Atrial fibrillation (AF) is now recognized as a potential therapeutic target in heart failure with preserved ejection fraction (HFpEF). However, few evidence-based therapies are available for its management.
The ATHENA trial, published in NEJM, established that dronedarone reduces the risk of cardiovascular events and death in patients who had high-risk paroxysmal or persistent AF or atrial flutter (AFL). Now, a post hoc analysis of that trial has determined dronedarone has the same benefits in patients whose AF/AFL is complicated by HFpEF or HF with mildly reduced EF (HFmrEF).
Muthiah Vaduganathan, MD, MPH, a cardiologist in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital, and colleagues published the results in the European Journal of Heart Failure.
ATHENA was conducted at 551 sites in 37 countries. In a double-blind fashion, 4,628 patients with high-risk paroxysmal or persistent AF/AFL were randomly assigned to either dronedarone 400 mg twice daily or a matching placebo.
The post hoc analysis considered three groups of patients:
- 534 (12%) had concomitant HFpEF or HFmrEF
- 422 (9%) had HF with reduced ejection fraction (HFrEF) or left ventricular ejection fraction (LVEF) ≤40%
- 3,672 (79%) did not have HF
In the analysis, HFpEF/HFmrEF was rigorously defined as:
- LVEF >40%
- Evidence of structural heart disease, defined as left atrial enlargement (length on M-mode ≥50 mm) or investigator-reported LV cardiomyopathy
- New York Heart Association functional class II/III or use of a diuretic other than spironolactone at baseline
The primary endpoint of ATHENA was a composite of death or cardiovascular hospitalization. In the post hoc analysis:
- Dronedarone consistently reduced the risk compared with placebo (HR, 0.76; 95% CI, 0.69–0.84) regardless of HF status
- In patients with HFpEF/HFmrEF, the HR was 0.79 (95% CI, 0.61–1.03)
- Consistent clinical benefit of dronedarone was observed across a range of LVEFs and extended to LVEF ≥60%
The components of the primary endpoint (rates of death and cardiovascular hospitalization) and HF hospitalization each directionally favored dronedarone in HFpEF/HFmrEF, but the treatment effects were not statistically significant.
In a sensitivity analysis, the researchers removed the requirement for structural heart disease from the definition of HFpEF/HFmrEF. Among the 2,353 individuals who met these less stringent criteria, dronedarone was associated with:
- Significantly lower risk of the primary endpoint (HR, 0.78; 95% CI, 0.68–0.89)
- Significant benefit on a number of secondary endpoints, including death (HR, 0.65; 95% CI, 0.45–0.95)
These broader selection criteria may lessen the certainty of a HFpEF diagnosis. Interestingly, though, a letter published in Circulation suggests the majority of patients with AF/AFL, preserved LV function, and dyspnea have occult HFpEF when evaluated with invasive hemodynamics.
In the subgroup with HFpEF/HFmrEF, rates of all treatment-emergent adverse events (TEAE) were identical in the two arms (36%), as were rates of serious TEAEs (13%). Rates of permanent drug discontinuation due to TEAEs were higher with dronedarone (7% vs. 4%); most were gastrointestinal events such as nausea or diarrhea.
Candidates for Dronedarone
In the ANDROMEDA trial, also published in NEJM, dronedarone was associated with increased mortality in patients recently hospitalized with decompensated HFrEF. The safety of dronedarone seems more favorable in stable, ambulatory patients such as those evaluated in ATHENA.
It’s worth noting dronedarone has class II anti-adrenergic and class IV vasodilatory properties. Patients with stable HF might benefit, whereas decompensated patients with severe LV dysfunction could be harmed by these effects.
Additionally, dronedarone is known to reduce creatinine clearance by 15%–20% (without causing kidney injury). That might have led to alteration of use or dosing of disease-modifying HF therapies in ANDROMEDA, leading to disease progression. In contrast, in otherwise stable patients with HFpEF, transient perturbations in creatinine clearance and resultant short-term changes in therapy may be less detrimental.