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

William T. Abraham, MD, FACP, FACC, Professor of Medicine, Chief, Division of Cardiovascular Medicine, Associate Director, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio

According to the recently published results of an echocardiographic substudy of the Carvedilol Post-infarct Survival Control in LV Dysfunction (CAPRICORN) trial,¹ carvedilol significantly reverses the process of progressive pathological left ventricular remodeling which occurs in patients with left ventricular dysfunction after acute myocardial infarction.² Specifically, statistically significant improvements in both left ventricular end-systolic volume and left ventricular ejection fraction were observed in carvedilol-treated patients compared to those treated with placebo after 6 months of therapy. The results of this substudy augment earlier findings that carvedilol improves clinical outcome and left ventricular remodeling in patients with heart failure,^3,4 and support the primary findings from CAPRICORN that optimal management of patients with left ventricular dysfunction after acute myocardial infarction should include the addition of carvedilol to currently accepted therapies.¹

Although cardiac remodeling is perceived as an initially compensatory response to maintain normal cardiac function following injury to the heart, progressive left ventricular remodeling (dilation and systolic dysfunction) leads to cardiac decompen-sation⁵ and is associated with poor prognosis following an acute myocardial infarction.^5,6 Therapeutic interventions that arrest, attenuate, or reverse this remodeling process could favorably alter the progression of cardiovascular diseases such as myocardial infarction, valvular heart diseases, myocarditis, heart failure and dilated cardiomyopathy.^5,6

It has been well established that the use of angiotensin-converting-enzyme (ACE) inhibitors has beneficial effects on left ventricular remodeling and improves clinical outcome in patients after acute myocardial infarction.^7-11 Beta-adrenergic antagonists have also shown favorable effects on left ventricular remodeling and improve clinical outcome in patients with chronic heart failure.^3,12-14 However, until recently, the effects of beta-adrenergic antagonism in patients with left ventricular dysfunction after acute myocardial infarction in combination with ACE inhibitors had not been conclusively studied. Results from CAPRICORN demonstrated that the use of carvedilol resulted in improved clinical outcome in this patient population. Specifically, all-cause mortality was significantly lower in carvedilol-treated patients compared with placebo (12% vs 15%, relative risk reduction 23%; P = .03).¹ To understand the underlying mechanism of the substantial beneficial effects of carvedilol in this setting, an echocardiographic substudy was undertaken to investigate the effects of carvedilol on left ventricular remodeling.

The purpose of this Cardiology Express Report^TM is to review the CAPRICORN echocardiographic substudy and discuss its implications on clinical practice.

Beneficial Effect of Carvedilol on Left Ventricular Remodeling

randomized, international, multicenter, placebo-controlled, echocardiographic substudy of the CAPRICORN trial was conducted to evaluate the effects of carvedilol on left ventricular remodeling in patients with left ventricular dysfunction after acute myocardial infarction treated with ACE inhibitors.² A total of 127 patients from 13 international study sites were randomly assigned to receive 6.25 mg carvedilol twice daily (n = 60) or placebo (n = 67). Carvedilol was titrated up to the highest tolerated dose, not exceeding 25 mg twice daily. Quantitative 2-dimensional echocardiography was performed within 24 hours prior to randomization, when the ACE inhibitor dose was stable. Mean time from index infarction to baseline echocardiogram was 9 days (Standard Deviation (SD) 5.7 days). Echocardiograms were repeated at the end of 1, 3, and 6 months of treatment.

The primary endpoint of the substudy was change in left ventricular end-systolic volume at 6 months. Secondary endpoints included change from baseline in left ventricular end-diastolic volume at 6 months and change in regional wall motion score index at 6 months. Additional endpoints included changes in left ventricular ejection fraction at 1, 3, and 6 months and changes in left ventricular end-systolic volume, left ventricular end-diastolic volume, and left ventricular wall motion score index at 1 and 3 months.

