Stephen J Nicholls1, John J P Kastelein2, Gregory G Schwartz3, Dianna Bash4, Robert S Rosenson5, Matthew A Cavender6, Danielle M Brennan4, Wolfgang Koenig7, J Wouter Jukema8, Vijay Nambi9, R Scott Wright10, Venu Menon4, A Michael Lincoff4, Steven E Nissen4. 1. South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, Australia. 2. Academic Medical Center, Amsterdam, the Netherlands. 3. Veterans Affairs Medical Center and University of Colorado, Colorado, Denver. 4. Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio. 5. Icahn School of Medicine at Mount Sinai, New York, New York. 6. Brigham and Women's Hospital, Boston, Massachusetts. 7. University of Ulm Medical Center, Ulm, Germany. 8. Leiden University Medical Center, Leiden, and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands. 9. Michael E. DeBakey Veterans Affairs Hospital and Baylor College of Medicine, Houston, Texas. 10. Mayo Clinic, Rochester, Minnesota.
Abstract
IMPORTANCE: Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2 inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measure was a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95% CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2 inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246.
RCT Entities:
IMPORTANCE: Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2 inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS:Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measure was a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95% CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2 inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246.
Authors: Preethi Mani; Rishi Puri; Gregory G Schwartz; Steven E Nissen; Mingyuan Shao; John J P Kastelein; Venu Menon; A Michael Lincoff; Stephen J Nicholls Journal: JAMA Cardiol Date: 2019-04-01 Impact factor: 14.676
Authors: Laurent Knerr; Fabrizio Giordanetto; Peter Nordberg; Daniel Pettersen; Nidhal Selmi; Hans-Georg Beisel; Hannah de la Motte; Thomas Olsson; Tim D J Perkins; Margareta Herslöf; Åsa Månsson; Mikael Dahlström; Ingemar Starke; Johan Broddefalk; Gabrielle Saarinen; Fredrik Klingegård; Eva Hurt-Camejo; Birgitta Rosengren; Johan Brengdahl; Frank Jansen; Mattias Rohman; Jenny Sandmark; Kenth Hallberg; Tomas Åkerud; Robert G Roth; Marie Ahlqvist Journal: ACS Med Chem Lett Date: 2018-06-23 Impact factor: 4.345