• Cardiology Clinical Trials
• Coronary Artery Disease

• Cardiology Clinical Trials
• Coronary Artery Disease
• Cardiology

An investigational, selective, orally active inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) failed to significantly reduce the risk for cardiovascular (CV) death, myocardial infarction (MI), or stroke in stable coronary heart disease (CHD) patients on optimal medical therapy.

The design and results of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial [STABILITY; The STABILITY Investigators. N Engl J Med 2014] were presented by Harvey D. White, DSc, Auckland City Hospital, Auckland, New Zealand.

Elevated plasma levels of Lp-PLA₂ are associated with an increased risk of coronary events. The enzyme is secreted by T cells and macrophages and circulates largely bound to low-density lipoproteins [Zalewski A, Macphee C. Arterioscler Thromb Vasc Biol 2005]. Within atheromatous plaque, it hydrolyzes oxidatively modified polyunsaturated fatty acids producing lysophosphatidylcholine and oxidized nonesterified fatty acids, explained Prof. White. “Unstable” plaques are characterized by a higher content of Lp-PLA₂ and other markers of inflammation [Corson MA et al. Am J Cardiol 2008].

Darapladib decreases Lp-PLA₂ levels by ∼60% [Serruys PW et al. Circulation 2008]. In preclinical investigations, it reduced Lp-PLA₂ levels and necrotic core area within atherosclerotic plaque [Wilensky RL et al. Nat Med 2008]. In humans, treatment with darapladib was shown to halt progression of coronary artery necrotic plaque core volume in patients with CHD, but not atheroma volume [Serruys PW et al. Circulation 2008].

STABILITY compared darapladib at a dosage of 160 mg/day with placebo in a double-blind, randomized, global trial of 15,828 patients with chronic CHD receiving standard of care. The median patient age was 65 years, ∼80% were white, and ∼80% were male. Fifty-nine percent had a qualifying diagnosis of MI for more than 1 month prior to randomization and 75% had undergone prior coronary revascularization. Fifteen percent had multivessel CHD at baseline. Very high rates of evidence-based background therapies were used at baseline and throughout the duration of the study (>90% use of aspirin; >95% use of statins; ∼80% use of β-blockers; and ∼50% use of angiotensin-converting enzyme inhibitors).

At a median follow-up of 3.7 years, the primary endpoint—a composite of CV death, MI, and stroke—occurred in 819 patients randomized to placebo (10.4%) compared with 769 patients randomized to darapladib (9.7%), corresponding to a hazard ratio of 0.94 (95% CI, 0.85 to 1.03) that did not achieve significance (p=0.20). Results for the components of the primary endpoint are shown in Table 1. There were no significant differences between darapladib and placebo on any of the individual components of the primary endpoint or all-cause mortality.

Coronary-specific endpoints suggested benefit to darapladib. Darapladib was associated with a reduction in the rate of the prespecified secondary endpoints of major coronary events (10.3% vs 9.3%; HR, 0.90; p=0.045) and total coronary events (16.1% vs 14.6%; HR, 0.91; p=0.019; Table 1). These findings should be considered exploratory in light of the lack of effect on the primary endpoint, said Prof. White.

Serious adverse events occurred at a similar frequency in the darapladib and placebo arms, 42.6% and 43.7%. Adverse events leading to study drug discontinuation occurred in 19.8% and 13.5% in the darapladib and placebo arms, respectively. Side effects that led to darapladib discontinuation included diarrhea, abnormal feces, abnormal skin odor, and abnormal urine odor.

In STABILITY, subgroup analyses based on biomarkers and genetics will further explore the potential utility of darapladib in specific high-risk patient subsets. The SOLID TIMI-52 trial [NCT010007277] which is testing darapladib in ∼13,000 post-ACS patients is expected to report results in 2014.

• © 2014 MD Conference Express®