Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), has revolutionized heart failure with reduced ejection fraction (HFrEF) management since its 2015 approval, demonstrating superior efficacy over ACE inhibitors in the PARADIGM-HF trial. However, real-world safety concerns, particularly regarding angioedema and renal effects, necessitate post-marketing surveillance. This study conducts a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) database to compare adverse drug events (ADEs) between sacubitril/valsartan and valsartan monotherapy, aiming to detect pharmacovigilance signals and guide clinical decision-making.
Data from January 2015 to December 2023 encompassed 1,247,892 individual case safety reports (ICSRs), with 28,456 (2.28%) involving sacubitril/valsartan and 15,234 (1.22%) valsartan. Demographics showed sacubitril/valsartan users were predominantly male (62.1%), aged ≥65 (58.4%), and treated for cardiac disorders (87.3%). Disproportionality metrics included reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayes geometric mean (EBGM), with signals deemed significant if ROR 95% CI lower limit >1 and PRR >2 with ≥3 cases.
Overall, sacubitril/valsartan exhibited 2,156 ADEs across 25 preferred terms (PTs) with signals, compared to 1,023 for valsartan (12 PTs). Cardiovascular events dominated, with hypotension (ROR=3.2, 95% CI: 2.8-3.7; n=1,247) and syncope (ROR=2.1, 95% CI: 1.6-2.8; n=456) markedly elevated. Angioedema, a class effect amplified by neprilysin inhibition, showed the strongest signal (ROR=4.5, 95% CI: 3.2-6.3; PRR=5.1; n=189), 3.7-fold higher than valsartan (ROR=1.2, 95% CI: 0.8-1.8). Renal and electrolyte imbalances were prominent, including acute kidney injury (ROR=1.9, 95% CI: 1.5-2.4; n=678) and hyperkalemia (ROR=1.8, 95% CI: 1.4-2.3; n=523). Nervous system disorders like dizziness (ROR=2.4, 95% CI: 2.0-2.9) and cough (ROR=1.6, 95% CI: 1.2-2.1) were also disproportionate. Serious outcomes (death, hospitalization) comprised 71.4% of sacubitril/valsartan reports versus 59.2% for valsartan.
Stratified analyses confirmed consistency across age, sex, and indication subgroups, with temporal trends peaking post-2020 amid expanded use. Compared to valsartan, sacubitril/valsartan displayed 2.1-fold more signals in System Organ Classes (SOCs) like vascular (ROR>2.5) and renal (ROR>1.8). Limitations include FAERS’s voluntary reporting bias, confounding by indication, and lack of causality inference. These findings highlight sacubitril/valsartan’s favorable yet nuanced profile, urging enhanced monitoring for at-risk populations (e.g., elderly, renally impaired). Clinicians should prioritize ARNI initiation in stable HFrEF patients while mitigating risks through dose titration and comorbidity management. Future studies integrating electronic health records could validate signals, refining ARNI’s therapeutic index in precision cardiology.
Link: https://www.tandfonline.com/doi/full/10.1080/14740338.2025.2591388?scroll=top&needAccess=true
