Nebivolol. The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) randomized 2128 patients older than 70 years with prior hospitalization for heart failure or an EF ≤35% to nebivolol (1.25-10 mg/d) or placebo. Nebivolol (which is not approved for the treatment of heart failure in the United States) reduced the composite end point of all-cause mortality and cardiovascular hospitalization (HR=0.86; 95% CI, 0.74-0.99; P=.039), but did not reduce the total mortality rate.6
Atenolol. Some retrospective analyses have suggested that heart failure patients do as well on atenolol as patients taking metoprolol or carvedilol.14,15 Because no RCTs have established the efficacy of atenolol, however, it is not recommended for the treatment of heart failure.
Is the dose sufficient to reduce heart rate?
The benefit of beta-blocker therapy for patients with heart failure is proportional to the degree of heart rate reduction, so it is important to find the highest tolerable dose.16,17 The COMET study detailed earlier sparked considerable controversy, with some observers contending that the dose of metoprolol used was too small to adequately lower the heart rate.18,19
A subsequent study, the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT), highlights the importance of rate reduction in heart failure outcomes. In this placebo-controlled trial of 6558 patients with EF ≤35%, treatment with the heart rate-reducing agent ivabradine reduced cardiovascular death and hospitalization from heart failure (HR=0.82; 95% CI, 0.75-0.90; P<.0001) compared with placebo.20 A subsequent analysis showed that the primary outcome increased by 16% for every 5 beats-per-minute (BPM) increase.21
Start low, go slow
When initiating and titrating beta-blockers, the major RCTs clearly illustrate the importance of the dictum, “Start low, go slow” (TABLE 2).1-3
In CIBIS II, patients were started on bisoprolol at a dose of 1.25 mg/d. After a week, the dosage was increased by 1.25 mg. Titration continued over a 4-week period until the maximum tolerable dose was reached. Although 43% of patients reached the 10 mg/d target, a third of those studied remained on <5 mg/d.1
In COPERNICUS, carvedilol was started at 3.125 mg twice a day and continued at that dosage for 2 weeks. The dose was then titrated up at 2-week intervals, to 6.25 mg bid, then 12.5 mg bid, before attempting to reach the target dose of 25 mg bid. Ultimately, 66% received the target dose.2
In MERIT-HF, metoprolol succinate was initiated at 12.5 mg daily and doubled every 2 weeks until the target (200 mg/d) was achieved. Nearly two-thirds (64%) of those in the treatment group reached the target dose.3
In COMET, the researchers used the same drug regimen for carvedilol that was used in COPERNICUS (starting at 3.125 mg bid and slowly titrating to reach a 25-mg bid target). Patients on metoprolol tartrate initially received 5 mg bid; the dose was increased every 2 weeks until the target—50 mg bid—was reached. Seventy-five percent of patients reached the targeted carvedilol dose, and 78% reached the metoprolol target.7
TABLE 2
Titrating beta-blocker therapy
| Trial | Agent | Initial dose | Interval on starting dose | Mean dose achieved | Target dose 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 succinate | 12.5 mg/d | 2 weeks | 159 mg/d | 200 mg/d (64%) |
| CIBIS-II, Cardiac Insufficiency Bisoprolol Study; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival; MERIT-HF, Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure. | |||||
Help beta-blocker therapy succeed
A significant number of patients with heart failure will be unable to tolerate an adequate dose of beta-blockers, at least on the first attempt.22 In such cases, a second attempt on another occasion—eg, after symptomatic bronchospasm or acute heart failure has been controlled—should be made.
In CIBIS II, 15% of the patients randomized to bisoprolol stopped taking it;1 in COPERNICUS, the withdrawal rate from carvedilol was also 15%;2 and in MERIT-HF, 10% of patients taking metoprolol experienced an adverse event that led to drug withdrawal.3 Although withdrawal rates were similar among patients on placebo in all 3 trials, they nonetheless suggest that even with the precautions and scrutiny characteristic of clinical trials, 10% to 15% of patients with heart failure will experience difficulty with beta-blocker treatment. (In a study of patients in one heart failure clinic, the withdrawal rate approached 40%.22)
Considering the benefits of beta-blockers for patients with all levels of heart failure, it is incumbent on physicians to prescribe them for as many of these patients as possible (See “Are beta-blockers contraindicated for these heart failure patients?”) and to attempt to reduce withdrawal rates.