No Survival Gain Seen From Beta-Blockers in Heart Failure With AF

February 04, 2013

GRONINGEN, the Netherlands — A new meta-analysis suggests that beta-blockers have little effect in heart-failure (HF) patients with atrial fibrillation (AF) [1]. The review included trials examining the four beta-blockers currently licensed for use in HF: bisoprolol, metoprolol controlled release (CR), nebivolol, and carvedilol.

"This finding is important, as most patients with HF and AF receive beta-blocker treatment," say Dr Michiel Rienstra (University Medical Center, Groningen, the Netherlands) and colleagues in their paper in the February 2013 issue of Journal of the American College of Cardiology: Heart Failure.

Senior author Dr Dirk J van Veldhuisen (University Medical Center) told heartwire : "AF is very common in patients with HF. We assume what we have found with beta-blockers in HF patients in sinus rhythm--a very powerful effect of about a 35% reduction in mortality--will be the same in those with AF, but remarkably, this meta-analysis shows really clearly that it's not found in those with AF; all the effect is in those with sinus rhythm.

This is a disturbing message that we found and felt we had to report.

"This is a disturbing message that we found and felt we had to report," he said. "These data may cause some controversy because I, and many others, are big fans of beta-blockers, but at the same time AF is a big problem in patients with HF." He noted that this paper was first submitted to but turned down by the Lancet: "They didn't know what to do with this message," he suggests, adding that guideline committees will need to look very carefully at these new data.

For the time being, van Veldhuisen does not recommend stopping beta-blocker therapy in HF patients with AF. This treatment is guideline-dictated, in both HF and AF, he notes, and there are many complex nuances, such as the fact that HF patients and their physicians may not even know that they have AF if it is intermittent.

However, the findings might, he says, make the decision to stop beta-blocker therapy in those with HF and AF "a little bit easier, it might lower the threshold," if the patient does not appear to be benefiting from beta-blocker therapy in terms of symptoms, for example.

Treatment of AF-HFREF is a major unmet need in cardiovascular therapies.

In an accompanying editorial comment [2], Dr Michael R Bristow (Arca Biopharma, Aurora, CO) and Dr Ryan G Aleong (University of Colorado, Aurora) say that these new data--as well as evidence that other HF therapies and many antiarrhythmic drugs don't work as well in HF patients with AF--suggest that this patient population "should be approached differently" from those in sinus rhythm. "The clinician is thus faced with a relative lack of therapeutic options in the heart failure with reduced left ejection fraction [HFREF] patient with AF. Based on the relatively high prevalence of AF and evidence that it worsens the mortality rate in HF patients, treatment of AF-HFREF is a major unmet need in cardiovascular therapies," they assert.

20% of Patients Have HF and AF; Beta-Blockers Do Not Prolong Life

Beta-blockers are a cornerstone of the treatment of heart failure and are recommended in the current guidelines for HF and AF treatment, "albeit for different indications," say Rienstra et al.

In HF recommendations, beta-blockers are indicated as standard therapy for all patients to reduce morbidity and mortality, without differentiation regarding rhythm. In addition, beta-blocker therapy has been shown to prevent new-onset or recurrent AF in patients with HF, with AF known to worsen the prognosis of HF, including perhaps contributing to an increased incidence of stroke, says van Veldhuisen.

In the AF treatment guidelines, however, beta-blockers are recommended for rate control to reduce AF-related symptoms but not to improve prognosis.

In the meta-analysis, Rienstra and colleagues included four trials that investigated the effect of placebo-controlled, randomized beta-blocker therapy in patients with HF with reduced systolic LVEF (<40%)--CIBIS II, MERIT-HF, SENIORS, and the US Carvedilol Trial.

The studies enrolled a total of 8680 patients with HF, 1677 of whom had AF at baseline (19%; mean 68 years of age; 30% women); of these, 842 were treated with beta-blockers and 835 with placebo.

In AF patients, beta-blockade did not reduce mortality (odds ratio [OR] 0.86; p=0.28), while in sinus-rhythm patients, there was a significant reduction (OR 0.63; p<0.0001) even after adjustment for potential confounders. Similarly, beta-blocker therapy was not associated with a reduction in HF hospitalizations in AF (OR 1.11; p=0.44), in contrast to sinus rhythm (OR 0.58; p <0.0001).

If we treat these [HF and AF] patients with beta-blockers it will not prolong their lives.

Van Veldhuisen said the findings indicate: "If we treat these [HF and AF] patients with beta-blockers it will not prolong their lives." Bristow and Aleong say that what these results effectively mean "is that beta-blockade is of little or no benefit in HFREF patients with AF."

They add that prospective studies are needed to further examine this issue, and it would appear to be ethical to compare placebo and a beta-blocker in AF-HFREF patients.

Van Veldhuisen says he is not sure he agrees that this approach would be ethical, but in any case such a trial is unlikely to be funded, given that all four beta-blockers licensed for heart failure are now off patent.

Not All Beta-Blockers May Be Equal When It Comes to HF With AF

Both the editorialists and authors discuss a number of potential reasons why beta-blockers may not be effective in HF patients with AF, and they also state that the findings could apply to some but not all beta-blockers, as differences in pharmacological profiles of individual agents may have played a role.

"At a minimum, data from the study by Rienstra et al suggest that AF-HFREF treatment should be approached differently from that for [sinus-rhythm]-HFREF, via therapies uniquely suited to dealing with this important subpopulation," say Bristow and Aleong.

At a minimum, data from the study by Rienstra et al suggest that AF-HFREF treatment should be approached differently from that for [sinus-rhythm]-HFREF.

For example, there is evidence of efficacy for the beta-blocker bucindolol in the AF subset ofthe BESTtrial--not included in this meta-analysis--they add. In fact, Bristow works for a pharmaceutical company that is developing bucindolol for the treatment of heart failure and atrial fibrillation.

Van Veldhuisen says it may well turn out that different beta-blockers have differential effects in HF and AF, and he acknowledges there is some published evidence that bucindolol could possibly work in this subset of patients.

However, bucindolol "is not licensed for heart failure," at least not in the US and Europe, he notes, adding that this indication would need to be approved before such treatment could be considered.

Rienstra has no conflicts of interest. Van Veldhuisen served on the steering committees of the MERIT-HF and SENIORS trials and has received fees for board membership for Vifor, BG Medicine, Solvent, and Johnson & Johnson. Disclosures for the coauthors are listed in the paper. Bristow is an officer and director of Arca Biopharma, which is developing bucindolol for the treatment of heart failure and atrial fibrillation. Aleong has no conflicts of interest.