The Effects of AF on Dapagliflozin Therapy in Patients With HFrEF or HFmrEF

In patients with heart failure with preserved ejection fraction, dapagliflozin therapy is not affected by the presence of atrial fibrillation.

Dapagliflozin therapy in patients with heart failure with mildly reduced ejection fraction (HFmrEF) and patients with heart failure with preserved ejection fraction (HFpEF) is unaffected by atrial fibrillation, according to findings published in the Journal of the American College of Cardiology.

The DELIVER (Dapagliflozin Evaluation to Improve Lives of Patients with Preserved Ejection Fraction Heart Failure; ClinicalTrials.gov Identifier: NCT03619213) trial is an event-driven, randomized, double-blind, controlled. Recognizing that the presence of atrial fibrillation (AF) is common among individuals with heart failure (HF) and is associated with worse outcomes compared with sinus rhythm, investigators sought to explore the effects of dapagliflozin based on the presence or absence of AF.

Patients were aged 40 years or older, had a diagnosis of HF for 6 weeks or longer and at least intermittent use of a diuretic agent, were New York Heart Association functional class II to IV, had left ventricular ejection fraction of more than 40%, had evidence of structural heart disease, and had a N-terminal pro-B-type natriuretic peptide concentration of 300 pg/mL or more. Both hospitalized and ambulatory patients were eligible for study enrollment.

A total of 6261 patients with HF who fulfilled all study criteria were randomly assigned to dapagliflozin or placebo. The primary study endpoint was a composite of cardiovascular (CV) death or worsening HF. The effects of dapagliflozin and clinical outcomes, based on an individual’s AF status, were evaluated.

These findings provide further evidence for dapagliflozin as a new treatment option for patients with HFmrEF/HFpEF.

Of the participants, 56.7% of them reported having AF at study initiation.

Results of the study showed that the risk for the primary endpoint was higher among participants with AF, in particular, among those with paroxysmal AF, which was driven by a higher rate of hospitalization for HF. In patients without AF the HF hospitalization rate per 100 person-years was 4.5 (95% CI, 4.0-5.1). In patients with paroxysmal AF the HF hospitalization rate per 100 person-years was 7.5 (95% CI, 6.4-8.7). In patients with persistent/permanent AF the HF hospitalization rate per 100 person-years was 6.4 (95% CI, 5.7-7.1; P <.001).

Findings showed that the benefit of dapagliflozin on the primary study outcome was consistent across all types of AF. In patients without AF the hazard ratio [HR] was 0.89 (95% CI, 0.74-1.08). In patients with paroxysmal AF the HR was 0.75 (95% CI, 0.58-0.97). In patients with persistent/permanent AF the HR was 0.79 (95% CI, 0.79; 95% CI, 0.66-0.95; Pinteraction =.49).

Consistent effects were reported for CV death, all-cause mortality, hospitalization for HF, and improvement in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score.

Limitations of the study include that the evaluation of secondary and exploratory outcomes by AF status was conducted post hoc. Additionally, the prespecified inclusion and exclusion criteria in DELIVER prevents the enrollment of very high-risk patients, possibly impacting the generalizability of the study results.

“…the beneficial effects of dapagliflozin, compared with placebo, on clinical events and symptoms were not modified by AF at baseline, irrespective of definition or type of AF,” the study authors wrote. “These findings provide further evidence for dapagliflozin as a new treatment option for patients with HFmrEF/HFpEF.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

References:

Butt JH, Kondo T, Jhund PS, et al. Atrial fibrillation and dapagliflozin efficacy in patients with preserved or mildly reduced ejection fraction. J Am Coll Cardiol. Published online August 27, 2022. doi: 10.1016/j.jacc.2022.08.718