%, 15%) were not different. Enoxaparin and nadroparin, accompanied by GP IIb/IIIa inhibitor therapy, have similar effects on the development of major cardiac events in patients presenting with unstable angina and high-risk characteristics.

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Am J Cardiol. 2003 Nov 6;92(9 Suppl):37-46.
Cardiovascular effects of tadalafil.
Kloner RA, Mitchell M, Emmick JT.
Division of Cardiovascular Medicine, Keck School of Medicine of the University of Southern California, (RAK), Los Angeles, California, USA

To determine the effects of tadalafil on the cardiovascular system, safety assessments were performed on a database of >4,000 subjects who received tadalafil in >60 clinical pharmacology, phase 2, phase 3, and open-label studies. In healthy subjects, tadalafil resulted in small changes in blood pressure, which are not believed to be clinically relevant. Daily administration of tadalafil 20 mg for 26 weeks in healthy male subjects or patients with mild erectile dysfunction resulted in blood pressure changes similar to those observed after placebo administration. In patients with coronary artery disease (CAD), tadalafil administration before nitrate administration resulted in small decreases in blood pressure. The resulting mean maximal change in standing systolic blood pressure (SBP) after coadministration of sublingual nitroglycerin in patients with chronic stable angina was -36 mm Hg for tadalafil 5 mg, -31 mm Hg for tadalafil 10 mg, and -28 mm Hg for placebo. In addition, a larger number of men had a standing SBP <85 mm Hg after coadministration of sublingual nitroglycerin and tadalafil 5 mg (p <0.001 vs placebo) or tadalafil 10 mg (p <0.01 vs placebo) compared with coadministration with placebo. In patients with chronic stable angina taking doses of isosorbide mononitrate on a long-term basis, the mean maximal change in standing SBP was -23 mm Hg for placebo, -23 mm Hg for tadalafil 5 mg, and -26 mm Hg for tadalafil 10 mg. In a study of older subjects (>/=55 years of age) with no overt evidence of CAD, the resulting mean maximal change in standing SBP after coadministration of sublingual nitroglycerin was -25 mm Hg for tadalafil 10 mg, -29 mm Hg for sildenafil 50 mg, and -25 mm Hg for placebo. Cardiac mortality rates in tadalafil studies are consistent with the expected rate in this male population. Across all studies, the incidence rate of myocardial infarction was low in tadalafil-treated patients (0.43 per 100 patient-years) compared with patients who received placebo (0.6 per 100 patient-years), and the incidence rate was comparable to that observed in the age-standardized male population (0.60 per 100 patient-years). The incidence rate of presumed thrombotic strokes in tadalafil studies (0.27 per 100 patient-years) is comparable to the expected rate in this patient population. The data presented herein suggest that tadalafil can be safely used by healthy subjects and by patients with cardiovascular diseases. As with sildenafil, the use of tadalafil is contraindicated in patients receiving nitrate therapy because of the potential for significant hypotensive effects.

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Am J Cardiol. 2003 Nov 15;92(10):1192-5.
Effect of atorvastatin on exercise-induced myocardial ischemia in patients with stable angina pectoris.
Bogaty P, Dagenais GR, Poirier P, Boyer L, Auclair L, Pepin G, Jobin J, Arsenault M.
Quebec Heart Institute, Laval Hospital, Ste-Foy, Quebec, Canada

To investigate whether marked and sustained lipid-lowering in subjects with stable angina pectoris and dyslipidemia reduces exercise-induced myocardial ischemia, 17 subjects were treated with dose-adjusted atorvastatin over 1 year and underwent serial evaluation of exercise electrocardiographic ischemic parameters, serum biomarkers, and brachial artery endothelial function. Endothelial function improved progressively and C-reactive protein, P-selectin, and tissue plasminogen activator inhibitor levels decreased, but there was no decrease in exercise electrocardiographic ischemia.

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Curr Med Res Opin. 2003;19(7):661-72.
Cardioprotective effects of trimetazidine: a review.
Marzilli M.
Cardiology Department, Siena University, Italy.

The efficacy of trimetazidine, an anti-ischaemic agent, has been largely assessed and presented in the international literature through its metabolic effects, selective and specific fatty acid oxidation inhibition and lack of haemodynamic effects in stable angina pectoris. As such, trimetazidine has opened up a new class of metabolic agents that reduce fatty acid oxidation: the 3-KAT (3-ketoacyl-CoA thiolase) inhibitors. The aim of this review article is to demonstrate the cardioprotective benefits of trimetazidine, and how this can be translated into positive effects in the treatment of cardiac disorders. Trimetazidine has been assessed in several double-blind randomised studies as a treatment of ischaemic heart disease or as an agent given prior to or during percutaneous transluminal coronary angioplasty, coronary artery bypass grafting and thrombolysis to prevent or limit ischaemia/reperfusion damage in the heart. All these studies demonstrate that trimetazidine protects the heart from the deleterious consequences of ischaemia by switching cardiac metabolism from fatty acid oxidation to glucose oxidation. Study results cast no doubts on the value of the cardioprotective effects of trimetazidine and support the fact that trimetazidine has a direct anti-ischaemic effect on human myocardial cells. Trimetazidine has proven antianginal efficacy, and can be also used in other cardiac diseases with ischaemic signs.

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Circulation. 2003 Oct 21;108(16 Suppl 1):III28-37.
Application of current guidelines to the management of unstable angina and non-ST-elevation
myocardial infarction.
Braunwald E.
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and The Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. ebraunwald@partners.org

Unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) is a common but heterogeneous disorder with patients exhibiting widely varying risks. Early risk stratification is at the center of the management program and can be achieved using clinical criteria and biomarkers, or a combination. In addition to anti-ischemic therapy and aspirin, the thienopyridine clopidogrel is indicated except in patients who are potential candidates for urgent coronary artery bypass grafting (CABG). Platelet glycoprotein (GP) IIb/IIIa antagonists are indicated in high-risk patients likely to undergo percutaneous coronary intervention (PCI) but are not indicated in the management of lower-risk patients who do not undergo PCI. There is a growing body of evidence to support the substitution of the low-molecular-weight heparin (LMWH) enoxaparin for unfractionated heparin (UFH). Three recent trials have demonstrated the benefit of an early invasive strategy with catheterization followed by revascularization in patients at high and intermediate risk. Lower-risk patients should undergo early noninvasive stress testing. An intensive program of secondary prevention is mandatory and should be begun before hospital discharge.

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J Am Coll Cardiol. 2003 Oct 1;42(7):1161-70.
Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy.
Henderson RA, Pocock SJ, Clayton TC, Knight R, Fox KA, Julian DG, Chamberlain DA; Second Randomized Intervention Treatment of Angina (RITA-2) Trial Participants.
Department of Cardiology, Nottingham City Hospital, Nottingham, United Kingdom. rhender1@ncht.trent.nhs.uk

OBJECTIVES: This study was designed to compare the long-term consequences of percutaneous transluminal coronary angioplasty (PTCA) and continued medical treatment. BACKGROUND: The long-term effects of percutaneous coronary intervention need evaluating, especially in comparison with an alternative policy of continued medical treatment. METHODS: The Second Randomized Intervention Treatment of Angina (RITA-2) is a randomized trial of PTCA versus conservative (medical) care in 1,018 patients considered suitable for either treatment option. Information on clinical events, interventions, and symptoms is available for a median seven years follow-up. RESULTS: Death or myocardial infarction (MI) occurred in 73 (14.5%) PTCA patients and 63 (12.3%) medical patients (difference +2.2%, 95% confidence interval -2.0% to +6.4%, p = 0.21). There were 43 deaths in both groups, of which 41% were cardiac-related. Among patients assigned PTCA 12.7% subsequently had coronary artery bypass grafts, and 14.5% required additional non-randomized PTCA. Most of these re-interventions occurred within a year of randomization, and after two years the re-intervention rate was 2.3% per annum. In the medical group, 35.4% required myocardial revascularization: 15.0% in the first year and an annual rate of 3.6% after two years. An initial policy of PTCA was associated with improved anginal symptoms and exercise times. These treatment differences narrowed over time, mainly because of coronary interventions in medical patients with severe symptoms. CONCLUSIONS: In RITA-2 an initial strategy of PTCA did not influence the risk of death or MI, but it improved angina and exercise tolerance. Patients considered suitable for PTCA or medical therapy can be safely managed with continued medical therapy, but percutaneous intervention is appropriate if symptoms are not controlled.

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Am J Cardiol. 2003 Oct 1;92(7):789-93.
Effect of trapidil on cardiovascular events in patients with coronary artery disease (results from the Japan Multicenter Investigation for Cardiovascular Diseases-Mochida [JMIC-M]).
Hirayama A, Kodama K, Yui Y, Nonogi H, Sumiyoshi T, Origasa H, Hosoda S, Kawai C; Japan Multicenter Investigation for Cardiovascular Diseases-Mochida Investigators.
Cardiovascular Division, Osaka Police Hospital, Osaka, Japan. ahirayama@oph.gr.jp

A large-scale study was conducted to assess the effect of long-term administration of trapidil on the prognosis of patients with angiographic evidence of coronary artery disease (CAD). A large-scale, multicenter study, the Japan Multicenter Investigation for Cardiovascular Diseases-Mochida was an open-label, randomized trial of 1,743 patients with CAD who were < or =70 years old and had angiographic evidence of >25% stenosis in any coronary artery. We randomly assigned the patients to receive medical treatment either with trapidil 100 mg 3 times daily (trapidil group, n = 873) or without trapidil (control group, n = 870). The mean follow-up period was 924 days. The incidence of cardiovascular events, including cardiac death, nonfatal myocardial infarction, angina pectoris/heart failure requiring hospitalization, and cerebrovascular events was 11.1% in the trapidil group and 14.9% in the control group (relative risk 0.75, 95% confidence interval 0.58 to 0.98, p = 0.036). Thus, long-term intervention with trapidil in CAD reduces the incidence of cardiovascular events and improves the prognosis of patients with CAD.

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Circulation. 2003 Oct 7;108(14):1682-7. Epub 2003 Sep 22.
Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.
Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, Diaz R, Commerford PJ, Valentin V, Yusuf S; Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Trial Investigators.
Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.

BACKGROUND: We studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of patients with acute coronary syndrome (ACS). METHODS AND RESULTS: In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, 12 562 patients with ACS using aspirin, 75 to 325 mg daily, were randomized to clopidogrel or placebo for up to 1 year. In this analysis, patients were divided into the following 3 aspirin dose groups: < or =100 mg, 101 through 199 mg, and > or =200 mg. The combined incidence of cardiovascular death, myocardial infarction, or stroke was reduced by clopidogrel regardless of aspirin dose, as follows: < or =100 mg, 10.5% versus 8.6% (relative risk [RR], 0.81 [95% CI, 0.68 to 0.97]); 101 to 199 mg, 9.8% versus 9.5% (RR, 0.97 [95% CI 0.77 to 1.22]); and > or =200 mg, 13.6% versus 9.8% (RR, 0.71 [95% CI, 0.59 to 0.85]). The incidence of major bleeding increased with increasing aspirin dose both in the placebo group (1.9%, 2.8%, and 3.7%, respectively; P=0.0001) and the clopidogrel group (3.0%, 3.4%, and 4.9%, respectively; P=0.0009); thus, the excess risk with clopidogrel was 1.1%, 1.2%, and 1.2%, respectively. The adjusted hazard ratio for major bleeding for the highest versus the lowest dose of aspirin was 1.9 (95% CI 1.29 to 2.72) in the placebo group, 1.6 (95% CI 1.19 to 2.23) in the clopidogrel group, and 1.7 (95% CI 1.36 to 2.20) in the combined group. CONCLUSIONS: In patients with ACS, adding clopidogrel to aspirin is beneficial regardless of aspirin dose. Bleeding risks increase with increasing aspirin dose, with or without clopidogrel, without any increase in efficacy. Our findings suggest that the optimal daily dose of aspirin may be between 75 and 100 mg, with or without clopidogrel.

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JAMA. 2003 Sep 24;290(12):1593-9.
Evaluation of prolonged antithrombotic pretreatment ("cooling-off" strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial.
Neumann FJ, Kastrati A, Pogatsa-Murray G, Mehilli J, Bollwein H, Bestehorn HP, Schmitt C, Seyfarth M, Dirschinger J, Schomig A.
Medizinische Klinik, Technische Universitat Munchen, Munich, Germany. Franz-Josef.Neumann@herzzentrum.de

CONTEXT: In unstable coronary syndromes, catheter intervention is frequently preceded by antithrombotic treatment to reduce periprocedural risk; however, evidence from clinical trials to support antithrombotic pretreatment is sparse. OBJECTIVE: To test the hypothesis that prolonged antithrombotic pretreatment improves the outcome of catheter intervention in patients with acute unstable coronary syndromes compared with early intervention. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial conducted from February 27, 2000, to April 8, 2002, and including patients admitted to 2 German tertiary care centers with symptoms of unstable angina plus either ST-segment depression or elevation of cardiac troponin T levels. INTERVENTIONS: Patients were randomly allocated to antithrombotic pretreatment for 3 to 5 days or to early intervention after pretreatment for less than 6 hours. In both groups, antithrombotic pretreatment consisted of intravenous unfractionated heparin (60-U/kg bolus followed by infusion adjusted to maintain partial thromboplastin time of 60 to 85 seconds), aspirin (500-mg intravenous bolus followed by 100-mg twice-daily oral dose), oral clopidogrel (600-mg loading dose followed by 75-mg twice-daily dose), and intravenous tirofiban (10- microg/kg bolus followed by continuous infusion of 0.10 microg/kg per min). MAIN OUTCOME MEASURE: Composite 30-day incidence of large nonfatal myocardial infarction or death from any cause. RESULTS: Of the 410 patients enrolled, 207 were allocated to receive prolonged antithrombotic pretreatment and 203 to receive early intervention. Elevated levels of cardiac troponin T were present in 274 patients (67%), while 268 (65%) had ST-segment depression. The antithrombotic pretreatment and the early intervention groups were well matched with respect to major baseline characteristics and definitive treatment (catheter revascularization: 133 [64.3%] vs 143 [70.4%], respectively; coronary artery bypass graft surgery: 16 [7.7%] vs 16 [7.9%]). The primary end point was reached in 11.6% (3 deaths, 21 infarctions) of the group receiving prolonged antithrombotic pretreatment and in 5.9% (no deaths, 12 infarctions) of the group receiving early intervention (relative risk, 1.96 [95% confidence interval, 1.01-3.82]; P =.04). This outcome was attributable to events occurring before catheterization; after catheterization, both groups incurred 11 events each (P =.92). CONCLUSION: In patients with unstable coronary syndromes, deferral of intervention for prolonged antithrombotic pretreatment does not improve the outcome compared with immediate intervention accompanied by intense antiplatelet treatment.

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Am Heart J. 2003 Aug;146(2):304-10.
Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial.
Michalis LK, Katsouras CS, Papamichael N, Adamides K, Naka KK, Goudevenos J, Sideris DA.
Division of Cardiology, Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece.

BACKGROUND: Low-molecular weight heparins have different pharmacokinetic and pharmacodynamic characteristics and may vary in efficacy. We compared the efficacy of enoxaparin with that of tinzaparin in the management of non-ST-segment elevation acute coronary syndromes (NSTACS). METHODS: A total of 438 patients with NSTACS were randomized to receive subcutaneous treatment with enoxaparin, 100 IU/kg twice daily (equivalent to 1 mg/kg twice daily; n = 220), or tinzaparin, 175 IU/kg once daily, (n = 218) for as long as 7 days. The primary composite end point was recurrent angina, myocardial infarction (or reinfarction), or death at day 7. Secondary end points were the primary end point at day 30 and the occurrence of individual events at days 7 and 30. RESULTS: The incidence of the primary end point was 12.3% in the enoxaparin group and 21.1% in the tinzaparin group (P =.015). At day 7, the rate of recurrent angina was lower with enoxaparin than with tinzaparin (11.8% vs 19.3%). At day 30, the incidences of the composite end point, recurrent angina, and myocardial infarction were also lower with enoxaparin, 17.7% vs 28.0% (P =.012), 17.3% vs 26.1% and 0.5% vs 2.8%, respectively. The rate of revascularization was lower in the enoxaparin group, 8.6% vs 17.9% (P =.010) at day 7 and 16.4% vs 26.1% (P =.019) at day 30. Rates of bleeding complications were similar in the 2 treatment groups. CONCLUSIONS: This study indicates a benefit of enoxaparin (100 IU/kg twice daily) as compared with tinzaparin (175 IU/kg once daily) in the treatment of patients with NSTACS, which is sustained for at least 30 days.

