Section III: Neurohormonal strategies in heart failure D. New data from HF outcome trials: Focus on ß-blockade Survival studies with ß-blockers in HF Content Points: Three major randomized, placebo-controlled trials have studied the effect on survival of ß-blockade added to baseline therapy with ACE inhibition and diuretics in patients with HF. CIBIS-II enrolled 2647 patients with New York Heart Association (NYHA) class III-IV heart failure who were treated with bisoprolol, a ß1-adrenergic receptor blocker.39 MERIT-HF enrolled 3991 patients with NYHA class II-IV heart failure who received treatment with ER metoprolol succinate, a ß1-adrenergic receptor blocker.35 The Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS) enrolled 2289 patients with NYHA class III and IV heart failure who received treatment with carvedilol, a ß1-,ß2-, α1-adrenergic receptor blocker.40 The individual and pooled results of these studies show that ß-blockade consistently improves survival rates in patients with NYHA class II to class IV heart failure.

CIBIS II: Survival results Content Points: This slide shows the survival results of CIBIS II, a randomized, placebo-controlled trial of the effect of ß-blockade with bisoprolol in patients with NYHA class III and IV heart failure. CIBIS-II involved 2647 patients with a LV ejection fraction of <35%.39 The rate of the primary outcome of total mortality was 17.3% in the placebo group and 11.8% in the bisoprolol group, which reflects a 34% relative risk reduction with bisoprolol. Hospitalizations for all causes, cardiovascular death, and the combined outcome of cardiovascular hospitalization and death were also significantly less common in patients treated with bisoprolol.

COPERNICUS: Survival results Content Points: COPERNICUS was a large-scale, prospective, randomized, double-blind, placebo-controlled trial of the effect of the ß-blocker carvedilol on the survival of 2289 patients with severe (class III or IV) heart failure.40 Patients had symptoms at rest or with minimal exertion despite optimal therapy with ACE inhibitors and diuretics. The main result of COPERNICUS was death due to all causes. The cumulative rate of death at 1 year was 18.5% in the placebo group and 11.4% in the carvedilol group, reflecting a 35% relative risk reduction. There was also a significant 24% decrease in the combined risk of death or hospitalization in the carvedilol group.

MERIT-HF: Primary outcomes Content Points: MERIT-HF enrolled 3991 patients with clinically stable NYHA functional class II to IV heart failure with LV ejection fractions <40%.35 Once daily ER metoprolol succinate added to optimum standard treatment (primarily ACE inhibitors and diuretics) reduced all cause mortality by 34%. The cumulative rate of death per patient-year of follow-up was 11.0% in the placebo group and 7.2% in the ER metoprolol succinate group. The incidence of total mortality and all-cause hospitalizations was 19% lower in the ER metoprolol succinate group than in the placebo group.41

MERIT-HF: Clinical outcomes with ß-blockade Content Points: In MERIT-HF, the relative risk of sudden death was decreased by 41% in the ER metoprolol succinate group; the risk of HF mortality was decreased by 49%. In addition to improving survival in patients with symptomatic HF, ER metoprolol succinate reduced the number of hospitalizations due to worsening HF by 30%. The number of days that patients were hospitalized for worsening HF was reduced by 36% in the ER metoprolol succinate group.

Effect of ß-blockade on survival in severe HF: Pooled trial results Content Points: The benefit of ß-blockade on survival in patients with severe HF (NYHA functional class III and IV and ejection fractions of <0.25) was similar in three major HF survival trials utilizing carvedilol, bisoprolol, and ER metoprolol succinate.42 The COPERNICUS trial enrolled 2289 patients with symptoms at rest or with minimal exertion despite optimal therapy with ACE inhibitors and diuretic therapy.40 Mean ejection fraction was 0.20. Mortality was reduced by 35% in the carvedilol group. A CIBIS II study subgroup analysis of patients with a mean ejection fraction of 0.20 (n = 752) revealed a similar mortality benefit in the bisoprolol group as that observed in the COPERNICUS trial.39 In the MERIT-HF trial, a subgroup with severe HF (n = 795) with a mean ejection fraction of 0.19 had a 39% reduction in total mortality with ER metoprolol succinate.42 The combined experience of all three studies, which included more than 3800 patients with severe HF, reveals a highly significant benefit with b-blockade in reduction in total mortality.42

