This report was reviewed for medical and scientific accuracy by Ronald S. Freudenberger, MD, Director, Heart Failure and Transplant Cardiology, Associate Professor of Medicine, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Expert Commentary

Barry H. Greenberg, MD, Professor of Medicine, University of California, San Diego; Director, Heart Failure/Cardiac Transplantation Program, UCSD Medical Center, San Diego, California

According to results presented at the 25^th Annual European Society of Cardiology Congress in September 2003 and at the 53^rd Annual Scientific Session of the American College of Cardiology in March 2004, carvedilol provides a superior beneficial clinical effect on cardiovascular endpoints after acute myocardial infarction when compared to treatment with atenolol.^1,2 The Carvedilol Acute Myocardial Infarction Study (CAMIS) evaluated global and regional left ventricular ejection fraction and cardiovascular endpoints in a total of 232 patients with normal ejection fractions (range 53% to 55%) randomly assigned to either carvedilol or atenolol therapy. Patients receiving carvedilol had significantly fewer total cardiovascular events compared to patients treated with atenolol. Interestingly, there was no difference in global or regional left ventricular ejection fraction, suggesting that mechanisms other than left ventricular remodeling likely contribute to the superiority of carvedilol over atenolol.

Multiple clinical trials have shown that β-blockade improves clinical outcomes in a variety of pathological settings, including chronic heart failure^3-6 and post-myocardial infarction.^7-12 However, it is not clear if all β-blockers provide similar beneficial cardiovascular effects. Indeed, available β-blockers are heterogeneous agents that vary with respect to pharmacology, receptor selectivity, hemodynamic effects, and tolerability. Although few studies have directly compared the clinical outcomes among β-blockers, a meta-analysis of 32 acute myocardial infarction clinical trials showed that β-blockers possessing β₂- and/or α₁-adrenergic blockade were more effective at reducing all-cause mortality compared with β₁-selective blockers or β-blockers with intrinsic sympatho-mimetic activity (ISA) (31% risk reduction versus 21% and 15%, respectively).¹³ Similar results were observed for a meta-analysis of 28 heart failure trials in which β-blockers possessing β₂- and/or α₁-adrenergic blockade produced a risk reduction of 42% compared to 33% and 10% for β₁-selective blockers or β-blockers with ISA, respectively.¹³ These results, as well as studies, suggest that there could be a difference in the clinical effectiveness among these agents.^13-17

Carvedilol is a lipophilic, nonspecific β-blocker with selective α₁-adrenergic receptor blockade and antioxidant properties.^18-20 In patients with chronic heart failure, carvedilol reduces mortality and morbidity and has a favorable effect on left ventricular remodeling.^3,21 Studies such as CAPRICORN have shown that carvedilol therapy reduces all-cause and cardiovascular mortality and lowers recurrent, non-fatal myocardial infarction in patients with left ventricular dysfunction after acute myocardial infarction treated with angiotensin-converting-enzyme (ACE) inhibitors.⁷ Echocardiography performed on a subset of post-myocardial infarction patients revealed that carvedilol inhibits left ventricular remodeling, with significant improvements in left ventricular systolic volume and left ventricular ejection fraction observed after 6 months of treatment compared with placebo.²²

The purpose of this Post-myocardial Infarction Express Report^TM is to review the results of the CAMIS study and discuss their clinical implications in the treatment of the post-myocardial infarction patient.

Carvedilol is Superior to Atenolol in Reducing Predefined Cardiovascular Events after Myocardial Infarction in Patients with Normal Ejection Fraction

The CAMIS study was designed to investigate changes in ejection fraction (a measure of cardiac remodeling) in post- myocardial infarction patients with normal ejection fractions (range 53% to 55%) treated with either carvedilol or atenolol, a hydrophilic, β₁-selective β-blocker that has been shown to reduce cardiovascular mortality in acute myocardial infarction. In this single-center, prospective, endpoint-blinded, parallel group study, a total of 232 post-myocardial infarction patients were randomized to receive carvedilol (n = 118) or atenolol (n = 114) for 12 months.^1,2 Study medication was administered orally within 24 hours of start of chest pain in patients with proven acute myocardial infarction. The target dose of carvedilol was 25 mg twice a day (starting dose 6.25 mg twice a day) and for atenolol 50 mg twice a day (starting dose 12.5 mg twice a day). Global and regional left ventricular ejection fractions were measured with gated blood pool scintigraphy at baseline and after 3 and 12 months of treatment to assess inhibition of left ventricular remodeling.

