1. Prognostic Utility of Secretory Phospholipase A 2 in Patients with Stable Coronary Artery Disease M. O'Donoghue, Z. Mallat, D.A. Morrow, J. Benessiano, S. Sloan, T. Omland, S.D. Solomon, E. Braunwald, A. Tedgui, and M.S. Sabatine http://www.clinchem.org/cgi/content/full/57/9/1311 October 2011 © Copyright 2011 by the American Association for Clinical Chemistry

2. © Copyright 2009 by the American Association for Clinical Chemistry Introduction  The secretory phospholipase A 2 (sPLA 2 ) family consists of 10 isoenzymes involved in a variety of biological processes  Growing evidence suggests sPLA 2 may play a causal role in atherogenesis  sPLA 2 -X promotes macrophage foam cell formation in murine models  Up-regulated sPLA 2 -IIA or –V expression has been shown to increase atherosclerotic lesion size in transgenic mice  Genetic deletion of sPLA 2 –V or direct inhibition of sPLA 2 activity reduces atherosclerotic lesion size in animals

3. © Copyright 2009 by the American Association for Clinical Chemistry Introduction  To date, a small number of studies have evaluated the utility of sPLA 2 mass or activity for risk stratification in primary prevention and after an acute coronary syndrome  The prognostic utility of sPLA 2 is not well established in a large population of patients with stable coronary artery disease (CAD)  We therefore evaluated the prognostic utility of sPLA 2 in the PEACE trial, a large trial population of patients with stable CAD

4. © Copyright 2009 by the American Association for Clinical Chemistry Questions  Is sPLA 2 useful for risk stratification in patients with stable CAD?  If yes, does it add any incremental value to established markers including high sensitivity troponin T, C-reative protein (hsCRP), lipoprotein- associated phospholipase A 2 (Lp-PLA 2 ), and NT-pro B-type natriuretic peptide (NT-proBNP)?

5. © Copyright 2009 by the American Association for Clinical Chemistry Methods  sPLA 2 activity (Aterovax) was measured at baseline in 3708 subjects  Median follow-up was 4.8 years  Cox regression models were used to adjust for baseline differences, apoB, apoA1, and medications  The incremental value of sPLA 2 was evaluated compared to established markers, including high sensitivity troponin T (Roche), Lp-PLA 2 mass (diaDexus), NT-proBNP (Roche), and hsCRP (Denka Seiken)

6. © Copyright 2009 by the American Association for Clinical Chemistry Baseline characteristics by quartile of sPLA 2 activity

7. © Copyright 2009 by the American Association for Clinical Chemistry Kaplan-Meier event rates & hazard ratios by quartile of sPLA 2 activity Table 2. Multivariable model: age, sex, tobacco use (current, former, never), eGFR, body mass index, systolic blood pressure, apoB, apoA1, history of hypertension, diabetes mellitus, lipid-lowering therapy, history of coronary revascularization, randomized treatment arm.

8. © Copyright 2009 by the American Association for Clinical Chemistry Cumulative incidence of CV death, MI or stroke by quartile of sPLA 2 activity

9. © Copyright 2009 by the American Association for Clinical Chemistry Cumulative incidence of CV death or heart failure by quartile of sPLA 2 activity

10. © Copyright 2009 by the American Association for Clinical Chemistry Multimarker analysis for sPLA 2, Lp-PLA 2 mass, hsCRP and risk of CV death, MI or stroke CV death, MI or stroke sPLA 2 activity Lp-PLA 2 mass hsCRP 1.47 (1.06-2.04) 1.35 (0.97-1.88) 1.25 (0.91-1.73) Adj HR Q4:Q1 (95% CI) 2.05.010.01.00.50.20.1 Figure 3. The independent association between sPLA 2 activity, Lp-PLA 2 mass, hsCRP, and the risk of cardiovascular death, MI or stroke. MV model includes the 3 biomarkers by quartile, age, sex, hypertension, diabetes mellitus, tobacco use, history of coronary revascularization, history of lipid-lowering therapy, body mass index, systolic blood pressure, eGFR, apoB, apoA1, and randomized treatment arm.

11. © Copyright 2009 by the American Association for Clinical Chemistry Figure 4. The independent association between sPLA 2 activity, NT-proBNP, and cardiac troponin T and the risk of cardiovascular death or HF. MV model includes the 3 biomarkers by quartile, age, sex, hypertension, diabetes mellitus, tobacco use, history of coronary revascularization, history of lipid-lowering therapy, body mass index, systolic blood pressure, eGFR, apoB, apoA1, and randomized treatment arm. Multimarker analysis for sPLA 2, NT-proBNP and troponin T and risk of CV death or HF

12. © Copyright 2009 by the American Association for Clinical Chemistry Multimarker Results (cont’d)  In ROC analysis, sPLA 2 activity significantly improved the AUC for identifying patients at risk of CV death, MI or stroke compared with clinical risk factors alone (P=0.01). Lp-PLA 2 and hsCRP did not improve the AUC  sPLA 2, NT-proBNP and troponin T all significantly improved the AUC as compared with clinical risk factors alone for identifying patients at risk of CV death or heart failure (P=0.02, P<0.001, P<0.001, respectively)

13. © Copyright 2009 by the American Association for Clinical Chemistry Conclusions  sPLA 2 activity provides independent prognostic information beyond established clinical risk factors in patients with stable CAD  sPLA 2 activity also provides incremental information for risk stratification independent of established markers including hsCRP, troponin T, Lp-PLA 2 mass and NT-proBNP

14. © Copyright 2009 by the American Association for Clinical Chemistry Questions  Would routine measurement of sPLA 2 activity help to improve outcomes in patients with stable CAD? Would it help to guide treatment decisions?  If sPLA 2 is causal in the pathway for atherogenesis, will direct inhibition of the sPLA 2 enzyme with the novel drug varespladib reduce the risk of CV events?

15. © Copyright 2009 by the American Association for Clinical Chemistry Thank you for participating in this month’s Clinical Chemistry Journal Club. Additional Journal Clubs are available at www.clinchem.org Follow us on