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Risk of Angioedema With Sacubitril-Valsartan vs. ACEI and ARB
Quick Takes
- This observational study aims to examine the risk of angioedema among users of the heart failure medication sacubitril-valsartan (SV) compared to users of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB).
- The study uses data from five large health plans, four US commercial, and one national insurance claims database contributing to the Sentinel Distributed Database.
- There was no increased risk of angioedema among SV new users compared to ACEI or ARB users. However, there was an increased risk of angioedema among SV users who recently switched from ACEI or ARB compared to SV new users.
Study Questions:
Is the incidence of angioedema higher with the use of sacubitril-valsartan (SV) compared to that of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB)?
Methods:
The study used observational data from five large health plans—four US commercial and one national insurance claims database contributing to the Sentinel Distributed Database (SDD) between January 2015 and February 29, 2020—and identified the cohort by specific International Classification of Diseases (ICD) codes for heart failure. The study evaluated different groups of patients, including new users of SV, ACEI, and ARB, and patients who switched from ACEI or ARB to SV. The primary outcome was angioedema, defined by specific ICD codes, and a secondary outcome was serious angioedema. Patients were followed up for 365 days or until the earliest occurrence of angioedema, loss of enrollment, death, end of data availability, or cessation of medication. The study uses propensity score matching to control for confounders in the analysis and estimates incidence rates and relative risks for angioedema among the exposure groups.
Results:
After applying inclusion and exclusion criteria, a total of 41,998 and 43,755 SV new users, 69,639 and 49,137 ACEI-SV and ARB-SV users, and 49,628 and 35,702 recent ACEI-SV and ARB-SV users were matched to ACEI and ARB new users, respectively. The study found that the crude incidence of angioedema per 1,000 person-years was 1.33, 6.74 (SV and ACEI users) and 1.35, 3.02 (SV and ARB users). Additionally, the incidence rate of angioedema was highest during the first 0-30 days for ACEI and ARB users but steadily diminished over time. The incidence rates for SV new users did not show the same time trends.
Compared to ACEI, SV new users showed a strong protective effect (adjusted hazard ratio [aHR], 0.18; 95% confidence interval [CI], 0.11-0.29) for angioedema; however, there was no difference in the risk of angioedema for SV new users compared to ARB new users (aHR, 0.59; 95% CI, 0.35-1.01). In the secondary analyses (ACEI-SV vs. ACEI new users and ARB-SV vs. ARB new users), the crude incidence of angioedema per 1,000 person-years was 2.14 for ACEI-SV users and 6.74 for ACEI new users and 2.05 for ARB-SV users and 3.02 for ARB new users. Even though the incidence of angioedema was higher than in the SV new user group, it was still lower than in the ACEI new user group and similar to the incidence in the ARB new user groups. The study also found that the incidence of angioedema was higher in blacks and females than in non-blacks and males.
Conclusions:
There was no increased risk of angioedema among SV new users compared to ACEI or ARB users. However, there was an increased risk of angioedema among SV users who recently switched from ACEI or ARB compared to SV new users.
Perspective:
While SV can lead to increased bradykinin levels by inhibiting neprilysin, which breaks down multiple different peptides including kinins (bradykinins and substance P), the study did not observe an increased angioedema risk for patients taking SV compared to ACEI users and there was no difference in risk when SV users were compared to ARB users. This may be due to differences between the study's population and the population in previous clinical trials. For example, both clinical trials subjected all participants to a run-in period of ACEI and ARB to exclude patients with a higher risk for angioedema, which may have underestimated the true risk of angioedema for the comparator arms in the clinical trials. The study found an increased risk of angioedema among switcher cohorts compared to SV new users, particularly when switching within 14 days of an ACEI or ARB episode. This suggests that the risk of angioedema may be higher when switching to SV from ACEI or ARB, and that continued surveillance of new initiations of SV is important to monitor for angioedema risk.
Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Angioedema, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Bradykinin, Heart Failure, Neprilysin, Risk, Secondary Prevention, Valsartan
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