• Cardiology Clinical Trials
• Coronary Artery Disease
• Cardiology

• Cardiology Clinical Trials
• Coronary Artery Disease

The Stability of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial [STABILITY; NCT00799903] showed that darapladib, an oral inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂), compared with placebo, did not significantly reduce the composite primary end point of cardiovascular (CV) death, myocardial infarction (MI), and stroke (HR, 0.94; 95% CI, 0.85 to 1.03; P = .20) in 15 828 patients with stable coronary heart disease (CHD) on optimal medical therapy [White HD et al. N Engl J Med. 2014]. The mean follow-up duration was 3.7 years. The secondary end point of major coronary events (CHD death, MI, and urgent coronary revascularization) was significantly reduced with treatment versus placebo (HR, 0.90; 95% CI, 0.82 to 1.00; P = .045).

Lars Wallentin, MD, PhD, Uppsala Clinical Research Center, Uppsala, Sweden, presented data from a predefined analysis of STABILITY designed to examine factors that contribute to high levels of Lp-PLA₂ activity, whether its activity predicted outcomes or identified patients who would have a greater benefit with darapladib, and whether darapladib would provide persistent, long-term reduction of Lp-PLA₂ activity.

For this analysis, blood samples were collected at baseline from 14 500 patients; of these, samples were also collected at all follow-up visits (months 1, 3, 6, and 18 and end of treatment) in 100 patients. The mean activity level of Lp-PLA₂ was 172 nmol/min/mL, with a normal distribution in relation to baseline demographics. The patients were evenly divided by tertiles of Lp-PLA₂ activity (tertile 1, ≥ 153.6 nmol/min/mL; tertile 2, 153.7–192.5 nmol/min/mL; tertile 3, > 192.5 nmol/min/mL).

The baseline characteristics and biomarkers that increased or decreased Lp-PLA₂ activity on multivariate analysis are shown in Table 1. In the subset of 100 patients, there was a 65% relative risk reduction in Lp-PLA₂ activity with darapladib that was seen 1 month after treatment began and persisted through the end of follow-up.

For the primary end point, the baseline level of Lp-PLA₂ activity predicted an increased risk for events, with a significant increase in tertile 3 versus tertile 1 (P < .001) and a nonsignificant (NS) increase in tertile 2 versus tertile 1 (Figure 1). A similar prognostic effect was seen for the secondary end point of major coronary events for tertile 3 versus tertile 1 (HR, 1.52; 95% CI, 1.34 to 1.73; P < .001) and tertile 2 versus tertile 1 (HR, 1.12; 95% CI, 0.97 to 1.28; P = NS).

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Figure 1.

Lp-PLA₂ Activity in Relation to Primary Outcome

C V, card iovascu la r; Lp-PL A₂, lipoprotein-associated phospholipase A₂; MI, myocardial infarction.Reproduced with permission from L Wallentin, MD, PhD.

No relation was found between treatment with darapladib and the composite primary or secondary outcomes in any tertile of Lp-PLA₂ activity (Table 2).

In addition to traditional risk factors that increased the risk for a primary outcome event, Lp-PLA₂ activity increased this risk (tertile 3 vs tertile 1; HR, 1.45; 95% CI, 1.25 to 1.69; P < .001). Darapladib versus placebo treatment did not influence the risk for the primary outcome (HR, 0.92; 95% CI, 0.83 to 1.03; P = .14).

This analysis of the STABILITY study showed that Lp-PLA₂ activity is an independent predictor of CV events, but its baseline activity did not predict the effect of darapladib on coronary events.

Further evaluation is needed to determine the value of measuring Lp-PLA₂ activity to predict CV risk in the absence of an indication for a specific treatment, stated Prof Wallentin.

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