CASE 1 c Hean T. Ong, FRCP, FACC, FESC; Fei P. Kow, MBBS, MMed Beta-blockers for heart failure: HT Ong Heart Clinic, Penang, Malaysia (Dr. Ong); BBAI Government Health Clinic, Why you should use them more Penang (Dr. Kow) [email protected] Many physicians are afraid to prescribe beta-blockers for patients with heart failure. Yet in most cases, not The authors reported no potential conflict of interest relevant to this article. prescribing them is a mistake. he evidence is clear: Beta-blockers reduce mortality Practice and hospitalization in patients with systolic heart fail- recommendatiOnS Ture.1-3 Yet this class of drugs is underutilized by phy- › Initiate beta-blocker sicians who fear that beta-blocker’s negative inotropic effect therapy in low doses for will lead to worsening heart failure.4 patients with heart fail- Our aim in presenting this review is to counter such con- ure, and increase the dose cerns by detailing the latest evidence. We draw on current gradually until the target research findings to answer questions about beta-blocker dosage is achieved. A selection and dosage and address common misconceptions. › The benefit of beta-blocker therapy for patients with heart failure is propor- Do beta-blockers lower mortality rates tional to the degree of for patients with heart failure? heart rate reduction. A Yes. Three beta-blockers—bisoprolol, carvedilol, and meto- › Consider beta-blocker prolol succinate—have been conclusively shown to reduce therapy for patients with morbidity as well as mortality in patients with systolic heart coexisting chronic obstruc- failure (TABLE 1).1-3,5,6 Here’s a look at the studies: tive pulmonary disease z Bisoprolol. The Cardiac Insufficiency Bisoprolol Study or decompensated heart (CIBIS II), a randomized controlled trial (RCT) involving 2647 failure, although treatment may have to be reduced or patients with New York Heart Association (NYHA) Class III or temporarily withheld. A IV heart failure and an ejection fraction (EF) ≤35%, found that bisoprolol reduced the primary end point of all-cause mor- Strength of recommendation (SOR) tality (hazard ratio [HR]=0.66; 95% confidence interval [CI], A Good-quality patient-oriented 0.54-0.81; P<.0001) compared with placebo. Cardiovascular evidence B Inconsistent or limited-quality mortality rates (HR=0.71; 95% CI, 0.56-0.90; P=.0049) and patient-oriented evidence hospitalization rates (HR=0.80; 95% CI, 0.71-0.91; P=.0006) C Consensus, usual practice, 1 were significantly reduced, as well. opinion, disease-oriented evidence, case series z Carvedilol. In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, an RCT featuring 2289 patients with EF <25%, carvedilol significantly reduced the total death rate (HR=0.65; 95% CI, 0.52-0.81; P=.0014) compared with placebo.2 z Metoprolol succinate. The Metoprolol CR/XL Ran- domized Intervention Trial in Congestive Heart Failure (MERIT-HF), a study of nearly 4000 patients with Class II to IV 472 The Journal of family PracTice | AUGuST 2011 | Vol 60, no 8 Bisoprolol, carvedilol, and metoprolol succinate have been conclusively shown to reduce morbidity as well as mortality in patients with systolic heart failure. Beta-blockers shown blocking the effects of epinephrine and norepinephrine at the receptor sites. heart failure and EF ≤40%, found that meto- for heart failure—and its ability to reduce prolol succinate lowered total mortality or morbidity and mortality in patients with all-cause hospitalization (HR=0.81; 95% CI, heart failure has not been established.8,9 0.73-0.90; P<.001) compared with placebo.3 Thus, metoprolol succinate, but not meto- prolol tartrate, is recommended for heart Carvedilol and metoprolol failure treatment by the American College go head-to-head of Cardiology, American Heart Associa- Although carvedilol and metoprolol have tion, and European Society of Intensive Care been shown to have similar hemodynamic Medicine.10,11 and heart rate effects, the Carvedilol or Meto- prolol European Trial (COMET) found that These agents lack evidence of efficacy carvedilol is superior in extending survival. Not all beta-blockers have therapeutic value More than 3000 patients with Class II to IV for patients with heart failure—or evidence to heart failure and an EF <35% were random- support them. ized to carvedilol (target dose 25 mg bid) or z Bucindolol. The Beta-blocker Evalu- metoprolol tartrate (target dose 50 mg bid). ation of Survival Trial (BEST), a trial of 2708 After 58 months, total mortality was signifi- patients with Class III or IV heart failure and cantly lower in the carvedilol arm (HR=0.83; an EF ≤35%, found no difference in total 95% CI, 0.74-0.93; P=.0017).7 mortality between bucindolol and placebo.5 i ma z Which metoprolol formulation? While As a result, the drug did not receive