What Type of β-Blocker Should Be Used to Treat Chronic Heart Failure?
2000; Lippincott Williams & Wilkins; Volume: 102; Issue: 5 Linguagem: Inglês
10.1161/01.cir.102.5.484
ISSN1524-4539
Autores Tópico(s)Receptor Mechanisms and Signaling
ResumoHomeCirculationVol. 102, No. 5What Type of β-Blocker Should Be Used to Treat Chronic Heart Failure? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWhat Type of β-Blocker Should Be Used to Treat Chronic Heart Failure? Michael R. Bristow Michael R. BristowMichael R. Bristow From the Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO 80262 Originally published1 Aug 2000https://doi.org/10.1161/01.CIR.102.5.484Circulation. 2000;102:484–486The success of β-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 β1-adrenergic receptor antagonism or if additional pharmacological properties of some compounds increase the efficacy inherent in all agents that block β1-receptors. The diverse adrenergic receptor activities of β-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 arguments234 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 β1-adrenergic-receptor–selective, "second generation" β-blocker metoprolol with the nonselective β/α-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 carvedilol46 or no difference7 between the 2 agents. Their data5 indicate that compared with metoprolol, carvedilol provides, as expected, a greater degree of β-blockade. Also, as expected and as previously reported in individual clinical trials,89 metoprolol produced a greater improvement in maximal exercise than carvedilol, which is likely related to the lower degree of β-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 β-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 β-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 β-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 β-blockade conferred by each agent using dobutamine dose-response curves.10 In addition to being a potent β1-adrenergic receptor blocking agent with an ≈12-fold higher affinity than metoprolol for β1-receptors, carvedilol at target doses blocks β2- and α1-receptors and mildly lowers cardiac adrenergic drive.14 Carvedilol also has the additional unique property of not up-regulating34 down-regulated β1-adrenergic receptors, as does metoprolol.341112 The result is a "more comprehensive" degree of adrenergic inhibition.1 This explains why in Metra et al's study5 and in previous trials,89131415 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 β-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 improve131416 or are at least not worsened,1718 which is similar to the effects of metoprolol.19On the basis of the "adrenergic hypothesis"22021 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 β-blockers have produced greater improvements in LV function than smaller doses.1518 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 β1,2223 β2,24 and α125 receptor pathways produces a pathological phenotype on a background of normal myocardial structure and function. Although in these models, evidence exists that the β1-receptor pathway is more pathogenic than the β2-receptor pathway,1222324 crosses of the β2-cardiac overexpressor mouse with other genetic models of cardiomyopathy result in an acceleration of myocardial failure and remodeling.2627 Thus, if the general mechanism of action of β-blocker therapy in chronic heart failure is prevention and partial reversal of adrenergically-mediated myocardial dysfunction and remodeling,2128 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 β-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 β1-compared with β2-receptor signaling, the approximate 2:1:1 dominance of β1:β2:α1 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 β1-selective agonist that is ≈20-fold more selective for human β1- versus β2-receptors and 10-fold more selective for β1-receptors versus human myocardial α1-receptors.30 Thus, in the failing human heart, the majority of the adverse biological effects of increased cardiac adrenergic drive is mediated by β1-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, β1-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 β2- and α1-receptor blockade to β1-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 β-blocker to be used in mild to moderate heart failure is still either a second generation, β1-selective compound such as metoprolol or bisoprolol or the third generation, nonselective β/α blocker carvedilol.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.(Circulation. 2000;102:484-486.)FootnotesCorrespondence to Michael R. Bristow, MD, PhD, the Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO 80262. 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Prakash A and Markham A (2000) Metoprolol, Drugs, 10.2165/00003495-200060030-00011, 60:3, (647-678), Online publication date: 1-Sep-2000. August 1, 2000Vol 102, Issue 5 Advertisement Article InformationMetrics Copyright © 2000 by American Heart Associationhttps://doi.org/10.1161/01.CIR.102.5.484 Originally publishedAugust 1, 2000 KeywordsEditorialshemodynamicsreceptors, adrenergic, betaheart failurePDF download Advertisement
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