Varespladib Trial Was Halted for Futility and Possible Harm in 2012
November 18, 2013
Patients with acute coronary syndrome who were treated with the experimental drug varespladib were more likely to experience additional cardiovascular events – including sudden death, heart attack and stroke – than those treated with placebo, according to research from the Cleveland Clinic Coordinating Center for Clinical Research (C5Research).
The results of the VISTA-16 (Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks) trial, which was halted last year for futility and possible harm, were presented today at the American Heart Association Scientific Sessions 2013 in Dallas and published simultaneously in the Journal of the American Medical Association (JAMA).
Varespladib inhibits production of the compound secretory phospholipase A2 (sPLA2), which promotes the vascular inflammation implicated in the development of atherosclerosis, or the clogging and hardening of arteries.VISTA-16 was designed to test whether the use of varespladib to reduce sPLA2 would lower the risk of cardiovascular events in patients with acute coronary syndrome. Patients with acute coronary syndrome have had a heart attack or experienced unstable angina, which can lead to a heart attack.
Rather than reduce additional cardiovascular events, including sudden death, heart attack, stroke, and unstable angina, the study found that patients treated with varespladib were more likely than those treated with placebo to experience these events. Both groups of patients were also treated with statin therapy and standard-of-care protocols. The primary endpoint, a composite of sudden death, heart attack, stroke and unstable angina, occurred in 6.1 percent of patients on varespladib compared to 5.1 percent of those on placebo.
In addition, the study found that varespladib was associated with a significantly greater risk of heart attack, occurring in 3.4 percent of the study population on varespladib and 2.2 percent of those on placebo.
After reviewing this data, the trial’s independent Data and Safety Monitoring Board called off the trial in March 2012.
“Despite prior experimental and observational data suggesting that varespladib would have beneficial cardiovascular effects, this trial proves the contrary, that it is actually detrimental to cardiovascular morbidity and mortality,” said VISTA-16 executive committee chair Stephen J. Nicholls, MD, Ph D, senior consultant to Cleveland Clinic’s C5Research and Professor of Cardiology and Deputy Director at the South Australian Health & Medical Research Institute (SAHMRI) in Adelaide, Australia.
“The drug cannot be used to prevent cardiovascular events in patients with acute coronary syndrome,” he said.
The researchers do not know whether the outcome of the VISTA-16 trial is attributable to the varespladib molecule itself, or the across-the-board inhibition of sPLA2, which is known to have both protective and inflammatory affects on the cardiovascular system.
“We know that vascular inflammation plays a significant role in the development of coronary disease, and it’s important for the scientific community to continue to pursue drugs that may ease the inflammatory process and reduce cardiovascular risk,” said Steven Nissen, MD, senior author on the JAMA paper and Chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic. “Unfortunately, the complexity of the inflammatory process continues to confound our efforts at taming it.”
VISTA-16 was a double-blind, randomized, placebo-controlled trial designed to enroll more than 5,000 patients at 362 academic and community hospitals in Australia, Europe, India, New Zealand, and North America. It was an academically directed trial developed by an independent executive steering committee with input from the sponsor, Anthera Pharmaceuticals, and monitored by a Data and Safety Monitoring Board independent from both the executive committee and the sponsor.
About Cleveland Clinic
Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S.News & World Report consistently names Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. More than 3,000 full-time salaried physicians and researchers and 11,000 nurses represent 120 medical specialties and subspecialties. The Cleveland Clinic health system includes a main campus near downtown Cleveland, more than 75 Northern Ohio outpatient locations, including 16 full-service Family Health Centers, Cleveland Clinic Florida, the Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, and, currently under construction, Cleveland Clinic Abu Dhabi. In 2012, there were 5.1 million outpatient visits throughout the Cleveland Clinic health system and 157,000 hospital admissions. Patients came for treatment from every state and from more than 130 countries. Visit us at http://my.clevelandclinic.org. Follow us at http://www.twitter.com/ClevelandClinic.
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