Lipoprotein(a), smoking, and diabetes are additive, but not interactive risk factors for major adverse cardiovascular events after acute coronary syndrome: An analysis of the ODYSSEY OUTCOMES trial
G G Schwartz, M Szarek, V Bittner, D L Bhatt, R Diaz, S G Goodman, R A Harrington, G Hassan, J W Jukema, I Stevanovic, H Tavori, S Thielen, H D White, P G StegAbstract
Background
There is growing recognition that lipoprotein(a) [Lp(a)] increases cardiovascular risk through atherogenic, thrombogenic, and inflammatory properties. Conventional risk factors of smoking and diabetes may also convey risk through these mechanisms. The degree to which Lp(a), smoking, and diabetes are additive or interactive risk factors is uncertain.
Purpose
We determined whether Lp(a), smoking, and diabetes are additive or interactive risk factors for major adverse cardiovascular events (MACE) in a post hoc analysis of the placebo group of the ODYSSEY OUTCOMES trial.
Methods
ODYSSEY OUTCOMES compared the effects of alirocumab or placebo in patients with recent acute coronary syndrome on optimized statin therapy. Baseline Lp(a) was measured by immunoassay in mass units and categorized by quartile. Smoking was categorized as current versus prior or never. Presence of diabetes was determined from history, laboratory, and prescription data. MACE (cardiovascular death, myocardial infarction, ischemic stroke, hospitalization for unstable angina, and ischemia-driven coronary revascularization) were determined over median (Q1, Q3) follow-up of 2.8 (2.3, 3.4) years. Cox regression models were adjusted for age, sex, geographic region, LDL-C, and systolic blood pressure and evaluated the association of Lp(a) with MACE, without and with further adjustment for smoking and diabetes.
Results
In 9462 patients assigned to placebo, median (Q1-Q3) Lp(a) was 21.6 (6.6-60.1) mg/dL, 24.1% were current smokers, and 29.1% had diabetes. The 4-year Kaplan-Meier cumulative incidence of MACE was 19.7% (1474 events). Lp(a) ≥median was associated with greater risk of MACE than Lp(a) <median. In both Lp(a) categories, risk of MACE increased when active smoking, diabetes, or both were present (Figure). In Cox models without adjustment for either smoking or diabetes, Lp(a) quartile was significantly associated with MACE (hazard ratio Q4 vs Q1 1.26 [1.09-1.46; quartiles Ptrend=0.0006]). When adjusted for smoking Lp(a) quartile remained associated with risk of MACE without Lp(a) x smoking interaction (hazard ratio Lp(a) Q4 vs Q1 1.27 [1.10-1.47; Lp(a) quartile Ptrend 0.0004; Pinteraction 0.86). Similarly, when adjusted for diabetes, Lp(a) quartile remained associated with risk of MACE without Lp(a) x diabetes interaction (hazard ratio Lp(a) Q4 vs Q1 1.29 [1.12-1.49; Lp(a) quartile Ptrend=0.0002; Pinteraction=0.31). When adjusted for both diabetes and smoking Lp(a) also remained a significant predictor of MACE (hazard ratio Lp(a) Q4 vs Q1 1.30 [1.13-1.51; quartile Ptrend=0.0001).
Conclusions
Lp(a), smoking, and diabetes are additive but not interactive risk factors for MACE after ACS. Lp(a) remains an independent risk factor for MACE after adjustment for both smoking and diabetes.