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(Circulation. 2000;102:484.)
© 2000 American Heart Association, Inc.

Editorial

What Type of ß-Blocker Should Be Used to Treat Chronic Heart Failure?

Michael R. Bristow, MD, PhD

From the Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO 80262

Correspondence to Michael R. Bristow, MD, PhD, the Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO 80262.

Key Words: Editorials • heart failure • receptors, adrenergic, beta • hemodynamics

The success of ß-blocking agents in treating mild to moderate heart failure has generated a debate over whether the salutary results are strictly a class effect caused by ß₁-adrenergic receptor antagonism or if additional pharmacological properties of some compounds increase the efficacy inherent in all agents that block ß₁-receptors. The diverse adrenergic receptor activities of ß-blocking agents that have been used successfully to treat chronic heart failure, the emerging role of the various adrenergic receptor pathways in the mediation of cardiomyopathic phenotypes in model systems (recently reviewed in Circulation¹ ), and the vigor of pharmaceutical company scientific marketing all contribute to the legitimacy and decibel level of the discussion. The original, largely theoretical arguments^{2 3 4} have led to increasingly more rigorous tests of the hypothesis that clinically important differences exist among these agents. In this issue of Circulation, Metra et al⁵ report the largest of these tests to date. They provide a direct comparison of the of the ß₁-adrenergic-receptor–selective, "second generation" ß-blocker metoprolol with the nonselective ß/-blocker, "third generation" compound carvedilol.

Metra et al⁵ measured left ventricular (LV) functional and hemodynamic effects in 150 subjects with heart failure who were prospectively randomized 1:1 to the recommended doses of each agent. Previous, smaller studies had reported either subtle differences in favor of carvedilol^{4 6} or no difference⁷ between the 2 agents. Their data⁵ indicate that compared with metoprolol, carvedilol provides, as expected, a greater degree of ß-blockade. Also, as expected and as previously reported in individual clinical trials,^{8 9} metoprolol produced a greater improvement in maximal exercise than carvedilol, which is likely related to the lower degree of ß-blockade. Most importantly, carvedilol provided a greater degree of improvement in LV function, which was the primary end point of the study.⁵ Although no differences existed between the 2 agents in the measured clinical end points,⁵ the sample size was not large enough to detect such differences.

The differences in LV functional improvement in favor of carvedilol in this trial⁵ included a change in LV ejection fraction (EF) of 10.9 EF units, compared with 7.2 EF units for metoprolol, and greater degrees of improvement in numerous exercise functional indices. Could the difference in LVEF response have been due to the loading condition changes produced by the ß-blocker/vasodilator carvedilol compared with the nonvasodilator compound metoprolol? This is not likely, because systemic vascular resistance and mean arterial pressure did not change in either group, and the slightly greater reduction in pulmonary wedge pressure noted in the carvedilol group would tend to reduce LVEF, not increase it. Moreover, the 2 treatment arms were exceptionally well balanced for baseline factors that can or could influence the effects of ß-blockers on myocardial function, including the percentage of ischemic/nonischemic cardiomyopathy, degree of LV dysfunction, age, sex, and New York Heart association class. Therefore, the data are consistent with improvements in intrinsic systolic LV function by both compounds, with quantitatively greater effects observed in the carvedilol group. Moreover, these quantitatively different effects occurred at respective target or actual administered doses (49 mg/d for carvedilol and 124 mg/d for metoprolol) that are as high or higher than doses that have been used in previous trials and that are, in each case, probably close to the maximum tolerated doses of each agent in heart failure patients.

The greater degree of ß-blockade produced by carvedilol, as assessed by a greater inhibition of exercise heart rate,⁵ is not surprising. This could be predicted from the differences in the pharmacology of the 2 agents¹ and from previously reported comparisons of the relative degree of ß-blockade conferred by each agent using dobutamine dose-response curves.¹⁰ In addition to being a potent ß₁-adrenergic receptor blocking agent with an 12-fold higher affinity than metoprolol for ß₁-receptors, carvedilol at target doses blocks ß₂- and ₁-receptors and mildly lowers cardiac adrenergic drive.^{1 4} Carvedilol also has the additional unique property of not up-regulating^{3 4} down-regulated ß₁-adrenergic receptors, as does metoprolol.^{3 4 11 12} The result is a "more comprehensive" degree of adrenergic inhibition.¹ This explains why in Metra et al’s study⁵ and in previous trials,^{8 9 13 14 15} subjects treated with metoprolol tend to have better maximal exercise responses than subjects treated with carvedilol or bucindolol, because the maximal exercise response in heart failure subjects is heart rate–dependent. However, as again demonstrated in the Metra et al trial,⁵ the greater degree of ß-blockade delivered by the standard target doses of carvedilol does not seem to compromise quality of life or submaximal exercise responses, both of which tend to improve^{13 14 16} or are at least not worsened,^{17 18} which is similar to the effects of metoprolol.¹⁹

