Far from reducing the risk of cardiovascular events in patients with recent acute coronary syndrome, the sPLA2 inhibitor varespladib actually raised the risk of MI in an international randomized clinical trial.
The drug did exert beneficial effects on inflammatory and lipid biomarkers as expected, "which theoretically should have translated to a lower propensity to plaque rupture" in the 16 weeks following ACS. But the study was terminated early "for futility" after an interim analysis of the outcomes for only 212 of the 5,012 randomized patients, said Dr. Stephen J. Nicholls and his associates in the VISTA-16 clinical trial, which was reported simultaneously at the American Heart Association scientific sessions and published online in JAMA (2013 Nov. 18 [doi:10.1001/jama.2013.282836]).
Compared with placebo, varespladib caused an excess of MIs and of the composite outcome of cardiovascular mortality, MI, and stroke. "These findings suggest that short-term sPLA2 inhibition with varespladib is harmful following ACS," said Dr. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, and his colleagues.
Dr. Stephen J. Nicholls
"Our findings ... reemphasize that identification of a circulating marker of cardiovascular risk does not necessarily imply that pharmacologic suppression or inhibition of the marker will reduce risk," they noted.
Varespladib is a nonspecific inhibitor of the family of secretory phospholipase A2 (sPLA2) enzymes that are involved in inflammation, some of which are present in atherosclerotic lesions and myocardial areas injured by ischemia. In initial studies, the drug reduced circulating levels of sPLA2 by more than 90%, lowered LDL cholesterol, and decreased C-reactive protein in ACS patients.
The VISTA-16 (Vascular Inflammation Suppression to Treat Acute coronary syndrome for 16 weeks) trial, sponsored by Anthera Pharmaceuticals, the maker of varespladib, was designed to assess the drug’s efficacy at preventing CV events during the high-risk period of the 4 months immediately following ACS.
A total of 5,145 patients were enrolled at 362 medical centers in 17 countries over the course of 3 years, within hours of presenting with ACS. They had a high prevalence of CV risk factors and established atherosclerotic disease, and most were already receiving appropriate therapy with antiplatelet agents, statins, beta-blockers, ACE inhibitors, or receptor blockers. Eighty percent underwent coronary revascularization after the index event.
The primary endpoint was a composite of CV mortality, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization. When the trial was terminated, outcomes in 212 patients had been documented after a mean of 13.4 weeks of treatment. The primary endpoint occurred in 6.1% of patients who took varespladib, compared with 5.1% of those who took placebo (hazard ratio, 1.25), the investigators said.
A secondary outcome, a composite of CV mortality, MI, and stroke, occurred in 4.6% of patients who took varespladib and 3.8% of those who took placebo (HR, 1.36).
"This was due primarily to a greater incidence of MI in the varespladib group compared with the placebo group (3.4% vs 2.2%; HR, 1.66)," the researchers said.
Six months after patients had discontinued study treatment, all-cause mortality was 2.7% in the varespladib group and 2.0% in the placebo group.
Twice as many patients taking the active drug (2.8%) as taking placebo (1.4%) discontinued treatment because of adverse or serious adverse events.
The reasons for varespladib’s adverse effect on MI are not yet known. "Whether this represents an adverse effect of the varespladib molecule or a consequence of pan-sPLA2 inhibition remains to be determined," Dr. Nicholls and his associates said.
The VISTA-16 trial was funded by Anthera Pharmaceuticals. Dr. Nicholls and his associates reported numerous ties to industry sources.