STABILITY Trial Results: Novel Plaque Inhibitor Darapladib Fails to Show Cardiovascular Benefit

Darapladib, a novel agent targeting an enzyme known to be associated with increased instability of atherosclerotic plaque, failed to show real-world benefit in a large global trial examining mortality and coronary outcomes.

Harvey White, MD, of the University of Auckland, New Zealand, presented results on behalf of the investigators of the STABILITY (Stablilization of Atherosclerotic Plaque By Initiation of Darapladib Therapy) trial at the American College of Cardiology 2014 Scientific Session on March 30, 2014, in Washington, DC.

Lipoprotein-associated phospholipase A2 (Lp PLA2) has been identified as an inflammatory marker. In previous work, a large multicenter study compared Lp PLA2 to conventional risk factors. This early work showed elevated Lp PLA2 activity to carry a similar relative risk as other more conventional risk factors, such as systolic blood pressure (SBP), non-high density lipoprotein cholesterol (HDL-C), and HDL-C.

Darapladib, studied here in the STABILITY trial, is a selective oral Lp PLA2 inhibitor that can decrease Lp PLA2 levels by about 60%, and is known to reduce Lp PLA2 levels both in human carotid and in pig plaque, and to stabilize coronary artery necrotic plaque core volume.

Stable plaque has low Lp PLA2, few inflammatory cells and a thick fibrous cap, even with significant stenosis. High Lp PLA2 content may signal vulnerable or ruptured plaque with a large lipid pool, a thin fibrous cap, and many inflammatory cells, even if the lumen is not significantly obstructed. The STABILITY study examined whether lowering Lp PLA2 levels would translate into benefit in terms of patient outcomes.

For the study, 15,828 patients with chronic coronary heart disease (including previous myocardial infarction, coronary artery disease, or cardiac revascularization) were randomized to darapladib 160 mg or placebo and followed for a median 3.7 years while receiving optimized treatment according to guidelines.

Median age was 65, with wide geographic distribution of enrollment; however, over 80% of subjects were male. Most patients (96%) were receiving a statin and most were also on aspirin and beta blockers on study enrollment; 59% had previous myocardial infarction (MI), and three quarters had undergone coronary revascularization. Median low density lipoprotein cholesterol (LDL-C) was 80.

Patients with planned coronary revascularization, liver disease, severe renal impairment, heart failure, or asthma, poorly controlled hypertension, or a history of anaphylaxis were excluded, as were patients with native low Lp-PLA2 activity.

Primary endpoints were identified as a composite of myocardial infarction (MI), stroke, or cardiovascular death. Secondary endpoints included both total coronary events and major coronary events. Enrichment criteria included current or recent former smoking, renal dysfunction, low HDL (<40), medication-requiring diabetes, polyvascular disease, or age over 60 years.

The study tracked time to first occurrence of death, major coronary events and stroke, as well as time to first occurrence of any coronary event (for which unstable angina and any coronary revascularization were added to coronary-related death, MI, and urgent revascularization).

There was no reduction in occurrence of the primary composite endpoint (cardiovascular death, MI, or stroke) in the intervention arm of this trial in patients with coronary artery disease followed out to a median of 3.7 years. For the composite secondary endpoint of major coronary events, darapladib-receiving subjects fared slightly better (9.3%) than those on placebo (10.3%, P = .045), as they did for another secondary composite of CV death, MI, any coronary revascularization, and hospitalization for unstable angina (16.1% vs. 14.6%, P = .02). Subgroup analysis for the primary composite endpoint showed that smokers seemed to receive more benefit from darapladib, with a hazard ratio of 0.77 (0.62, 0.96, P = .044).

In concluding, White urged further investigation of the relationships between Lp PLA2 reduction and other biomarkers, as well as investigation of phenotypic and genotypic subsets to see whether darapladib might have increased benefit for some individuals, as the subgroup analysis of smokers might suggest.