Boston, MA - The novel biomarker lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is not useful for risk stratification in the immediate aftermath of acute coronary syndrome, but it is linked to an increased risk of cardiovascular events 30 days later, a new analysis of the PROVE IT-TIMI 22 study shows [1].

Dr Michelle O'Donoghue (Brigham and Women's Hospital, Boston, MA) and colleagues report their findings in the April 11, 2006 issue of Circulation.

O'Donoghue told heartwire: "Lp-PLA₂ levels do not appear to be reliably useful for risk assessment during hospitalization for ACS. However, when measured later, Lp-PLA₂ can offer prognostic information incremental to that provided by traditional risk markers, including both LDL and CRP [C-reactive protein]."

O'Donoghue explained that several previous studies have shown an association between higher levels of Lp-PLA₂ and the risk of cardiovascular events, but these have been mostly in primary-prevention populations. A few small studies have suggested that Lp-PLA₂ may also be useful for risk stratification in coronary artery disease, but until now there has been little information regarding the role of Lp-PLA₂ in ACS. "The current study gives us additional insight into when and how to measure this marker," she says.

In this analysis, the researchers measured both Lp-PLA₂ activity and Lp-PLA₂ mass at two distinct time points in the PROVE IT-TIMI 22 trial—baseline (n=3648) and 30 days (n=3265). Baseline samples were measured a median of seven days after ACS. All patients were randomized to either atorvastatin 80 mg/day or pravastatin 40 mg/day.

The primary end point was death, myocardial infarction, unstable angina, revascularization, or stroke. At baseline, the risk of recurrent CV events was similar across all quintiles of Lp-PLA₂ activity. There was also no significant difference in Lp-PLA₂ mass across the groups.

In contrast, at 30 days, after adjustment for confounding factors (including LDL cholesterol and CRP), Lp-PLA₂ activity in the highest quintile was associated with a significant 33% increase in the relative risk of cardiovascular events (p=0.002).

However, the relationship between Lp-PLA₂ mass at 30 days and cardiovascular events was not significant after adjustment.

O'Donoghue explained to heartwire that Lp-PLA₂ mass is measured with a commercially available assay, the PLAC test (diaDexus Inc), which was used in most previous studies of Lp-PLA₂. The assessment of enzyme activity was done in cooperation with GlaxoSmithKline; there is currently no commercially available test to measure Lp-PLA₂ activity, she notes.

O'Donoghue says further work is required to determine whether inhibition of the Lp-PLA₂ enzyme itself will prove to be a valuable therapeutic target. "In the current study, we found that intensive statin therapy was associated with a larger reduction in Lp-PLA₂ levels compared with more moderate statin treatment. This was beyond what could be explained by LDL lowering alone.

"Although this finding is quite encouraging, we don't yet know for certain whether inhibiting the Lp-PLA₂ enzyme, either with statins or new Lp-PLA₂ inhibitors, will be associated with improved outcomes."

GlaxoSmithKline is developing an Lp-PLA₂ inhibitor, which is currently in phase 2/3 trials.