Section III: Neurohormonal strategies in heart failure E. Extending treatment to special populations BEST: Effect of ß-blockade in subgroups with advanced HF Content Points: The Beta-Blocker Evaluation of Survival Trial (BEST) studied the effect of bucindolol on survival in patients with more advanced HF. 46 The study involved a demographically diverse group of patients (N = 2708) with NYHA class III (92%) or IV (8%) heart failure and an LV ejection fraction of <35%. Patients were randomly assigned to treatment with either bucindolol or placebo. The primary outcome was death from any cause. Bucindolol did not have a significant overall survival benefit. The secondary outcomes of death from cardiovascular causes and hospitalization because of worsening HF were significantly reduced by bucindolol. One possibility for the difference between the reduction in mortality found in BEST compared with MERIT-HF and CIBIS-II is that the populations were different. The BEST study enrolled a substantial number of women, and the results did not demonstrate a sex-related effect of bucindolol. The results also suggested that bucindolol may be beneficial in nonblack patients, but not in black patients. The apparent difference in mortality outcomes in BEST compared with other ß-blocker HF survival studies may derive from the unique pharmacologic properties of bucindolol. Bucindolol, like carvedilol, is a nonselective ß-blocker with vasodilatory properties. Because of its strong ß2-adrenergic blocking properties it also blocks the release of norepinephrine, and thus exerts a profound sympatholytic response, which may limit its efficacy.47 Findings of the study raised questions about the efficacy of ß-blockade in African Americans. The next slide discusses findings in other ß-blocker HF studies that examined the impact of race on outcomes.

ß-Blocker HF studies: Effect of race Content Points: In the US Carvedilol HF trial, black and nonblack patients with class II to IV heart failure who were treated with carvedilol had similar reductions in death and worsening HF and similar improvements in NYHA functional class and LV ejection fraction.48 In COPERNICUS, race did not affect the benefit of carvedilol on major clinical events with severe HF (symptoms at rest or on minimal exertion). Treatment with carvedilol led to similar reductions in death and hospitalizations for worsening HF in black (n = 121) and nonblack (n = 2168) patients.49 The MERIT-HF trial included 208 black patients among the total group of 3993 patients. Among patients who were randomized to treatment with ER metoprolol succinate, black and nonblack patients had similar reductions in all deaths or hospitalizations for any cause.50 In a small study that involved 54 patients with NYHA class II to IV HF, Freudenberger and colleagues reported that patients who took metoprolol had similar results when patients were divided along racial lines.51 The groups had similar improvements in LV ejection fraction, hemodynamic parameters, and exercise tolerance. Therefore, these analyses of recent b-blocker HF trials do not support a lack in benefit of ß-blockers in black patients with HF. Long-term ß-blockade lessened symptoms and reduced the risk of death and hospitalizations regardless of race.

US Carvedilol Trials: Survival without hospitalization among black vs nonblack patients Content Points: In the US Carvedilol HF Trials Program, 217 black and 877 nonblack patients in NYHA class II, III, or IV heart failure and with an LV ejection fraction of <35% were randomly assigned to receive carvedilol or placebo for up to 15 months.48 The effect of carvedilol on outcomes was retrospectively compared in both racial groups. Carvedilol reduced the risk of death from any cause or hospitalization for worsening HF by 48% in black patients and by 30% in nonblack patients. As a single outcome, carvedilol reduced the risk of worsening HF by 54% in black patients and by 51% in nonblack patients. Overall, the benefit of carvedilol was of similar magnitude in both black and nonblack patients.

Response to ß-blockade in HF: Effect vs race Content Points: Freudenberger et al studied the effect of race on response to b-blockade with metoprolol in 54 patients with dilated cardiomyopathy (NYHA class II to IV).51 In a 3-month follow-up, both racial groups demonstrated similar beneficial effects of ß-blocker therapy. Black and nonblack patients had similar improvements in exercise capacity, and in hemodynamic and neurohormonal responses. ß-Blockade resulted in significant and similar improvements in LV stroke volume, LV ejection fraction, maximal oxygen consumption, and exercise capacity.

MERIT-HF: Effect of ß-blockade on hospitalizations in female patients Content Points: Ghali and coworkers did a post hoc analysis of outcomes in the 898 women in MERIT-HF.52 This is the second-largest study to examine gender difference in the treatment of HF and the largest study to include treatment with a ß-blocker. An analysis of hospitalizations among the women in the MERIT-HF study showed that ß-blockade reduced the number of all hospitalization by 19%, cardiovascular hospitalizations by 29%, and hospitalizations for worsening HF by 42%. Among 183 women with severe HF (Class III and IV, ejection fraction <0.25) the group treated with ER metoprolol succinate had 44% fewer hospitalizations for all-causes, 57% fewer hospitalizations for cardiovascular causes, and 72% fewer hospitalizations for increased symptoms of HF compared with the group on standard therapy. These data demonstrate that ß-blockade benefits women with HF as much as men, including women with clinically stable, severe HF.