The carvedilol and placebo treatment groups were generally well balanced with respect to infarct characteristics, site of myocardial infarction, and echocardiographic indices (Table 1). Mean patient age was 61 years (SD 12 years) and 81% were men. Hypertension was present in 42% of all patients and prior history of congestive heart failure and myocardial infarction in 42% and 24% of all patients, respectively. The site of index myocardial infarction was anterior in 57% of patients. Ninety-three percent of patients were receiving ACE inhibitors at baseline. Increased left ventricular volumes were recorded at baseline; mean left ventricular end-diastolic volume was 132.4 mL (SD 43.9 mL), mean left ventricular end-systolic volume was 81.9 mL (SD 34.9 mL), and mean left ventricular ejection fraction was 39.3% (SD 8.0%).

Left ventricular end-systolic volumes measured at 1, 3 and 6 months were reduced in patients taking carvedilol and were significantly different from placebo at 6 months. After 1 month of carvedilol therapy, left ventricular end-systolic volume decreased by 2.0 mL (Standard Error of the Mean (SEM) 2.1 mL). Carvedilol patients continued to experience a reduction in left ventricular end-systolic volume at 3 months (-4.8 mL, SEM 2.5 mL) and at 6 months (-4.8 mL, SEM 4.9 mL). In contrast, left ventricular end-systolic volumes increased for placebo-treated patients rising by 4.9 mL (SEM 3.0 mL) at 1 month, by 3.1 mL (SEM 2.7 mL) at 3 months, and by 4.5 mL (SEM 2.8 mL) at 6 months. The difference in left ventricular end-systolic volumes between carvedilol-treated patients and placebo at 6 months was 9.2 mL (95% Confidence Interval (CI), -17.1 to -1.3 mL; 2-tailed P = .023) (Table 2).

Increases in left ventricular end-diastolic volumes were consistently greater in the placebo-treated patients compared to carvedilol-treated patients at 1, 3, and 6 months. Whereas left ventricular end-diastolic volumes did not vary considerably for carvedilol-treated patients during the treatment period, placebo-treated patients experienced left ventricular end-diastolic volume increases of 4.5 mL (SEM 3.3 mL) at 1 month, 3.8 mL (SEM 3.0 mL) at 3 months, and 8.4 mL (SEM 3.3 mL) at 6 months. At 6 months, there was no statistically significant difference in left ventricular end-diastolic volume between carvedilol- and placebo-treated patients, although the trend clearly favored carvedilol.

Significant decreases from baseline for left ventricular wall motion score index were observed in carvedilol-treated patients (P<.05 at 1, 3, and 6 months). After 1 month of carvedilol treatment, patients showed a 0.10 (SEM 0.05) reduction in left ventricular wall motion score index, which improved to decreases of 0.12 (SEM 0.06) and 0.12 (SEM 0.05) at 3 and 6 months, respectively. Values in placebo-treated patients did not change during the treatment period. A statistically significant difference of -0.16 between carvedilol- and placebo-treated patients was seen at 1 month (95% CI, -0.31 to -0.02; 2-tailed P = .028).

Carvedilol increased left ventricular ejection fraction after 1, 3, and 6 months of therapy, and the increase was significantly greater than placebo at 6 months. Carvedilol-treated patients experienced increases in left ventricular ejection fraction of 3.3% (SEM 0.9%), 4.6% (SEM 1.1%), and 5.0% (SEM 1.1%) at 1, 3, and 6 months, respectively. Left ventricular ejection fraction did not change substantially over the course of treatment in placebo-treated patients. A significant difference of 3.9% in left ventricular ejection fraction between carvedilol- and placebo-treated patients was observed at 6 months (95% CI, 0.8-7.1%; 2-tailed P = .015).

Carvedilol administration for 1 and 3 months was associated with significant increases in left ventricular stroke volume compared to placebo. Left ventricular stroke volume was increased by 4.7 mL (SEM 1.4 mL) at 1 month and 5.3 mL (SEM 1.7 mL) at 3 months in carvedilol-treated patients, with a difference of 5.4 mL and 4.8 mL at 1 month (95% CI, 1.3-9.5 mL; 2-tailed P = .01) and 3 months (95% CI, 0.21-9.3 mL; 2-tailed P = .04), respectively, compared to placebo. Differences in left ventricular stroke volume at 6 months were not significant between carvedilol- and placebo-treated patients.