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J Clin Epidemiol. 2003 Aug;56(8):775-81.
Short versus prolonged bed rest after uncomplicated acute myocardial infarction: a systematic review and meta-analysis.
Herkner H, Thoennissen J, Nikfardjam M, Koreny M, Laggner AN, Mullner M.
Department of Emergency Medicine, Vienna General Hospital, Waehringer Guertel 18-20, A-1090 Vienna, Austria.

BACKGROUND: Recently updated guidelines by the American College of Cardiology/American Heart Association and the European Society of Cardiology recommend at least 12 hours bed rest in patients with uncomplicated myocardial infarction. METHODS: We performed a systematic literature review and meta-analysis of randomized and quasi-randomized controlled trials comparing short versus prolonged bed rest in patients with uncomplicated acute myocardial infarction. RESULTS: We found 15 trials with 1332 patients assigned to a short period of bed rest (range 2 to 12 days) and 1326 patients assigned to prolonged bed rest (range 5 to 28 days). Generally, the studies were outdated and seemed to be of poor methodologic reporting quality. There was no evidence that shorter bed rest was more harmful than longer bed rest in terms of death, reinfarction, post-infarction angina, or thromboembolic events. CONCLUSION: We concluded that bed rest ranging from 2 to 12 days seems to be as safe as longer periods of bed rest.

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Am J Cardiol. 2003 Jul 1;92(1):21-5.
Effect of cilostazol on vasomotor reactivity in patients with vasospastic angina pectoris.
Watanabe K, Ikeda S, Komatsu J, Inaba S, Suzuki J, Sueda S, Funada J, Kitakaze M, Sekiya M.
Department of Cardiology, Uwajima City Hospital, Uwajima, Japan. kawatana@uwajima-mh.go.jp

We examined the effects of cilostazol on impaired coronary arterial responses in patients with vasospastic angina (VSA). Thirty patients who were diagnosed with VSA based on an acetylcholine provocation test and 10 subjects with normal coronary arteries were enrolled. The patients were divided into the following 3 groups: no antiplatelet agent treatment group, aspirin treatment, or cilostazol treatment groups. Coronary flow reserve (CFR), coronary flow volume at maximum hyperemia, and epicardial coronary artery diameter after administration of N(G)-monomethyl-L-arginine (L-NMMA) were examined using a Doppler flow wire before and 6 months after the start of this study. CFR, coronary flow volume at maximum hyperemia, and diameter changes by L-NMMA were significantly increased in the cilostazol treatment group compared with the other 2 groups. In conclusion, cilostazol increased CFR and flow-dependent coronary dilation; these changes were attributable to nitric oxide. Cilostazol may improve coronary vascular endothelial dysfunction and coronary hemodynamics in patients with VSA.

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Kyobu Geka. 2003 Jul;56(8 Suppl):682-7.
[Off-pump coronary artery bypass grafting for octogenarians with acute coronary syndrome]
[Article in Japanese]
Matsumoto Y, Endo M, Kasashima F, Abe Y, Kosugi I, Sasaki H.
Department of Cardiovascular Surgery, National Kanazawa Hospital, Kanazawa, Japan.

In recent years, experiences with performing off-pump coronary artery bypass (OPCAB) has increased dramatically. Many early reports suggest that this approach may improve outcome by lowering postoperative complications. The benefit of this procedure to elderly patients seems appealing but is not well studied. We sought to review our experience with OPCAB in octogenarians with acute coronary syndrome (ACS) to better define the potential benefit of this approach in this high-risk group of patients. Until March 2003, OPCAB was performed in 21 octogenarians (10 men and 11 women with mean age of 82.9 +/- 2.8 years) with ACS at the department of cardiovascular surgery of National Kanazawa Hospital. Two had myocardial infarction and 3 unstable angina. Mean left ventricular ejection function was 41.2%. 14 patients had a history of previous cerebral infarction. All procedures were completed without hemodynamic deterioration and conversion to on-pump coronary artery bypass grafting (CABG). There was no operative mortality and no occurrence of major complications such as low output syndrome, re-exploration for bleeding, cerebral infarction, perioperative myocardial infarction, and mediastinitis. And no further deterioration of organ function occurred in patients with preexisting central nervous system dysfunction or kidney. Peak CK-MB concentrations after surgery were within normal limits. This study demonstrates that CABG can be performed safely on high-risk ACS patients 80 years of age and older without the use of cardiopulmonary bypass. OPCAB may be the operation of choice for octogenarians with ACS requiring surgical myocardial revascularization.

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Postgrad Med J. 2003 Jun;79(932):332-6.
Management of stable angina.
Jain A, Wadehra V, Timmis AD.
London Chest Hospital, London, UK. ajay106@hotmail.com

Ischaemic heart disease may present as a wide variety of clinical entities including unstable or stable angina pectoris, acute myocardial infarction, and occasionally heart failure. Chronic stable angina is a common condition and results in a considerable burden for both the individual and society. The goals in management are (i) treatment of other conditions that may worsen angina; (ii) modification of risk factors and treatment with medications for coronary artery disease to improve outcome; and (iii) effective relief of anginal symptoms. There are limitations to the methods available to risk-stratify patients, and the optimal treatment strategy remains unclear. The benefits of lifestyle modification cannot be over-emphasised, and appropriate attention to modifiable risk factors is paramount. The mortality benefit of lipid lowering treatment and antiplatelet therapy is well proved. However the evidence base for anti-ischaemic therapy is less rigorous, being based mainly on extrapolations from studies of acute coronary syndromes. Angioplasty has been shown to be more effective in relief of symptoms than medical therapy alone, but provides no mortality benefit. Coronary artery bypass surgery, however, has been shown to reduce mortality in patients with severe proximal coronary disease when compared with medical management alone.

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Ann Thorac Surg. 2003 Jun;75(6):1842-7; discussion 1847-8.
Quality of life and survival after transmyocardial laser revascularization with the holmium:YAG laser.
Guleserian KJ, Maniar HS, Camillo CJ, Bailey MS, Damiano RJ Jr, Moon MR.
Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.

BACKGROUND: The purpose of this investigation was to assess postoperative survival and quality of life with transmyocardial laser revascularization (TMR) in high-risk patients. METHODS: During a 24-month period, 81 consecutive patients underwent either sole therapy TMR (n = 34) or TMR with coronary artery bypass grafting (n = 47) using a holmium:yttrium-aluminum-garnet (YAG) laser. Outcomes were assessed in three high-risk groups, including patients with left ventricular dysfunction (ejection fraction < or = 0.40) (n = 37), unstable angina (n = 30), and congestive heart failure (n = 33). Disease-specific quality of life was assessed using the Seattle Angina Questionnaire in 58 late survivors and compared with an age-matched cohort undergoing coronary artery bypass grafting only (no TMR) (n = 20). RESULTS: Overall mortality was 6% +/- 3% (+/- 70% confidence limit) and appeared higher with left ventricular dysfunction (11% +/- 5% vs 2% +/- 2%), but the difference did not reach statistical significance (p = 0.17; power = 0.16). There was also no statistical difference with unstable angina (10% +/- 6% vs 4% +/- 3%; p > 0.53) or congestive failure (9% +/- 5% vs 4% +/- 3%; p > 0.66). However, survival at 18 months was significantly lower with left ventricular dysfunction (62% +/- 9% vs 90% +/- 5%; p < 0.003) and congestive failure (48% +/- 10% vs 96% +/- 3%; p < 0.001). For sole therapy TMR, quality of life was diminished comparing TMR with coronary artery bypass grafting (p < 0.004) and coronary artery bypass grafting only (p < 0.002). CONCLUSIONS: Transmyocardial laser revascularization can be performed in high-risk patients, but survival is significantly impaired in patients with left ventricular dysfunction and congestive failure, and quality of life is diminished without some degree of direct revascularization.

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Med Klin (Munich). 2003 Jun 15;98(6):326-34.
[Update cardiology 2001/2002-part II. From unstable coronary syndrome to terminal heart failure]
[Article in German]
Fries R, Bohm M.
Medizinische Klinik und Poliklinik, Innere Medizin III (Kardiologie/Angiologie), Universitatskliniken des Saarlandes, Hamburg/Saar. fries@med-in.uni-saarland.de

The cardiovascular continuum describes the way from risk factors to atherosclerosis, acute cardiovascular events (unstable angina and myocardial infarction), and development of terminal heart failure and its complications. Following this way, advances are reported in the therapy of acute coronary syndrome, heart failure, ventricular and supraventricular tachyarrhythmias, and stroke in patients with patent foramen ovale. The following issues are reported in detail: (1) significance of statins and statin withdrawal, glycoprotein IIb/IIIa receptor blocker, acute coronary interventions, aspirin and clopidogrel in unstable coronary syndromes, (2) pathogenesis of acute pulmonary edema associated with hypertension, (3) cardiac regeneration capability after transplantation and myocardial infarction, (4) beta-blocker therapy, efficacy of additional angiotensin receptor blocker therapy and multisite biventricular pacing in symptomatic (advanced) heart failure, (5) prognosis after ablation of the atrioventricular node in patients with atrial fibrillation, (6) primary prevention with an implantable defibrillator and resumption of driving after implantation, and (7) therapeutic options after cryptogenic stroke and patent foramen ovale.

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Eur Heart J. 2003 Jun;24(12):1120-7.
The effect of a neuropeptide Y Y1 receptor antagonist in patients with angina pectoris.
Gullestad L, Bjuro T, Aaberge L, Apelland T, Skardal R, Kjekshus E, Nordlander M, Ablad B, Pernow J.
Department of Cardiology Rikshospitalet University Hospital, Oslo, Norway.

AIMS: Neuropeptide Y (NPY) is a potent vasoconstrictor released during sympathetic activation that may be involved in myocardial ischaemia. We examined the effect of a Y1 receptor antagonist on haemodynamic and ischaemic responses to exercise in patients with coronary artery disease. METHODS AND RESULTS: Eighty-two evaluable male patients were included in a randomized, double blind, two-way crossover study with a low dose (6.7 microg/kg/min; n=59)and a high dose (13.3 microg/kg/min; n=23) of the Y1 receptor antagonist AR-H040922 given as infusions for 2h or placebo. Myocardial ischaemia during a symptom-limited exercise test was monitored by conventional ST-segment analysis and heart rate (HR)-adjusted ST changes including the ST/HR slope and ST/HR recovery. Administration of the high dose AR-H040922 attenuated systolic blood pressure by 6-11 mmHg (p<0.05) during and after exercise without affecting HR. None of the two doses of AR-H040922 influenced any of the ischaemic parameters or duration of exercise, however. The maximal increase in NPY was higher during AR-H040922 (p<0.05) compared with placebo. CONCLUSIONS: Selective NPY Y1 receptor blockade attenuates the increase in blood pressure during exercise indicating a role for endogenous NPY in blood pressure regulation. Despite this effect, the Y1 receptor antagonist did not influence exercise-induced ischaemic parameters in patients with coronary artery disease.

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Ter Arkh. 2003;75(4):47-51.
[Immediate and long-term outcomes after "Ephesos" coronary stent implantation in patients with stable or unstable angina]
[Article in Russian]
Samko AN, Pershukov IV, Batyraliev TA, Niiazova-Karben ZA, Kalenich O, Karaus A, Giuler N, Erenuchu B, Kadaifchi S, Temamogullari A, Ozgul' S, Akgul' F, Levitskii IV, Sozytkin AV, Besnili F, Arful' F, Zhamgyrchiev ShT, Serchelik A, Shengul Kh, Daniiarov BS, Demirbash O, Belenkov IuN.

AIM: An open non-randomized trial was initiated to assess clinical and angiographic results of using the coronary stent "Ephesos" in 457 patients with stable or unstable angina pectoris and native coronary affections. MATERIAL AND METHODS: 268 stents have been implanted in 231 patients with stable angina (SA) and 271 stents--in 226 patients with unstable angina (UA). 46% lesions were complicated. The length of stenosis was 12.9 +/- 6.7 mm in the group SA and 14.1 +/- 7.4 mm in the group UA, 30% stenoses were long. RESULTS: Successful stenting was stated in 99% without cases of acute thrombosis. Non-fatal myocardial infarction took place in hospital in 1.3% of SA patients and in 2.6% of UA patients. Incidence of cardiac complications (death, recurrent angina pectoris, myocardial infarction, restenosis, repeated revascularization) for 6-month follow-up was 15.6% in SA group and 18.1% in UA group. At angiographic control, the index of vascular diameter loss made up 0.22 +/- 0.2 in SA group and 0.3 +/- 0.27 in UA group. Incidence of restenosis was 12 and 14%, respectively. 18-month follow-up found no differences in frequency of complications: 21.6 and 22.6% in groups SA and UA, respectively. CONCLUSION: Implantation of the stent "Ephesos" is effective in prevention of thrombosis and restenosis in patients with stable or unstable angina pectoris at high risk of intervention.

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Ann Cardiol Angeiol (Paris). 2003 Jun;52(3):169-72.
[Premedication by thienopyridine before percutaneous coronary interventions in unstable angina]
[Article in French]
Blanchard D, Demicheli T, Danchin N.
Clinique Saint-Gatien, 8, place de la-Cathedrale, 37000 Tours, France. didier.blanchard@wanadoo.fr

Ticlopidine or clopidogrel combined with aspirin decrease major cardiac events (Mace) after PTCA with stent implantation. It has not be proven yet that pretreatment by T or C was superior to conventional post-treatment, especially in unstable patients. The aim of the present study was to determine the influence of thienopyridine pretreatment on the risk of Mace (death, Q wave myocardial infarction, need for repeat PTCA or surgery, angina recurrence, stent thrombosis) during the hospitalization period in a population prospectively included in 2 multicentre registries of patients undergoing placement of a S670 or S7 stent (Medtronic) implanted in native coronary arteries (> or = 3.0 mm). Among the 2929 patients included into the registries, 1205 had unstable angina (41%). 50.2% of the patients were pretreated by T or C (T = 15.7%, C = 34.5%); 85.5% received aspirin before the procedure; definition of pretreatment was the administration of drug at least 6 hours before stent implantation. GPIIb-IIIa antagonists were administered in only 13.9% of patients. Mace were observed in 2% of the patients. Factors correlated with Mace by univariate and multivariate analyses were: age > 73 years (RR: 2.37; 95% CI: 1.05-5.36, P < 0.037), previous myocardial infarction (RR: 2.56; 95% CI: 1.08-6.11, P < 0.034), pretreatment by T or C (RR: 0.389; 95% CI: 0.16-0.95, P < 0.038). In patients who did not receive GPIIb-IIIa antagonists, age > 73, and pretreatment by T or C were the only independent predictors of Mace.

