A novel agent that targets the inflammation process believed involved in cardiovascular events failed to reduce heart attack, stroke, or cardiovascular death in at-risk individuals when compared with placebo, researchers reported here and online in the New England Journal of Medicine.
The composite endpoint was experienced by 9.7% of the patients with chronic coronary heart disease who were treated with the new agent, darapladib, while that endpoint was experienced by 10.4% of patients assigned to placebo (P=0.199), said Harvey D. White, MD, director of the coronary care unit at Auckland City Hospital in Auckland, New Zealand, and a co-chair of the study.
However, secondary endpoints offered promise that darapladib might be helpful in subsets of people in the study, White suggested during his presentation of the at the annual scientific sessions of the American College of Cardiology. For example, he noted that the relative risk reduction for time to first occurrence of major coronary events, which also included urgent coronary revascularization, was decreased by 10% with darapladib when compared with placebo (P=0.045).
However, Howard Bauchner, MD, editor in chief of the Journal of the American Medical Association, who discussed the study at a press conference, told MedPage Today, “This was the finding of a secondary endpoint and when you have a number of secondary endpoints, if you look hard enough there is usually something that meets statistical significance.
“I think they are going to have to go back to ground zero to design a new trial that may work for certain individuals for this drug,” he said.
In the “Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY)” trial, White and colleagues in nine countries enrolled 15,828 individuals who had experienced a prior myocardial infarction, had undergone prior coronary revascularization or had documented multivessel coronary artery disease. He said 7,904 patients in the study were assigned to placebo and 7,924 patients received darapladib 160 mg once daily.
The patients were all being treated with aspirin therapy, statin and anti-hypertensive medication as indicated, and then were randomly assigned to either darapladib or placebo on top of their optimized medical treatment.
After 48 months, researchers observed 819 events in the placebo arm of the study and 769 events in the patients on darapladib.
White said the goal of the study was to determine if treatment with darapladib which inhibits Lp-PLA2, a biomarker of inflammation in blood vessels, could prevent intra-bloodstream events that lead to cardiovascular events. In the bloodstream, Lp-PLA2 is generally found on LDL cholesterol. High Lp-PLA2 levels are a risk factor for coronary heart disease. In animal models, Lp-PLA2 is linked with vulnerable plaque.
He said that the treatment was well tolerated over the median follow-up of 3.7 years in the international, phase III double-blind trial.
“These events are clinically important, with substantial consequences for patients,” said White. “The effects on these endpoints could support the hypothesis that inhibition of Lp-PLA2 with darapladib may alter the composition of atherosclerotic plaques to a less vulnerable state and reduce ischemic events related to coronary artery plaque progression and rupture.”
White said that patients in the study were under good care by their physicians. At baseline, 93% of patients were taking aspirin, 97% were on statins, 79% were taking beta-blockers, and 77% were on antihypertensive ACE-inhibitors. “We set out to test the incremental effect of darapladib on top of optimal treatment,” he said.
STABILITY is the first study to test this inflammation-prevention mechanism for reducing the likelihood that plaque will become an artery-blocking clot. Ongoing analysis of biomarkers, including Lp-PLA2 levels, and genetic sub-studies of STABILITY may help provide insight about darapladib’s potential effects on the prevention of coronary events in patients with stable coronary heart disease.