Using darapladib after an acute coronary syndrome (ACS) event to directly inhibit lipoprotein-associated phospholipase A2 (Lp-PLA2) did not successfully reduce the risk of major coronary events, according to the SOLID-TIMI 52 trial presented Aug. 31 at ESC Congress 2014 and published simultaneously in the Journal of the American Medical Association.

Led by Michelle O'Donoghue, MD, MPH, Cardiovascular Division, Brigham and Women's Hospital, the SOLID-TIMI 52 trial was a double-blind, placebo-controlled study that enrolled 13,026 subjects within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI] at 868 sites in 36 countries). Randomized to once daily darapladib (160 mg enteric-coated tablet daily) or matching placebo, the enquiry's primary endpoint was the composite of coronary heart disease, death, MI, or urgent coronary revascularization for myocardial ischemia. Patients were then followed up for a median of 2.5 years between Dec. 7, 2009 and Dec. 6, 2013.

Additional Resources ESC Congress 2014 Meeting Coverage SOLID-TIMI 52 Trial Summary Presentation Slides

Results showed that during the 2.5 years, the primary endpoint occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3 percent vs. 15.6 percent at three years; hazard ratio [HR], 1.00 [95 percent CI, 0.91-1.09]; P = 0.93). The composite of cardiovascular death, stroke, or MI occurred in 824 in the darapladib group and 838 in the placebo group (15.0 percent vs. 15.0 percent at three years; HR, 0.99 [95 percent CI, 0.90-1.09]; P = 0.78). No differences were shown between the treatment groups for the individual components of the primary endpoints, for additional secondary endpoints, or all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3 percent vs 7.1 percent at three years; HR, 0.94 [95 percent CI, 0.82-1.08]; P = 0.40).

The investigators conclude that their findings "do not support a strategy of targeted Lp-PLA2 inhibition with darapladib in patients stabilized after an ACS event." They add that, overall their results "highlight some of the challenges that may occur during the development of novel therapeutics that are directed toward the inflammatory cascade. In particular, inflammation acts along many complex and redundant pathways that may attenuate the utility of blocking highly specific targets. Further, reliable surrogate end points are lacking to gain insights into a drug's efficacy prior to phase three testing. Although promising advances have been made in imaging modalities that allow for detailed plaque assessment, whether these surrogate end points can be translated into clinical events remains unknown."

Keywords: Inflammation, Myocardial Infarction, Acute Coronary Syndrome, Stroke, Platelet Aggregation Inhibitors, Biomarkers, Ticlopidine, 1-Alkyl-2-acetylglycerophosphocholine Esterase

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