MERIT-HF: Effect of ß-blockade in patients with severe HF Content Points: A MERIT-HF study subgroup analysis examined the effect of ER metoprolol succinate in patients with severe HF.42 In the cohort of 795 patients with NYHA functional class III/IV heart failure and ejection fractions of <0.25, 399 patients were randomized to ER metoprolol succinate and 396 patients were randomized to placebo. Patients with severe HF were slightly older, had lower ejection fractions, and were more likely to have HF symptoms. The beneficial effects of ß-blockade in patients with severe HF were similar to those observed in the total MERIT-HF trial. Outcomes compared with placebo included the following. – 34% reduction in death from all causes – 45% reduction in sudden death – 55% reduction in death due to worsening HF – 44% reduction in all deaths and hospitalizations for worsening HF – 45% reduction in hospitalizations for worsening HF – 31% fewer patients discontinued the study medication.

Dosage: CIBIS-II, MERIT-HF, COPERNICUS Content Points: ß-Blockade improves survival, reduces hospitalizations for HF, and improves LV function when given over a long period of time to patients who are also receiving standard therapy with diuretics and ACE inhibitors, with or without digoxin. Concern that ß-blockade might lead to worsening HF makes many physicians reluctant to use these agents.42 Clinicians have also questioned whether all patients need to reach the maximum ß-blocker dose to receive benefit.43 In the recent HF trials (CIBIS-II, MERIT-HF, and COPERNICUS), ß-blockade was initiated at a very low dose and titrated very slowly to a defined maximum target dose, or highest tolerated dose.35,39,40 Doses were modified according to protocol guidelines. Because sicker patients need to be monitored carefully, titration began with lower doses and proceeded cautiously in patients with more severe HF. Doses were modified according to the physician’s judgment, based on frequency of increased symptoms during titration, identification of patients at risk, and the time course of any possible deterioration. Most patients reached the maximum target dose, although many patients were titrated to the maximum tolerated dose.

MERIT-HF: Patient response during titration Content Points: Gottlieb and coworkers studied the response of patients during the first 90 days of MERIT-HF to investigate potential evidence of ß-blockade–related clinical deterioration.43 Their analysis demonstrates the tolerability of ER metoprolol succinate in patients with HF. The initial dose was 25 mg/day in class II patients and 12.5 mg/day in class III and IV patients. Titration was at the investigators’ discretion. Most patients reached the target dose. For those who didn’t, low heart rate was the most common reason. Most patients initiated at the 25-mg/day dose were on the targeted 200 mg/day by week 8. For those who were not, the chief reason was low heart rate (9.1% of the metoprolol group vs 2.4% in the placebo group). There was no difference in the incidence of delayed titration for low blood pressure (3.9% vs 3.8%). Of the metoprolol group, 5.2% reported increasing symptoms of HF compared with 4.6% of the placebo group. Most patients initiated at the 12.5-mg/day dose were titrated successfully to 100 or 200 mg/day. Again, low heart rate was the chief limiting factor for delayed titration: 11.3% of patients taking ß-blocker therapy versus 3.3% taking placebo were not on the target dose at 3 months. Other reasons for not being on the target dose at 3 months were low BP (metoprolol 7.6% vs placebo 5.9%) and HF symptoms (metoprolol 8.7% vs placebo 5.4%). These results indicate that when carefully titrated, ER metoprolol succinate can be used safely in the large majority of patients with stable, mild-to-moderate HF.

MERIT-HF: Deaths and hospitalizations during titration phase Content Points: During the first 90 days, there were no differences in early mortality between groups that received placebo and study medication in MERIT-HF.43 The risk of any deterioration caused by ß-blockade appears greatest during the first 4 to 8 weeks of drug-treatment initiation. By 8 weeks, mortality and hospitalization rates started to trend in favor of ß-blockade for all patients randomized as well as for those with more severe heart failure. Again, these results provide reassurance that ß-blockers can be given safely to the general population of patients with stable, mild-to-moderate HF. However, improvement does not occur immediately and the present study supports the need to watch patients carefully during titration.

