• Cardiology Clinical Trials
• Inflammatory Disease
• Myocardial Infarction

• Cardiology & Cardiovascular Medicine
• Cardiology Clinical Trials
• Inflammatory Disease
• Myocardial Infarction

Inflammation has been implicated in atherosclerosis, and evidence suggests that some of the benefit seen with statin treatment may be related to an anti-inflammatory effect. Secretory phospholipase A₂ (sPLA₂) is found in atherosclerotic plaques and has been shown to participate in the inflammatory pathway. The objective of the Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks study [VISTA-16; Nicholls SJ et al. JAMA 2013] was to determine whether varespladib, a pan-sPLA₂ inhibitor, would have an effect on cardiovascular (CV) outcomes in patients treated for the first 16 weeks after an acute coronary syndrome (ACS).

Stephen J. Nicholls, MD, South Australian Health and Medical Research Institute, Adelaide, Australia, presented the results of the VISTA-16 trial. A total of 5145 patients with ACS were randomized in a double-blind fashion to treatment with varespladib 500 mg/day (n=2572) or placebo (n=2573) in addition to atorvastatin (at least 20 mg/day) and standard care. Eligible patients also had to have one of the following additional risk factors for cardiovascular (CV) events: diabetes, metabolic syndrome, high-density lipoprotein cholesterol <42 mg/dL, estimated glomerular filtration rate <60 mL/minute, stroke or transient ischemic attack, peripheral artery disease, myocardial infarction (MI), or coronary revascularization. Randomized patients began treatment within 96 hours of an ACS and double-blind treatment was continued for 16 weeks. The primary endpoint was the composite of CV death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina.

Baseline clinical characteristics were well-balanced in the randomized treatment groups Table 1. The data safety monitoring board (DSMB) conducted a prespecified interim analysis on 212 primary events, 55% of the projected total. In March 2012, the DSMB recommended stopping the trial for futility and possible harm.

There were no statistically significant differences between the treatment groups.

There was no significant difference between treatment groups in the primary endpoint (HR, 1.25; 95% CI, 0.97 to 1.61; p=0.08). However, secondary efficacy endpoint analyses indicated a significantly higher risk in the composite CV death/MI/stroke endpoint for varespladib treatment compared with placebo (p=0.04). This finding was driven by the 66% increase in risk of nonfatal MI seen in varespladib-treated patients compared with placebo-treated patients (HR, 1.66; 95% CI, 1.16 to 2.39; p=0.005). The trial was designed to also assess 6-month mortality; however, the sponsor obtained 6-month mortality for only 31% of the patients (1588 out of 5145). Dr. Nicholls believes the sponsor was remiss in study follow-up activities, as the lack of 6-month survival data in the majority of patients led to difficulties in determining whether the higher rate of MI led to more deaths.

In a subgroup analysis of the primary endpoint, there was no heterogeneity in the outcomes for any specific subgroup treated with varespladib. Additional analyses found that patients randomized to varespladib that did not undergo percutaneous coronary intervention were at significantly higher risk for MI (p=0.04), with a similar trend observed in patients with non-ST segment elevation MI (p=0.06). Patients randomized to varespladib also had higher rates of discontinuation due to adverse events (n=72 vs n=36 placebo) and more cases of elevated liver enzymes (n=38 vs n=6 for placebo). This highlights the importance of performing outcome trials of novel agents, concluded Dr. Nicholls, since varespladib proved to be harmful despite promising smaller Phase 2 studies.

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