Inflammatory-Enzyme Shown to Predict Risk of Ca...

PHILADELPHIA, April 11 /PRNewswire/ --

- New Study Published in Circulation

    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 [phone]

    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.


PHILADELPHIA, April 11 /PRNewswire/ --

Web site: http://www.gsk.com