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Eur J Cardiothorac Surg. 2003 May;23(5):657-64; discussion 664.
Is total arterial myocardial revascularization with composite grafts a safe and useful procedure in the elderly?
Muneretto C, Negri A, Bisleri G, Manfredi J, Terrini A, Metra M, Nodari S, Cas LD.
Department of Cardiac Surgery, University of Brescia Medical School, Brescia, Italy. munerett@master.cci.unibs.it

OBJECTIVE: The aim of the study was to evaluate the mid-term results of total arterial myocardial revascularization (TAMR) with composite grafts in patients older than 70 years when compared to standard CABG technique, since the usefulness of TAMR in the elderly has not been demonstrated yet. METHODS: A prospective randomized study was designed with the following end-points: post-operative complications, death, recurrence of angina, graft occlusion, any cardiac event and reinterventions. One hundred and eighty-eight patients older than 70 years were enrolled and assigned to Group 1(G1)=94 pts, for total arterial revascularization or Group 2(G2)=94 pts, for standard CABG (LITA on LAD plus additional saphenous veins). The groups were comparable in terms of pre-operative characteristics and Euroscore (mean: G1=8.4 vs. G2=8.2). RESULTS: No differences between the groups were observed in terms of mean number of grafted vessels (G1=2.1 vs. G2=2.3), mean aortic cross-clamping time (G1=34+/-8 vs. G2=33+/-6min), mechanical ventilation time (G1=23+/-4 vs. G2=22+/-4hr), ICU stay (G1=40+/-10 vs. G2=39+/-9hr), post-operative complications and hospital mortality (G1=5.3% vs. G2=4.2%). At a mean follow-up of 12+/-4 months, cumulative incidence of angina recurrence was 2.1% in G1 vs. 11% in G2 (P=0.021). Angiographic evaluation showed 98.2% arterial patency in G1 vs. 86% saphenous vein graft patency in G2 (P<0.001). Multivariate analysis identified conventional CABG surgery as independent predictor of angina recurrence, graft occlusion and late cardiac events. CONCLUSIONS: Total arterial revascularization with composite grafts proved to be a safe and effective procedure also in the elderly. Composite arterial grafts provided superior clinical outcome with a lower rate of angina recurrence, graft occlusion and late cardiac events when compared to conventional CABG strategy.

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Acta Radiol. 2003 May;44(3):294-301.
Elective placement of covered stents in native coronary arteries.
Sovik E, Klow NE, Brekke M, Stavnes S.
Department of Cardiovascular Radiology, Heart and Lung Center, Ulleval University Hospital, Oslo, Norway.

PURPOSE: To study the feasibility of placing a polytetrafluoroethylene (PTFE)-covered stent graft into native coronary arteries and assess the complications and the restenosis rate. MATERIAL AND METHODS: Fifty consecutive patients with stable angina pectoris were included and the stent graft was placed into native coronary arteries. Clinical and angiographic follow-up were performed after 6 months. RESULTS: The stent grafts were successfully placed in all patients. The mean reference diameter was 3.3 +/- 0.6 mm. During follow-up the stent grafts occluded in patients after 1, 2 and 2.5 months and one more was occluded at 6 months. Three patients experienced myocardial infarction, 2 Q wave and one non-Q wave. After 6 months 42 (84%) patients had angina NYHA class 0 or 1. Target vessel revascularization was done in 11 cases for restenosis in the graft (n = 4), outside the graft (n = 3) and both (n = 4), giving a restenosis rate of 24%. The total major adverse coronary events at 6 months was 24%. CONCLUSION: The stent graft was deployed with a high success rate. The restenosis rate was not higher than expected for bare stents. However, this study showed that subacute occlusion may occur more frequently and we therefore recommend that ticlopidine or clopidogrel treatment should be prolonged to at least 3 months.

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Rev Port Cardiol. 2003 Mar;22(3):367-74.
Revascularization and prognosis in female patients with non-ST-segment elevation acute coronary syndromes.
[Article in English, Portuguese]
Timoteo AT, Ferreira J, Aguiar C, Almeida Mde S, Ribeiro MA, Cavaco DM, Trabulo M, Seabra-Gomes R.
Servico de Cardiologia, Hospital de Santa Cruz, Carnaxide.

BACKGROUND: After an acute myocardial infarction, women have a higher risk of death or reinfarction. In unstable angina, female gender seems to be protective. On the other hand, studies suggest that women are less frequently given coronary angiography. OBJECTIVES: To evaluate, in our population of patients admitted for non-ST-elevation acute coronary syndrome (ACS), the influence of gender in prognosis and in the use of invasive procedures. POPULATION AND METHODS: We studied 387 consecutive patients, 20% female, admitted to our ICU for non-ST-segment elevation ACS. We compared demographic and clinical variables, the use of coronary angiography and myocardial revascularization procedures, according to gender. We analyzed the combined endpoint of death or (re)infarction at 30 days and for the total follow-up period of 420 +/- 322 days. RESULTS: The women were older (65 +/- 10 vs. 62 +/- 11 years, p = 0.05), and more frequently had a history of hypertension (p = 0.005), diabetes mellitus (p = 0.07), previous surgical myocardial revascularization (p = 0.048) and higher heart rate on admission (p = 0.048). Smoking was more frequent in men (p < 0.001). The most frequent diagnosis was unstable angina; 76% for women vs. 66% in men (p = 0.12). Coronary angiography was performed during hospitalization in 87%, in both genders. Myocardial revascularization was performed in 62% of the women and 69% of the men (p = 0.26). At 30 days, the frequency of death or (re)infarction was 11% for women and 10% for men (log-rank, p = 0.79). By multivariate analysis (Cox regression), the independent predictors of outcome at 30 days were previous myocardial revascularization and heart failure on admission. For the total follow-up, we did not find differences in the occurrence of the combined endpoint, and the independent predictors of outcome were previous surgical myocardial revascularization, heart failure on admission, ST segment depression on the admission ECG and surgical myocardial revascularization. CONCLUSIONS: In non-ST-elevation ACS, women present some differences in their demographic and clinical profile. We did not find differences in the use of invasive procedures or prognosis in the short and medium term.

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Heart. 2003 May;89(5):531-4.
Effects of L-arginine on flow mediated dilatation induced by atrial pacing in diseased epicardial coronary arteries.
Tousoulis D, Davies GJ, Tentolouris C, Crake T, Goumas G, Stefanadis C, Toutouzas P.
Cardiology Unit, Hippokration Hospital, Athens University Medical School, Greece.

OBJECTIVE: To examine the effects of L-arginine on basal coronary tone and flow mediated dilatation induced by atrial pacing in patients with coronary artery disease and stable angina. DESIGN: Atrial pacing was performed during intracoronary infusions of normal saline and L-arginine (150 micromol/min) in 8 patients with coronary artery disease and stable angina. The luminal diameter of epicardial coronary arteries was assessed by quantitative angiography. RESULTS: L-arginine administration significantly increased the diameter of all the coronary segments and stenoses. During atrial pacing with saline infusion, luminal diameter of the proximal, distal, and stenosis reference segments increased significantly (p < 0.01 versus saline) but stenosis diameter did not change. L-arginine administration did not change the magnitude (NS) of atrial pacing induced dilatation in proximal and distal segments and in coronary stenoses and their reference segments. CONCLUSIONS: Non-stenotic segments of diseased coronary arteries dilate in response to atrial pacing but stenoses do not. L-arginine dilates coronary segments and stenoses but does not increase the magnitude of the response to atrial pacing in proximal and distal segments and in coronary stenoses and their reference segments. These findings provide evidence that the shear stress responsive mechanism is absent at stenoses but present in non-stenotic segments of diseased coronary arteries. They also indicate a relative deficiency of L-arginine, except in the shear response mechanism.

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Rev Prat. 2003 Mar 15;53(6):624-8.
[Medical treatment of acute coronary syndrome without ST-segment elevation]
[Article in French]
Collet JP, Choussat R, Montalescot G.
Institut de cardiologie Groupe hospitalier La Pitie-La Salpetriere 75651 Paris. jean-philippe.collet@psl.ap-hop-paris.fr

Unstable angina is the most frequent acute coronary syndrome. Risk stratification to predict coronary morbidity and mortality and the risk of major haemorrhage are the key steps of the medical approach. Combined antithrombotic therapy (including aspirin, clopidogrel, low-molecular weight heparins and, eventually glycoprotein IIb/IIIa receptor antagonists) has led to a substantial reduction of major coronary events with a good tolerance because of the short duration of such aggressive strategy. This combined antithrombotic also allowed to increase the benefit of an early invasive strategy including coronary angiogram with stent percutaneous coronary angioplasty.

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Drugs Today (Barc). 2003 Apr;39(4):249-64.
Clopidogrel in acute coronary syndromes (unstable angina and non-Q-wave myocardial infarction).
Heras M, Sionis A.
Institut Clinic de Malalties Cardiovasculars, Hospital Clinic, Barcelona, Spain. mheras@clinic.ub.es

Given the importance of thrombosis in acute coronary syndromes, antithrombotic therapy has become standard treatment for these conditions. This article reviews the mechanism of action and the major evidence supporting the clinical use of clopidogrel, a potent antiplatelet agent of the thienopyridines class, focusing on its role in the setting of acute coronary syndromes without persistent ST segment elevation (unstable angina and non-Q wave myocardial infarction). Some unanswered questions relating to this medication are also highlighted. Finally, current updates on clinical guidelines for the use of clopidogrel in acute coronary syndromes are discussed. Prous Science 2003. All rights reserved.

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Curr Med Res Opin. 2003;19(2):107-13.
Tolerability of percutaneous coronary interventions in patients receiving nadroparin calcium for unstable angina or non-Q-wave myocardial infarction: the Angiofrax study.
Bassand JP, Berthe C, Bethencourt A, Bolognese L, Wojcik J; Angiofrax Study Group.
University Hospital Jean-Minjoz, Besancon, France. jean-pierre.bassand@ufc-chu.univ-fcomte.fr

BACKGROUND: Nadroparin, a low-molecular-weight heparin (LMWH), is an alternative to unfractionated heparin for the acute management of patients with non-ST elevation acute coronary syndrome (ACS): unstable angina or non-Q-wave myocardial infarction. However, unfractionated heparin can be substituted for LMWH in patients requiring percutaneous coronary interventions (PCIs) for the duration of the procedure. The tolerability of this anti-thrombotic regimen (i.e. unfractionated heparin for the duration of PCIs, preceded and followed by subcutaneous injection of nadroparin) is not yet documented. DESIGN AND METHODS: This open-label 6-day study was carried out in 302 patients to test the tolerability of this anti-thrombotic regimen in patients requiring PCIs. The primary end-point of the study was the incidence of major haemorrhage over the whole study duration (6 days). The secondary end-point was the need for transfusion and vascular repair after PCI. RESULTS: The incidence of major haemorrhage in patients undergoing coronary angiography (CA) without or with PCIs was 1.4% and 1.3%, respectively, and the incidence of minor haemorrhage was 10.7% and 23.5%, respectively. These results are consistent with published data. CONCLUSIONS: These results suggest that CA and PCIs can be performed safely in patients being treated for unstable angina or non-Q-wave myocardial infarction receiving nadroparin pre- and post-coronary procedure and/or intervention, substituted by unfractionated heparin for the duration of the intervention.

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Am J Cardiol. 2003 Apr 15;91(8):951-5.
Immediate and long-term clinical outcome after spinal cord stimulation for refractory stable angina pectoris.
Di Pede F, Lanza GA, Zuin G, Alfieri O, Rapati M, Romano M, Circo A, Cardano P, Bellocci F, Santini M, Maseri A; Investigators of the Prospective Italian Registry of SCS for Angina Pectoris.
Ospedale Umberto I, Mestre, Italy.

The treatment of patients with angina pectoris refractory to medical therapy and unsuitable for revascularization procedures has yet not been well standardized. Previous retrospective studies and small prospective studies have suggested beneficial effects of spinal cord stimulation (SCS) in these patients. We created a Prospective Italian Registry of SCS to evaluate the short- and long-term clinical outcome of patients who underwent SCS device implantation because of severe refractory angina pectoris. Overall, 104 patients were enrolled in the registry (70 men, aged 68 +/- 17 years), most of whom (83%) had severe coronary artery disease. Average follow-up was 13.2 +/- 8 months. Overall, 17 patients (16%) died, 8 (8%) due to cardiac death. Among clinical variables, only age was found to be significantly associated both with total mortality (p = 0.04) and cardiac mortality (p = 0.02) on Cox regression analysis. A significant improvement of anginal symptoms (> or =50% reduction of weekly anginal episodes, compared with baseline) occurred in 73% of patients, and Canadian Cardiovascular Society angina class improved by > or =1 class in 80% and by > or =2 classes in 42% of patients, with a relevant reduction in the rate of hospital admission and days spent in the hospital because of angina (p <0.0001 for both). No life-threatening or clinically serious complications were observed. The most frequent side effect consisted of superficial infections, either at the site of puncture of electrode insertion or of the abdominal pocket, which occurred in 6 patients. In conclusion, our prospective data point out that SCS can be performed safely and is associated with a sustained improvement of anginal symptoms in a relevant number of patients with refractory stable angina pectoris

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Coron Artery Dis. 2003 Apr;14(2):171-9.
Efficacy and tolerability of trimetazidine in stable angina: a meta-analysis of randomized, double-blind, controlled trials.
Marzilli M, Klein WW.
Cattedra di Cardiologia, Universita di Siena, Italy. marzilli@unisi.it

OBJECTIVE: The objective of this meta-analysis was to evaluate the efficacy and tolerance of the metabolic agent trimetazidine (TMZ), both in monotherapy and in combination with other antianginal agents, in the treatment of stable angina pectoris. A search of literature published between 1985 and 2001 was performed on computerized databases (MEDLINE and EMBASE). METHODS: Only double-blind, randomized, controlled trials were included in this meta-analysis. Patients had to be treated for at least 2 weeks. Four parameters were selected, one clinical parameter (number of weekly angina attacks) and three ergometric parameters (time to 1 mm ST-segment depression, total work and exercise duration at peak exercise). They were evaluated at baseline and at the end of the treatment period.The quality of the trials was assessed on specific methodological criteria. Standard statistical methods, pooled odds ratio and 95% confidence intervals for subjective symptoms and pooled z and P for objective symptoms, were used. RESULTS: Twelve clinical studies meeting our criteria were analyzed. Results showed that TMZ significantly reduced the number of weekly angina attacks in coronary patients and improved time to 1 mm segment depression and total work at peak exercise, while exercise duration at peak exercise showed a trend toward improvement (P = 0.09). CONCLUSION: This meta-analysis confirms the efficacy of TMZ in the treatment of stable angina, compared with placebo or conventional antianginal agent, as well as in monotherapy or in combination with conventional antianginal agents. TMZ is well tolerated in monotherapy as well as in combination.

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Am J Cardiol. 2003 Apr 15;91(8):925-30.
Comparison of effects on markers of blood cell activation of enoxaparin, dalteparin, and unfractionated heparin in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial infarction (the ARMADA study).
Montalescot G, Bal-dit-Sollier C, Chibedi D, Collet JP, Soulat T, Dalby M, Choussat R, Cohen A, Slama M, Steg PG, Dubois-Rande JL, Metzger JP, Tarragano F, Guermonprez JL, Drouet L; ARMADA Investigators.
Institut de Cardiologie, Bureau 2-236, Groupe Hospitalier Pitie-Salpetriere Hospital, AP-HP, 47 Boulevard de l'Hopital, 75013 Paris, France. gilles.montalescot@psl.ap-hop-paris.fr

The low-molecular-weight heparins (LMWHs) enoxaparin and dalteparin have shown superior and equivalent efficacy, respectively, over unfractionated heparin (UFH) in patients with unstable angina pectoris (UAP) or non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to identify markers of blood cell activation that are independent predictors of outcomes at 1 month and to compare the effects of enoxaparin, dalteparin, and UFH on any such markers. In this multicenter, prospective, open-label study, 141 patients with UAP or NSTEMI were randomized to treatment for 48 to 120 hours with enoxaparin (n = 46), dalteparin (n = 48), or UFH (n = 47). Blood samples were taken at the time of randomization and after > or =48 hours of treatment but before catheterization. Multivariate analysis identified increased plasma levels of von Willebrand factor (vWF) and decreased platelet levels of glycoprotein Ib/IX complexes as independent predictors of 1-month adverse outcome (a composite of death, myocardial infarction, and recurrent ischemia). vWF release was strongly related to and may have been released by inflammation as measured by C-reactive protein. Both LMWHs reduced the release of vWF in plasma (as well as C-reactive protein) compared with UFH. Enoxaparin had a more favorable effect on glycoprotein Ib/IX complexes than either dalteparin or UFH. The incidence of the composite clinical efficacy end point was: 13% (enoxaparin), 19% (dalteparin), and 28% (UFH). vWF and its receptor glycoprotein Ib/IX play a key role in acute coronary syndromes. vWF is linked to inflammation and, like glycoprotein Ib/IX, is affected more favorably by the LWMHs than by UFH.

