Lipoprotein-Associated Phospholipase A2 a Novel Risk Marker
"[When measured per this protocol,] Lp-PLA 2 can offer prognostic information incremental to that provided by traditional risk markers including LDL and CRP."
New results from a major cardiovascular study show that when measured approximately 30 days after an acute coronary event such as angina or myocardial infarction (MI), elevated levels of lipoprotein-associated phospholipase A 2 (Lp-PLA 2) activity are an independent risk marker for death or recurrent cardiovascular events. The information provided by this marker is incremental to that obtained from traditional risk factors such as low-density lipoprotein (LDL) and C-reactive protein (CRP), researchers say.
Lp-PLA 2, also known as platelet-activating factor acetylhydrolase, is found in blood and atherosclerotic plaque and has been associated with the risk of cardiovascular events in primary prevention, but little has been known about its prognostic role in patients following acute coronary syndromes (ACS). The new data, published in the April 11 issue of Circulation, come from a substudy of the PRavastatin Or atorVastatin Evaluation and Infection Therapy (PROVE IT-TIMI 22) trial, a study that compared intensive vs moderate lipid lowering with statins for the prevention of major cardiac events in 4162 patients who had been hospitalized after an episode of ACS. Participants were followed for a mean of 24 months for incidence of fatal or nonfatal MI or stroke, unstable angina, revascularization, and all other causes of death.
The substudy analyzed plasma Lp-PLA 2 levels measured in 3648 subjects at baseline and at the 30-day follow-up visit, which corresponded to approximately 7 days and 37 days, respectively, after the onset of the acute event. When participants were divided into 5 equal-sized groups (quintiles) based on Lp-PLA 2 activity, those in the group with the highest levels of Lp-PLA 2 activity were found to be at significantly higher risk of experiencing death or a cardiovascular event compared with participants whose Lp-PLA 2 activity levels were in the lowest quintile (26.4% vs 17.7%, respectively). Lp-PLA 2 activity in the highest quintile remained an independent predictor of death or recurrent cardiovascular events after the data had been adjusted for age, index diagnosis, prior MI, prior renal impairment, diabetes mellitus, treatment arm, and achieved LDL and C-reactive protein levels after 30 days of statin use (hazard ratio 1.32). When type of event was restricted to occurrence of MI, high circulating levels of Lp-PLA 2 were significantly independently associated with a doubling of risk.
"In this large study of Lp-PLA 2 in patients with ACS, there were several important findings that may influence the clinical use of this emerging biomarker," said study lead author Michelle O'Donoghue, MD, research fellow in the TIMI Study Group, Brigham and Women's Hospital (Boston, Massachusetts). She stressed that Lp-PLA 2 was not associated with an increased risk of recurrent cardiovascular events when measured early after ACS and so Lp-PLA 2 levels cannot be advocated for risk stratification during hospitalization for ACS. "However, when measured at a time when patients are distanced from biologic fluctuations associated with the acute event, Lp-PLA 2 can offer prognostic information incremental to that provided by traditional risk markers including LDL and CRP," she said. "This research demonstrates that Lp-PLA 2 levels can be an important tool toward better understanding patient risk for future cardiovascular events."
The study also demonstrated lowering of Lp-PLA 2 activity with intensive statin therapy, confirming previous smaller studies. Treatment with atorvastatin 80 mg/day was associated with a 20% reduction in Lp-PLA 2 activity, whereas Lp-PLA 2 rose 3.6% in patients taking pravastatin 40 mg/day. In the patients on pravastatin, but not in those on atorvastatin, Lp-PLA 2 was a significant predictor of MI, revascularization, and the composite primary endpoint of the trial. The researchers said that although no definitive interaction with treatment group was observed, these findings "raise the possibility that intensive statin therapy may help to partially attenuate the risk associated with higher levels of Lp-PLA 2." Pharmacologic interventions aimed at inhibiting Lp-PLA 2 may provide incremental benefit to intensive lipid-lowering therapy, they suggested.
The company that supported the PROVE IT-TIMI 22 substudy, GlaxoSmithKline (Brentford, UK), already has an Lp-PLA 2 inhibitor, darapladib (GSK480848), in phase 2/3 of clinical development for treatment of atherosclerosis.
The current PROVE IT-TIMI 22 substudy was funded by grants from GlaxoSmithKline. Support for the original PROVE IT-TIMI 22 trial was provided by Bristol-Myers Squibb and Sankyo.
Reference
"[When measured per this protocol,] Lp-PLA 2 can offer prognostic information incremental to that provided by traditional risk markers including LDL and CRP."