On the basis of the "adrenergic hypothesis"^{2 20 21} of the progression of myocardial failure and remodeling, it has been argued that a more comprehensive degree of adrenergic blockade is a desirable property of an antiadrenergic agent used to treat chronic heart failure.²¹ This hypothesis is directly supported by dose-response studies in patients with mild to moderate heart failure, in whom larger doses of ß-blockers have produced greater improvements in LV function than smaller doses.^{15 18} This general concept is also supported by work in transgenic mouse models that overexpress adrenergic receptors in the heart. In these cardiac overexpressor models, heightened and sustained myocardial signaling through the human ß₁,^{22 23} ß₂,²⁴ and ₁²⁵ receptor pathways produces a pathological phenotype on a background of normal myocardial structure and function. Although in these models, evidence exists that the ß1-receptor pathway is more pathogenic than the ß₂-receptor pathway,^{1 22 23 24} crosses of the ß₂-cardiac overexpressor mouse with other genetic models of cardiomyopathy result in an acceleration of myocardial failure and remodeling.^{26 27} Thus, if the general mechanism of action of ß-blocker therapy in chronic heart failure is prevention and partial reversal of adrenergically-mediated myocardial dysfunction and remodeling,^{21 28} it would make sense to block the full cytotoxic and growth-promoting effects of norepinephrine (and potentially epinephrine), which can theoretically be mediated by all 3 of the aforementioned receptors. Therefore, the data reported by Metra et al⁵ are consistent with the pharmacological effects of each agent, work in model systems, and the current conceptual framework of how antiadrenergic treatment improves the natural history of heart failure.

What about the relative clinical effects of metoprolol and carvedilol or, more generally, second versus third generation ß-blocking agents? The comparison trials, including Metra et al’s,⁵ have not been large enough to reach conclusions regarding clinical end points, and so one is left comparing the results of different trials conducted with each type of agent. Because of differences in the patient populations of these trials (recently reviewed in Circulation¹ ), a comparison of clinical effects between individual trials is not particularly useful. What may be generally concluded is that both second- and third-generation compounds reduce mortality and morbidity in mild to moderate chronic heart failure.¹ This is also not surprising in view of the apparently greater pathogenic consequences of ß₁-compared with ß₂-receptor signaling, the approximate 2:1:1 dominance of ß₁:ß₂:₁ receptors in the failing human heart,²⁹ and the understanding that the major source of increased adrenergic activity is cardiac neuronal-derived norepinephrine.

Norepinephrine is a ß₁-selective agonist that is 20-fold more selective for human ß₁- versus ß₂-receptors and 10-fold more selective for ß₁-receptors versus human myocardial ₁-receptors.³⁰ Thus, in the failing human heart, the majority of the adverse biological effects of increased cardiac adrenergic drive is mediated by ß₁-adrenergic receptors and, on the basis of this reality, it would be predicted that large differences would not exist between the myocardial or clinical effects of second generation, ß₁-selective versus third generation, comprehensive antiadrenergic agents. The LV functional differences between metoprolol and carvedilol reported in the Metra et al study⁵ are consistent with such a small but measurable incremental effect of adding ß₂- and ₁-receptor blockade to ß₁-blockade. Whether comparable clinical differences exist will have to be determined from large direct comparison trials, such as the Carvedilol and Metoprolol European Trial (COMET). Until these data are available, the answer to the question of what type of ß-blocker to be used in mild to moderate heart failure is still either a second generation, ß₁-selective compound such as metoprolol or bisoprolol or the third generation, nonselective ß/ blocker carvedilol.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

(Circulation. 2000;102:484-486.)

References

1. Bristow MR. ß-Adrenergic receptor blockade in chronic heart failure. Circulation.. 2000;101:558–569.[Free Full Text]
   
2. Bristow MR. Pathophysiologic and pharmacologic rationales for clinical management of chronic heart failure with beta-blocking agents. Am J Cardiol. 1993;71:12C–22C.[Medline] [Order article via Infotrieve]
   
3. Yoshikawa T, Port JD, Asano K, et al. Cardiac adrenergic receptor effects of carvedilol. Eur Heart J. 1996;17(suppl B):8–16.
   
4. Gilbert EM, Abraham WT, Olsen S, et al. Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation. 1996;94:2817–2825.[Abstract/Free Full Text]
   
5. Metra M, Giubbini R, Nodari S, et al. Differential effects of beta-blockers in patients with heart failure. A prospective, randomized, double-blind comparison of the long-term effects of metoprolol vs. carvedilol. Circulation.. 2000;102:546–551.[Abstract/Free Full Text]
   
6. Bristow MR, Abraham WT, Yoshikawa T, et al. Second- and third-generation beta-blocking drugs in chronic heart failure. Cardiovasc Drugs Ther. 1997;11:291–296.
   
