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Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome: The VISTA-16 Randomized Clinical Trial
Study Questions:
What are the effects of secretory phospholipase A2 (sPLA2) inhibition with varespladib on cardiovascular outcomes?
Methods:
VISTA-16 (Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks), a double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America, of 5,145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2,572) or placebo (n = 2,573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012) was conducted. Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. 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 endpoint events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary endpoint occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.97-1.61; log-rank p = 0.08). 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 = 0.005). The composite secondary endpoint 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 = 0.04).
Conclusions:
The authors concluded that in patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI.
Perspective:
This study reports that sPLA2 inhibition with varespladib administration did not reduce cardiovascular ischemic complications and resulted in an excess rate of MI and the composite of cardiovascular mortality, MI, and stroke in patients with ACS. Whether this represents an adverse effect of the varespladib molecule or a consequence of pan-sPLA2 inhibition remains to be determined in future studies. Moreover, despite lower achieved levels of low-density lipoprotein cholesterol and C-reactive protein, there was no evidence of a beneficial reduction in the primary cardiovascular outcome. These findings re-emphasize the fact that identification of a circulating marker of cardiovascular risk does not necessarily imply that pharmacologic suppression or inhibition of the marker will reduce risk, and clinical trials should focus on hard clinical endpoints.
Keywords: New Zealand, Phospholipases A2, Secretory, Inflammation, Myocardial Infarction, Acute Coronary Syndrome, North America, Stroke, Clinical Trials Data Monitoring Committees, Risk Factors, Heptanoic Acids, Europe, Pyrroles, Cholesterol, C-Reactive Protein, Biomarkers, Indoles, Australia, India, Cardiovascular Diseases, Medical Futility, Confidence Intervals
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