Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial

JAMA. 2014 Sep 10;312(10):1006-15. doi: 10.1001/jama.2014.11061.

Abstract

Importance: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme.

Objective: To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event.

Design, setting, and participants: SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries.

Interventions: Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013.

Main outcomes and measures: The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years.

Results: During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%).

Conclusions and relevance: In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events.

Trial registration: clinicaltrials.gov Identifier: NCT01000727.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / drug therapy*
  • Aged
  • Benzaldehydes / adverse effects
  • Benzaldehydes / therapeutic use*
  • Blood Proteins / adverse effects
  • Blood Proteins / therapeutic use*
  • Cardiovascular Diseases / mortality
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Humans
  • Incidence
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / epidemiology
  • Myocardial Ischemia / epidemiology
  • Myocardial Ischemia / prevention & control
  • Myocardial Ischemia / therapy
  • Oximes / adverse effects
  • Oximes / therapeutic use*
  • Secondary Prevention

Substances

  • Benzaldehydes
  • Blood Proteins
  • Oximes
  • PLIalpha
  • darapladib

Associated data

  • ClinicalTrials.gov/NCT01000727