Varespladib and cardiovascular events in patients with an acute coronary syndrome: The VISTA-16 randomized clinical trial

VISTA-16 Investigators

Research output: Contribution to journalArticle

140 Citations (Scopus)

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 measurewas 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.

Original languageEnglish (US)
Pages (from-to)252-262
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume311
Issue number3
DOIs
StatePublished - Jan 1 2014

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varespladib
Acute Coronary Syndrome
Randomized Controlled Trials
Secretory Phospholipase A2
Myocardial Infarction
Placebos
Clinical Trials Data Monitoring Committees
Stroke
Medical Futility
Mortality
Unstable Angina
Community Hospital
North America
New Zealand

ASJC Scopus subject areas

  • Medicine(all)

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Varespladib and cardiovascular events in patients with an acute coronary syndrome : The VISTA-16 randomized clinical trial. / VISTA-16 Investigators.

In: JAMA - Journal of the American Medical Association, Vol. 311, No. 3, 01.01.2014, p. 252-262.

Research output: Contribution to journalArticle

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title = "Varespladib and cardiovascular events in patients with an acute coronary syndrome: The VISTA-16 randomized clinical trial",
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 measurewas 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.",
author = "{VISTA-16 Investigators} and Nicholls, {Stephen J.} and Kastelein, {John J.P.} and Schwartz, {Gregory G.} and Dianna Bash and Rosenson, {Robert S.} and Cavender, {Matthew A.} and Brennan, {Danielle M.} and Wolfgang Koenig and Jukema, {J. Wouter} and Vijay Nambi and Wright, {R. Scott} and Venu Menon and Lincoff, {A. Michael} and Nissen, {Steven E.} and C. Hennekens and Brown, {W. V.} and D. DeMets and M. Pfeffer and J. Roleau and J. Abraham and J. Gebel and C. Huff and I. Katzan and M. Shishehbor and A. Rassi and K. Uchino and A. Vest and E. Zishiri and Heckman, {M. J.} and C. Balog and A. Dart and J. Amerena and C. Prasad and A. Farshid and B. Gunalingam and P. Thompson and N. Collins and M. Arstall and {van Gaal}, W. and C. Aroney and L. Mahar and G. Youssef and J. Horowitz and D. Anand and J. Rodes-Cabau and P. Polasek and C. Lai and T. Huynh and E. Brilakis and S. Marso",
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TY - JOUR

T1 - Varespladib and cardiovascular events in patients with an acute coronary syndrome

T2 - The VISTA-16 randomized clinical trial

AU - VISTA-16 Investigators

AU - Nicholls, Stephen J.

AU - Kastelein, John J.P.

AU - Schwartz, Gregory G.

AU - Bash, Dianna

AU - Rosenson, Robert S.

AU - Cavender, Matthew A.

AU - Brennan, Danielle M.

AU - Koenig, Wolfgang

AU - Jukema, J. Wouter

AU - Nambi, Vijay

AU - Wright, R. Scott

AU - Menon, Venu

AU - Lincoff, A. Michael

AU - Nissen, Steven E.

AU - Hennekens, C.

AU - Brown, W. V.

AU - DeMets, D.

AU - Pfeffer, M.

AU - Roleau, J.

AU - Abraham, J.

AU - Gebel, J.

AU - Huff, C.

AU - Katzan, I.

AU - Shishehbor, M.

AU - Rassi, A.

AU - Uchino, K.

AU - Vest, A.

AU - Zishiri, E.

AU - Heckman, M. J.

AU - Balog, C.

AU - Dart, A.

AU - Amerena, J.

AU - Prasad, C.

AU - Farshid, A.

AU - Gunalingam, B.

AU - Thompson, P.

AU - Collins, N.

AU - Arstall, M.

AU - van Gaal, W.

AU - Aroney, C.

AU - Mahar, L.

AU - Youssef, G.

AU - Horowitz, J.

AU - Anand, D.

AU - Rodes-Cabau, J.

AU - Polasek, P.

AU - Lai, C.

AU - Huynh, T.

AU - Brilakis, E.

AU - Marso, S.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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 measurewas 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.

AB - 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 measurewas 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.

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