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Angiology. 2003 Mar-Apr;54(2):211-8.
Differential benefits and outcomes of tirofiban vs abciximab for acute coronary syndromes in current clinical practice.
Gowda MS, Vacek JL, Lakkireddy DJ, Brosnahan K, Beauchamp GD.
University of Kansas Medical Center, Kansas City, KS, USA.

Little comparative data exist for glycoprotein IIb/IIIa inhibitors in acute coronary syndromes (ACS). Two hundred twenty-eight patients were studied: 114 received tirofiban (TI) and 114 received abciximab (AB) for either unstable angina (UA) or myocardial infarction (MI). All patients received aspirin, heparin, and ticlopidine or clopidogrel. Baseline characteristics were similar between the 2 groups for admitting diagnosis (UA vs MI), age, gender, ejection fraction, diabetes mellitus, prior coronary artery disease, prior myocardial infarction (MI), prior bypass surgery, hypertension, congestive heart failure, hyperlipidemia, MI type (Q vs non-Q), or location. Drug administration time (mean) was 13 hours (AB) and 24 hours (TI). All AB was administered in the catheterization laboratory as compared to TI (34% in laboratory and 66% before laboratory). More AB patients received angioplasty or stent (92% vs 80%, p = 0.008) while more TI patients had CABG (10% vs 3%, p = 0.027). In-hospital complications including death, MI, urgent revascularization, cerebrovascular accidents or transient ischemic attacks, and access site bleeding were similar (p = NS). Multivariate predictors of events (odds ratios) were prior coronary artery bypass graft (2.3), diabetes (1.7), and prior percutaneous transluminal coronary angioplasty (1.7), but not the agent used. Over a mean follow-up of 13 months, the individual endpoints of death, MI, revascularization, or hospitalization were similar for both groups. The AB patients had improved freedom from revascularization (100% vs 81%, p = 0.015) in an emergent setting and TI patients had improved freedom from revascularization (93% vs 77%, p = 0.038) with elective procedures. Tirofiban and abciximab appear effective and safe when used for ACS when recommended dosing and precautions are followed. Major adverse outcomes are rare and bleeding complications uncommon.

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Nurs Res. 2003 Mar-Apr;52(2):108-18.
The symptoms of unstable angina: do women and men differ?
DeVon HA, Zerwic JJ.
Marquette University, Milwaukee, College of Nursing, Wisconsin 53201, USA. Holli.devon@Marquette.edu

BACKGROUND: Research has shown that there are differences between women and men in the epidemiology, presentation, and outcomes of coronary heart disease. OBJECTIVES: The purpose of this study was to determine if there were sex differences in the symptoms of unstable angina (UA) and if so, to determine if these differences remained after controlling for age, diabetes, anxiety, depression, and functional status. METHOD: This descriptive study used a nonexperimental, quantitative design. A convenience sample of 50 women and 50 men, hospitalized with UA, were recruited from an urban and a suburban medical center. Instruments included the Unstable Angina Symptoms Questionnaire (UASQ), the Hospital Anxiety and Depression Scale (HADS), and the Canadian Cardiovascular Society (CCS) classification of angina. RESULTS: Multivariate analysis indicated that women experienced significantly (p <.05) more shortness of breath (74% vs. 60%), weakness (74% vs. 48%), difficulty breathing (66% vs. 38%), nausea (42% vs. 22%), and loss of appetite (40% vs. 10%) than men. After controlling for age, diabetes, anxiety, depression, and functional status, women were still more likely than men to report weakness (p =.03), difficulty breathing (p =.02), nausea (p =.03), and loss of appetite (p =.02). Chi-square analysis of symptom descriptors revealed that women disclosed more (p <.05) upper back pain (42% vs. 18%), stabbing pain (32% vs. 12%), and knifelike pain (28% vs. 12%). Women also had a significantly higher incidence of depression (22% vs. 2%, p <.01). CONCLUSIONS: Findings suggest that women and men have similar symptoms during an episode of UA, however, a higher proportion of women have less typical symptoms.

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Crit Care Nurs Q. 2003 Jan-Mar;26(1):69-75.
Transmyocardial Laser Revascularization revisited.
Lindsay MR.
The Bay Medical Center, Panama City, FL 32406, USA. MLinds0310@email.msn.com

Transmyocardial Revascularzation (TMR) is a relatively new surgical procedure used to treat angina that persists, despite other interventions (i.e. angioplasty, stenting or coronary artery bypass surgery). TMR is accomplished via an incision that exposes the heart muscle and permits application of the laser hand piece that creates new channels in the myocardium, thus improving myocardial perfusion and oxygen supply to the left ventricle. This article will explain the procedure, review patient selection criteria and discuss the nursing care for the TMR patient.

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Int J Cardiol. 2003 Mar;88(1):83-9.
Treatment of stable angina with low dose diltiazem in combination with the metabolic agent trimetazidine.
Manchanda SC.
Department of Cardiology, All India Institute of Medical Sciences, Ansari Nagar, 110 029, New Delhi, India. reivers@bom3.vsnl.net.in

BACKGROUND: The risk/benefit of moderate to high doses of calcium antagonists in stable angina is uncertain. This study investigates the efficacy and acceptability of low dose diltiazem in combination with trimetazidine for the treatment of stable angina. METHODS: In a 28-day, randomized, double blind study, treatment with 90 mg diltiazem in combination with 60 mg trimetazidine or placebo per day was compared in 50 patients with stable angina. The primary outcomes were time to 1-mm ST segment depression and the Duke treadmill score. RESULTS: Of the 25 patients in each treatment group, the number (%) of patients responding to trimetazidine compared to placebo was, in time to 1-mm ST segment depression, 13 (52) versus 5 (20), P<0.05; in the Duke treadmill score, 18 (72) versus 8 (32), P<0.01; and in angina 17 (68) versus 3 (12), P<0.01. Compared to placebo there was an improvement with trimetazidine in mean exercise time to 1-mm ST segment depression of 128 s (95% confidence interval 45.0-208.5; P<0.01); in the mean Duke treadmill score of 57.4% (95% confidence interval 9.9-100; P<0.02); and in mean anginal attacks of 5.1 per week (95% confidence interval, 3.1-7.3, P<0.01). CONCLUSION: The combination of low dose diltiazem with trimetazidine is effective with few side-effects in the symptomatic control of patients with stable angina.

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J Cardiovasc Nurs 2003 Jan-Mar;18(1):38-43
Gene therapy with vascular endothelial growth factor reduces angina.
Merkle CJ, Montgomery DW.
College of Nursing, The University of Arizona, and Southern Arizona VA Medical Center, Tucson, Arizona, USA.

A placebo-controlled, double-blind, randomized study found that subjects randomized to the vascular endothelial growth factor (VEGF) gene-receiving treatment group showed a greater level of angina reduction in comparison to control subjects who received saline as a placebo. These data provide hope for a new treatment option for those who are not candidates for invasive therapeutic procedures and are refractory to medical therapy for angina. Furthermore, the findings are important to the areas of therapeutic angiogenesis and gene therapy as a whole. This article discusses VEGF and its brief history as a form of gene therapy in the context of the VEGF gene therapy trial that the American Heart Association has recognized as one of the top 10 scientific advances of 2001.

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JAMA 2003 Mar 5;289(9):1117-23
Comment in: JAMA. 2003 Mar 5;289(9):1157-8.
Outcome of elderly patients with chronic symptomatic coronary artery disease with an invasive vs optimized medical treatment strategy: one-year results of the randomized TIME trial.
Pfisterer M, Buser P, Osswald S, Allemann U, Amann W, Angehrn W, Eeckhout E, Erne P, Estlinbaum W, Kuster G, Moccetti T, Naegeli B, Rickenbacher P; Trial of Invasive versus Medical therapy in Elderly patients (TIME) Investigators.
Department of Cardiology, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. pfisterer@email.ch

CONTEXT: The risk-benefit ratio of invasive vs medical management of elderly patients with symptomatic chronic coronary artery disease (CAD) is unclear. The Trial of Invasive versus Medical therapy in Elderly patients (TIME) recently showed early benefits in quality of life from invasive therapy in patients aged 75 years or older, although with a certain excess in mortality. OBJECTIVE: To assess the long-term value of invasive vs medical management of chronic CAD in elderly adults in terms of quality of life and prevention of major adverse cardiac events. DESIGN: One-year follow-up analysis of TIME, a prospective randomized trial with enrollment between February 1996 and November 2000. SETTING AND PARTICIPANTS: A total of 282 patients with Canadian Cardiac Society class 2 or higher angina despite treatment with 2 or more anti-anginal drugs who survived for the first 6 months after enrollment in TIME (mean age, 80 years [range, 75-91 years]; 42% women), enrolled at 14 centers in Switzerland. INTERVENTIONS: Participants were randomly assigned to undergo coronary angiography followed by revascularization (if feasible) (n = 140 surviving 6 months) or to receive optimized medical therapy (n = 142 surviving 6 months). MAIN OUTCOME MEASURES: Quality of life, assessed by standardized questionnaire; major adverse cardiac events (death, nonfatal myocardial infarction, or hospitalization for acute coronary syndrome) after 1 year. RESULTS: After 1 year, improvements in angina and quality of life persisted for both therapies compared with baseline, but the early difference favoring invasive therapy disappeared. Among invasive therapy patients, later hospitalization with revascularization was much less likely (10% vs 46%; hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.11-0.32; P<.001). However, 1-year mortality (11.1% for invasive; 8.1% for medical; HR, 1.51; 95% CI, 0.72-3.16; P =.28) and death or nonfatal myocardial infarction rates (17.0% for invasive; 19.6% for medical; HR, 0.90; 95% CI, 0.53-1.53; P =.71) were not significantly different. Overall major adverse cardiac event rates were higher for medical patients after 6 months (49.3% vs 19.0% for invasive; P<.001), a difference which increased to 64.2% vs 25.5% after 12 months (P<.001). CONCLUSIONS: In contrast with differences in early results, 1-year outcomes in elderly patients with chronic angina are similar with regard to symptoms, quality of life, and death or nonfatal infarction with invasive vs optimized medical strategies based on this intention-to-treat analysis. The invasive approach carries an early intervention risk, while medical management poses an almost 50% chance of later hospitalization and revascularization.

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Circulation 2003 Feb 25;107(7):966-72
Comment in: Circulation. 2003 Feb 25;107(7):e9012-3.
Early and late effects of clopidogrel in patients with acute coronary syndromes.
Yusuf S, Mehta SR, Zhao F, Gersh BJ, Commerford PJ, Blumenthal M, Budaj A, Wittlinger T, Fox KA; Clopidogrel in Unstable angina to prevent Recurrent Events Trial Investigators.
Population Health Research Institute and Division of Cardiology, McMaster University, Hamilton, Canada. yusufs@mcmaster.ca

BACKGROUND: The risk of ischemic events is high, both early and late after acute coronary syndromes (ACS). We examine the benefits and risks associated with the use of adding clopidogrel to aspirin within the first 30 days and later (31 days to 12 months) in 12 562 patients with ACS. METHODS AND RESULTS: A total of 12 562 ACS patients were randomized to receive clopidogrel (300 mg initially followed by 75 mg/d) or placebo for 3 to 12 months. The proportion of patients experiencing cardiovascular death, myocardial infarction, or strokes (primary outcome) at 30 days was 5.4% in the placebo group and 4.3% in the active group (relative risk 0.79, 95% CI 0.67 to 0.92). Beyond 30 days, the corresponding rates were 6.3% versus 5.2% (relative risk 0.82, 95% CI 0.70 to 0.95). There was no significant excess in life-threatening bleeds in each period (0.97% versus 1.28%, relative risk 1.32, 95% CI 0.95 to 1.84 for 0 to 30 days; 0.83% versus 0.91%, relative risk 1.09, 95% CI 0.75 to 1.59 for 31 days to 12 months). Further subdivision of the early data indicates benefits within 24 hours with consistently lower rates of the primary outcome in combination with refractory or severe ischemia. CONCLUSIONS: Clopidogrel reduces the risk of ischemic vascular events, with the benefits emerging within 24 hours of initiation of treatment and continuing throughout the 12 months (mean 9 months) of the study.

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Circulation 2003 Feb 18;107(6):817-23
Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial.
Borer JS, Fox K, Jaillon P, Lerebours G; Ivabradine Investigators Group.
Weill Medical College of Cornell University, New York, NY, USA. CanadaD45@aol.com

BACKGROUND: Heart rate reduction should benefit patients with chronic stable angina by improving myocardial perfusion and reducing myocardial oxygen demand. This study evaluated the antianginal and antiischemic effects of ivabradine, a new heart rate-lowering agent that acts specifically on the sinoatrial node. METHODS AND RESULTS: In a double-blind, placebo-controlled trial, 360 patients with a > or =3-month history of chronic stable angina were randomly assigned to receive ivabradine (2.5, 5, or 10 mg BID) or placebo for 2 weeks, followed by an open-label 2- or 3-month extension on ivabradine (10 mg BID) and a 1-week randomized withdrawal to ivabradine (10 mg BID) or placebo. Primary efficacy criteria were changes in time to 1-mm ST-segment depression and time to limiting angina during bicycle exercise (exercise tolerance tests), performed at trough of drug activity. In the per-protocol population (n=257), time to 1-mm ST-segment depression increased in the 5 and 10 mg BID groups (P<0.005); time to limiting angina increased in the 10 mg BID group (P<0.05). Deterioration in all exercise tolerance test parameters occurred in patients who received placebo during randomized withdrawal (all P<0.02) but not in those still receiving ivabradine. No rebound phenomena were observed on treatment cessation. CONCLUSIONS: Ivabradine produces dose-dependent improvements in exercise tolerance and time to development of ischemia during exercise. These results suggest that ivabradine, representing a novel class of antianginal drugs, is effective and safe during 3 months of use; longer-term safety requires additional assessment.

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Chest 2003 Feb;123(2):380-6
Limitations of medical therapy in patients with pure coronary spastic angina.
Sueda S, Kohno H, Fukuda H, Watanabe K, Ochi N, Kawada H, Uraoka T.
Department of Cardiology, Saiseikai Saijo Hospital, Saijo City, Japan.

OBJECTIVES: To assess the efficacy of medication for the treatment of pure coronary spastic angina, 71 consecutive patients with this diagnosis who had undergone coronary arteriography in a hospital with a follow-up of at least 2 years were studied. Methods and results: All 71 patients without significant organic stenosis were treated with long-acting calcium antagonists. The disappearance of chest pain attacks while receiving medical therapy was observed in 27 patients (38%), whereas the remaining 44 patients (62%) had chest pain attacks. Of special interest, 30 patients had more than one attack per month irrespective of the administration of calcium antagonists or isosorbide dinitrate. Medical treatment showed a good response in female patients (63% vs 31%, respectively; p < 0.05) and those with ST-segment elevation during selective spasm provocation tests (63% vs 30%, respectively; p < 0.05). In contrast, patients with a longer history of chest pain attacks before hospital admission and those with diffuse spasms (77% vs 34%, respectively; p < 0.01) had poor responses to medical treatment. In this study, neither sudden death nor acute myocardial infarction was observed during the follow-up periods. CONCLUSION: The limitations of medical therapy, including the administration of long-acting calcium antagonists, were observed in 30 of 71 patients (42%) with pure coronary spastic angina. Medical treatment was effective in only 38% of patients with pure coronary spastic angina in Japan.

