Darapladib, a novel inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂), may slow expansion of the necrotic core of atherosclerotic plaques in patients with acute coronary syndrome (ACS) or other symptomatic coronary diseases, according to mixed results from the Integrated Biomarker and Imaging Study-2 (IBIS-2; NCT00268996).

Lp-PLA₂, an enzyme that promotes inflammation and plaque formation, is highly expressed in the necrotic core of atherosclerotic lesions. By suppressing Lp-PLA₂, darapladib theoretically reduces endothelial inflammation and growth of the necrotic core.

In IBIS-2, 330 patients were randomly assigned to treatment with darapladib (n=175) or placebo (n=155) in addition to optimal medical therapy to evaluate the effects of Lp-PLA₂ inhibition on coronary plaque deformability, composition, and size. William Wijns, MD, PhD, OLV Hospital, Aalst, Belgium, reported findings from IBIS-2, which were simultaneously published online in Circulation [Serruys PW et al. Circulation 2008].

Neutral Primary Endpoint

Investigators used intravascular ultrasound (IVUS) to visualize several parameters of plaque stability, including the plaque's necrotic core, dense calcium areas, and fibrous tissue. Another technique, called IVUS palpography, was used to measure the levels of tissue strain along segments of the target vessel.

Dr. Wijns and colleagues also measured high-sensitivity C-reactive protein (hsCRP) levels as a marker of systemic inflammation. The co-primary endpoints in IBIS-2 were changes in IVUS palpography and hsCRP at 12 months compared with baseline.

After 1 year of treatment, the between-group difference in plaque deformability was not statistically significant (−0.08; p=0.22). In addition, although mean hsCRP levels declined in all patients, the mean hsCRP levels at 12 months in the placebo (1.0 mg/L) and darapladib (0.9 mg/L) groups were comparable (p=0.35).

Promising Secondary Endpoint Results

Although the IBIS-2 trial did not meet either of its co-primary endpoints, the comparison of secondary endpoints did suggest some benefit with darapladib. For example, while the volume of the necrotic core increased over 12 months in the placebo group (4.5± 17.9 mm³; p=0.009), plaque growth appeared to arrest in the darapladib group (–0.5±13.9 mm³; p=0.71), resulting in a significant difference between the 2 treatment groups of 5.2 mm³, favoring darapladib (p=0.012).

Darapladib also had a beneficial effect on inflammatory biomarkers. As expected, patients in the darapladib group had a significant 59% reduction in Lp-PLA₂ activity compared with those in the placebo group (62 vs 153 μmol/min¹/L¹; p<0.001). Other inflammatory biomarkers, including oxidized phospholipid/apolipoprotein B, did not change significantly. However, in a post hoc analysis, a higher proportion of patients in the darapladib group achieved hsCRP levels <1 mg/L compared with placebo (62% vs 45%; p=0.008).

The IBIS-2 trial was not powered to evaluate the effects of darapladib on cardiovascular outcomes, and no differences were observed. A safety analysis showed no differences in serious adverse events or clinical outcomes between the treatment groups, although there was a slightly higher systolic blood pressure, measured noninvasively (+3.0 mm Hg. 95% CI +0.3 to +5.7 mm Hg; p=0.031), in patients who were treated with darapladib.

In summary, IBIS-2 failed to show that Lp-PLA₂ inhibition improves plaque stability, as measured by IVUS palpography. However, analyses of the IBIS-2 secondary endpoints suggest that necrotic core expansion occurs despite optimal medical therapy, even in the absence of an overall change in plaque size. In addition, treatment with darapladib appears to halt this process in patients with established coronary disease. This trial was relatively small, and patients were followed for only 12 months; thus, future clinical trials will be required to evaluate whether Lp-PLA₂ inhibition, by stopping expansion of the necrotic core, can prevent recurrent cardiovascular events in high-risk patients.