The carvedilol and atenolol treatment groups were generally well balanced with respect to baseline infarct characteristics, medical history, demographics, and treatment with aspirin, statins, and ACE inhibitors. The mean patient age for carvedilol-treated patients was 59.5 years compared to 61.7 years in atenolol-treated patients. There was a prior history of hypertension and diabetes in 20% and 8% of carvedilol-treated patients, respectively, compared to 19% and 14% in atenolol-treated patients. In carvedilol-treated patients, the site of myocardial infarction was 41% and 44% for anterior and inferior, respectively, compared to 43% and 33% for atenolol-treated patients. At baseline, global left ventricular ejection fraction [mean ± standard deviation (SD)] for carvedilol-treated patients was 54.8% (SD 10.9) and 53.0% (SD 15.3) in atenolol-treated patients (P = .175). No significant differences were observed in baseline regional left ventricular ejection fraction between the two treatment groups. Acute treatment of myocardial infarction did not differ between treatment groups except for diuretic therapy which was more frequently prescribed to atenolol-treated patients (15% vs 4%; P = .006), and also at discharge (21% vs 8%; P = .004).

Over the 12-month treatment period, the mean dose of carvedilol was 36.2 mg (SD 15.1) and 72.1 mg (SD 30.6) for atenolol. Both carvedilol and atenolol increased left ventricular ejection fraction after 3 and 12 months of treatment. Left ventricular ejection fractions improved from a baseline value of 54.8% (SD 10.9) to 57% (SD 10) at 3 months and 57% (SD 10) at 12 months in carvedilol-treated patients and from 53% (SD 15.3) to 56% (SD 10) and 56% (SD 9) after 3 and 12 months, respectively, in atenolol-treated patients. There was no significant difference in global left ventricular ejection fraction or regional left ventricular ejection fractions between treatment with carvedilol or atenolol after 3 or 12 months of therapy.

Despite the similarity in left ventricular ejection fraction, carvedilol-treated patients had significantly fewer cardiovascular endpoints, 90 (76.3%) versus 104 (91.2%) in atenolol-treated patients (relative risk 0.84; 95% Confidence Interval [CI], 0.74-0.94; P = .002) (Table 1). Treatment with carvedilol was associated with significantly less patient-reported cold hands and feet than atenolol (20% vs 33%; P = .025).

From the previous CAPRICORN study,⁷ carvedilol has already demonstrated an incremental 23% all-cause mortality benefit on top of modern therapy in acute myocardial infarction patients with left ventricular dysfunction (ejection fractions ≤40%). The CAMIS study is of particular importance as it demonstrates incremental benefit of carvedilol over atenolol in myocardial infarction patients with normal ejection fractions (55%).

Patients treated with carvedilol experienced a significantly longer survival free of first cardiovascular event period compared to treatment with atenolol (Figure 1). Patients treated with carvedilol consistently demonstrated a higher survival function as long as 1,600 days post-randomization (risk reduction = 25%, 95% CI, 6%-26%; P = .002), suggesting that carvedilol not only reduces the number of cardiovascular events, but also prolongs the period before experiencing a first cardiovascular event.

Conclusion

β-blockers have been shown to reduce morbidity and mortality in acute myocardial infarction, although the precise mechanism underlying this beneficial effect is uncertain. One possibility is that inhibition of left ventricular remodeling following myocardial infarction could improve morbidity and mortality among myocardial infarction patients. β-blockers comprise a heterogeneous group of agents that could have differential effects on left ventricular remodeling in this patient population. From CAPRICORN, carvedilol demonstrated an incremental 23% all-cause mortality benefit on top of modern therapy in acute myocardial infarction patients with left ventricular dysfunction (ejection fractions ≤40%). The CAMIS study was designed to compare the effects of two β-blockers, carvedilol and atenolol, on left ventricular ejection fraction, a measure of left ventricular remodeling, and predefined cardiovascular endpoints in patients with normal ejection fractions. Results of CAMIS demonstrate that both carvedilol and atenolol comparably increased global and regional left ventricular ejection fraction after 12 months of therapy. However, carve-dilol provided superior reduction of cardiovascular endpoints compared to atenolol, suggesting that carvedilol functions to improve cardiovascular health by mechanisms other than cardiac remodeling. Moreover, carvedilol might achieve this beneficial outcome because of its unique, nonselective β¹- and β²-receptor and selective α¹-adrenergic receptor blocking properties.

References

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Disclosure

Barry H. Greenberg, MD
Grant/Research Support-Aventis; Consultant-Abbott Laboratories, AstraZeneca, GlaxoSmithKline, Merck; Speakers Bureau-AstraZeneca, GlaxoSmithKline, Merck

Ronald S. Freudenberger, MD
Speakers Bureau-GlaxoSmithKline; Stock Shareholder (directly purchased)-GlaxoSmithKline

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Post-myocardial Infarction Express Report^TM was made possible through an educational grant from GlaxoSmithKline.

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