Darapladib Halts Expansion of Coronary Atherosclerotic Plaque: Presented at ESC

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Title: Darapladib Halts Expansion of Coronary Atherosclerotic Plaque: Presented at ESC
URL: http://www.pslgroup.com/dg/22AC92.htm
Doctor's Guide
September 4, 2008

By Chris Berrie

MUNICH, Germany -- September 4, 2008 -- The selective lipoprotein-associated phospholipase A₂ (Lp-PLA₂) inhibitor darapladib plus standard-of-care treatment is safe and halts the expansion of the necrotic core compared with standard care alone in patients with acute coronary syndrome or chronic coronary artery disease, according to a multicentre, randomised, double-blind, placebo-controlled study.

The study was presented here on September 2 at the European Society of Cardiology 2008 Congress by William Wijns, MD, PhD, Cardiovascular Centre, OLV Hospital, Aalst, Belgium, on behalf of the Integrated Biomarker and Imaging Study-2 (IBIS-2) investigators.

For reduction of cardiovascular events, most approaches target conventional risk factors. Despite optimal control at this level, there remains a residual risk, and recurrent cardiovascular events continue to occur in some patients, Dr. Wijns explained.

"Accordingly, the evaluation of novel plaque-modifying therapies added to standard-of-care treatments requires assessments of coronary plaque extending beyond measurements of its size and focusing on changes in plaque composition," he said.

The enzyme Lp-PLA₂ is responsible for intraplaque generation of proinflammatory and proapoptotic products. Therefore its inhibition should theoretically reduce endothelial inflammation and expansion of the necrotic core.

In their study, Dr. Wijns and colleagues randomised 155 patients with a mean age of 57 years (male, 83%) to placebo and 175 patients with a mean age of 59 years to darapladib 160 mg (male, 81%). Both groups also received standard-of-care treatment.

Patient demographics, risk factors, and index hospitalisation were not significantly different in the 2 treatment groups except for a high prevalence of hypertension in the darapladib group (67% vs 59% for placebo).

Intravascular ultrasound (IVUS) virtual histology imaging was used to visualise the plaque's necrotic core, dense calcium areas, and fibrofatty and fibrous tissue, while IVUS palpography imaging was used to visualise tissue strain levels.

Coprimary endpoints were plaque deformability visualised by IVUS palpography and high-sensitivity C-reactive peptide (hsCRP) level as a marker of systemic inflammatory burden. Key secondary endpoints were plaque composition (by IVUS virtual histology as volume of the necrotic core), overall plaque size, and plasma Lp-PLA₂ activity.

At a median time to IVUS follow-up of 364 days, with plaque deformability as mean changes from baseline, there were no significant differences for the active treatment group versus placebo for the entire region of interest or for the worst 10-mm subsegment.

For the secondary endpoint of plaque composition, with a significant increase in placebo (4.5 mm³; P = .009) and a block with darapladib, there was a significant treatment difference of -5.2 mm³ (P = .012). Significant benefit was also seen for darapladib in the worst 10-mm subsegment (P = .003).

Dr. Wijns noted, "Treatment effect in favour of darapladib was highly consistent among several clinical subgroups of interest."

For biomarkers, the coprimary endpoint of plasma hsCRP at 12 months showed no significant difference between placebo and darapladib (1.11 vs 0.86 mg/L). However, in a post hoc analysis, a significantly higher proportion of patients treated with darapladib achieved hsCRP levels <1 mg/L compared with placebo (62% vs 45%; P = .008).

The secondary endpoint of Lp-PLA₂ activity showed a significant 59% reduction for darapladib treatment over placebo (62 vs 153 mcmol/min/L; P < .001).

For the safety analysis across all adverse events and clinical outcomes, there were no significant differences between these treatment groups, Dr. Wijns said.

The full study results were published simultaneously online in Circulation (DOI: 10.1161/CIRCULATIONAHA.108.771899).

[Presentation title: The Effects of the Direct Lp-PLA₂ Inhibitor, Darapladib on Human Coronary Atherosclerotic Plaque. Abstract 3206]

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