Resumen de Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome The VISTA-16 Randomized Clinical Trial

Stephen J. Nicholls, John J.P. Kastelein, Gregory G. Schwartz

• 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 Despite a high rate of use of contemporary therapies, patients with acute coronary syndrome (ACS) face a substantial risk of early, recurrent adverse cardiovascular events.1 Increasing evidence supports a potential role of inflammation in the progression and clinical instability of coronary heart disease.2 Necropsy studies show inflammatory cells within atherosclerotic plaques,3 and clinical outcomes trials show an association between systemic inflammatory markers and cardiovascular risk.4 Conversely, reductions in inflammatory markers associate with reductions in cardiovascular events in clinical trials and may contribute to the benefit of statins.4 These observations provide a rationale to test novel agents that target specific inflammatory factors implicated in atherosclerosis to determine if it reduces cardiovascular risk.5 The secretory phospholipase A2 (sPLA2) family of enzymes hydrolyze fatty acids of glycophospholipids, generating bioactive lipid species involved in inflammation.6 However, although some sPLA2 isoforms are proatherogenic (groups IIA and V), other isoforms are protective (group X).7 Considerable evidence implicates a potential role for groups IIA and V sPLA2 in cardiovascular disease. Higher circulating levels of sPLA2-IIA concentration and activity associate with cardiovascular risk in asymptomatic individuals and patients with established coronary disease.8 Pathologic studies demonstrate the presence of sPLA2 isoforms groups IIA, III, V, and X in atherosclerotic lesions and myocardial regions that have sustained ischemic injury.6,9,10 These observations have stimulated interest in the potential value of sPLA2 inhibition as a cardioprotective strategy.5 Varespladib methyl is a nonspecific pan-sPLA2 inhibitor with favorable effects on atherosclerotic lesions in animal studies.11 Initial studies demonstrated that varespladib reduced levels of sPLA2-IIA by more than 90%, in addition to lowering low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) in patients with stable coronary disease and ACS.12- 14 The Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks (VISTA-16) study was designed to evaluate the effects of varespladib on cardiovascular risk in patients with ACS.15