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VISTA-16: Varespladib linked to greater incidence of MI in ACS patients
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DALLAS — Varespladib, a novel secretory phospholipase A2 inhibitor, did not reduce the risk for recurrent CV events in patients with ACS and was linked to greater risk for MI.
Because of the MI findings, the VISTA-16 study was terminated early after a recommendation by its Data Safety Monitoring Board.
Previous research demonstrated that varespladib (Anthera Pharmaceuticals) had a positive effect on lipid and inflammatory markers. The VISTA-16 study was designed to investigate the drug’s impact on CV outcomes, Stephen J. Nicholls, MD, PhD, of the University of Adelaide and Royal Adelaide Hospital in Australia, said at a press conference.
Stephen J. Nicholls
Researchers enrolled 5,145 patients with ACS. Approximately half were assigned varespladib 500 mg/day for 16 weeks and half were assigned placebo for 16 weeks. Both groups also received atorvastatin and other established therapies.
The primary endpoint was a composite of CV death, nonfatal MI, nonfatal stroke and hospitalization for unstable angina with evidence of ischemia.
At the time of study termination, patients assigned varespladib had a 3.3% rate of nonfatal MI compared with 2.1% for those assigned placebo (HR=1.66; 95% CI, 1.14-2.5).
When the study was closed, the primary endpoint had occurred in 5.9% of patients assigned varespladib vs. 4.7% of patients assigned placebo (HR=1.25, 95% CI, 0.95-1.63). Adverse events occurred in 72 patients in the varespladib group vs. 36 patients in the placebo group.
“Not only were adverse events greater in the varespladib group than in the placebo group, but there were signs of biochemical toxicity as well,” Nicholls said. “The findings call into question whether sPLA2 is a valid target for therapy in atherosclerosis.”
Nicholls said the VISTA-16 study was “a logical extension of the phase 2 program” and that “the sponsor did the right thing and accepted immediately the recommendation by the DSMB to terminate the study.”
Of note, Nicholls said, is that “the study protocol prespecified that 6 months after the end of treatment patients be contacted to ascertain 6-month status. The sponsor, despite receiving a letter of insistence from the academic steering committee that they should continue to do that even if the study was stopped, only collected that data in one-third of the patients.
“The inability … to ascertain complete follow-up at 6 months puts us in a position where we don’t know whether that MI signal ultimately translates into an excess risk for mortality,” he said. – by Erik Swain
For more information:
Nicholls S. LBCT.04. Therapeutic advances in coronary and peripheral vascular disease. Presented at: the American Heart Association Scientific Sessions; Nov. 16-20, 2013; Dallas.
Disclosure: Nicholls reports financial ties with Amgen, Anthera Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Merck, Novartis, Omthera, Roche, Resverlogix and Takeda.
Perspective
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W. Douglas Weaver, MD, MACC, FAHA
There have now been two recent negative trials for secretory phospholipase A2 inhibitors: VISTA-16 and the STABILITY study evaluating darapladib (GlaxoSmithKline). We just don’t have an answer yet as to whether these drugs work. The surrogate markers so far have not correlated with outcomes. It may be because inflammation is not enough by itself to explain those outcomes. I’m not sure why, and it’s something we have to figure out. There is another darapladib study coming out early next year, and it will be interesting to see the results.
As for the conduct issues, that was horrible, no doubt about it. I’m uncertain about the sponsor’s reasoning. But it’s not a common occurrence, and industry for the most part has been a very good partner to academics.
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