(C-237) Assessing the Risk of Angioedema in Adult Sacubitril/Valsartan Users With Heart Failure: Results From a Post-Authorization Safety Study in Seven European Electronic Healthcare Databases

Background: Sacubitril/valsartan (sac/val) was approved in the European Union for adult patients with symptomatic chronic heart failure (HF) and a reduced ejection fraction in November 2015. A post-authorisation safety study (PASS) was conducted to assess the risk of various important identified or potential risks listed in the Risk Management Plan (RMP) with a primary focus on the risk of angioedema associated with sac/val under real-world conditions.

Objectives: To assess the risk of angioedema associated with sac/val versus angiotensin converting enzyme inhibitor (ACEI) use in adult HF patients in 7 European electronic healthcare databases.

Methods: The study population included patients aged ≥18 years who initiated sac/val or used ACEIs (date of first prescription/dispensing; index date) during the study period (Dec 2015 to Dec 2019) and a diagnosis of HF before or within 90 days after the index date. Four exposure cohorts were identified for sac/val initiators and ACEI users: regardless of prior ACEI/angiotensin receptor blocker [ARB] use (cohort 1, cohort 3) and naïve to ACEI/ARBs (cohort 2, cohort 4). Angioedema was identified by in- or outpatient diagnoses, excluding patients with prior angioedema. Patients were followed from index date until the date of angioedema, death, treatment discontinuation or change to another renin-angiotensin-aldosterone system blocking agent, or end of data. Age- and sex-standardized incidence rates (IRs) per 1,000 person years and 95% confidence intervals (CIs) of angioedema were estimated for all databases combined. For less than ten events of angioedema 95% CIs are not presented. The adjusted relative risks of angioedema expressed as hazard ratios (HRs) with corresponding 95% CIs were estimated for sac/val versus ACEI cohorts, using a Cox regression model with overlap weighting.

Results: Of 676,505 HF patients exposed to sac/val or ACEI, 39,616 were initiating sac/val (cohort 1). Of those, 4,548 (11%) were naïve to ACEIs/ARBs (cohort 2). Sac/val initiators were on average 72 years old and 71% were men. The IR of angioedema was 0.6 (95% CI 0.4-0.9) in exposure cohort 1 (0.9 in cohort 2 [ < 10 events]) and was 0.9 (95% CI 0.8-0.9) in exposure cohort 3 (1.2 (95% CI 1.0-1.4) in cohort 4). No indication of an increased risk for angioedema between patients initiating sac/val (cohort 1) and patients using ACEIs (cohort 3: HR+ 0.9 [95% CI 0.5-1.7]; cohort 4: HRadjusted 0.7 [95% CI 0.2-2.7]) was found in the comparative analyses.

Conclusions: The risk of angioedema was low in all exposure cohorts, with no indication of an increased risk of angioedema in patients initiating sac/val compared to patients initiating or using ACEIs. This finding should be interpreted with caution as angioedema was rare in all cohorts and potential bias may exist.