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Am J Cardiol 2003 Feb 1;91(3):274-9
Comparison of effects of nisoldipine-extended release and amlodipine in patients with systemic hypertension and chronic stable angina pectoris.
Pepine CJ, Cooper-DeHoff RM, Weiss RJ, Koren M, Bittar N, Thadani U, Minkwitz MC, Michelson EL, Hutchinson HG; Comparative Efficacy and Safety of Nisoldipine and Amlodipine (CESNA-II) Study Investigators.
University of Florida College of Medicine, Gainesville, Florida 32610, USA.

The efficacy and safety of nisoldipine-extended release (ER) and amlodipine were compared in a 6-week multicenter, randomized, double-blind, double-dummy, parallel group, titration-to-effect trial in patients with stage 1 to 2 systemic hypertension (90 to 109 mm Hg diastolic blood pressure [BP]) and chronic stable angina pectoris. After a 3-week placebo run-in period, patients (n = 120) were randomly assigned to active treatment with either nisoldipine-ER (20 to 40 mg) or amlodipine (5 to 10 mg) once daily, titrated as necessary after 2 weeks to achieve diastolic BP <90 mm Hg. After 6 weeks, the mean reduction in systolic/diastolic BP from baseline was 15/13 mm Hg with nisoldipine-ER and 13/11 mm Hg with amlodipine (p = NS/p = NS). Both drugs resulted in similar BP responder rates (diastolic BP <90 mm Hg in 87% of patients who received nisoldipine-ER and 78% of patients on amlodipine, p = NS) and anti-ischemic responder rates (increasing exercise time >20% in 20% and 27%, respectively [p = NS], and increasing exercise time >60 seconds in 32% and 29% of patients, respectively [p = NS]. Also, after 6 weeks of active therapy, there was a similar mean increase in total exercise duration (23 seconds in the nisoldipine-ER group and 21 seconds in the amlodipine group, p = NS). Neither drug increased heart rate and both decreased frequency of anginal episodes. Adverse events were infrequent, and typically were vasodilator-related effects (including headache and peripheral edema) that occurred with somewhat higher incidence in the nisoldipine-ER group. Thus, nisoldipine-ER and amlodipine provided comparable antihypertensive and anti-ischemic efficacy, and both were generally well tolerated.

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Eur Heart J 2003 Jan;24(1):77-85
Comment in: Eur Heart J. 2003 Jan;24(2):136-7.
Elevated troponin T and C-reactive protein predict impaired outcome for 4 years in patients with refractory unstable angina, and troponin T predicts benefit of treatment with abciximab in combination with PTCA.
Lenderink T, Boersma E, Heeschen C, Vahanian A, de Boer MJ, Umans V, van den Brand MJ, Hamm CW, Simoons ML; CAPTURE Investigators.
Department of Cardiology, Thoraxcentre, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands.

AIMS: Treatment with the glycoprotein IIb/IIIa receptor antagonist abciximab before and during coronary intervention in refractory unstable angina improves early outcome. We collected 4-year follow-up data to assess whether this benefit is sustained. Additionally, we investigated the predictive value of baseline troponin T and CRP for long-term cardiovascular events. METHODS AND RESULTS: Of 1265 patients enrolled in the CAPTURE trial follow-up was available in 94% of the patients alive after 6 months (median 48 months). Survival was similar in both groups. Both elevated troponin T and CRP were associated with impaired outcome, independently of other established risk factors, but with a different time course. Elevated troponin was associated with increased procedure related risk, and elevated CRP with increased risk for subsequent events. Lower rates of the composite end-point of death or myocardial infarction with abciximab vs. placebo were sustained during long-term follow up: 15.7% vs 17.2% at 4 years (P=ns), particularly in patients with elevated troponin T: 16.9% with abciximab vs 28.4% with placebo: P=0.015. Elevated CRP was not associated with specific benefit of abciximab. CONCLUSION: Troponin T as a marker of thrombosis and CRP as a marker of inflammation are independent predictors of impaired outcome at 4 years follow-up. The initial benefit from abciximab with regard to death and myocardial infarction was preserved at 4 years. No specific benefit with abciximab was observed for patients with elevated CRP, suggesting that a chronic inflammatory process is not affected by abciximab. In contrast the benefit of treatment in patients with elevated troponin T implies that the acute thrombotic process in refractory unstable angina is treated effectively.

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Klin Med (Mosk) 2002;80(11):24-6
[Comparative long-term outcomes of balloon angioplasty of uni- or multi-vessel lesions in
coronary disease]
[Article in Russian]
Asanova AZh, Semitko SP, Ianitskaia MV, Ioseliani DG.

A study has been carried out on long-term results of transluminal balloon angioplasty (TLBAP) in case of mono- and multivascular lesion of coronary bed (CB). During long-term follow-up (16.3 +/- 3.8 months) a high survival rate was observed after treatment procedure both in mono- (97.1%) and multivascular (98.75%) lesion. However, patients with monovascular lesion had lesser probability of being subjected to additional revascularization procedure and greater probability of avoiding angina pectoris in long-term follow-up unlike patients with multivascular lesion of coronary arteries (85.7% vs 63.8%). At the same time a good angiographic angioplastic effect of dilated vessel remained in equal number of patients: 66.7% with monovascular lesion and 68.6% with multivascular lesion. Therefore, it is advantageous to use TLBAP both in mono- and multivascular CB lesion.

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Tidsskr Nor Laegeforen 2002 Sep 10;122(21):2102-4
[Preoperative expectations and clinical outcome of transmyocardial laser treatment in patients with
angina pectoris]
[Article in Norwegian]
Einvik G, Tjomsland O, Kvernebo K, Stavnes S, Ekeberg O.
Institutt for medisinske atferdsfag Universitetet i Oslo Postboks 1111 Blindern 0317 Oslo. gunnar.einvik@studmed.uio.no

BACKGROUND: The aims of this study were to evaluate the effect of transmyocardial laser treatment on quality of life and to assess the correlation between preoperative expectations and clinical improvement after one year. MATERIAL AND METHODS: 13 patients (median age 56 years) with disabling angina pectoris were subjected to transmyocardial holmium: YAG laser. Quality of life was assessed preoperatively and at three and 12 months by Hospital Anxiety and Depression Scale (HAD), Physical Symptom Distress Index (PSDI) and Life Satisfaction Index (LSI). Expectations were evaluated by Leedham's scale. RESULTS: A significant improvement in Canadian Cardiovascular Society Score (CCS) from 3.4 +/- 0.5 (mean +/- SD) preoperatively to 1.6 +/- 1.0 and 1.7 +/- 0.8 three and 12 months after treatment was observed (p < 0.01). Quality of life (PSDI and LSI) improved. No significant changes in ejection fraction or exercise performance were found. Preoperative expectations were generally high, but did not correlate significantly with improvements in CCS or quality of life. INTERPRETATION: Although no changes in objective parameters were found, the lack of significant correlations between preoperative expectation and subjective clinical improvement indicate that the improvement of angina pectoris only partly can be explained by placebo effects.

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J Am Coll Cardiol 2003 Jan 15;41(2):173-83
Myocardial laser revascularization for the treatment of end-stage coronary artery disease.
Saririan M, Eisenberg MJ.
Division of Cardiology, McGill University Health Center, Montreal, Quebec, Canada.

Myocardial laser revascularization is a novel therapeutic technique aimed at delivering oxygenated blood via a series of channels to the ischemic regions of the heart. These channels may be created surgically or via a less invasive percutaneous approach. In patients with end-stage coronary artery disease, both transmyocardial laser revascularization (TMR) and percutaneous myocardial laser revascularization (PMR) have been associated with a reduction in symptoms, improved exercise tolerance, and enhanced quality of life. However, the mechanism of action of laser therapy is incompletely understood, the results of objective cardiac perfusion measurements are inconclusive, and multiple randomized trials have failed to demonstrate an increase in survival. In addition, the positive results seen in TMR trials have been questioned because of a lack of blinding, raising the possibility that the benefit may have been due to the placebo effect. Finally, two recent sham-controlled, randomized clinical trials of PMR have not shown any benefit of the procedure, but instead have highlighted the important role of the placebo effect in the response to PMR. Further research is, therefore, needed to elucidate the value of myocardial laser revascularization.

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JAMA 2003 Jan 15;289(3):331-42
Use of low-molecular-weight heparins in the management of acute coronary artery syndromes and percutaneous coronary intervention.
Wong GC, Giugliano RP, Antman EM.
TIMI Study Group, Brigham and Women's Hospital, Boston, Mass 02115, USA.

CONTEXT: Low-molecular-weight heparins (LMWHs) possess several potential pharmacological advantages over unfractionated heparin as an antithrombotic agent. OBJECTIVE: To systematically summarize the clinical data on the efficacy and safety of LMWHs compared with unfractionated heparin across the spectrum of acute coronary syndromes (ACSs), and as an adjunct to percutaneous coronary intervention (PCI). DATA SOURCES: We searched MEDLINE for articles from 1990 to 2002 using the index terms heparin, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight heparin, myocardial infarction, unstable angina, coronary angiography, coronary angioplasty, thrombolytic therapy, reperfusion, and drug therapy, combination. Additional data sources included bibliographies of articles identified on MEDLINE, inquiry of experts and pharmaceutical companies, and data presented at recent national and international cardiology conferences. STUDY SELECTION: We selected for review randomized trials comparing LMWHs against either unfractionated heparin or placebo for treatment of ACS, as well as trials and registries examining clinical outcomes, pharmacokinetics, and/or phamacodynamics of LMWHs in the setting of PCI. Of 39 studies identified, 31 fulfilled criteria for analysis. DATA EXTRACTION: Data quality was determined by publication in the peer-reviewed literature or presentation at an official cardiology society-sponsored meeting. DATA SYNTHESIS: The LMWHs are recommended by the American Heart Association and the American College of Cardiology for treatment of unstable angina/non-ST-elevation myocardial infarction. Clinical trials have demonstrated similar safety with LMWHs compared with unfractionated heparin in the setting of PCI and in conjunction with glycoprotein IIb/IIIa inhibitors. Finally, LMWHs show promise as an antithrombotic agent for the treatment of ST-elevation myocardial infarction. CONCLUSIONS: The LMWHs could potentially replace unfractionated heparin as the antithrombotic agent of choice across the spectrum of ACSs. In addition, they show promise as a safe and efficacious antithrombotic agent for PCI. However, further study is warranted to define the benefit of LMWHs in certain high-risk subgroups before their use can be universally recommended.

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JAMA 2002 Dec 25;288(24):3124-9
Comment in: JAMA. 2002 Dec 25;288(24):3161-4.
Benefit of an early invasive management strategy in women with acute coronary syndromes.
Glaser R, Herrmann HC, Murphy SA, Demopoulos LA, DiBattiste PM, Cannon CP, Braunwald E.
Department of Medicine, University of Pennsylvania, Philadelphia, USA. howard.herrmann@uphs.upenn.edu

CONTEXT: Women who present with acute coronary syndromes (ACSs) have different characteristics than men. Reports have conflicted about whether different outcomes exist for women with use of a routine invasive management strategy. However, these studies were performed prior to the widespread use of platelet glycoprotein IIb/IIIa inhibitors and intracoronary stents. OBJECTIVE: To determine sex differences in baseline characteristics and outcomes in ACS and whether women benefit from a contemporary early invasive management strategy. DESIGN AND SETTING: Prospective analysis of women and men enrolled in the TACTICS-TIMI 18 randomized trial, conducted December 1997 to December 1999 in 169 centers in 9 countries in North America and Europe, with follow-up at 1 and 6 months. PARTICIPANTS: A total of 2220 patients (757 women and 1463 men) with ACS. INTERVENTIONS: All patients received aspirin, 325 mg/d; intravenous unfractionated heparin; and tirofiban for 48 hours or until revascularization, with tirofiban administered for at least 12 hours after percutaneous coronary revascularization. Patients assigned to the early invasive strategy (n = 1114) underwent coronary angiography 4 to 48 hours after randomization and revascularization when appropriate. Patients assigned to the early conservative strategy (n = 1106) were treated medically and underwent coronary angiography and appropriate revascularization only if they met specified criteria. MAIN OUTCOME MEASURES: Baseline characteristics and the primary composite end point of death, myocardial infarction, or rehospitalization for ACS at 6 months in women and men assigned to early invasive vs conservative management. RESULTS: Women were older and more frequently had hypertension (P<.001 for both). Women less frequently had previous myocardial infarction, coronary artery bypass grafting, and elevations in cardiac markers (P<.001 for all), but there was no difference in distribution of TIMI risk scores (P =.76). Angiography and intervention rates were similar, but women had less severe coronary artery disease, including no critical lesions in 17% of women vs 9% of men (P<.001). Women had a 28% odds reduction in the primary end point with an early invasive strategy (adjusted odds ratio [OR], 0.72; 95% confidence interval [CI], 0.47-1.11), similar to the benefit in men (adjusted OR, 0.64; 95% CI, 0.47-0.88; P =.60 for sex interaction). When adjusted for baseline characteristics, the benefit of invasive therapy in women with elevated troponin T levels was further enhanced (adjusted OR, 0.47; 95% CI, 0.26-0.83). CONCLUSIONS: Despite differences between women and men in baseline characteristics, the benefit of an early invasive strategy incorporating tirofiban and intracoronary stents was similar in women and men and was enhanced in women presenting with markers of increased risk.

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Arch Mal Coeur Vaiss 2002 Nov;95 Spec No 7:37-42
[Non-ST acute coronary syndromes]
[Article in French]
Collet JP, Choussat R, Montalescot G.

Institut de cardiologie, groupe hospitalier La Pitie-Salpetriere, AP-HP, 47, boulevard de l'Hopital, 75013 Paris.

Acute coronary syndromes are the first cause of death in France. Unstable angina is the most frequent acute coronary syndrome. Risk stratification to predict morbimortality and the risk of major hemorrhage is the key step of the medical approach. Combined antithrombotic therapy (aspirine + clopidogrel + LMWH) has led to a substantial reduction of major coronary events with a good tolerance because of the short duration of such aggressive strategy. This combined antithrombotic also allowed to increase the benefit of an early invasive strategy including coronary angiogram with stent percutaneous coronary intervention.

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J Cardiovasc Manag 2002 Nov-Dec;13(6):20-5
Enhanced external counterpulsation--a therapeutic option for patients with chronic
cardiovascular problems.
Linnemeier G.
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.

EECP is a non-invasive outpatient treatment for cardiovascular disease refractory to medical and/or surgical therapy. It has been cleared by the Food and Drug Administration for the treatment of a variety of cardiac conditions including congestive heart failure and chronic stable angina. A course of therapy consists of 35 one-hour treatments given once or twice daily. Augmented diastolic pressure and retrograde flow improve myocardial perfusion, while systolic unloading reduces cardiac workload and oxygen requirements. As a result of this treatment, most patients experience increased time to onset of ischemia, increased exercise tolerance, a reduction in the number and severity of anginal episodes, and improved quality of life. Evidence has been presented that this effect lasts well beyond the immediate post-treatment period with some patients symptom-free for several years. Because patients principally seek medical care to live longer or feel better, heart programs need to offer their patients the latest medical advances which have the potential of improving patient survival and health status (symptoms, functioning, and quality of life). Heart programs face a challenging economic future. Increased competition makes it necessary to implement strategies for market differentiation. Those programs most attuned to what their patients define as critical to quality would be most likely to succeed. Over the past decade, there have been a growing number of patients with chronic angina who have exhausted the standard revascularization armamentarium. Because coronary artery bypass grafts occlude and restenosis occurs at angioplasty sites, many patients no longer have suitable coronary anatomy for additional procedures. Also, as the population ages, the proportion of patients with diffuse coronary disease, congestive heart failure, significant co-morbid illness, and poor functional status increases. The incapacitating effects of angina on patients' abilities to work, maintain regular social interactions, and participate in the usual activities of daily living are well described. In spite of the ongoing successes of catheter-based revascularization techniques, the population of patients with intractable angina continues to grow; and ironically, advancements in medical therapy have resulted in an increasing number of patients who are living with severe left ventricular dysfunction and congestive heart failure. Recent studies have estimated that approximately 5-15% of patients undergoing coronary angiography may be considered to have advanced coronary artery disease. Considering that 1,713,000 cardiac catheterizations were performed in 1996 in the United States, approximately 100,000-250,000 patients per year may be eligible for newer treatments for coronary artery disease. More recent statistics in the AHA Heart and Stroke Update report that in 2001, nearly one million patients had coronary artery bypass graft surgery or percutaneous coronary intervention, (Figure 1). Of these, 125,650 patients experienced persistent angina.

