Commentary

Do β-blockers improve morbidity and mortality in patients with heart failure? 3 large trials have shown the benefits of bisoprolol,¹ carvedilol,² and metoprolol³ on morbidity and mortality among patients with NYHA class II or III heart failure, and have had important implications for how patients with mild-to-moderate heart failure are treated. On the basis of these studies, it has now become standard practice to treat such patients with one of these β-blockers. Whether patients with severe heart failure would also benefit from β-blockade has been unanswered. Patients with severe heart failure have the highest sympathetic outflow and theoretically may benefit most from β-blockade. These patients also have the least inotropic reserve and, thus, are most susceptible to decompensation when treated with β-blockade.

These 2 studies (BEST and COPERNICUS) have provided important data that allow us to assess the benefit of β-blockers in patients with severe heart failure. What is certain is that the benefit of β-blockers is largely dependent on the type of patients who receive them. Unfortunately, assessing the value of β-blockers in patients with severe heart failure is problematic. First, measuring and comparing severity is difficult. The NYHA functional classification is a useful guide, but, as pointed out by Braunwald,⁴ it is subjective and inherently imprecise. An alternative way of comparing the severity of heart failure among patients in different trials is to use placebo mortality rates. Subsets of patients in whom the annual placebo mortality rate is high (eg, 20%) are said to have very severe heart failure. This measure also has its limitations because it does not reflect only mortality caused by heart failure and it does not include any measure of severity of symptoms, frequency of hospitalisation, or quality of life.

We are left with 2 well-designed studies, only 1 of which shows a substantial benefit of β-blocker treatment on mortality in patients with severe heart failure. These differing conclusions may have resulted from study populations that were different or from differences in the pharmacological actions of bucindolol and carvedilol. The benefits of carvedilol may be related to its unique α-adrenergic, antioxidant, or antiendothelin effects.

The positive results from the BEST study—namely, the decrease in mortality specific to cardiovascular causes and the decrease in overall mortality among non-black patients—should not be ignored. The results of previous studies and these 2 new investigations, coupled with our increasing understanding of the role of the adrenergic nervous system in heart failure, can be used to derive a rational set of recommendations. First, patients with mild or moderate heart failure should receive β-blockers. As heart failure becomes more severe in these same patients, β-blockade must strike a delicate balance so it is forceful enough to block the adverse effects of the sympathetic nervous system and yet gentle enough to maintain any positive role this system plays in survival. For this reason, patients receiving β-blockers who develop progressive heart failure must be closely monitored. When patients with mild-to-moderate chronic heart failure who are treated with other β-blockers progress to severe heart failure, switching them to carvedilol should be considered. Additional evidence is needed before more widespread use of β-blockers in patients with severe heart failure can be recommended. Because the type of β-blocker may be very important, a trial directly comparing bucindolol and carvedilol would provide valuable evidence.