Nebivolol For Heart Failure — Compelling Evidence Or A Me Too Trial?

Should elderly patients with heart failure receive beta-blockers?  SENIORS — a parallel group, randomized, double-blind, multi-center trial comparing nebivolol to placebo — attempted to answer this question.¹  Concern about the tolerability of beta-blockers in elderly patients persists despite some evidence that they are likely safe in older adults with heart failure (HF).^2,3,4  The current American Heart Association (AHA) guidelines recommend that all clinically stable patients with HF and reduced left ventricular ejection fraction (LVEF) and who do not have contraindications be treated with one of the beta-blockers proven to reduce mortality in heart failure (i.e. bisoprolol, carvedilol, or metoprolol succinate).⁵ The European HF guidelines have similar recommendations and include nebivolol as an appropriate beta-blocker.⁶  The AHA guidelines cite five large clinical trials that evaluated beta-blockers and all-cause mortality in HF patients. However, in a meta-analysis of these trials, only 36.3% of the patients were considered elderly.³

The purpose of the SENIORS trial was to determine the effects of nebivolol on mortality and morbidity in patients ≥70 years old (mean = 76 years) with stable HF.  More than 90% of the patients had NYHA class II or III HF at study entry, 88% of patients were taking an angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB), 85% were taking diuretics, and 27% were taking aldosterone antagonists.

Inclusion Criteria
History of chronic HF with one of the following:
   Documented hospital admission within the previous 12 months with 
      a discharge diagnosis of congestive HF
   Documented LVEF <35% within the previous 6 months

Exclusion Criteria
   New drug therapy for HF within 6 weeks
   Change in cardiovascular (CV) drug therapy within 2 weeks
   Uncorrected valvular heart disease
   Contraindication for beta-blockers
   Current use of beta-blockers
   Significant hepatic or renal dysfunction
   Cerebrovascular accidents within 3 months

A total of 2,135 patients were enrolled from 11 countries.  2,000 patients were required to meet statistical power, and 2,128 patients were included in the results using an intention-to-treat analysis.  There was no appreciable difference in baseline characteristics between the treatment groups.

The initial dose of nebivolol or identical placebo was 1.25 mg once daily, titrated up to the target of 10 mg once daily (mean nebivolol dose = 7.7mg) as tolerated over a maximum of 16 weeks. Post-titration follow-up visits were scheduled at 4 and 6 months after randomization, and then every 3 months until the end of the study.  The mean duration of follow-up was 21 month. There was little difference in rates of treatment discontinuation between the nebivolol and placebo groups (27% and 25%, respectively). 

Nebivolol significantly lowered all cause mortality or CV hospitalization when compared to placebo (31.1% and 35.35%, respectively; p = 0.039) with a number needed to treat (NNT) of 24.  In addition, there was a lower rate of CV mortality or CV hospitalization (a secondary outcome) in the nebivolol group compared to the placebo group (28.6% and 33.0%, respectively; p-value = 0.027).  With regard to safety, nebivolol was well tolerated with a few anticipated beta-blocker class adverse effects at rates higher than placebo. Bradycardia occurred in 11.1% of the patients in the nebivolol group and only 2.6% in the placebo group with a number needed to harm (NNH) of 12.

Discussion:
The results of SENIORS are perhaps not surprising – like other beta-blockers, nebivolol reduced the risk of mortality or CV hospitalization when compared to placebo.  The benefit was observed after only 6 months of treatment and increased over the duration of study.   Moreover, nebivolol was well-tolerated in this elderly, but closely monitored population.  These findings are comforting and validate our current clinical practice guidelines.  Perhaps the most interesting finding — in a post-hoc analysis of the SENIORS trial — nebivolol had similar benefits in patients with preserved EF (>35%) in terms of all-cause mortality or CV hospitalizations (HR 0.82, CI 0.62-1.08).⁷  Although the study was not powered to detect a difference in any subgroup, this information suggests a need for further studies to evaluate beta-blockade treatment in patients with preserved EF, since current heart failure guidelines do not recommend treatment in this population.^5,6

The SENIORS study raises several clinically important questions.  This was the first prospective study powered to demonstrate efficacy of beta-blockade in elderly heart failure patients … and yet, nebivolol is not approved for the treatment of HF in the United States.  Moreover, it is a high-cost brand name drug.  So, many clinicians have been reluctant to recommend nebivolol for the treatment of HF.  But consider this — pharmacologically nebivolol has some modest vasodilating properties, thus the results of SENIORS may not be generalizable to other beta-blockers.  Do we need additional clinical trials in the elderly withapproved beta-blockers to determine if they have the same benefit as nebivolol?  Or, if we really believe in evidence-based medicine, shouldn’t we be recommending nebivolol over other beta-blockers in our elderly patients?  And what about patients with preserved EF?  Are the findings of the post-hoc analysis convincing enough?   What do you think?