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Medicina (Kaunas) 2002;38(6):585-91
[Transmyocardial laser revascularization: a past or future treatment method? (review of the literature)]
[Article in Lithuanian]
Kinduris S.
Kauno medicinos universiteto Biomedicininiu tyrimu institutas, Eiveniu 4, 3007 Kaunas. kinsar@one.lt

Despite the success of current medical and surgical management of ischemic heart disease, a growing number of patients have diffuse obstructive coronary artery disease that is not amenable to coronary artery bypass grafting or catheter based interventions. This problem has stimulated interest in developing alternative therapeutic approaches. The construction of subendocardial channels to perfuse ischemic areas of the myocardium has been investigated since the 1950s. Before coronary artery bypass grafting, PTCA, and transmyocardial laser revascularization, mechanical methods to create transmural channels and thereby to revascularize the myocardium were reported. Early attempts at indirect myocardial revascularization had limited success. Transmyocardial laser revascularization is a new procedure for the treatment of angina pectoris. This article reviews the historical background of transmyocardial laser revascularization and possible mechanisms by which it may work, and discusses existing evidences for and against the procedure and how it may be applied in the future. The most important experimental studies and randomized prospective clinical trials from 1996 to 2001 were examined. The literature review concluded that transmyocardial laser revascularization does not have a life-saving effect, nor does it improve myocardial function. However, the method has a considerable short-term symptomatic effects, the mechanism of which is not understood. Neoangiogenesis, myocardial inflammation, denervation and placebo may play a role. Therefore, transmyocardial laser revascularization is potentially indicated for patients with severe angina that is refractory to medical therapy and who have contraindications for more traditional therapies (coronary artery bypass grafting, PTCA and heart transplantation). More expert groups recommend further research to clarify the mechanisms of transmyocardial laser revascularization treatment.

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Eur Heart J 2002 Dec;23(24):1946-54
Comment in: Eur Heart J. 2002 Dec;23(24):1898-9.
Beneficial clinical effects of perhexiline in patients with stable angina pectoris and acute coronary syndromes are associated with potentiation of platelet responsiveness to nitric oxide.
Willoughby SR, Stewart S, Chirkov YY, Kennedy JA, Holmes AS, Horowitz JD.
Cardiology Unit, The Queen Elizabeth Hospital, Department of Medicine, The University of Adelaide, Adelaide, Australia.

AIMS: To examine whether the prophylactic antianginal agent perhexiline potentiates platelet responsiveness to nitric oxide (NO) in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS: unstable angina pectoris or non-Q-wave myocardial infarction). METHODS AND RESULTS: Blood samples were obtained from patients before and after initiation of treatment with perhexiline. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP) were determined via impedance aggregometry in whole blood (WB) and platelet-rich plasma (PRP). Intraplatelet cGMP content was assayed by RIA, and superoxide (O(2)(-)) level by lucigenin-derived chemiluminescence. In patients with ACS not receiving perhexiline (n=12), platelet responsiveness to SNP did not vary significantly over the first 3 days post admission to hospital. Therapy with perhexiline for 3 days was associated with increases in SNP-induced inhibition of aggregation from 29+/-2% to 43+/-4% (n=50,P <0.001) in WB and from 20+/-5% to 42+/-7% (n=12, P<0.01) in PRP. Resolution of symptomatic ischaemia (n=39) was associated with significantly greater (P<0.01) increases than non-resolution (n=11). Similar increases in SNP responsiveness (P<0.001) occurred following institution of perhexiline therapy in patients with SAP (n=30), associated with a 85% decrease in anginal frequency. Treatment with perhexiline potentiated the cGMP-elevating effects of SNP in platelets (n=9,P =0.03). Although perhexiline did not alter whole blood O(2)(-) concentration ex vivo, it inhibited (P<0.01) O(2)(-) release from neutrophils in vitro. CONCLUSION: Perhexiline potentiates platelet responsiveness to NO both in SAP and ACS patients; in the latter group this improvement was predictive of resolution of ischaemic symptoms. The predominant mechanism of perhexiline effect is an increase in platelet cGMP responsiveness. Perhexiline also may reduce the potential for NO clearance by neutrophil-derived O(2)(-).

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Congest Heart Fail 2002 Nov-Dec;8(6):297-302
Enhanced external counterpulsation as treatment for chronic angina in patients with left ventricular dysfunction: a report from the International EECP Patient Registry (IEPR).
Soran O, Kennard ED, Kelsey SF, Holubkov R, Strobeck J, Feldman AM.
Cardiovascular Institute, UPMC Health System, Pittsburgh, PA, USA.

The International Enhanced External Counterpulsation (EECP) Patient Registry tracks acute and long-term outcome for consecutive patients treated for chronic angina. Although EECP has previously been shown to be a safe and effective treatment for angina, little information is available on its use in patients with left ventricular (LV) dysfunction. This report compares the acute outcome and 6-month follow-up for a group of patients with severe LV dysfunction and a group of patients without LV dysfunction. Of 1,402 patients in the registry recruited in 1998-1999 who had recorded values of LV ejection fraction (LVEF) at baseline, 1,090 (77.7%) had preserved LV function (LVEF >35%) and 312 (22.3%) had LV dysfunction (LVEF </=35%). Six-month follow-up was available on 84% of these patients. Pre-EECP patients with LV dysfunction had a longer history of coronary artery disease (12.9 years vs. 9.1 years; p<0.001), a higher rate of congestive heart failure (60.6% vs. 20.1%; p<0.001) and myocardial infarction (83.5% vs. 61.9%; p<0.001). Patients with LV dysfunction had more severe pre-EECP angina, with 86.2% presenting with Canadian Cardiovascular Society Class III/IV vs. 73.6%; p<0.01. Patients with LV dysfunction, consistent with their more severe baseline profile, suffered more adverse events (death, unstable angina, and exacerbation of heart failure) during the treatment period and were less likely to complete the full course. Immediately post-EECP, angina decreased by at least one class in 67.8% of patients with LV dysfunction (vs. 76.2%; p<0.01), and 35.9% of LV dysfunction patients vs. 39.0% had discontinued nitroglycerin use (p=ns). At 6-month follow-up, patients with LV dysfunction showed higher rates of death (9.3% vs. 2.2%; p<0.001) and exacerbation of congestive heart failure (9.9% vs. 3.7%; p<0.001). Rates of the composite outcome of death/myocardial infarction/coronary artery bypass grafting/percutaneous coronary intervention (15.4% vs. 8.3%; p<0.001) were also higher for patients with LV dysfunction. However, patients not reporting such an event showed maintenance of their improved anginal status, with 81% of LV dysfunction vs. 83.8% of patients without LV dysfunction (p=ns) reporting angina at 6 months equal to or less severe than immediately post-EECP, and nitroglycerin use was still reduced at 46.1% for LV dysfunction vs. 37.4% (p<0.05). The rate of event-free angina maintenance at 6 months was 67.0% for patients with LV dysfunction and 70.6% of patients with preserved LV function (p=ns). Patients with LV dysfunction achieved a less robust reduction in angina than did those without LV dysfunction. For the majority of the patients in the registry, this reduction was maintained at 6 months. Copyright 2002 CHF, Inc.

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Jpn Heart J 2002 Sep;43(5):443-53
Nicorandil-induced preconditioning as evidenced by troponin T measurements after coronary angioplasty in patients with stable angina pectoris.
Sakai K, Yamagata T, Teragawa H, Matsuura H, Chayama K.
First Department of Internal Medicine, Hiroshima University School of Medicine, Japan.

Nicorandil has been reported to have a preconditioning effect which suppresses the ST-segment shift or lactate production during coronary angioplasty in patients with stable angina pectoris. The present study investigated whether the preconditioning effect of nicorandil affects troponin T (TnT) levels after coronary angioplasty. Twenty-four patients with stable angina pectoris were randomized to receive a 1-minute intravenous infusion of nicorandil (100 microg/kg) or normal saline. Five minutes later they underwent three 2-minute balloon inflations 5 minutes apart. The sum of ST-segment elevation in all leads (Sum-ST) was determined at the end of each balloon inflation. Serum levels of TnT were measured 6 and 18 hours after the procedure, and the higher value of the two measurements was compared between the groups. SumST decreased progressively during the three sequential balloon inflations in both groups and was less in the nicorandil group than in the control group. The TnT level after the procedure was significantly lower in the nicorandil group than in the control group (0.05+/-0.05 vs 0.11+/-0.10 ng/mL). In conclusion, pretreatment with intravenous nicorandil suppresses TnT release after coronary angioplasty as well as ST-segment elevation during coronary angioplasty, suggesting pharmacological preconditioning by nicorandil.

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Jpn Heart J 2002 Sep;43(5):433-42
Head-to-head comparison of two different low-molecular-weight heparins in acute coronary syndrome: a single center experience.
Ozdemir M, Erdem G, Turkoglu S, Cemri M, Timurkaynak T, Boyaci B, Ridvan Y, Cengel A, Dortlemez O, Dortlemez H.
Department of Cardiology, School of Medicine, Gazi University, Ankara, Turkey.

Low-molecular-weight heparins (LMWH) of different types have yielded different results when used in the setting of unstable angina (UA) or non Q-wave myocardial infarction (NQMI). We compared the safety and therapeutic efficacy of two different LMWHs, namely dalteparin (Dalt.) and enoxaparin (Enox.), in the acute phase (first 5 days) of UA or NQMI. One hundred and forty-two patients with UA/NQMI were randomly assigned to treatment with either Dalt. [120 IU/kg twice daily by subcutaneous (SC) injection] or Enox. [1 mg/kg twice daily by SC injection]. The occurrence of any one of death, myocardial infarction, or angina recurrence within 5 days of the first LMWH injection was the endpoint of the study. There were 69 patients in the Enox. group (53 males, 16 females, mean age: 60.3+/-11.9) and 73 patients in the Dalt. group (54 males, 19 females, mean age: 59.6 +/-10.3). The baseline characteristics of the patients in the two groups were similar. There were no deaths in either group. Myocardial infarction occurred in two patients in the Dalt. group (4%). Angina recurrence was seen in 11 patients in the Enox. group (16%) and in 11 patients in the Dalt. group (15%). Overall, any of the events that made up the endpoint occurred in 11 (16%) and 14 (19%) patients in the Enox. and Dalt. groups, respectively (P>0.05). The time to occurrence of the first event, however, was significantly longer in the Enox. group (82.3+/-33.2 versus 37.6+/-23.4 hours, P=0.007). Thrombocytopenia and allergic reactions were not detected in any patient. Major bleeding was seen in I patient in the Enox. group. Minor bleeding occurred in 17 (25%) and 21 (29%) patients in the Enox. and Dalt. groups, respectively (P>0.05). Enoxaparin and dalteparin were found to be equally safe and effective for the early management of UA/NQMI, but enoxaparin appeared to delay the occurrence of MI or angina recurrence as compared to dalteparin in this setting.

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J Am Coll Cardiol 2002 Nov 20;40(10):1761-8
Relationship between baseline white blood cell count and degree of coronary artery disease and mortality in patients with acute coronary syndromes: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy—Thrombolysis in Myocardial Infarction (18 trial substudy).
Sabatine MS, Morrow DA, Cannon CP, Murphy SA, Demopoulos LA, DiBattiste PM, McCabe CH, Braunwald E, Gibson CM.
TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. msabatine@partners.org

OBJECTIVES: This study was designed to determine the relationship between baseline white blood cell (WBC) count and angiographic and clinical outcomes in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI) and to see if WBC count was a significant predictor of outcomes independent of other biomarkers. BACKGROUND: Inflammation has been shown to play a role in atherosclerosis and acute coronary syndromes. METHODS: We evaluated the relationship between baseline WBC count, other baseline variables and biomarkers, angiographic findings, and clinical outcomes in 2,208 patients in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) trial. RESULTS: Higher baseline WBC counts were associated with lower Thrombolysis In Myocardial Infarction (TIMI) flow grades (p = 0.0045) and TIMI myocardial perfusion grades (p = 0.03) as well as a greater extent of coronary artery disease (CAD) (p < 0.0001). A higher baseline WBC count was predictive of higher six-month mortality, ranging from 1.5% to 3.6% to 5.1% for patients with low, intermediate, and high WBC counts, respectively (p = 0.0017). In a multivariable proportional hazards model, patients with a low C-reactive protein (CRP) but an elevated WBC remained at significantly higher risk of death at six months (hazard ratio [HR] 4.3, p = 0.049), and patients with a high CRP were at even higher risk (HR 8.6, p = 0.004). conclusions: In patients with UA/NSTEMI, elevations in a simple, widely available blood test, the WBC count, were associated with impaired epicardial and myocardial perfusion, more extensive CAD, and higher six-month mortality. After adjustment for traditional risk factors and other biomarkers, assessment of two inflammatory markers, WBC count and CRP, can be used to stratify patients across an eightfold gradation of six-month mortality risk.

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Clin Cardiol 2002 Nov;25(11 Suppl 1):I16-22
Defining the scope of evidence-based practice for low-molecular-weight heparin therapy in high-risk patients with unstable angina and non-ST-elevation myocardial infarction.
Ferguson JJ.
Cardiology Research, St Luke's Episcopal Hospital, Texas Heart Institute, Houston 77030, USA. jferguson100@hotmail.com

Various therapies have been utilized for the treatment of unstable angina and non-ST-elevation myocardial infarction (NSTEMI). Each therapy has both advantages and disadvantages with regard to clinical outcomes and an increased risk of bleeding. One emerging primary therapy is low-molecular-weight heparin (LMWH). Concerns have emerged, however, over the use of LMWH in patients going to the catheterization laboratory or who receive platelet glycoprotein IIb/IIIa inhibitors. Available trial data point to the safety and efficacy of LMWH in these patients. Eventually, LMWH will probably replace unfractionated heparin (UFH) for the majority of patients with acute coronary syndromes (ACS). At present, however, practitioners need to consider individually how comfortable they are with the available data.

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J Am Coll Cardiol 2002 Nov 6;40(9):1555-66
Percutaneous coronary intervention versus coronary bypass graft surgery for diabetic patients with unstable angina and risk factors for adverse outcomes with bypass: outcome of diabetic patients in the AWESOME randomized trial and registry.
Sedlis SP, Morrison DA, Lorin JD, Esposito R, Sethi G, Sacks J, Henderson W, Grover F, Ramanathan KB, Weiman D, Saucedo J, Antakli T, Paramesh V, Pett S, Vernon S, Birjiniuk V, Welt F, Krucoff M, Wolfe W, Lucke JC, Mediratta S, Booth D, Murphy E, Ward H, Miller L, Kiesz S, Barbiere C, Lewis D; Investigators of the Dept. of Veterans Affairs Cooperative Study #385, the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME).
Section of Cardiology, 12W, New York VA Medical Center, 423 East 23rd Street, New York, NY 10010, USA. steven.sedlis@med.va.gov

OBJECTIVES: This study compared survival after percutaneous coronary intervention (PCI) with survival after coronary artery bypass graft surgery (CABG) among diabetics in the Veterans Affairs AWESOME (Angina With Extremely Serious Operative Mortality Evaluation) study randomized trial and registry of high-risk patients. BACKGROUND: Previous studies indicate that CABG may be superior to PCI for diabetics, but no comparisons have been made for diabetics at high risk for surgery. METHODS: Over five years (1995 to 2000), 2,431 patients with medically refractory myocardial ischemia and at least one of five risk factors (prior CABG, myocardial infarction within seven days, left ventricular ejection fraction <0.35, age >70 years, or an intra-aortic balloon being required to stabilize) were identified. A total of 781 were acceptable for CABG and PCI, and 454 consented to be randomized. The 1,650 patients not acceptable for both CABG and PCI constitute the physician-directed registry, and the 327 who were acceptable but refused to be randomized constitute the patient-choice registry. Diabetes prevalence was 32% (144) among randomized patients, 27% (89) in the patient-choice registry, and 32% (525) in the physician-directed registry. The CABG and PCI survival rates were compared using Kaplan-Meier curves and log-rank tests. RESULTS: The respective CABG and PCI 36-month survival rates for diabetic patients were 72% and 81% for randomized patients, 85% and 89% for patient-choice registry patients, and 73% and 71% for the physician-directed registry patients. None of the differences was statistically significant. CONCLUSIONS: We conclude that PCI is a relatively safe alternative to CABG for diabetic patients with medically refractory unstable angina who are at high risk for CABG.