7. Kukin ML, Charney RH, Levy DK, et al. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation. 1999;99:2645–2651.[Abstract/Free Full Text]
   
8. Engelmeier RS, O’Connell JB, Walsh R, et al. Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulation. 1985;72:536–546.[Abstract/Free Full Text]
   
9. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet. 1993;342:1441–1446.[Medline] [Order article via Infotrieve]
   
10. Lowes BD, Abraham, WT, Dutcher DL, et al. Comparative anti-adrenergic affects of carvedilol and metoprolol in a randomized, placebo-controlled-trial. Circulation. 1996;94(suppl):I-664.
    
11. Heilbrunn SM, Shah P, Bristow MR, et al. Increased ß-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy. Circulation. 1989;79:483–490.[Abstract/Free Full Text]
    
12. Waagstein F, Caidahl K, Wallentin I, et al. Long-term ß-blockade in dilated cardiomyopathy. Circulation. 1989;80:551–563.[Abstract/Free Full Text]
    
13. Olsen SL, Gilbert EM, Renlund DG, et al. Carvedilol improves left ventricular function and symptoms in heart failure: a double-blind randomized study. J Am Coll Cardiol. 1995;25:1225–1231.
    
14. Krum H, Sakner-Bernstein JD, Goldsmith RL, et al. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation. 1995;92:1499–1506.[Abstract/Free Full Text]
    
15. Bristow MR, O’Connell JB, Gilbert EM, et al, for the Bucindolol Investigators. Dose-response of chronic ß-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Circulation. 1994;89:1632–1642.[Abstract/Free Full Text]
    
16. Metra M, Nardi M, Giubbini R, et al. Effects of short-and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1994;24:1678–1687.
    
17. Packer M, Colucci WS, Sackner-Bernstein JD, et al, for the PRECISE Study Group. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the PRECISE trial. Circulation. 1996;94:2793–2799.[Abstract/Free Full Text]
    
18. Bristow MR, Gilbert EM, Abraham WT, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation. 1996;94:2807–2816.[Abstract/Free Full Text]
    
19. Böhm M, Deutsch HJ, Hartmann D, et al. Improvement of postreceptor events by metoprolol treatment in patients with chronic heart failure. J Am Coll Cardiol. 1997;30:992–996.[Abstract]
    
20. Bristow MR, Kantrowitz NE, Ginsburg R, et al. ß-adrenergic function in heart muscle disease and heart failure. J Mol Cell Cardiol. 1985;17(suppl 2):41–52.
    
21. Bristow MR. Mechanism of action of beta-blocking agents in heart failure. Am J Cardiol.. 1997;80:26L–40L.[Medline] [Order article via Infotrieve]
    
22. Engelhardt S, Hein L, Wiesman F, et al. Progressive hypertrophy and heart failure in ß₁-adrenergic receptor transgenic mice. Proc Natl Acad Sci U S A. 1999;96:7059–7064.
    
23. Bisognano JD, Weinberger HD, et al. Myocardial-directed overexpression of the human ß₁-adrenergic receptor in transgenic mice. J Mol Cell Cardiol.. 2000;32:817–830.[Medline] [Order article via Infotrieve]
    
24. Liggett SB, Tepe NM, Lorenz JN, et al. Early and delayed consequences of ß₂-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation. In press.
    
25. Milano CA, Dolber PC, Rockman HA, et al. Myocardial expression of a constitutively active _1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy. Proc Natl Acad Sci U S A. 1994;91:10109–10113.[Abstract/Free Full Text]
    
26. Rockman HA, Chien KR, Choi D-J, et al. Expression of a ß-adrenergic receptor kinase I inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci U S A. 1998;95:7000–7005.[Abstract/Free Full Text]
    
27. Freeman K, Iaccarino G, Bohlmeyer T, et al. Overexpression of the ß₂ adrenergic receptor accelerates heart failure in hypertrophic cardiomyopathy mice. Circulation. 2000;100(suppl I):I-493.
    
28. Eichhorn EJ, Bristow MR. Medical therapy can improve the biologic properties of the chronically failing heart: a new era in the treatment of heart failure. Circulation. 1996;94:2285–2296.[Abstract/Free Full Text]
    
29. Bristow MR. Changes in myocardial and vascular receptors in heart failure. J Am Coll Cardiol. 1993;22(suppl A):61A–71A.
    
30. Bristow MR, Port JD, Kelly RA. Treatment of heart failure: pharmacologic methods. In: Braunwald Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. In press.
    

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