Abstract Body (Do not enter title and authors here): Background
Sacubitril /valsartan, an angiotensin-receptor–neprilysin inhibitor (ARNI), improves survival in heart failure, yet its impact on clinically significant arrhythmias remains uncertain.
Hypothesis
We hypothesised that ARNI therapy reduces ventricular tachycardia or fibrillation (VT/VF) and atrial fibrillation or flutter (AF/AFL) compared with angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) therapy.
Methods
PubMed and ClinicalTrials.gov were searched from January 2000 to May 2025. Randomised controlled trials and observational studies comparing ARNI with ACEI / ARB and reporting VT/VF or AF/AFL were eligible. Two reviewers independently screened records and extracted study-level data with a standardised form. Pooled log-odds ratios (LogOR) with 95% confidence intervals (CI) were calculated using random-effects models; heterogeneity was assessed with the Q statistic.
Results
Twenty-three studies (12 randomised, 11 observational) enrolling 20799 participants (10515 ARNI, 9261 control) met inclusion criteria. Mean weighted age was 67.1 years; 32.1 % were women. Baseline left-ventricular ejection fraction averaged 41 % (range 24–62). Guideline-directed medical therapy and baseline arrhythmia were documented in 74% of studies.
VT/VF: Seven randomized trials demonstrated fewer ventricular arrhythmia events with ARNI (LogOR –0.23; OR 0.79, 95% CI 0.64–0.98; p = 0.03; Q = 3.6, p = 0.73). When all 12 studies reporting VT/VF, including the seven RCTs, were analyzed, the association still favored ARNI but did not reach statistical significance (LogOR –0.37; OR 0.69, 95% CI 0.41–1.18; p = 0.18; Q = 44.9, p = 0.02).
AF/AFL : Fifteen studies, including both randomized trials and observational studies, demonstrated a 31% risk reduction with ARNI (LogOR –0.37; OR 0.69, 95% CI 0.53–0.91; p = 0.01; Q = 45.3, p < 0.001). In the randomized subset (seven trials), the effect trended in favor of ARNI but did not reach statistical significance (LogOR –0.09; OR 0.91, 95% CI 0.73–1.14; p = 0.42; Q = 16.4, p = 0.13).
Conclusions
Sacubitril/valsartan significantly decreases ventricular arrhythmias in randomised evidence and lowers atrial arrhythmias when observational data are included. These findings support its use to mitigate arrhythmic risk and highlight the need for rhythm-focused randomised trials.