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Wien Klin Wochenschr 2002 Jun 28;114(12):443-7
Blood pressure and heart rate during an episode of unstable angina as predictors of in-hospital outcome.
Ploj T, Bajuk K, Studen P, Noc M, Horvat M.
Center for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia. tom.ploj@guest.arnes.si

PURPOSE: Risk stratification in patients with unstable angina remains a challenging task. Troponins, electrocardiographic changes and clinical characteristics are the most widely employed parameters. Blood pressure and heart rate are proven predictors of short-term outcome; no study, however, has investigated the dynamics of these variables. We postulated that measurements of these parameters performed at the beginning of an ischemic episode would reflect the extent of coronary disease and would predict short-term outcome. METHODS: Analysis of variance and multivariate logistic regression were used to analyze the relationship of systolic blood pressure and heart rate during ischemic episodes with the occurrence of adverse ischemic events (death, infarction, need for revascularization) prior to hospital discharge. RESULTS: In a group of 193 patients mortality rate was 4.2%, infarction rate 8.4% and revascularization rate 42.4%. Systolic blood pressure increased during ischemic episodes compared to baseline values in the group of survivors (p < 0.0001), while there were no significant changes in the group of non-survivors. The rise in heart rate during ischemic episodes was greater in non-survivors, even though significant changes were observed in both groups. Systolic pressure and heart rate were independent predictors of mortality (p = 0.01 and p = 0.003, respectively), but were not predictive of infarction or revascularization. CONCLUSION: Low systolic blood pressure and high heart rate at the beginning of an ischemic episode predict higher in-hospital mortality in patients with unstable angina. Clinical presentation during the ischemic episode should be considered in risk stratification.

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Am Heart J 2002 Nov;144(5):826-33
Angina 1 year after percutaneous coronary intervention: a report from the NHLBI Dynamic Registry.
Holubkov R, Laskey WK, Haviland A, Slater JC, Bourassa MG, Vlachos HA, Cohen HA, Williams DO, Kelsey SF, Detre KM; NHLBI Dynamic Registry. Registry Investigators.
Department of Epidemiology, Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa 15261, USA. holubkov@edc.gsph.pitt.edu

BACKGROUND: As percutaneous coronary intervention (PCI) is most commonly performed for relief of angina, it is important to identify factors associated with recurrence of anginal symptoms. METHODS: We examined symptoms at 1-year follow-up in 1755 consecutive NHLBI Dynamic Registry patients who underwent PCI in the setting of symptoms or acute infarction. RESULTS: At 1-year follow-up, 26% of patients reported angina in the previous 6 weeks. Younger patients and females reported more symptoms. History of coronary artery bypass graft (CABG) or PCI, prior myocardial infarction (MI), diabetes, graft disease, and extensive coronary artery disease (CAD) (>4 significant lesions) were also associated with follow-up angina. Patients receiving stents reported less angina (24% vs 29%, P <.05). Completely revascularized patients and those with residual single-vessel disease had comparable 1-year angina rates (23% both subgroups), while 32% of patients with residual multivessel CAD reported symptoms. Patients undergoing repeat PCI during follow-up reported more 1-year angina than others (34% vs 24%, P <.001), whereas those undergoing CABG after post-PCI hospitalization had less symptoms (15% vs 26%, P <.05). After adjustment for baseline symptom status and outcome of index PCI, residual CAD, and reintervention during follow-up, patient characteristics significantly predictive of angina included female sex, age <62 years, and prior MI. CONCLUSIONS: While approximately three quarters of patients receiving PCI are angina-free at 1 year, females continue to have more symptoms, as do other subgroups including patients with history of MI or previous intervention. As these symptoms are associated with self-reported activity and quality of life limitation, evaluations of PCI should include angina as a key follow-up outcome.

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Am Heart J 2002 Nov;144(5):E9
Esmolol in acute ischemic syndromes.
Mitchell RG, Stoddard MF, Ben-Yehuda O, Aggarwal KB, Allenby KS, Trillo RA, Loyd R, Chang CT, Labovitz AJ.
St Louis University Health Sciences Center, St Louis, Mo 63110-1250, USA.

BACKGROUND: beta-Blockers have been shown to reduce both morbidity and mortality rates in patients with acute coronary syndromes. However, because of potential side effects, their use is limited in patients who might benefit the most from such therapy. It was thought that the use of an ultra-short-acting intravenous beta-blocker might produce similar results with fewer complications in those patients with relative contraindications to beta-blocker therapy. METHODS: Accordingly, we evaluated the use of esmolol in patients with acute coronary syndromes and relative contraindication to beta-blocker therapy in a prospective randomized trial. One hundred eight patients at 21 sites received an infusion of intravenous esmolol or standard therapy on admission and were followed for 6 weeks from the day of admission. The primary efficacy outcome was a composite event consisting of any of the following that occurred during the index hospitalization: death, myocardial (re)infarction, recurrent ischemia, or arrhythmia as well as silent myocardial ischemia assessed by ambulatory electrocardiographic monitoring. Safety end points including hypotension, bradyarrhythmias, new or worsening congestive heart failure, and bronchospasm were also recorded. RESULTS: Event rates for primary end points were similar in the 2 groups: death (2% in the standard care group vs 4% in the group receiving esmolol), myocardial (re)infarction (4% standard vs 7% esmolol), ischemia (12% vs 13%), arrhythmias (4% vs 2%), and silent ischemia (13% vs 15%). There was a higher incidence of transient hypotension in the group receiving esmolol (2% vs 16%), but all such events were noted to resolve after discontinuation of the esmolol infusion. There were no additional differences in safety end points: bradycardia (2% for those receiving standard care vs 9% receiving esmolol), new congestive heart failure (10% vs 16%), bronchospasm (0% vs 7%), and heart block (2% vs 2%). CONCLUSIONS: The use of an ultra-short-acting beta-blocker such as esmolol might offer an alternative to patients with contraindications to standard beta-blocker therapy. Although this trial had limited power to detect safety and efficacy differences between the 2 therapies, it was observed that safety end points, which occurred during esmolol administration, resolved readily when the infusions were decreased or discontinued. Additional testing is needed to substantiate these findings.

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Arch Cardiol Mex 2002 Jul-Sep;72(3):209-19
[Decrease of total hemorrhage with reduced doses of enoxaparin in high risk unstable angina. ENHNFAI study. (Enoxaparin vs non-fractionated heparin in unstable angina). Preliminary report]
[Article in Spanish]
Campos JV, Juarez Herrera U, Rosas Peralta M, Lupi Herrera E, Gonzalez Pacheco H, Martinez Sanchez C, Chuquiure Valenzuela E, Vieyra Herrera G, Cardozo Zepeda C, Barrera Sanchez C, Reyes Corona J, Cortina de la Rosa E, de la Pena Diaz A, Izaguirre Avila R, de la Pena Fernandez A.
Unidad Coronaria del Instituto Nacional de Cardiologia lgnacio Chavez, INCICH, Juan Badiano No. 1, Col. Seccion XVI, Tlalpan, 14080 Mexico, D.F.

In this prospective, randomized and controlled study, we compare complications in 2 groups of patients: group 1, enoxaparin 0.8 mg/kg, subcutaneous every 12 hours during 5 days, and group 2, intravenous unfractionated heparin during 5 days, by infusion treated to activate partial tromboplastin time 1.5-2 the upper limit of normal. Blood samples were obtained at 4, 12, 24 hours and at day 5 of treatment, to measure anti-Xa levels, and also, evaluated end points at 30 days, between groups. Univariate and multivariate logistic regression analyses were performed with clinical and angiographic variables between groups, with p < 0.05. RESULTS: 203 consecutive patients, average age of 60.5 +/- 11.2 years, and 80% men, were included. There were no differences in clinical and angiographic characteristics. All patients with enoxaparin had therapeutic levels of anti-Xa, of 0.5 to 0.67 U/mL. There was increasing risk of total bleeding in group 2 (18.7%) than in group 1 (5.6%), with RR = 1.72 (95% CI 1.29, 2.29), p = .003. Also, there was 33.3% of MACE in group 2, and only 17.8% in group 1, with RR = 1.88 (CI 95% 1.29, 2.29), p = .011. CONCLUSIONS: 1) Low doses of enoxaparine achieve therapeutic levels, since the first 4 hours of treatment. 2) A significant reduction of total bleeding occurred with the low doses of enoxaparin, with the same efficacy to reduce MACE during follow-up.

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Ter Arkh 2002;74(9):36-41
[Decrease in the sensitivity to the anti-ischemic effect of propranolol and prospects for correcting it in patients with stable angina pectoris]
[Article in Russian]
Butina EK, Kokurina EV, Dmitrieva NA, Bochkareva EV.

AIM: To study incidence of low sensitivity to an antiischemic effect of propranolol and feasibility of its correction with a metabolic drug--trimetazidine. MATERIAL AND METHODS: Paired treadmill and bicycle exercise tests were made until depression of segment ST > 1 mm and a typical angina episode. The trial included 147 men with ischemic heart disease, stable angina pectoris (functional class II-III). The antiischemic effect of propranolol single doses 40 or 80 mg were assessed in 117 patients. Single doses of propranolol 40 mg, trimetazidine 20 mg and their combination were examined for an antiischemic effect in 30 patients. The absence of the above effect of propranolol was stated in 20 patients who participated in a double blind, randomised, placebo-controlled study with conduction of 2-week courses of regular administration of propranolol in a dose 120 mg/day, trimetazidine 60 mg/day and their combination. Echo-CG was made initially and in the end of each course. RESULTS: Propranolol's antiischemic effect of a single dose 40 mg was not found in 45.3% patients, 40-80 mg--in 21%. Among 20 patients without effect of the single propranolol dose, an increment of the threshold load made up 20.7 +/- 15.7 s, after intake of trimetazidine 16.3 +/- 18.6 s. The combination of these drugs significantly increases the increment of the threshold load duration to 90.8 +/- 80.4 s. The same picture was observed in the course treatment. The above increment in the course administration of propranolol was 46.3 +/- 15.3 s, of trimetazidine 22.8 +/- 20.2 s, of their combination 122.7 +/- 21.8 s (p = 0.02). In the absence of propranolol effect, echo-CG registered deterioration of disorder of left ventricular diastolic function. 10 patients with effect of the single propranolol dose this deterioration was not observed in combined use of propranolol and trimetazidine. CONCLUSION: The antiischemic effect of propranolol in a single dose 40 mg was not recorded in about half of the examined anginal patients. Combined use of propranolol and trimetazidine in cases with no propranolol effect provides a synergetic effect both in single and course administration.

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J Cardiovasc Pharmacol 2002 Nov;40(5):751-61
Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina:
a multicenter study.
Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida H, Osada H, Katagiri T, Yamauchi K, Yui Y, Minamino T, Nakashima M, Kato K.
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. shimo@cardiol.med.kyushu-u.ac.jp

Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia. In this multicenter phase II study, the anti-anginal effect of fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was examined in patients with stable effort angina. In the phase IIa trial, after a 2-week washout period of anti-anginal drugs, 45 patients received increasing doses of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment significantly prolonged the maximum exercise time and the time to the onset of 1-mm ST segment depression on treadmill exercise test (both p < 0.01), whereas blood pressure and heart rate during exercise were unchanged before and after the treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in 22 patients in the same manner with similar positive results. In the phase IIb trial, after a 2-week washout period of anti-anginal drugs, 125 patients were assigned, in a double-blind manner, to a 4-week oral treatment with a different dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was performed before and after the treatment. Again, both maximum exercise time and time to the onset of 1-mm ST segment depression were prolonged in all groups. A significant dose-response relation was noted across the treatment groups for the exercise tolerance index that was determined by the combined effect of exercise time and ST segment depression (p = 0.006). Fasudil was well tolerated in both trials without any serious adverse reactions. These results suggest the efficacy and adequate safety profile of fasudil, the first drug in a novel class of vasodilators, for the treatment of stable effort angina.

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Ital Heart J 2002 Sep;3(9 Suppl):943-8
["Cure" and "tactics" interventional strategies in unstable angina/non-Q infarction]
[Article in Italian]
De Servi S, Vandoni P, D'Urbano M, Poli A, Fetiveau R, Cafiero F.
U.O. di Cardiologia, Ospedale Civile, Via Candiani, 2 20025 Legnano, MI. emodinamica.legnano@calcol.it

Early risk stratification and an invasive approach (coronary angiography and reperfusion if indicated) have recently emerged as the treatment of choice in non-ST elevation acute coronary syndromes. An aggressive pharmacologic therapy, i.e. glycoprotein IIb/IIIa antagonists, is also more effective in case of risk assessment at the time of the admission of the patient in the coronary care unit. Recent data have assessed the advantages of abciximab over tirofiban in unstable patients submitted to percutaneous coronary intervention (PCI), whereas non-anticorpal molecules (tirofiban, integrilin) are indicated for the medical treatment of high-risk patients in order to reduce myocardial necrosis during the acute phase. A good platelet inhibition with the oral tienopiridine derivative clopidogrel, resulted in a lower incidence of major cardiovascular events at follow-up both in patients treated conservatively as well as in patients submitted to PCI (CURE and PCI-CURE trials). The early risk of myocardial necrosis before coronary revascularization was also reduced by clopidogrel in patients submitted to PCI, an effect already demonstrated with tirofiban and integrilin ("small molecules like" effect). A new therapeutic scheme including, at the time of admission, oral clopidogrel for platelet inhibition, an early risk assessment and the subsequent use of abciximab in the cath lab, if indicated is proposed for the treatment of unstable angina. The advantages associated with the proposed treatment have to be validated by ad hoc studies.

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Gan To Kagaku Ryoho 2002 Oct;29(10):1805-8
[Angina attack caused by 5-fluorouracil infusion—report of a case and review of the literature]
[Article in Japanese]
Yokoyama T, Hosoya Y, Aoki T, Saito S, Nihei Y, Kobayashi N, Shoji M, Saito Y, Nagai H.
Dept. of Surgery, Utsunomiya Social Insurance Hospital.

Cardiac toxicity of 5-fluorouracil (5-FU) has been rarely reported. We encountered a case of angina attack caused by 5-FU. A 58-year-old Japanese woman underwent sigmoidectomy for a sigmoid colon carcinoma with multiple liver metastases. Two months after surgery, she received chemotherapy comprising hepatic arterial infusion of 5-FU. During the 2nd chemotherapy session 7 days after the first, she complained of anterior chest pain. Her electrocardiograms showed elevations of the ST segment in almost all leads, confirming the diagnosis of angina pectoris. Soon after the third chemotherapy session the same type of attack occurred again. The close association of the attacks with 5-FU administration suggested that the angina might have been induced by 5-FU. Further attacks were avoided by discontinuing the 5-FU thereafter. The incidence of cardiac toxicity 5-FU has been reported to be 1.6-7.6%. Labianca et al. found 17 cases of 5-FU-associated cardiopathy, 15 of which were angina pectoris, out of 1,083 patients treated with the drug for various kinds of neoplasm. Analysis of 6 domestic cases including ours revealed that all patient lacked a previous history of cardiac disease except one who had an arrhythmia. There seemed to be no dose-dependent correlation with 5-FU-induced angina. Cardiac events were found even in the earlier phase of chemotherapy. Since 5-FU is widely used in the treatment of a number of gastrointestinal malignancies, one should bear in mind its cardiac toxicity, manifested as angina pectoris.