FDA G e © K RCTs have found that metoprolol tartrate has approval.12 The FDA has since designated o S a favorable effect on EF and hemodynamic the investigation of bucindolol (trade name T udio data, it is not approved by the US Food and Gencaro) for the reduction of cardiovascular S Drug Administration (FDA) as a treatment hospitalizations and mortality of heart failure JfPonline.com Vol 60, no 8 | AUGuST 2011 | The Journal of family PracTice 473 TABLE 1 Beta-blockers for heart failure patients: What the studies show mean rr; 95% ci; Trial Study group (n) follow-up agent tested Primary end point P value BeST5 class iii-iV hf, 2 y Bucindolol all-cause death 0.90; 0.78-1.02; ef ≤35% (2708) .13 ciBiS ii1 class iii-iV hf, 1.3 y Bisoprolol all-cause death 0.66; 0.54-0.81; ef ≤35% (2647) <.0001 coPernicuS2 hf symptoms, 10.4 mo carvedilol all-cause death 0.65; 0.52-0.81; ef ≤25% (2289) .0014 meriT-hf3 class ii-iV hf, 1 y metoprolol composite* 0.81; 0.73-0.90; ef ≤40% (3991) succinate <.001 SeniorS6 age >70 y and 21 mo nebivolol all-cause death and 0.86; 0.74-0.99; hospitalization for hf cVd hospitalization .039 or ef ≤35% (2128) *all-cause mortality and all-cause hospitalization. BeST, Beta-blocker evaluation of Survival Trial; ci, confidence interval; ciBiS ii, cardiac insufficiency Bisoprolol Study; coPernicuS, carvedilol Prospec- tive randomized cumulative Survival; cVd, cardiovascular disease; ef, ejection fraction; hf, heart failure; meriT-hf, metoprolol cr/Xl randomized intervention Trial in congestive heart failure; rr, relative risk; SeniorS, Study of the effects of nebivolol intervention on outcomes and rehospitalisa- tion in Seniors with heart failure. patients with a particular genotype as a Fast degree of heart rate reduction, so it is impor- Track development program.13 tant to find the highest tolerable dose.16,17 The z nebivolol. The Study of the Effects of COMET study detailed earlier sparked consid- Nebivolol Intervention on Outcomes and erable controversy, with some observers con- Rehospitalisation in Seniors with Heart Fail- tending that the dose of metoprolol used was ure (SENIORS) randomized 2128 patients too small to adequately lower the heart rate.18,19 older than 70 years with prior hospitalization A subsequent study, the Systolic Heart for heart failure or an EF ≤35% to nebivolol Failure Treatment with the I(f) Inhibitor (1.25-10 mg/d) or placebo. Nebivolol (which Ivabradine Trial (SHIFT), highlights the im- is not approved for the treatment of heart fail- portance of rate reduction in heart failure ure in the United States) reduced the com- outcomes. In this placebo-controlled trial of posite end point of all-cause mortality and 6558 patients with EF ≤35%, treatment with cardiovascular hospitalization (HR=0.86; the heart rate-reducing agent ivabradine 95% CI, 0.74-0.99; P=.039), but did not reduce reduced cardiovascular death and hospital- the total mortality rate.6 ization from heart failure (HR=0.82; 95% CI, z Atenolol. Some retrospective analyses 0.75-0.90; P<.0001) compared with placebo.20 have suggested that heart failure patients do A subsequent analysis showed that the pri- as well on atenolol as patients taking meto- mary outcome increased by 16% for every prolol or carvedilol.14,15 Because no RCTs have 5 beats-per-minute (BPM) increase.21 established the efficacy of atenolol, however, it is not recommended for the treatment of Start low, go slow heart failure. When initiating and titrating beta-blockers, the major RCTs clearly illustrate the im- portance of the dictum, “Start low, go slow” is the dose sufficient to reduce (TABLE 2).1-3 heart rate? In CIBIS II, patients were started on bi- The benefit of beta-blocker therapy for -pa soprolol at a dose of 1.25 mg/d. After a week, tients with heart failure is proportional to the the dosage was increased by 1.25 mg. Titration 474 The Journal of family PracTice | AUGuST 2011 | Vol 60, no 8 BETA-BLOCKERS FOR HEART FAILURE TABLE 2 Titrating beta-blocker therapy interval on mean dose Target dose Trial agent initial dose starting dose achieved achieved ciBiS ii1 Bisoprolol 1.25 mg/d 1 week 8.5 mg/d 10 mg/d (43%) coPernicuS2 carvedilol 3.125 mg bid 2 weeks 18.5 mg bid 25 mg bid (66%) meriT-hf3 metoprolol 12.5 mg/d 2 weeks 159 mg/d 200 mg/d (64%) succinate ciBiS-ii, cardiac insufficiency Bisoprolol Study; coPernicuS, carvedilol Prospective randomized cumulative Survival; meriT-hf, metoprolol cr/Xl randomized intervention Trial in congestive heart failure. continued over a 4-week period until the max- In MERIT-HF, metoprolol succinate was imum tolerable dose was reached. Although initiated at 12.5 mg daily and doubled ev- 43% of patients reached the 10 mg/d target, a ery 2 weeks until the target (200 mg/d) was third of those studied remained on <5 mg/d.1 achieved.