However, critics of the program were equally vehement. There was no question about the findings of the US Carvedilol program. Lives had been saved. But, what did this collection of studies of just over 1, patients imply about the population of millions of patients with heart failure? Sample extrapolation is a dangerous process, and discipline, not hope should govern what sample results should be extended from the sample to the population.
Samples are replete with "facts'; most of these facts apply only to the sample and not to the entire population. Healthcare has seen these kinds of failures of generalization before. Experience e. Additionally, pre-specification of the anticipated analysis in the protocol of a trial has been an accepted standard among clinical trial workers [18] and certainly must be included in a manuscript describing that trial's results.
In addition, the non-reporting of non-significant endpoints in clinical trials has been criticized [19]. Each of these principles was clearly violated in the manuscript published in The New England Journal of Medicine. The scientific community expects, and clinical trial workers require that analyses be provided for all prospectively stated endpoints.
The fact that the results of a program claiming major benefit did not specifically define and report the analysis of the primary endpoint is a serious deficiency in the manuscript that purports to describe the effects of therapy.
The mortality findings for the US Carvedilol were a surprise finding. They were an intriguing result, but the cardiology community was reminded that surprise "good findings are not uncommonly followed by surprise bad findings as the vesnarinone experience demonstrated.
Vesnarinone was a positive inotropic agent that increased the pumping ability of the heart, holding out initial promise for improving the treatment of CHF.
Effects of vesnarinone on morbidity and mortality in patients with heart failure. Hemodynamic improvement after oral hydralazine in left ventricular failure: a comparison with nitroprusside infusion in 16 patients. Ann Intern Med. Beta blockade after myocardial infarction: systematic review and meta regression analysis. Is beta-blockage useful in heart failure patients with atrial fibrillation? An analysis of data from two previously completed prospective trials.
Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Effects of increasing maintenance dose of digoxin on left ventricular function and neurohormones in patients with chronic heart failure treated with diuretics and angiotensin-converting enzyme inhibitors. Effects of nebivolol in elderly heart failure patients with or without systolic left ventricular dysfunction: results of the SENIORS echocardiographic substudy.
Cardiomyocyte death and the ageing and failing heart. Exp Physiol. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Cardiopulmonary receptor modulation of plasma rennin activity in normotensive and hypertensive subjects.
Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. Congestive cardiac failure. Central role of the arterial blood pressure.
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Adverse consequences of high sympathetic nervous activity in the failing human heart. Clinical events leading to the progression of heart failure: insights from a national database of hospital discharges.
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Baseline predictors of tolerability to carvedilol in patients with chronic heart failure. Lack of evidence for peripheral alpha 1 - adrenoceptor blockade during long-term treatment of heart failure with carvedilol. Metabolic effects of beta-adrenoceptor antagonists with special emphasis on carvedilol. Am J Cardiovasc Drugs. Titration of carvedilol in elderly heart failure patients.
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Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin converting enzyme inhibitors.
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J Appl Physiol. Forgot your user name or password? Search for this keyword. Advanced search. Log in via Institution. Email alerts. Article Text. Article menu. Statistics from Altmetric. View this table: View inline View popup. Heart 79 suppl 2 : S29 — S Circulation 90 : — Lancet : — N Engl J Med : — Fundam Clin Pharmacol 11 : — Lancet : 9 — Circulation 99 : — Int J Cardiol 66 : 1 — Am J Cardiol 80 : J54 — J Packer M Effects of beta-adrenergic blockade on survival in patients with chronic heart failure.
Am J Cardiol 80 suppl : 46 — 54L. In the COMET trial no evaluation of the relative beta1-blockade of the two beta-blockers used was performed. The only information collected was the resting HR. A significant albeit small difference in the reduction of HR obtained was observed in the carvedilol arm, no difference in HR was seen beyond the f irst year of observation Figure 2 Packer As carvedilol exert different adrenoceptor blocking properties besides its antioxidative effect, it is of interest to know which mechanism gives carvedilol its favorable effect in superiority to metoprolol on mortality.
