P-Blockers have a profound ability to change the clinical course of the heart failure syndrome. Multicenter trials vs placebo have consistently shown highly significant decreases in the incidence of hospitalization, cardiovascular events, exacerbations of heart failure, and indications for heart transplantation. A recent metaanalysis showed a hospitalization rate for heart failure of 9.6% on P-blockers vs 17% on placebo (-41%; 95% confidence interval: 26% to 52%; P<0.001).
Combined end points have also been analyzed. In the Cardiac Insufficiency Bisoprolol Study II (CIBIS II), bisoprolol decreased clinical progression, defined as death or hospitalization, by 21%. Similarly, in the Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise (PRECISE), the Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA), and the Australia-New Zealand trials, the decreases in the combined end point of death and hospitalization in the patients assigned to carvedilol vs placebo were 39%, 49%, and 26%, respectively. In the mild heart failure study group of the US Carvedilol Heart Failure Trials Program, carvedilol decreased clinical progression, defined as death, hospitalization for heart failure, or a sustained increase in background medication, by 48%. In patients with severe heart failure in the CarvedilOl ProspEctive RaNdomlzed Cumulative Survival study group (COPERNICUS), carvedilol reduced the combined risk of death or hospitalization by 24%.
The impact of P-blockade on mortality in heart failure was initially disputed. The Metoprolol in Dilated Cardiomyopathy (MDC) trial and CIBIS I yielded no significant mortality findings despite the overall improvement in left ventricular function and clinical course. This apparent discrepancy reflected the methodological limitations of these studies: too few randomized patients, a low incidence of end point events, and a relatively short follow-up. The recently concluded Randomized Evaluation of Strategies fOr Left Ventricular Dysfunction (RESOLVD) followed patients for only 6 months after randomization to controlled-release metoprolol or placebo. The P-blocker was associated with lower mortality but a higher hospitalization rate for heart failure, probably reflecting hospitalization during the metoprolol initiation phase.
Large studies have yielded different results. The combined survival data in 1094 patients enrolled in US Carvedilol Heart Failure Trials Program showed significantly lower mortality in patients randomized to carvedilol vs placebo, with a risk reduction of 65% during a median follow-up of 6.5 months. This effect was independent of age, gender, cause of heart failure, left ventricular ejection fraction, exercise tolerance, heart rate, or systolic blood pressure. If we consider the individual trials that were combined in the program, the reduction in mortality was highly significant in one trial, slightly significant in another, and nonsignificant in the other two. However, death was not a primary end point in these studies, and the short follow-up may have influenced the magnitude-of the results. Thus although annual mortality in the placebo group was similar to that of the enalapril-treated patients in previous trials, the number of deaths was small, with 22 deaths among the 696 patients randomized to carvedilol and 31 deaths among the 398 randomized to placebo.
In the more recent CIBIS II, death was a primary end point: 2647 patients with NYHA class III to IV heart failure were randomized to bisoprolol or placebo and followed for a mean 1.3 years. All-cause mortality decreased significantly vs placebo in the patients on the p-blocker, with a risk reduction of 34%. This effect was achieved mainly by a 44% decrease in the incidence of sudden death, although the decrease in the incidence of death due to pump failure or myocardial infarction was not significant, despite the lower hospitalization rate. MERIT-HF randomized 3991 patients with moderate to severe heart failure to metoprolol titrated up to 200 mg per day or placebo. This trial was stopped early in October 1998 because of the significant 34% reduction in all-cause mortality on metoprolol, associated with decreases of 38% in cardiovascular mortality, 41% in sudden deaths, and 49% in deaths due to progressive heart failure.
The (i-Blocker Evaluation Survival Trial (BEST) has randomized some 2800 patients with NYHA class III or IV heart failure to placebo or bucindolol on top of their conventional therapy and will be following them for a minimum of 18 months. The primary end point is allcause mortality; the secondary end points are cardiovascular death, death from worsening heart failure, sudden death, quality of life, hospitalization and costs, left ventricular ejection fraction after 3 and 12 months, and myocardial infarction. The sample size was calculated to detect a 25% decrease in annual mortality. This study should improve our knowledge about the effects of 13-blockers on the clinical course of heart failure.
Intrinsic sympathomimetic activity
(3-Blockers devoid of intrinsic sympathomimetic activity reduce mortality after myocardial infarction, an effect not seen with any intrinsic sympathomimetic except acebutolol, possibly because these agents have less effect on heart rate and the ventricular fibrillation threshold. Studies with xamoterol, a Pj -selective blocker with 45% intrinsic sympathomimetic activity, showed improvements in hemodynamics, exercise tolerance, and symptoms in mild-to-moderate heart failure but an increase in mortality in moderate to severe heart failure. Thus an intrinsic sympathomimetic P-blocker is best avoided in moderate-to-severe heart failure.
In the failing heart, P2-adrenoceptors may comprise up to 40% of the adrenoceptor pool due to Pj-receptor downregulation. On the other hand, they may mediate all the cyclic AMP-dependent effects of sympathetic stimulation generally ascribed only to Pr adrenoceptors.
Unlike in other species, human PT-adrenoceptors are more tightly coupled to the Gs/cyclic AMP pathway than Pj-adrenoceptors, and the administration of selective Pj-blockers may further enhance cardiac sensitivity to P2-adrenergic stimulation.
Moreover, presynaptic P2-receptors facilitate norepinephrine release. Thus, the nonselective agents which block presynaptic P2-receptors may decrease cardiac norepinephrine release and plasma norepinephrine levels. Metoprolol, on the other hand, does not change cardiac norepinephrine release, and may even increase it, acutely, possibly due to the reflex increase in cardiac sympathetic drive secondary to the negative inotro-pism of P-blockade.
P2-Adrenoceptors may also be responsible for the arrhythmogenic effects of sympathetic stimulation. This has been shown in dogs with a healed anterior myocardial infarction in whom increased susceptibility to ventricular fibrillation was selectively mediated by P2-adrenoceptor stimulation through a cyclic AMP-independent pathway. p2-adrenoceptors might also indirectly facilitate malignant arrhythmia via hypokalemia secondary to the p2-mediated shift of potassium into the cells. Thus, nonselective agents have decreased the incidence of sudden death in subjects with or without a history of heart failure, while results with selective agents have been less consistent, with a reduction in the incidence of sudden death in some studies but not in others.
Carvedilol has also antiproliferative and antioxidant activities that may yield additional protection against new ischemic events and oxidative stress. As the disease progresses, reactive oxygen species induce lipid peroxidation in myocytes and trigger cell death. The multiple events associated with oxidative stress are also observed in the endothelium, a cardiovascular component which is particularly vulnerable in heart failure. Oxidative stress-mediated apoptosis is a major contributor to endothelial dysfunction.
p-blocker; pathophysiology; neurohumoral activation; symptomatic effect; left ventricular function; functional status; side effect