Darapladib No Benefit in ACS Patients: SOLID-TIMI 52

August 31, 2014

BARCELONA, SPAIN — Acute coronary syndrome (ACS) patients who received darapladib, a selective inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), on top of optimal medical therapy fared no better than ACS patients who received optimal medical therapy alone, according to the results of a new study[1].

During a median follow-up of 2.5 years, darapladib failed to reduce the risk of CHD death, MI, and urgent coronary revascularization compared with placebo in 13 026 patients stabilized following an ACS event. In fact, treatment with darapladib failed to positively affect any cardiovascular end point, including the individual components of the primary end point.

"These results were consistent across key subgroups, including those stratified by baseline LDL-cholesterol concentration and baseline Lp-PLA2 activity level," according to the investigators. "Our findings therefore do not support a strategy of targeted Lp-PLA2 inhibition with darapladib in patients stabilized after an ACS event who are similar to those enrolled into this trial."

The study, known as SOLID-TIMI 52 , was led by Dr Michelle O'Donoghue (Brigham and Women's Hospital, Boston, MA) and presented today at the European Society of Cardiology 2104 Congress . It was published concurrently in the Journal of the American Medical Association.

Dr Michelle O'Donoghue

Speaking with the media at an ESC press conference, O'Donoghue said the findings do not argue against the role of inflammation in atherosclerosis but "highlight the unique challenges that are faced on the road to developing anti-inflammatory therapeutics." To date, reliable surrogate end points for inflammation are currently lacking, she added.

"Conceptually, we all believe that inflammation plays a crucial role, and there are certainly a lot of novel anti-inflammatory therapeutics being developed," she said. "The issue may be that inflammation is just such a complex and redundant series of pathways that if we narrow in on too specific a target, perhaps there's compensation along others. But that's just speculation at this point."

For the SOLID-TIMI 52 investigators, although the negative results do not support a role for Lp-PLA2 as a therapeutic target, they concede it was an uphill battle to demonstrate an incremental benefit for Lp-PLA2 inhibition beyond existing therapies for ACS management. For example, statins also reduce Lp-PLA2 activity and mass, and the extent of the reduction can't be predicted based on LDL-cholesterol levels alone.

Earlier this year at the American College of Cardiology 2014 Scientific Sessions, Dr Harvey White (University of Auckland, New Zealand) presented the results of the STABILITY trial with darapladib. As reported by heartwire , STABILITY was also negative, with investigators reporting that treatment with darapladib on top of guideline-recommended therapy did not reduce the risk of cardiovascular mortality, MI, or stroke in patients with stable coronary heart disease. There was a hint of a benefit in the secondary end points—a 10% reduction in the risk of major coronary events and a 9% reduction in total coronary events—but the findings were deemed exploratory only.

Following the negative SOLID-TIMI 52 and STABILITY studies, GlaxoSmithKline, the maker of darapladib, said it has no plans to seek regulatory approval.

GlaxoSmithKline funded the SOLID-TIMI 52 study. O'Donoghue reports institutional grants from GlaxoSmithKline, Eisai, and AstraZeneca; honoraria from diaDexus; and consulting fees from Aegerion. Disclosures for the coauthors are listed in the article.

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