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JAMA 2002 Oct 16;288(15):1851-8
Comment in: J Fam Pract. 2003 Jan;52(1):24-8. JAMA. 2002 Oct 16;288(15):1905-7.
Cost and cost-effectiveness of an early invasive vs conservative strategy for the treatment of unstable angina and non-ST-segment elevation myocardial infarction.
Mahoney EM, Jurkovitz CT, Chu H, Becker ER, Culler S, Kosinski AS, Robertson DH, Alexander C, Nag S, Cook JR, Demopoulos LA, DiBattiste PM, Cannon CP, Weintraub WS; TACTICS-TIMI 18 Investigators. Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction.
Emory Center for Outcomes Research, Division of Cardiology, Department of Medicine, Emory University School of Medicine, 1256 Briarcliff Rd, Suite 1N, Atlanta, GA 30306, USA. emahone@emory.edu

CONTEXT: In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-Thrombolysis in Myocardial Infarction (TIMI) 18 trial, patients with either unstable angina or non-ST-segment elevation myocardial infarction (UA/NSTEMI) treated with the platelet glycoprotein (Gp IIb/IIIa) inhibitor tirofiban had a significantly reduced rate of major cardiac events at 6 months with an early invasive vs a conservative strategy. OBJECTIVE: To examine total 6-month costs and long-term cost-effectiveness of an invasive vs a conservative strategy. DESIGN: Randomized controlled trial including a priori economic end points. SETTING: Hospitalization for UA/NSTEMI with 6-month follow-up period. PATIENTS: A total of 2220 patients with UA/NSTEMI; economic data from 1722 patients at US-non-VA hospitals. INTERVENTION: Early invasive strategy with routine catheterization and revascularization as appropriate vs a conservative strategy with catheterization performed only for recurrent ischemia or a positive stress test. MAIN OUTCOME MEASURE: Total 6-month costs and incremental cost-effectiveness ratio. RESULTS: The average initial hospitalization costs among those in the invasive strategy group were $15714 vs $14047 among those in the conservative strategy group, a difference of $1667 (95% confidence interval [CI], $387-3091). The in-hospital costs were offset significantly at the 6-month follow-up, with an average cost in the invasive group of $6098 vs $7180 in the conservative group, a difference of $1082 (95% CI, -$2051 to $76). The average total costs at 6 months, including productivity costs, for the invasive group was $21 813 vs $21 227 for the conservative group, a $586 difference (95% CI, -$1087 to $2486). The average 6-month costs excluding productivity costs in the invasive group was $19 780 vs $19 111 in the conservative group, a difference of $670, 95% CI; (-$1035 to $2321). Estimated cost per year of life gained for the invasive strategy, based on projected life expectancy, was $12739 for the base case, and ranged from $8371 to $25769, based on model assumptions. CONCLUSIONS: In patients with UA/NSTEMI treated with the Gp IIb/IIIa inhibitor tirofiban, the clinical benefit of an early invasive strategy was achieved with a small increase in cost, yielding favorable projected estimates of cost per year of life gained. These results support the broader use of an early invasive strategy in these patients.

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Mayo Clin Proc 2002 Oct;77(10):1085-92
Statin lipid-lowering therapy for acute myocardial infarction and unstable angina: efficacy and
mechanism of benefit.
Wright RS, Murphy JG, Bybee KA, Kopecky SL, LaBlanche JM.
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minn 55905, USA. wright.scott@mayo.edu

The use of statin agents in patients with acute coronary syndromes (ACSs) remains an area of intense clinical interest. Statin therapy has an established secondary preventive benefit in patients with coronary artery disease, and its extension to ACS seems logical. A number of observational studies have shown an association between initiation of statin therapy early in ACS and improved clinical outcome. Additionally, 4 randomized controlled trials have examined the use of statin therapy for ACS: the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, the Pravastatin Turkish Trial, the Fluvastatin on Risk Diminishing After Acute Myocardial Infarction (FLORIDA) study, and the Lipid-Coronary Artery Disease (L-CAD) study. Three of these trials showed a benefit with early initiation of statin therapy, whereas 1 trial demonstrated neither benefit nor harm. All the available trials lacked the power and design to sufficiently evaluate whether early initiation of statin therapy reduces mortality and reinfarction in patients with ACS. Four ongoing trials have been designed and sufficiently powered to determine whether statin therapy reduces the risk of death and reinfarction when initiated early in ACS treatment. A body of evidence suggests that the pleiotropic actions of statin agents might modulate benefit in ACS. This article summarizes the available data and provides a rationale for early initiation of statin therapy for patients with ACS.

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Pol Arch Med Wewn 2002 Jun;107(6):509-17
[Comparative evaluation of the clinical effectiveness and the adverse effects of three different forms of nitrates in high oral doses in patients with stable angina pectoris]
[Article in Polish]
Kosmicki M, Kowalik I, Jedrzejczyk B, Sadowski Z.
Klinika Choroby Wiencowej Instytutu Kardiologii w Warszawie.

The aim of this study was the comparative evaluation of antianginal efficacy and the adverse effects of 3 nitrates in oral doses: isosorbide dinitrate 80 mg in slow release form (ISDN-80), nitroglycerin 15 mg--slow release (NITRO-15) and pentaerythritol tetranitrate 100 mg in normal tablets (PENTA-100) in patients (pts) with stable angina pectoris. In a randomized, double-blind, cross-over and placebo (P) controlled study 15 men, with mean age 54.8 +/- 8.0 years, with stable angina, received single doses of: ISDN-80, NITRO-15, PENTA-100 or P. Clinical efficacy of the drugs was evaluated by analysis of the walking times: total (TT), to angina (TA), and to ischemia (TI) on treadmill during stress tests performed 2 and 6 hours (h) after drug ingestion; the adverse effects were registered during 6 h follow up. RESULTS: 2 h after ingestion all 3 study drugs improved significantly: TT, TA and TI in comparison to P. After 6 h the same parameters were improved by: ISDN-80 and NITRO-15, but PENTA-100 improved only TT and TA. After 6 h ISDN-80 significantly improved in comparison to NITRO-15: TT by 19.7% (p < 0.01), TA by 21.2% (p < 0.01) ant TI by 25.0% (p < 0.05), and in comparison to PENTA-100: TT by 32.1% (p < 0.001), TA by 33.4% (p < 0.001) and TI by 41.1% (p < 0.01). After 6 h NITRO-15 significantly improved TI in comparison to PENTA-100 by 13.1% (p < 0.05). The headaches, the most frequent adverse effects, occurred after ingestion of ISDN-80 in 6 pts, NITRO-15 in 4 pts, PENTA-100 in 3 pts and P in 1 pt. Among three evaluated nitrates ISDN-80 significantly improved the effort tolerance and the coronary reserve in the strongest way, NITRO-15 was intermediate in the clinical efficacy, but PENTA-100, the drug with the weakest antianginal efficacy, was the reason of the least number of the adverse effects.

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Pol Merkuriusz Lek 2002 Jul;13(73):52-5
[Development of nitrate tolerance in individual patients with stable angina pectoris in various phases of therapy with oral isosorbide dinitrate]
[Article in Polish]
Kosmicki M, Szwed H, Kowalik I, Sadowski Z.
Klinika Choroby Wiencowej Instytutu Kardiologii w Warszawie. Marek7372069@pharmanet.com.pl

The aim of the work was an individual assessment of the effect on coronary reserve exerted by the widely used drug from the group of nitrates--isosorbide dinitrate (ISDN) in conventional and slow-release (SR) presentations, in various doses. The patients--38 males with stable coronary disease were given orally, by randomised double blind method, conventional isosorbide dinitrate (ISDN) in 10 and 20 mg doses, and slow-release isosorbide dinitrate in 20 mg SR, 40 mg SR, 80 mg SR and 120 mg SR doses, or placebo for the first time and for 7 days: four times daily, three times daily (with a 12-hour break), twice daily (with an 18-hour break) and once daily. In each of the therapeutic methods, walking times were analysed during exercise test six hours following drug administration, that is total time (TT), time to angina (TA) and time to ischaemia (TI). A prolongation by > or = 20% of walking times after ISDN administration as compared to placebo in > 50% of patients was accepted as significant improvement. Six hours after the first administration, a significant improvement of TT, TA and TI as compared to placebo was observed in the case of ISDN 20 mg, 40 mg SR, 80 mg SR and 120 mg SR. After administration of the drugs four times daily no significant improvement was observed after any dose. After administration of the drugs thrice daily, significant improvement was found in the case of TA (80 mg SR) and TI (20 mg SR, 40 mg SR and 120 mg SR), after twice daily administration--in the case of TI (40 mg SR and 80 mg SR) and after once daily administration--in the case of TT (80 mg SR), TA (120 mg SR) and TI (40 mg SR, 80 mg SR and 120 mg SR). In > 50% of patients, the coronary activity of ISDN in higher doses persists for six hours in the case of the first time administration; continuous therapy leads to tolerance development and intermittent therapy makes possible to avoid it. Tolerance does not depend on patients' sensitivity to nitrates.

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Circulation 2002 Sep 24;106(13):1690-5
Comment in: Circulation. 2002 Sep 24;106(13):1595-8.
Effects of atorvastatin on stroke in patients with unstable angina or non-Q-wave myocardial infarction: a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy.
Waters DD, Schwartz GG, Olsson AG, Zeiher A, Oliver MF, Ganz P, Ezekowitz M, Chaitman BR, Leslie SJ, Stern T; MIRACL Study Investigators.
Division of Cardiology, San Francisco General Hospital, and the University of California, San Francisco School of Medicine, San Francisco, Calif 94110, USA. dwaters@medsfgh.ucsf.edu

BACKGROUND: This report describes the effect of intensive cholesterol lowering with atorvastatin on the incidence of nonfatal stroke, a secondary end point, in a randomized, placebo-controlled trial of patients with unstable angina or non-Q-wave myocardial infarction. The primary end point, a composite of death, nonfatal myocardial infarction, resuscitated cardiac arrest, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization, was reduced from 17.4% in the placebo group to 14.8% in the atorvastatin group over the 16 weeks of the trial (P=0.048). METHODS AND RESULTS: Strokes were adjudicated by a blinded end-point committee using standard clinical and imaging criteria. The outcomes of nonfatal stroke and fatal plus nonfatal stroke were analyzed by time to first occurrence during the 16-week trial. Of 38 events (in 36 patients) adjudicated as fatal or nonfatal strokes, 3 were classified as hemorrhagic, one as embolic, and 29 as thrombotic or embolic; 5 could not be categorized. Nonfatal stroke occurred in 9 patients in the atorvastatin group and 22 in the placebo group (relative risk, 0.40; 95% confidence intervals, 0.19 to 0.88; P=0.02). Fatal or nonfatal stroke occurred in 12 atorvastatin patients and 24 placebo patients (relative risk, 0.49; 95% confidence intervals, 0.24 to 0.98; P=0.04). All 3 hemorrhagic strokes occurred in the placebo group. CONCLUSION: Intensive cholesterol lowering with atorvastatin over 16 weeks in patients with acute coronary syndromes reduced the overall stroke rate by half and did not cause hemorrhagic stroke. These findings need to be confirmed in future trials.

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Clin Cardiol 2002 Sep;25(9):436-41
Medical treatment of patients with stable angina pectoris referred for coronary angiography: failure of treatment or failure to treat.
Carasso S, Markiewicz W.
Department of Cardiology, Rambam Medical Center and the Bruce Rappaport School of Medicine of the Technion, Haifa, Israel.

BACKGROUND: Patients referred for elective coronary arteriography because of stable angina pectoris frequently do not receive appropriate medical therapy prior to arteriography. Persistence of symptoms due to lack of appropriate therapy may influence the decision to catheterize and the treatment chosen following catheterization. HYPOTHESIS: The present study evaluates whether patients with stable angina pectoris referred for cardiac catheterization received optimal therapy prior to the procedure. We also evaluated whether medical therapy was optimized as a result of the hospitalization for catheterization. METHODS: We evaluated prospectively the adequacy of medical therapy in 333 consecutive patients undergoing elective coronary arteriography. Of these, 160 had stable angina pectoris as their main problem and constituted the study group. RESULTS: Mean duration of angina was 7.5 +/- 6.3 months. Canadian Cardiovascular Society angina grade 1 was present in 20, grade 2 in 77, grade 3 or 4 in 63 patients. Arteriography showed a > or = 50% coronary stenosis in 141 of 160 patients. Aspirin was used by 96%, and 86% received at least one drug aimed at relieving anginal symptoms: beta blockers in 69%, calcium blockers in 30%, and long-acting nitrates in 29%. Antianginal drugs and drugs aimed at treating risk factors were usually taken at a low, subtherapeutic dosage. Only 35 of 110 patients taking beta blockers had a resting heart rate of <60/min. Following catheterization, 88 of 141 patients with coronary stenosis of > or = 50% underwent percutanous intervention and 5 had urgent surgery. Optimization of treatment was advised in only 7 of 48 patients for whom medical therapy or elective surgery was recommended. CONCLUSION: Patients with stable angina pectoris are frequently referred for cardiac catheterization without making a serious attempt to control their symptoms by medical therapy. Risk factors are undertreated. With proper pharmacotherapy, many patients might have become asymptomatic and have chosen not to undergo catheterization and subsequent percutaneous interventions.

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Lancet 2002 Sep 7;360(9335):743-51
Comment in: J Fam Pract. 2002 Dec;51(12):1011.
Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina.
Fox KA, Poole-Wilson PA, Henderson RA, Clayton TC, Chamberlain DA, Shaw TR, Wheatley DJ, Pocock SJ; Randomized Intervention Trial of unstable Angina Investigators.
Cardiovascular Research, Department of Medical and Radiological Sciences, Royal Infirmary, Edinburgh EH3 9YW, UK. k.a.a.fox@ed.ac.uk

BACKGROUND: Current guidelines suggest that, for patients at moderate risk of death from unstable coronary-artery disease, either an interventional strategy (angiography followed by revascularisation) or a conservative strategy (ischaemia-driven or symptom-driven angiography) is appropriate. We aimed to test the hypothesis that an interventional strategy is better than a conservative strategy in such patients. METHODS: We did a randomised multicentre trial of 1810 patients with non-ST-elevation acute coronary syndromes (mean age 62 years, 38% women). Patients were assigned an early intervention or conservative strategy. The antithrombin agent in both groups was enoxaparin. The co-primary endpoints were a combined rate of death, non-fatal myocardial infarction, or refractory angina at 4 months; and a combined rate of death or non-fatal myocardial infarction at 1 year. Analysis was by intention to treat. FINDINGS: At 4 months, 86 (9.6%) of 895 patients in the intervention group had died or had a myocardial infarction or refractory angina, compared with 133 (14.5%) of 915 patients in the conservative group (risk ratio 0.66, 95% CI 0.51-0.85, p=0.001). This difference was mainly due to a halving of refractory angina in the intervention group. Death or myocardial infarction was similar in both treatment groups at 1 year (68 [7.6%] vs 76 [8.3%], respectively; risk ratio 0.91, 95% CI 0.67-1.25, p=0.58). Symptoms of angina were improved and use of antianginal medications significantly reduced with the interventional strategy (p<0.0001). INTERPRETATION: In patients presenting with unstable coronary-artery disease, an interventional strategy is preferable to a conservative strategy, mainly because of the halving of refractory or severe angina, and with no increased risk of death or myocardial infarction.

   

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