Sacubitril/Valsartan-Associated Adverse Drug Reactions: An Updated Comprehensive Review of Clinical and Real-World Pharmacovigilance Evidence

Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established component of guideline-directed medical therapy for heart failure. Although randomized clinical trials have demonstrated substantial reductions in cardiovascular mortality and heart failure hospitalization, continued pharmacovigilance remains important because patients treated in routine practice often differ from those enrolled in clinical trials. [1,4] . Objective: To comprehensively review the adverse drug reactions associated with sacubitril/valsartan by integrating evidence from randomized clinical trials, observational studies, spontaneous reporting systems, and contemporary pharmacovigilance analyses. Methods: A narrative review was conducted using published literature indexed in biomedical databases. Priority was given to pivotal randomized trials, systematic reviews, observational studies, and post-marketing pharmacovigilance investigations evaluating sacubitril/valsartan safety, with particular emphasis on hypotension, hyperkalemia, renal dysfunction, angioedema, and emerging adverse-event signals identified through the Food and Drug Administration Adverse Event Reporting System (FAERS). Results: Clinical trials consistently identified hypotension as the most frequent adverse effect associated with sacubitril/valsartan. Hyperkalemia and renal dysfunction require monitoring, although comparative trials have not consistently shown a higher incidence than with conventional renin-angiotensin system inhibitors. Angioedema is uncommon but potentially life-threatening. Contemporary FAERS analyses have confirmed established adverse-event patterns and identified additional potential signals involving hearing impairment, cognitive symptoms, and renal events; these observations remain hypothesis-generating because spontaneous reporting systems cannot establish causality or incidence. [1,2,3,4] Conclusion: The overall safety profile of sacubitril/valsartan remains favorable when appropriately prescribed and monitored. Integration of clinical trial evidence with real-world pharmacovigilance provides a more complete understanding of its adverse drug reactions, and clinical pharmacists play an important role in identifying patients at increased risk, monitoring laboratory parameters, counseling patients, and reporting suspected adverse reactions. [1,4,5,6,7,8]