Drug Therapies and Incident Heart Failure in Atrial Fibrillation: A Systematic Review

Background/Objectives: Atrial fibrillation (AF), the most common cardiac arrhythmia, significantly elevates the risk of new-onset heart failure (HF). We aimed to systematically map and appraise available evidence on drug therapies and incident HF in patients with AF. Methods: We searched Medline, Embase, Cochrane Central Register of Controlled Trials, and Scopus up to 16 September 2026 for relevant randomized controlled trials (RCTs), sub-analyses of RCTs, and observational/cohort studies. Results: Seventeen studies (397,991 participants) were included. The only randomized signal came from a prespecified subgroup of the ACTIVE-I trial, in which irbesartan was associated with fewer first HF hospitalizations than the placebo (HR 0.81, 95% CI 0.69–0.96; moderate certainty). Observational studies showed an association with lower first HF hospitalization for sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes (pooled HR 0.68, 95% CI 0.48–0.95; two studies; low certainty) and lower incident HF diagnosis in a larger cohort that included patients without diabetes (HR 0.86, 95% CI 0.82–0.89). The remaining cohort evidence largely reflected prescribing patterns rather than drug effects. Statins showed an inconsistent association. The higher HF incidence among users of diuretics, mineralocorticoid receptor antagonists, digoxin and renin-angiotensin system inhibitors was consistent with confounding by indication (very low certainty). Conclusions: Evidence on drug therapies to prevent HF in AF is limited to one randomized subgroup signal for irbesartan. The remaining findings were associations rather than demonstrated treatment effects. High-quality research, including RCTs in broader AF populations, is needed. PROSPERO Registration: CRD42024587926.