Yee Soo Kim1, Simerjeet Brar1, Natalie D'Albo1, Amit Dey2, Sachin Shah3, Sarju Ganatra3, Sourbha S Dani4. 1. Department of Internal Medicine, Lahey Hospital and Medical Center, Burlington, MA, 01805, USA. 2. Department of Internal Medicine, Georgetown University Medical Center, Washington, DC, 20057, USA. 3. Beth Israel Lahey Health, Department of Cardiovascular Medicine, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA, 01805, USA. 4. Beth Israel Lahey Health, Department of Cardiovascular Medicine, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA, 01805, USA. Sourbha.s.dani@lahey.org.
Abstract
PURPOSE: In PARADIGM-HF, sacubitril/valsartan showed a significant reduction in mortality and hospitalization for patients with heart failure with reduced ejection fraction. Despite proven efficacy, sacubitril/valsartan has moderate uptake in clinical practice. This study explores the safety profile of sacubitril/valsartan by comparing adverse events in RCT and real-world use. METHODS: We studied hypotension, renal dysfunction, hyperkalemia, and angioedema associated with sacubitril/valsartan in RCTs and pharmacovigilance databases. A random-effects meta-analysis was performed with six RCTs investigating sacubitril/valsartan vs. control/comparators in heart failure patients. WHO's VigiBase, FAERS, and EMA's EudraVigilance were mined to obtain spontaneously reported real-world adverse events. Disproportionality analysis was performed with the FDA's OpenVigil 2.0. RESULTS: Six RCTs enrolled 15,538 patients with heart failure with reduced and preserved ejection fractions. There was no statistical difference for the composite of hypotension, renal dysfunction, hyperkalemia, and angioedema between sacubitril/valsartan and its comparators viz. ACEi or ARBs (OR 1.23, CI 0.98-1.56; p = 0.08). A total of 103,038 adverse events were registered in the spontaneous reporting systems. Hypotension was the most reported adverse event. Proportions of composite adverse events were 20% in VigiBase, 17% in FAERS, and 39% with EudraVigilance. Disproportionality analysis showed a lower risk of adverse events with sacubitril/valsartan than other guideline-directed heart failure medications used in clinical practice. CONCLUSION: With increased uptake of sacubitril/valsartan, risks of hypotension, renal dysfunction, hyperkalemia, and angioedema appear low and acceptable in RCTs and global clinical practice.
PURPOSE: In PARADIGM-HF, sacubitril/valsartan showed a significant reduction in mortality and hospitalization for patients with heart failure with reduced ejection fraction. Despite proven efficacy, sacubitril/valsartan has moderate uptake in clinical practice. This study explores the safety profile of sacubitril/valsartan by comparing adverse events in RCT and real-world use. METHODS: We studied hypotension, renal dysfunction, hyperkalemia, and angioedema associated with sacubitril/valsartan in RCTs and pharmacovigilance databases. A random-effects meta-analysis was performed with six RCTs investigating sacubitril/valsartan vs. control/comparators in heart failure patients. WHO's VigiBase, FAERS, and EMA's EudraVigilance were mined to obtain spontaneously reported real-world adverse events. Disproportionality analysis was performed with the FDA's OpenVigil 2.0. RESULTS: Six RCTs enrolled 15,538 patients with heart failure with reduced and preserved ejection fractions. There was no statistical difference for the composite of hypotension, renal dysfunction, hyperkalemia, and angioedema between sacubitril/valsartan and its comparators viz. ACEi or ARBs (OR 1.23, CI 0.98-1.56; p = 0.08). A total of 103,038 adverse events were registered in the spontaneous reporting systems. Hypotension was the most reported adverse event. Proportions of composite adverse events were 20% in VigiBase, 17% in FAERS, and 39% with EudraVigilance. Disproportionality analysis showed a lower risk of adverse events with sacubitril/valsartan than other guideline-directed heart failure medications used in clinical practice. CONCLUSION: With increased uptake of sacubitril/valsartan, risks of hypotension, renal dysfunction, hyperkalemia, and angioedema appear low and acceptable in RCTs and global clinical practice.
Authors: Clyde W Yancy; Mariell Jessup; Biykem Bozkurt; Javed Butler; Donald E Casey; Monica M Colvin; Mark H Drazner; Gerasimos Filippatos; Gregg C Fonarow; Michael M Givertz; Steven M Hollenberg; JoAnn Lindenfeld; Frederick A Masoudi; Patrick E McBride; Pamela N Peterson; Lynne Warner Stevenson; Cheryl Westlake Journal: Circulation Date: 2016-05-20 Impact factor: 29.690
Authors: Adam D DeVore; C Larry Hill; Laine Thomas; Puza P Sharma; Nancy M Albert; Javed Butler; J Herbert Patterson; John A Spertus; Fredonia B Williams; Carol I Duffy; Kevin McCague; Adrian F Hernandez; Gregg C Fonarow Journal: Circ Heart Fail Date: 2018-09 Impact factor: 8.790
Authors: Akshay S Desai; Scott Solomon; Brian Claggett; John J V McMurray; Jean Rouleau; Karl Swedberg; Michael Zile; Martin Lefkowitz; Victor Shi; Milton Packer Journal: Circ Heart Fail Date: 2016-06 Impact factor: 8.790
Authors: Orly Vardeny; Brian Claggett; Jessica Kachadourian; Scott M Pearson; Akshay S Desai; Milton Packer; Jean Rouleau; Michael R Zile; Karl Swedberg; Martin Lefkowitz; Victor Shi; John J V McMurray; Scott D Solomon Journal: Circ Heart Fail Date: 2018-04 Impact factor: 8.790
Authors: Ruwen Böhm; Leocadie von Hehn; Thomas Herdegen; Hans-Joachim Klein; Oliver Bruhn; Holger Petri; Jan Höcker Journal: PLoS One Date: 2016-06-21 Impact factor: 3.240