MERIT-HF: Tolerability of ß-blockade is similar to placebo Content Points: This analysis of MERIT-HF demonstrates that ER metoprolol succinate is well tolerated in patients with HF.43 During the first 90 days after titration, a similar number of patients with class III or IV heart failure discontinued treatment (5.9% vs 8.1%, adjusted P = NS). From day 90 until the end of the study, more patients discontinued study medicine in the placebo group. There were no significant excesses of discontinuation in the metoprolol group at the end of the study for any BP or heart rate subgroup.

MERIT-HF: Achieved ß-blocker dose vs outcomes Content Points: Clinicians have questioned whether all patients actually need to reach the maximum ß-blocker dose to receive benefit from treatment. An analysis of MERIT-HF data shows that approximately one third of the patients treated with ER metoprolol succinate achieved a dose of <100 mg once daily, falling into the low-dose group.44 Compared with patients in the high-dose group (>100 mg once daily), patients in the low-dose group were slightly older, more likely to have presented with class III or IV heart failure (67% vs 53%), and more likely to have a history of MI. The data show that despite being at higher risk, patients who do not tolerate the maximum target dose still derive benefit from ß-blocker therapy.44 The risk reduction in mortality was the same in the low- and high-dose groups (38%). There was a 50% reduction in sudden deaths in the low-dose group compared with 41% in the high-dose group. Heart rate at baseline was similar between the low- and high-dose groups (82 and 90 beats per minute, respectively). Interestingly, heart rate was reduced after three months to 67 beats per minute for both low-dose and high-dose groups. This indicates a similar level of ß-blockade, despite large dosing differences. The data do not imply that the maximum target dose of 200 mg once daily should be reduced for patients with HF. Rather, the results support the concept of tailoring dose titration guided by response and patient tolerability. Prognosis clearly seems to be improved even for patients who do not achieve the maximum target dose.

Val-HeFT: ARB vs usual therapy in HF—Study overview Content Points: Actions of angiotensin II may contribute to the progression of HF despite treatment with currently recommended drugs. Therefore the long-term effects of adding the angiotensin-receptor blocker valsartan to standard therapy for HF were investigated in the Valsartan Heart Failure Trial (Val-HeFT).45 A total of 5010 patients with HF were randomly assigned to receive valsartan 160 mg or placebo twice daily. At baseline, most patients were taking standard therapy, including ACE inhibitors (93%), diuretics (86%), ß-blockers (36%), and digoxin (67%). The primary outcomes were mortality and the combined end point of mortality and morbidity, defined as the incidence of cardiac arrest with resuscitation, hospitalization for HF, or receipt of intravenous inotropic or vasodilator therapy for at least 4 hours.

Val-HeFT: Morbidity and mortality in subgroups Content Points: Overall mortality was similar in the valsartan and placebo groups after 2 years of follow-up. The combined outcome of all-cause morbidity and mortality was 13.2% lower in the group receiving valsartan, predominantly because of fewer patients hospitalized for HF.45 In a post hoc analysis of combined morbidity and mortality in subgroups defined according to baseline treatment with ACE inhibitors or ß-blockers, valsartan had a favorable effect in patients receiving either an ACE inhibitor or a ß-blocker, but an unfavorable effect in patients receiving both types of drugs. Within the 30% of the population that was being treated with both an ACE inhibitor and a b-blocker at baseline, there was a significant adverse effect of valsartan on mortality and a nearly significant adverse effect on morbidity. The post hoc observation of an adverse effect on mortality and morbidity in the subgroup receiving valsartan plus ACE inhibitor plus a ß-blocker raises concern about the potential safety of this specific combination. In patients with symptomatic LV dysfunction, angiotensin-receptor blockade is suggested for patients who are being treated with digitalis, diuretics, plus a ß-blocker and who cannot tolerate an ACE inhibitor.