Adverse events with sacubitril/valsartan in the real world: emerging signals to target preventive strategies from the FDA adverse event reporting system

Aims: The aim of this study was to characterise clinical priority of adverse events with sacubitril/valsartan for targeting preventive measures. Methods: We used the US Food and Drug Administration adverse event reporting system (worldwide pharmacovigilance database) to compare adverse events recording sacubitril/valsartan as suspect with other cardiovascular drugs. Disproportionality analyses were performed by calculating the reporting odds ratios, deemed significant when the lower limit of the 95% confidence interval was greater than 1. Clinical priority was assigned to adverse events with significant disproportionality by scoring (range 0–10 points) five features (number of events, magnitude of the lower limit of the 95% confidence interval, mortality frequency, important/designated medical event, biological plausibility). Results: Sacubitril/valsartan was recorded in 20,021 reports, with 178 adverse events associated with significant disproportionality: 71.9%, 25.9% and 2.2% were classified as weak, moderate and strong clinical priorities, respectively. Increased reporting emerged for several cardiovascular adverse events, including ‘renal failure’ (N = 388; lower limit of the 95% confidence interval 2.26), ‘hyperkalaemia’ (314; 2.42) and ‘angioedema’ (309; 1.56). Sudden cardiac death (priority score 9 points) was the only designated medical event with strong clinical priority. Notably, sudden cardiac death occurred early after sacubitril/valsartan administration (average onset 124 days), with concomitant drugs known for pro-arrhythmic potential (e.g. amiodarone, escitalopram, mirtazapine, loop diuretics) in 26.2% of records. Conclusion: The increased cardiovascular reporting of sacubitril/valsartan in the real world was largely predictable from pre-approval evidence, underlying disease and likely patients’ comorbidities. The unexpected reporting of sudden cardiac death occurred well before the complete development of positive electrical remodelling induced by sacubitril/valsartan, and calls for stringent clinical monitoring (to reduce the pro-arrhythmic burden related to co-medications), and further investigation on appropriate combination with other preventive measures.