Sourbha S Dani1, Sarju Ganatra2, Muthiah Vaduganathan3. 1. Division of Cardiovascular Medicine, Lahey Hospital Medical Center, Burlington, MA, United States of America; London School of Economics, Department of Health Policy, London, UK. Electronic address: Sourbha.s.dani@lahey.org. 2. Division of Cardiovascular Medicine, Lahey Hospital Medical Center, Burlington, MA, United States of America. 3. Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, United States of America.
Abstract
BACKGROUND: Sacubitril/valsartan reduces the risk of hospitalizations and death among patients with heart failure (HF) with reduced ejection fraction; its use is poised to increase worldwide. As bradykinin is a substrate of neprilysin, angioedema was a theoretical concern potentiated by neprilysin inhibition. METHODS: We explored angioedema in clinical trials and real-world pharmacovigilance data. We conducted a trial-level random-effects meta-analysis of 5 RCTs studying the effects of sacubitril/valsartan in heart failure. FDA Adverse Event Reporting System (FAERS) provided real-world pharmacovigilance data in the US. RESULTS: The 5 trials enrolled 14,841 patients with follow-up ranging from 2 to 27 months. The collective rate of angioedema in RCTs was 0.5% in sacubitril/valsartan arms vs. 0.3% in control arms (pooled odds ratio of 1.35; 95% confidence interval - 0.45 to 4.1; P = .59) with moderate heterogeneity (I2 55.2.%). These relative effects were driven by the larger PARADIGM-HF and PARAGON-HF experiences. FAERS pharmacovigilance data identified 426 angioedema cases over the last 5 years out of 40,559 adverse events reported related to sacubitril/valsartan. CONCLUSIONS: Rates of angioedema with sacubitril/valsartan are reported to be low in RCTs and real-world clinical practice.
BACKGROUND:Sacubitril/valsartan reduces the risk of hospitalizations and death among patients with heart failure (HF) with reduced ejection fraction; its use is poised to increase worldwide. As bradykinin is a substrate of neprilysin, angioedema was a theoretical concern potentiated by neprilysin inhibition. METHODS: We explored angioedema in clinical trials and real-world pharmacovigilance data. We conducted a trial-level random-effects meta-analysis of 5 RCTs studying the effects of sacubitril/valsartan in heart failure. FDA Adverse Event Reporting System (FAERS) provided real-world pharmacovigilance data in the US. RESULTS: The 5 trials enrolled 14,841 patients with follow-up ranging from 2 to 27 months. The collective rate of angioedema in RCTs was 0.5% in sacubitril/valsartan arms vs. 0.3% in control arms (pooled odds ratio of 1.35; 95% confidence interval - 0.45 to 4.1; P = .59) with moderate heterogeneity (I2 55.2.%). These relative effects were driven by the larger PARADIGM-HF and PARAGON-HF experiences. FAERS pharmacovigilance data identified 426 angioedema cases over the last 5 years out of 40,559 adverse events reported related to sacubitril/valsartan. CONCLUSIONS: Rates of angioedema with sacubitril/valsartan are reported to be low in RCTs and real-world clinical practice.