SOLID-TIMI 52: Darapladib a dud for acute coronary syndrome

Acute coronary syndrome patients did not experience benefit from using darapladib in a study published Aug. 31 in JAMA.

Investigators taking part in the multinational Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) trial enrolled 13,026 patients at 868 sites in 36 countries. This phase 3 clinical trial intended to determine whether darapladib was a safe and effective treatment for acute coronary syndrome patients if started within 30 days post-hospitalization compared with a placebo.

Patients were enrolled between 2009 and 2011. Follow-up occurred over a median of 2.5 years; the longest duration of follow-up was 3.8 years.

Michelle L. O’Donoghue, MD, MPH, of Brigham and Women’s Hospital in Boston, and colleagues had found prior research into the activity of darapladib to inhibit Lipoprotein-associated phospholipase A2 (Lp-PLA2) promising, however, the promise was not realized as part of this study.

Instead, very little significance was seen between outcomes for patients, regardless of sex, ethnicity, or race -– previously identified as potentially affecting outcomes -– in rates of coronary heart disease or cardiovascular-related death, emergency coronary revascularization for MI, stroke or MI, either as a composite or individually. Nor did it have much of an effect on lowering blood cholesterol concentrations over time, in spite of reports from prior research.

Major coronary events occurred in 16.3 percent of darapladib patients over the course of three years, while the placebo group had a rate of 15.6 percent over three years. Cardiovascular death, MI, or stroke occurred in 15 percent of both darapladib and placebo patients. Risk for all-cause mortality was also similar between the two groups: darapladib patients at 7.3 percent vs.  placebo patients at 7.1 percent.

Seventeen percent of darapladib patients discontinued the drug against 12 percent taking placebo.

However, similar previous reports, odor concerns and diarrhea were reported with significantly increased frequency in patients taking darapladib against the placebo.

O’Donoghue et al did not recommend the use of darapladib in patients with stabilized acute coronary syndrome, nor did they recommend targeted Lp-PLA2 inhibitor therapy for these patients as no clinical benefit was noted in this large, ethnically and racially diverse population.

They were left, however, with one key question regarding the role of Lp-PLA2 in the development of atherosclerosis and the inflammatory processes surrounding it. O’Donoghue et al were unable to account for differences seen in the in vitro and in vivo results using this drug against the clinical application.

O’Donoghue et al wrote that further research was needed to determine how these processes may affect outcomes in acute coronary syndrome patients.