The alpha-blocking properties have been tested. Doxazosin, a selective alpha1-blocker, versus placebo was tested in 73 patients with CHF DiBianco et al Both investigators and patients assessment of symptomatic change was improved after treatment with doxazosin.
When doxazosin was added to the beta1-blocker metoprolol in patients with heart failure, no improvement in hemodynamic measurements were seen, when compared with patients only treated with metoprolol Kukin et al Even though carvedilol does not have the same pharmacokinetic properties as the combination of doxazosin and metoprolol, this study indicates that the beneficial effect seen with carvedilol is less likely to be caused solely by the alpha1-blocking properties of carvedilol.
The beta2-blocking effect affects the pre-synaptic release of NE, which reduces the amount of NE that can stimulate the beta1-receptors. Sub-studies from the COMET trial showed a decreased number of new-onset diabetes in the carvedilol arm, this sub-study is published as an abstract Torp-Pedersen, Cleland, et al This was in contrast to earlier findings from beta-blocker trials showing an increased number of new-onset diabetes when treated with traditional beta1-receptor blockers Dahlof et al That carvedilol might have a beneficial effects on the glucose metabolism was already shown in a study by Jacob and colleagues In this study metoprolol was compared with carvedilol in a group of patients with hypertension.
An improvement in insulin sensitivity was seen among those treated with carvedilol. Guigliano also showed improved insulin sensitivity when treated with carvedilol. The changes were shown by making an insulin clamp testing.
Recently a large randomized trial in which the two beta-blockers were compared concerning their abilities in affecting the metabolic control in patients with diabetes and hypertension was published Bakris et al An increase in glycosylated hemoglobin was seen in the metoprolol arm, whereas no change was seen in the carvedilol arm.
Improvement in insulin sensitivity was seen in the carvedilol group and no change was seen among the patients treated with metoprolol. In both trials the IR metoprolol was used.
The beneficial role of carvedilol is speculated to be caused by its alpha-blocking properties and thereby causing vasodilation. Peripheral vasodilation facilitates glucose uptake in skeletal muscle and thereby improves insulin sensitivity Smith and Warren Other anti-hypertensives that also increase peripheral blood-flow have the same benef icial effect on insulin sensitivity Lind and Lithell Whether the increased peripheral blood-flow is solely to explain the benefit of carvedilol on insulin sensitivity is doubtful.
The combined effect of carvedilol, including its antioxidative properties, is more likely to be the explanation. The perspective of COMET can be divided in 3 parts: the importance of beta-1 inhibition, the importance of other effects of carvedilol and the clinical consequence.
Three beta-blockers with beta-1 activity have been shown to reduce mortality in CHF. One interpretation of COMET is that a more effective inhibition by carvedilol, either because of a higher dose being given or because carvedilol has a higher affinity for the beta-1 receptor, explained the marked difference.
Thus effective beta-1 inhibition with as high a dose as possible is clearly important for the treatment of CHF. Therefore, it is likely that other effects of carvedilol compared with metoprolol are important for the treatment of heart failure. Further research is necessary to clarify whether beta-2 inhibition, alpha-1 inhibition, antioxidative properties of, inhibition of endothelin-1biosynthesis, or yet another effect is beneficial Table 1.
The possible effect of the adrenoreceptors in the progression of heart failure. Beta-blockers in heart failure: are pharmacological differences clinically important? Heart Fail Rev, — As for the clinical consequence at this time what remains is a continuing debate. National Center for Biotechnology Information , U. Vasc Health Risk Manag. Author information Copyright and License information Disclaimer. All rights reserved. This article has been cited by other articles in PMC.
Abstract Beta-blockers have been shown to improve survival in patients with chronic heart failure. Keywords: beta-blockers, chronic heart failure, carvedilol. Introduction Heart failure is a growing problem with an increasing number of affected people and with an increasing burden on society Greenberg Beta-blocker treatment in heart failure Beta-blockers have been shown to be of clinical benefit in patients with chronic heart failure Greenberg Open in a separate window.
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