Reductions in heart rate and blood pressure from baseline to 6 months of treatment were greater for patients receiving carvedilol. Compared with the placebo-treated patients, carvedilol-treated patients experienced a significant reduction in heart rate at 1, 3, and 6 months (P<.05). After 1 and 3 months of therapy, carvedilol-treated patients also showed reductions of 6.6 mm Hg and 6.1 mm Hg, respectively, in systolic blood pressure relative to placebo (P = .016 at 1 month and P = .06 at 3 months). A significant difference in diastolic blood pressure was also observed for carvedilol-treated patients at 1 month (reduction of 7.2 mm Hg; 95% CI, -11.3 to -3.1; P<.0001).

Investigators concluded that carvedilol taken over 6 months inhibited progression of pathological left ventricular remodeling in patients with left ventricular dysfunction subsequent to acute myocardial infarction treated with ACE inhibitors. The mechanism of action underlying these beneficial effects on ventricular remodeling are likely multifactorial and probably involve the beta-blocking (reduced myocardial oxygen consumption, reduced filling pressures, and neurohormonal blockade), alpha-blocking (vasodilating), and antioxidant properties of carvedilol. In addition, improvements in left ventricular ejection fraction could be mediated by enhanced function of ischemic myocardium, as has been observed in chronic heart failure due to ischemic left ventricular systolic dysfunction.¹⁵

Conclusion

Left ventricular remodeling is a devastating consequence of acute myocardial infarction that can lead to progressive cardiac decompensation and is associated with poor prognosis. Results of an echocardiographic substudy from CAPRICORN indicate that carvedilol inhibits progressive left ventricular remodeling in patients with left ventricular dysfunction after acute myocardial infarction. Importantly, this effect was seen in patients already receiving ACE inhibitors. To date, carvedilol is the only beta-blocker with clinical evidence demonstrating inhibition of adverse cardiac remodeling in this patient population. Moreover, the primary results of CAPRICORN demonstrate significantly improved survival when carvedilol is added to other standard post-myocardial infarction therapies. For these reasons, carvedilol is the only beta-adrenergic-blocking agent that is FDA-approved for the treatment of post-myocardial infarction patients with left ventricular systolic dysfunction. The results of this CAPRICORN substudy support the addition of carvedilol to standard ACE inhibitor therapy to treat patients with left ventricular dysfunction after acute myocardial infarction.

References

1. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001;357:1385-1390.
2. Doughty RN, Whalley GA, Walsh HA, Gamble GD, Lopez-Sendon J, Sharpe N on behalf of the CAPRICORN Echo Study Investigators. Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN Echo Substudy. Circulation. 2004;109:201-206.
3. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349-1355.
4. Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group. J Am Coll Cardiol. 1997;29:1060-1066.
5. Takano H, Hasegawa H, Nagai T, Komuro I. Implication of cardiac remodeling in heart failure: mechanisms and therapeutic strategies. Intern Med. 2003;42:465-469.
6. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000;35:569-582.
7. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med. 1988;319:80-86.
8. Sharpe N, Smith H, Murphy J, Greaves S, Hart H, Gamble G. Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting-enzyme inhibition. Lancet. 1991;337:872-876.
9. St. John Sutton M, Pfeffer MA, Plappert T, et al. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril. Circulation. 1994;89:68-75.
10. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327:669-677.
11. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet. 1993;342:821-828.
12. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13.
13. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet. 1999;353:2001-2007.
14. Packer M, Coats AJ, Fowler MB, et al for the Carvedilol Prospective Randomised Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651-1658.
15. Cleland JG, Pennell DJ, Ray SG, et al. Myocardial viability as a determinant of the ejection fraction response to carvedilol in patients with heart failure (CHRISTMAS trial): randomised controlled trial. Lancet. 2003; 362:14-21.

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Disclosure

William T. Abraham, MD, FACP, FACC
Consultant-GlaxoSmithKline; Speakers Bureau-GlaxoSmithKline

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

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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 Cardiology Express Report(tm) does not include discussion of treatment and indications outside of current approved labeling. This Cardiology Express Report(tm) was made possible through an educational grant from GlaxoSmithKline.

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