Lipoprotein-Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease

Lars Wallentin, Claes Held, Paul W Armstrong, Christopher P Cannon, Richard Y Davies, Christopher B Granger, Emil Hagström, Robert A Harrington, Judith S Hochman, Wolfgang Koenig, Sue Krug-Gourley, Emile R Mohler 3rd, Agneta Siegbahn, Elizabeth Tarka, Philippe Gabriel Steg, Ralph A H Stewart, Robert Weiss, Ollie Östlund, Harvey D White, STABILITY Investigators, Andrzej Budaj, Diego Ardissino, Alvaro Avezum, Philip E Aylward, Alfonso Bryce, Hong Chen, Ming-Fong Chen, Ramon Corbalan, Anthony J Dalby, Nicolas Danchin, Robbert J De Winter, Stefan Denchev, Rafael Diaz, Moses Elisaf, Marcus D Flather, Assen R Goudev, Liliana Grinfeld, Steen Husted, Hyo-Soo Kim, Ales Linhart, Eva Lonn, José López-Sendón, Athanasios J Manolis, José C Nicolau, Prem Pais, Alexander Parkhomenko, Terje R Pedersen, Daniel Pella, Marco A Ramos-Corrales, Mikhail Ruda, Mátyás Sereg, Saulat Siddique, Peter Sinnaeve, Piyamitr Sritara, Henk P Swart, Rody G Sy, Tamio Teramoto, Hung-Fat Tse, W Douglas Weaver, Margus Viigimaa, Dragos Vinereanu, Junren Zhu, Lars Wallentin, Claes Held, Paul W Armstrong, Christopher P Cannon, Richard Y Davies, Christopher B Granger, Emil Hagström, Robert A Harrington, Judith S Hochman, Wolfgang Koenig, Sue Krug-Gourley, Emile R Mohler 3rd, Agneta Siegbahn, Elizabeth Tarka, Philippe Gabriel Steg, Ralph A H Stewart, Robert Weiss, Ollie Östlund, Harvey D White, STABILITY Investigators, Andrzej Budaj, Diego Ardissino, Alvaro Avezum, Philip E Aylward, Alfonso Bryce, Hong Chen, Ming-Fong Chen, Ramon Corbalan, Anthony J Dalby, Nicolas Danchin, Robbert J De Winter, Stefan Denchev, Rafael Diaz, Moses Elisaf, Marcus D Flather, Assen R Goudev, Liliana Grinfeld, Steen Husted, Hyo-Soo Kim, Ales Linhart, Eva Lonn, José López-Sendón, Athanasios J Manolis, José C Nicolau, Prem Pais, Alexander Parkhomenko, Terje R Pedersen, Daniel Pella, Marco A Ramos-Corrales, Mikhail Ruda, Mátyás Sereg, Saulat Siddique, Peter Sinnaeve, Piyamitr Sritara, Henk P Swart, Rody G Sy, Tamio Teramoto, Hung-Fat Tse, W Douglas Weaver, Margus Viigimaa, Dragos Vinereanu, Junren Zhu

Abstract

Background: We evaluated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial.

Methods and results: Plasma Lp-PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA2 activity levels and outcomes. At baseline, the median Lp-PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1-204.2 μmol/min per liter). Comparing the highest and lowest Lp-PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp-PLA2 activity. There were no associations between on-treatment Lp-PLA2 activity or changes of Lp-PLA2 activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA2 activity or changes in Lp-PLA2 activity levels and the effects of darapladib on outcomes.

Conclusions: Although high Lp-PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA2 activity.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.

Keywords: atherosclerosis; coronary disease; inflammation; lipoprotein; myocardial infarction.

© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Quartile groups of baseline Lp‐PLA2 activity (in μmol/min per liter) in relation to outcomes by Kaplan–Meier analysis. A, Major adverse cardiac events (cardiovascular death, myocardial infarction, or stroke). B, Cardiovascular death. Q indicates quartile; Lp‐PLA2; lipoprotein‐associated phospholipase A2.
Figure 2
Figure 2
Baseline Lp‐PLA 2 activity (μmol/min per liter) quartile groups in relation to outcomes in (A) all patients, (B) in women, and (C) in men, adjusted for demographics, baseline characteristics, routine biochemical variables, and prognostic biomarkers. The x‐axis presents a logarithmic scale. MACE indicates CV death, MI, or stroke; MCE indicates coronary heart disease death, MI, or urgent coronary revascularization. Event rates are Kaplan–Meier rates. Adjustment variables: randomized treatment, geographic region, age, sex, body mass index, current smoking, hypertension, diabetes mellitus, prior MI, prior coronary revascularization, multivessel coronary heart disease, polyvascular disease, significant renal dysfunction, routine biochemical variables (hemoglobin, white blood cell count, estimated glomerular filtration rate [Chronic Kidney Disease Epidemiology Collaboration], low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and triglycerides), and prognostic biomarkers (N‐terminal proB‐type natriuretic peptide, high‐sensitivity cardiac troponin T, cystatin C, high‐sensitivity C‐reactive protein, and interleukin 6). CV indicates cardiovascular; HR, hazard ratio; Lp‐PLA2, lipoprotein‐associated phospholipase A2; MACE, major adverse cardiac events; MCE, major coronary events; MI, myocardial infarction; Q, quartile.
Figure 3
Figure 3
Lp‐PLA 2 activity (μmol/min per liter) over time during treatment with darapladib and placebo in a subset of 100 patients with available plasma samples for Lp‐PLA 2 activity measurements until end of follow‐up. Symbols illustrate means and CIs for the respective darapladib (blue) and placebo (red) groups at baseline; at follow‐up visits at 1, 3, 6, and 18 months; and at the EOT visit. D, darapladib; EOT, end of treatment; Lp‐PLA2, lipoprotein‐associated phospholipase A2; P, placebo.
Figure 4
Figure 4
Effect of darapladib compared with placebo in relation to baseline Lp‐PLA 2 activity (μmol/min per liter) quartile groups concerning all outcomes. MACE specifies CV death, MI, or stroke; MCE specifies coronary heart disease death, MI, or urgent coronary revascularization. Event rates are Kaplan–Meier rates. CV indicates cardiovascular; HR, hazard ratio; Lp‐PLA2, lipoprotein‐associated phospholipase A2; MACE, major adverse cardiac events; MCE, major coronary events; MI, myocardial infarction.
Figure 5
Figure 5
Continuous Lp‐PLA 2 activity (μmol/min per liter) at baseline in relation to major adverse cardiac events (cardiovascular death, myocardial infarction, or stroke) during treatment with darapladib (red line) and placebo (black line) using restricted cubic splines using a Cox proportional hazards model including treatment group, LpPLA 2, and treatment by LpPLA 2 interaction as covariates. Lp‐PLA2, lipoprotein‐associated phospholipase A2; Q, quartile.

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