Healthcare Industry News:  Acute Coronary Syndrome 

Biopharmaceuticals Diagnostics Cardiology

 News Release - April 11, 2006

Inflammatory-Enzyme Shown to Predict Risk of Cardiovascular Events After Acute Coronary Syndromes

New Study Published in Circulation

PHILADELPHIA, April 11 (HSMN NewsFeed) -- New results from a major cardiovascular study showed that when measured approximately 30 days after an acute coronary event such as chest pain or heart attack, elevated levels of Lp-PLA2 (lipoprotein-associated phospholipase A2) activity are an independent risk marker for death or recurrent cardiovascular (CV) events.(1) Lp-PLA2 activity has been associated with the development and progression of atherosclerosis, a process that may lead to heart attack, stroke or other serious CV events but until now, little information has been available on the prognostic role of Lp-PLA2 in patients following Acute Coronary Syndromes (ACS).(1) Results from this substudy of the PRavastatin Or atorVastatin Evaluation and Infection Therapy (PROVE IT-TIMI 22) trial were published today in the American Heart Association's journal Circulation.

"In this large study of Lp-PLA2 in patients with ACS, there were several important findings that may influence the clinical use of this emerging biomarker," said Michelle O'Donoghue, MD, Research Fellow in the TIMI Study Group, Brigham and Women's Hospital, and lead author of the study. "As with other biomarkers influenced by the acute event such as LDL, Lp-PLA2 levels are not reliably useful for risk assessment during hospitalization for ACS. However when measured at a time when patients are distanced from biologic fluctuations associated with the acute event, Lp-PLA2 can offer prognostic information incremental to that provided by traditional risk markers including LDL and CRP. This research demonstrates that Lp-PLA2 levels can be an important tool toward better understanding patient risk for future CV events. I look forward to the results of ongoing research into inhibition of this enzyme as a therapeutic target."

This study also demonstrated lowering of the enzyme's activity with intensive statin therapy, confirming previous smaller studies.(1) One possible explanation may be due to corresponding statin-associated low-density lipoprotein (LDL) reduction, since LDL is the predominant carrier of circulating levels of Lp-PLA2. The current study suggests, however, that LDL lowering alone cannot entirely explain the larger reduction in Lp-PLA2 levels observed with intensive statin therapy. Other explanations should be considered in future research. Although lipid-lowering therapies, including statins, may lower Lp-PLA2 levels, pharmacologic interventions are now being studied to find ways of best inhibiting the Lp-PLA2 enzyme and potentially providing incremental benefit to intensive lipid-lowering therapy.(2)

"Despite advances in cardiovascular medicine and therapeutics, residual risk for cardiac events remains a significant concern for patients and physicians. This research adds to the rapidly emerging field of Lp-PLA2 enzyme levels as an independent predictor of heart disease," said Lawson Macartney, Senior Vice President, Cardiovascular and Metabolic Medicine Development Center, GlaxoSmithKline. "Moreover, this study provides evidence that high levels of circulating Lp-PLA2 measured approximately one month post- event can predict risk of death or a second CV event among patients experiencing acute symptoms of cardiovascular disease. Clinical trials will help determine whether Lp-PLA2 inhibition will prove to be a viable therapeutic target and GlaxoSmithKline is committed to innovative research that may one day save lives through early detection and intervention for inflammatory markers such as Lp-PLA2."

About Lp-PLA2

Lp-PLA2 is an enzyme found in blood and atherosclerotic plaque. The underlying process in most heart attacks and strokes is atherosclerosis, which is an inflammatory disease characterized by the build-up of plaque within the walls of arteries. The rupture of unstable atherosclerotic plaque is the causative event in most heart attacks and strokes.(3)

About PROVE IT-TIMI 22

The PROVE IT-TIMI 22 trial includes 4,162 participants and is one of the Thrombolysis in Myocardial Infarction (TIMI) trials that examine new treatment strategies for heart disease.(1) Participants were followed for a mean of 24 months for incidence of fatal or non-fatal heart attack or stroke, unstable angina, revascularization and all other causes of death.(1) Participants with a CV event prior to 30 days follow-up were excluded from the 30-day analyses.(1)

In this sub study of the primary PROVE IT-TIMI 22 study, Lp-PLA2 levels in plasma were measured at baseline and at the 30-day visit, which corresponded to approximately 7 days and 37 days, respectively, after the onset of the acute event. When participants were divided into five equally-sized groups (quintiles) based on Lp-PLA2 activity, those in the group with the highest levels of Lp-PLA2 activity were at significantly higher risk of experiencing death or a CV event compared with participants whose Lp-PLA2 activity levels were in the lowest quintile.(1) Moreover, Lp-PLA2 activity in the highest quintile remained an independent predictor of death or recurrent CV events when the data were adjusted for age, index diagnosis, prior myocardial infarction, prior renal impairment, diabetes mellitus, treatment arm, and achieved LDL levels and C-reactive protein (CRP) levels after 30 days of statin use (hazard ratio of 1.3).(1) When type of event was restricted to occurrence of heart attacks, high circulating levels of Lp-PLA2 were significantly independently associated with a doubling of risk.

The current PROVE IT-TIMI 22 substudy was funded by grants from GlaxoSmithKline. Grant support for the PROVE IT-TIMI 22 trial was provided by Bristol-Myers Squibb and Sankyo.

GlaxoSmithKline (NYSE: GSK; London) is developing Lp-PLA2 inhibitors as potential therapies for atherosclerosis. These inhibitors may represent a new generation of drugs that may help further reduce cardiovascular disease, one of the leading causes of death and disability around the world.(4,5)

About GlaxoSmithKline

GlaxoSmithKline is one of the world's leading research-based pharmaceutical and health care companies. GlaxoSmithKline is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information visit http://www.gsk.com.

Inquiries:

US/UK Media Inquiries: Suzannah Palinkas +1-202-835-9407

References:

1. O'Donoghue M, Morrow DA, Sabatine MS, Murphy SA, McCabe C, Cannon CP, Braunwald E. Lipoprotein-Associated Phospholipase A2 and Its Association with Cardiovascular Outcomes in Patients with Acute Coronary Syndromes in the PROVE IT-TIMI 22 Study. Circulation 2006; 113: In press.

2. Blackie JA, Bloomer JC, Brown MJ, et al. The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein associated phospholipase A2. Bioorg Med Chem Lett. Mar 24 2003; 13(6):1067-1070.

3. Data on file, GlaxoSmithKline, King of Prussia.

4. World Heart Federation. "Myths and Facts," http://www.worldheart.org/call-to-action-myths-facts.php.

5. "CVD Facts and Risk Factors," http://www.worldheart.org/call-to-action-cvd.php.


Source: GlaxoSmithKline

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