Research Scientist Harvard Pilgrim Health Care Institute Boston, United States
Background: Sacubitril/valsartan (S/V) is approved for treatment of heart failure (HF) with reduced ejection fraction. Limited data from the approval trial suggested a potential increased risk of serious angioedema among Black patients treated with S/V relative to angiotensin converting enzyme inhibitors (ACEI).
Objectives: To provide real-world estimates of serious angioedema risk among Black patients initiating S/V relative to ACEI.
Methods: We conducted a retrospective cohort study by implementing a common protocol in 3 nationally representative US electronic health record and claims data sources: the Cardiovascular Research Network (CVRN), the Innovation in Medical Evidence Development and Surveillance Distributed Data Network (IMEDS-DDN), and the Centers for Medicare and Medicaid Services Fee-For-Service database (CMS). We conducted our study among adult (≥18 years) patients who were recorded as Black race, did not have a previous angioedema diagnosis, and were diagnosed with HF prior to initiation of S/V or an ACEI between July 7, 2015 (US S/V approval date) and December 31, 2019. Initiation was defined by no dispensings in the prior year. We calculated incidence rates (IR) and 95% confidence intervals (CI) of serious angioedema (defined as a hospital discharge diagnosis) within 365 days of S/V or ACEI initiation at each data source. We applied inverse probability of treatment weighting to estimate adjusted hazard ratios (HR) and 95% CI for serious angioedema comparing S/V vs. ACEI initiators. We repeated all analyses among non-Black patients and using an any angioedema (defined as a diagnosis in any setting) outcome as secondary analyses.
Results: We identified 19,018 S/V initiators and 56,627 ACEI initiators. Mean age (years) of S/V initiators varied by data source (61.3 in CVRN, 67.6 in IMEDS, and 66.5 in CMS). Less than 11 cases of serious angioedema were identified among S/V users, precluding pooling of IRs due to small cell count policies. Corresponding IRs per 1,000 person-years (95% CI) at CVRN, IMEDS-DDN, and CMS were 0.00 (0.00 – 16.1), 0.00 (0.00 – 3.2), and 2.13 (1.02 – 3.92), respectively. The IRs among ACEI users were 3.89 (1.26 – 9.08), 5.87 (3.57, 9.07), and 7.29 (5.99 – 8.78). Relative to ACEI initiators, S/V initiators were more likely to be male, younger, have higher cardiovascular comorbidity, and have severe HF. HRs were not estimable at CVRN or IMEDS-DDN because no events were observed among S/V initiators. In CMS data, the adjusted HR (95% CI) for serious angioedema was 0.30 (0.16 – 0.66). Hazard ratios were similar in non-Black patients and for the any angioedema outcome.
Conclusions: Our study did not observe an increased risk of serious angioedema among Black or non-Black HF patients initiating S/V compared to ACEI in real-world settings.
