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

Abstract

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.

Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System

“…We classified AEs into four categories, according to their predictability [32]: (a) expected AEs with a detected signal, which referred to predictable events on the basis of esketamine or ketamine mechanism of action or anticipated from pre-marketing pivotal trials with a safety signal (in at least 5% of participants); (b) expected AEs without a signal, which referred to predictable events based on the above criteria, but without a signal; (c) disease-related AEs: events for which underlying TRD poses per se a risk factor; and (d) unexpected AEs, which referred to unexpected or previously unreported events [32].…”

Sinergy between drugs and devices in the fight against sudden cardiac death and heart failure

“…The reverse left ventricular remodelling induced by sacubitril/valsartan may actually be the key mechanism for reducing SCD 7 but some months are required for this process to occur, thus with exposure to a residual risk of SCD especially in the first 3 months after treatment initiation. 99 These data, even if observational, strongly suggest the advantages of a combined use or sacubitril/valsartan and ICD, when indicated according to guidelines, without delaying the device implant, in order to fully achieve the benefits that these two treatments may independently exert, and with the potential for synergistic effects.…”

“…12 • The value of ICD back-up to minimize the residual risk of SCD in patients with an established indication and who are candidate to initiate sacubitril/valsartan is further supported by some data on the initial period of treatment with sacubitril/valsartan. [97][98][99] These data are observational and related to case reports or to a collection of pharmacovigilance reports and even if they do not put into question the evidence of benefit of sacubitril/valsartan on SCD at long term, are of interest for considerations on the time course and the determinants of the effect of this agent on arrhythmogenesis and the cardiac substrate. The reverse left ventricular remodelling induced by sacubitril/valsartan may actually be the key mechanism for reducing SCD 7 but some months are required for this process to occur, thus with exposure to a residual risk of SCD especially in the first 3 months after treatment initiation.…”

Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system

“…All gastrointestinal AEs with at least ten reports were selected to reduce the likelihood of false positives. We then performed signal strength of reports of semaglutide at both PT (gastrointestinal AEs) and SOC levels in FAERS database, and a positive signal was considered when the lower limit of the ROR 95% confidence interval (CI) exceeded one ( 19 ). The serious and non-serious reports were also compared to clarify the severity of the detected safety signals and identify risk factors (gender, age and weight) in patients.…”