1. During a median follow-up of 3.7 years, there was no difference in the occurrence of the primary end point (a composite of cardiovascular death, myocardial infarction, and stroke) among medically-optimized stable coronary heart disease patients randomized to a darapladib or placebo.
2. Significantly more patients in the darapladib group discontinued the study drug.
3. The rate of adverse events was higher in the darapladib group.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Previous studies have shown that lipoprotein-associated phospholipase A2 increases the production of proinflammatory mediators in atherosclerotic plaques, and that there is a continuous association between this enzyme’s activity and the risk of coronary heart disease. Darapladib is a reversible oral inhibitor of lipoprotein-associated phospholipase A2, and had previously been shown to halt the progression in the volume of the necrotic core of coronary artery plaques. However, in STABILITY, a large, multicenter, randomized controlled study, the authors did not find a significant reduction in risk of the primary end point (composite of cardiovascular death, myocardial infarction, and stroke) in patients with stable coronary heart disease who were optimized in terms of medical management of their coronary heart disease. Additionally, there was an increased risk of drug discontinuation within the darapladib group due to diarrhea and abnormal odors (feces, urine, skin) as well as an unexplained increased risk of renal failure in the treatment arm.
Strengths of this study include the large number of patients who participated across 39 countries, as well as the excellent study follow-up over a median of 3.7 years. The robust, well-powered study design lends credence to the null result in terms of the primary study outcome. Additionally, investigators were encouraged to optimize the medical management of patients’ underlying coronary heart disease, thus providing a real-world depiction of the efficacy of adding darapladib to an optimized regiment including statins and aspirin.
The study was funded by GlaxoSmithKline, the producer of darapladib.
In-Depth [randomized controlled trial]: The STABILITY trial evaluated the clinical efficacy and safety of darapladib in patients with stable coronary heart disease. In this study, 15,828 patients with a history of coronary heart disease and an additional cardiovascular risk factor were assigned to receive darabladib or placebo. Investigators were strongly encouraged to optimize patients’ medical management of coronary heart disease for the duration of the study. The primary end point was a composite of cardiovascular death, myocardial infarction, and stroke.
During a median follow-up of 3.7 years, the primary end point occurred in 9.7% of patients in the darapladib group compared to 10.4% of the placebo group (hazard ratio in darapladib group, 0.94; 95% CI, 0.85 to 1.03; P=0.20), with virtually superimposed Kaplan Meyer survival curves. No significant effects of darapladib were seen in preventing cardiovascular death, MI, or stroke, or all-cause mortality. Darapladib reduced the rate of major coronary events (9.3% vs. 10.3%, P=0.045) as well as total coronary events (14.6% vs. 16.1%, P=0.02).
Of note, more patients in the darapladib group discontinued the study drug (32.7% vs. 26.8%; hazard ratio, 1.29; 95% CI, 1.22 to 1.37), and the rate of adverse events was increased in the darapladib group. Common reasons for discontinuation included diarrhea and abnormal odor of feces, urine, and skin. There were also more serious adverse events of renal failure in the darapladib group compared to the placebo group (1.5% vs 1.1%; hazard ratio, 1.35, 95% CI, 1.03 to 1.78).
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