New results from a major cardiovascular study show that when measured approximately 30 days after an acute coronary event such as angina or myocardial infarction (MI), elevated levels of lipoprotein-associated phospholipase A 2 (Lp-PLA 2) activity are an independent risk marker for death or recurrent cardiovascular events. The information provided by this marker is incremental to that obtained from traditional risk factors such as low-density lipoprotein (LDL) and C-reactive protein (CRP), researchers say.
Lp-PLA 2, also known as platelet-activating factor acetylhydrolase, is found in blood and atherosclerotic plaque and has been associated with the risk of cardiovascular events in primary prevention, but little has been known about its prognostic role in patients following acute coronary syndromes (ACS). The new data, published in the April 11 issue of Circulation, come from a substudy of the PRavastatin Or atorVastatin Evaluation and Infection Therapy (PROVE IT-TIMI 22) trial, a study that compared intensive vs moderate lipid lowering with statins for the prevention of major cardiac events in 4162 patients who had been hospitalized after an episode of ACS. Participants were followed for a mean of 24 months for incidence of fatal or nonfatal MI or stroke, unstable angina, revascularization, and all other causes of death.
The substudy analyzed plasma Lp-PLA 2 levels measured in 3648 subjects at baseline and at the 30-day follow-up visit, which corresponded to approximately 7 days and 37 days, respectively, after the onset of the acute event. When participants were divided into 5 equal-sized groups (quintiles) based on Lp-PLA 2 activity, those in the group with the highest levels of Lp-PLA 2 activity were found to be at significantly higher risk of experiencing death or a cardiovascular event compared with participants whose Lp-PLA 2 activity levels were in the lowest quintile (26.4% vs 17.7%, respectively). Lp-PLA 2 activity in the highest quintile remained an independent predictor of death or recurrent cardiovascular events after the data had been adjusted for age, index diagnosis, prior MI, prior renal impairment, diabetes mellitus, treatment arm, and achieved LDL and C-reactive protein levels after 30 days of statin use (hazard ratio 1.32). When type of event was restricted to occurrence of MI, high circulating levels of Lp-PLA 2 were significantly independently associated with a doubling of risk.
"In this large study of Lp-PLA 2 in patients with ACS, there were several important findings that may influence the clinical use of this emerging biomarker," said study lead author Michelle O'Donoghue, MD, research fellow in the TIMI Study Group, Brigham and Women's Hospital (Boston, Massachusetts). She stressed that Lp-PLA 2 was not associated with an increased risk of recurrent cardiovascular events when measured early after ACS and so Lp-PLA 2 levels cannot be advocated for risk stratification during hospitalization for ACS. "However, when measured at a time when patients are distanced from biologic fluctuations associated with the acute event, Lp-PLA 2 can offer prognostic information incremental to that provided by traditional risk markers including LDL and CRP," she said. "This research demonstrates that Lp-PLA 2 levels can be an important tool toward better understanding patient risk for future cardiovascular events."
The study also demonstrated lowering of Lp-PLA 2 activity with intensive statin therapy, confirming previous smaller studies. Treatment with atorvastatin 80 mg/day was associated with a 20% reduction in Lp-PLA 2 activity, whereas Lp-PLA 2 rose 3.6% in patients taking pravastatin 40 mg/day. In the patients on pravastatin, but not in those on atorvastatin, Lp-PLA 2 was a significant predictor of MI, revascularization, and the composite primary endpoint of the trial. The researchers said that although no definitive interaction with treatment group was observed, these findings "raise the possibility that intensive statin therapy may help to partially attenuate the risk associated with higher levels of Lp-PLA 2." Pharmacologic interventions aimed at inhibiting Lp-PLA 2 may provide incremental benefit to intensive lipid-lowering therapy, they suggested.
The company that supported the PROVE IT-TIMI 22 substudy, GlaxoSmithKline (Brentford, UK), already has an Lp-PLA 2 inhibitor, darapladib (GSK480848), in phase 2/3 of clinical development for treatment of atherosclerosis.
The current PROVE IT-TIMI 22 substudy was funded by grants from GlaxoSmithKline. Support for the original PROVE IT-TIMI 22 trial was provided by Bristol-Myers Squibb and Sankyo.
Reference
O'Donoghue M, Morrow DA, Sabatine MS, et al. Lipoprotein-associated phospholipase a2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy -- Thrombolysis In Myocardial Infarction) trial. Circulation. 2006;113:1745-1752.