Atrial Fibrillation Complicates Treatment, Monitoring of Heart Failure

SEPTEMBER 20, 2017
Kenneth Bender
Patients with heart failure have a more difficult course if they also have atrial fibrillation (Afib), and researchers have found that treatment and monitoring strategies also become more complicated.

Results from the largest randomized trial to date in patients with both heart failure and atrial fibrillation (AFib) support recommendations for using beta-blocker medications for heart failure with reduced ejection fraction (HFrEF), despite a recent metaanalysis  questioning their use when there is concurrent AFib.

Julia Cadrin-Tourigny, MD, Montreal Heart Institute, Universit. de Montr.al, Quebec, Canada, and colleagues reported a significantly lower mortality rate in patients with heart failure receiving betablockers regardless of concurrent AFib, although without finding a corresponding reduction in rate of hospitalization.

An accompanying editorial by Jonathan Piccini MD and Larry Allen MD, with the subtitle “Don’t Bury the Beta-Blockers Just Yet”, described the co-occurrence of AFib and heart failure as “two colliding epidemics.” In attempting to reconcile the findings of the current study from the AF-CHF trial, and those of the previous meta-analysis from the Beta-Blockers Heart Failure Collaborative Group, Piccini and Allen conclude, "in short, one cannot.”

They do, however, concur with Cadrin-Tourigny and colleagues in affirming the role of beta-blockers in this circumstance, stating that “at present, we believe clinicians should initially default to prescribing evidence-based beta-blockers in all patients with HFrEF regardless of AFib status.”

The AF-CHF trial randomized 1,376 patients with AF and HFrEF to receive rhythm control treatment (n=694) or rate control treatment (n=682). In this sub-study of the trial, the impact of beta-blockers on outcomes was assessed against the pattern or burden of AFib in propensity-matched cohorts; with 426 on a beta-blocker medication and 229 without, and 42% of each group receiving amiodarone.

Cadrin-Tourigny and colleagues reported that the beta-blockers were associated with a 28% reduction in all-cause mortality, and that this result persisted regardless of concurrent AFib, or whether the AFib was paroxysmal or persistent, long or short duration, or presenting a high or low burden.

The researchers suggested several possibilities for the divergence of their findings from those of the meta-analysis, including that the meta-analysis combined a sizeable proportion of patients with non-persistent AFib with those having no AFib.

While beta-blocker medication was associated with reduced mortality, there was no corresponding reduction in hospitalizations. The researchers speculated that the beneficial effects of beta-blockers may have been countered, in part, by a trend toward higher rate of hospitalization with AFib.

HEART FAILURE INDICATOR MISSES MARK WITH CONCURRENT AFIB
The reliability of natriuretic peptide levels as a prognostic indicator and gauge of treatment effect in heart failure was brought into question by a recent analysis of outcomes when there is concurrent atrial fibrillation or flutter (AFF).

Previous results from the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT trial) associated the renin inhibitor aliskiren (Tekturna, Novartis) with a sustained significant reduction in the levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), albeit without affecting clinical outcomes.

The current analysis, involving a 1-year follow-up of over 1,300 patients, found that the neuropeptide levels were reduced in only the patients without AFib or flutter at baseline.

“To our knowledge, we present the first analysis exploring the influence of AFF on the longitudinal NT-proBNP level,” indicated lead author, Stephen Greene, MD, Division of Cardiology, Duke University Medical Center, Durham North Carolina, and colleagues. “The lack of an independent association between baseline AFF status and NT-proBNP trajectory found here suggests that other patient characteristics (eg, renal function) tracking with rhythm status may account for differences in longitudinal NT-proBNP concentration and argues against a causal relationship.”

In an accompanying editorial, Spyridon Deftereos, MD, PhD, Second Department of Cardiology, National and Kapodistrian University of Athens, Greece, and colleagues pointed out that the study results could affect both clinical practice and drug evaluation.

In addition to cautioning that natriuretic peptide-guided management may no longer be recommended for heart failure patients with atrial fibrillation, they warned that “an even more important implication would pertain to the definition of surrogate endpoints in Phase II trials of heart failure medications.”

The 2 fractions of the pro-B-type natriuretic peptide, NT-proBNP and BNP, have been considered 2 of the most successful biomarkers in medical practice, Deftereos pointed out. The current study findings suggest, however, that reduction in levels should no longer serve as surrogate indices of clinical improvement, or guide titration of heart failure medication if there is concurrent AFF.

In addition, use of natriuretic peptide levels to gauge heart failure treatment in phase 2 clinical trials may reduce experimental effect if the study population includes subjects from the estimated 30% to 50% of heart failure patients with concurrent AFF.

From 1,615 patients in the placebo-controlled ASTRONAUT efficacy cohort, 1,358 were included in the present analysis, with 492 having had baseline AFF. In addition to study endpoints of all-cause death and the composite of cardiovascular death within 12 months, the NT-proBNP levels were obtained at 1, 6 and 12 months after hospital discharge.

Greene and colleagues reported that patients with AFF treated with aliskirin had numerically lower, but not statistically significantly lower, NT-proBNP levels than those receiving placebo at each time point. For those without AFF, however, the reduced levels at each post-discharge time point were statistically significantly lower with active treatment than with placebo.

The significant reduction in NT-proBNP with aliskiren in only patients without AFF suggests several possibilities, including that elevated levels of natriuretic peptides may be released from the atria with AFF, independent of heart failure and in excess of that countered by the treatment.

Greene and colleagues also found that AFF was not associated with increased mortality or hospitalization during the follow-up period, contrasting with the traditional view that AFib is an independent predictor of mortality. The investigators speculate that this could reflect a heterogeneity of heart rhythms in the cohort, with different associated adverse outcomes.

With the new study indicating that natriuretic peptide levels may not serve as surrogate endpoints in heart failure when there is concurrent AFF, Deftereos and colleagues observe, "the road to translation of suggestive basic observations, attractive pathophysiological premises, and promising preclinical results into actual clinical benefit for the suffering patient is fraught with disappointments. 

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