ß-Blocker HF studies: Effect of treatment on mortality by gender Content Points: Ghali and coworkers also combined the data on women in MERIT-HF (which was not powered to address total survival in women) with the data on women from the CIBIS-II and COPERNICUS trials to study the impact of ß-blockers on total survival in women.52 The pooled data show that the three ß-blockers—ER metoprolol succinate, bisoprolol, and carvedilol—increase total survival in women comparably to the increase in men. Pooling of total mortality data by sex showed similar, statistically significant survival benefits in women as in men (relative risk of 0.69 in women and 0.66 in men).

MERIT-HF: Risk reductions with ß-blockade in the elderly Content Points: Heart failure is the leading cause of death and disability in the elderly.1 This subanalysis of the MERIT-HF trial examined the efficacy and tolerability of b-blockade in older versus younger patients with HF.53 Patients aged >65 years achieved the maximum target dose of 200 mg ER metoprolol succinate less often compared with those aged <65 years (54% vs 71%, respectively), although they tolerated b-blockade as well as younger patients in the study. Survival improved in patients aged <65 and >65 years who were treated with ER metoprolol succinate once daily. There was an impressive reduction in hospital admissions due to worsening HF in both age groups. There were no notable differences in the efficacy and tolerability of ß-blockade between older patients compared with younger patients.

MERIT-HF: Risk reductions in diabetic patients Content Points: A post hoc MERIT-HF subgroup analysis of 984 patients with diabetes shows the benefits of ß-blockade in reduced morbidity and mortality due to HF were similar to benefits patients without diabetes.54 Compared with patients receiving standard HF therapy, those who also received ER metoprolol succinate had reductions of 21% in death from any cause, 15% in deaths or hospitalization for any cause, and 29% in death from any cause or hospitalization for worsening HF (P = 0.007). Many physicians avoid ß-blockers in diabetic patients due to concerns regarding potential adverse effects on diabetes.55 The findings in MERIT-HF add to the evidence that ß-blockers benefit diabetic patients with cardiovascular disease.55

COPERNICUS: Effects of carvedilol in diabetic vs nondiabetic patients with severe HF Content Points: To determine whether physicians’ concerns about prescribing ß-blockers in diabetic patients are justified, the COPERNICUS investigators compared the effects of placebo and carvedilol in 589 diabetic and 1700 nondiabetic patients enrolled in the trial.56 During a mean follow-up of 10 months, carvedilol produced favorable effects on all outcomes that were similar in both diabetic and nondiabetic patients. The study found that neither group had an increase in hyperglycemia or renal dysfunction (not shown on slide). Overall, avoidance of ß-blocker treatment in diabetic patients with HF seems unjustified and deprives these patients of an effective means of reducing the risk of death and hospitalization.

Myths about ß-blockers in HF Content Points: Research has provided data that refute prevalent myths about the use of ß-blockers in patients with HF. Myth: ß-Blockers are difficult to initiate. Fact: Data from the major HF survival trials indicate that ß-blockers can be safely initiated in the majority of patients with mild to moderate HF.35,39,40 The initial dose should be lower in patients with more severe HF than in those with milder disease. Myth: ß-Blockers are difficult to up-titrate to maximal doses. Fact: When carefully titrated, ß-blockers can be given safely to the overwhelming majority of patients with stable, mild-to-moderate HF with minimal side effects or deterioration during the titration phase.43 Even patients who cannot reach the target dose benefit from lower doses of ß-blockers.44 Myth: ß-Blockers should not be used in patients with advanced HF. Fact: Pooled data from COPERNICUS, MERIT-HF, and CIBIS-II that included more than 3800 patients with class III and IV heart failure with LV ejection fractions of <25% demonstrate that ß-blockers reduce mortality significantly in patients with severe HF. Compared with standard therapy, ß-blockade reduces mortality by 34% to 35% in patients with severe HF. Myth: ß-Blockers are not effective in patients with diabetes mellitus. Fact: Data from COPERNICUS and MERIT-HF show that diabetic patients with HF benefit substantially from ß-blockade.54,56 Diabetic and nondiabetic patients with class III and IV heart failure achieve similar benefits from treatment.56 Myth: ß-Blockers are not effective in the African American patient. Fact: Data from major HF trials (eg, US Carvedilol HF Trials, COPERNICUS, and MERIT-HF) indicate that African American and nonAfrican American patients receive similar benefits from ß-blockade.48-50