Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial

Michael Szarek, Vera A Bittner, Philip Aylward, Marie Baccara-Dinet, Deepak L Bhatt, Rafael Diaz, Zlatko Fras, Shaun G Goodman, Sigrun Halvorsen, Robert A Harrington, J Wouter Jukema, Patrick M Moriarty, Robert Pordy, Kausik K Ray, Peter Sinnaeve, Sotirios Tsimikas, Robert Vogel, Harvey D White, Doron Zahger, Andreas M Zeiher, Ph Gabriel Steg, Gregory G Schwartz, ODYSSEY OUTCOMES Investigators, Michael Szarek, Vera A Bittner, Philip Aylward, Marie Baccara-Dinet, Deepak L Bhatt, Rafael Diaz, Zlatko Fras, Shaun G Goodman, Sigrun Halvorsen, Robert A Harrington, J Wouter Jukema, Patrick M Moriarty, Robert Pordy, Kausik K Ray, Peter Sinnaeve, Sotirios Tsimikas, Robert Vogel, Harvey D White, Doron Zahger, Andreas M Zeiher, Ph Gabriel Steg, Gregory G Schwartz, ODYSSEY OUTCOMES Investigators

Abstract

Aims: Lipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events.

Methods and results: Cardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio Ptrend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median -5.0 [-13.6, 0] mg/dL) and corrected LDL-C (median -51.3 [-67.1, -34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events.

Conclusion: Baseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS.

Trial registration: ClinicalTrials.gov NCT01663402.

Keywords: Acute coronary syndrome; Alirocumab; LDL; Lipoprotein.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Cumulative incidence functions for total cardiovascular events by quartile of baseline lipoprotein(a) (P  trend < 0.0001). Hazard ratios and P-value reflect adjustment for age, sex, race, geographic region, body mass index, smoking status, diabetes status, time from index acute coronary syndrome to randomization, and baseline low-density lipoprotein cholesterol corrected for lipoprotein(a) cholesterol.
Figure 2
Figure 2
Relative and absolute treatment effects on total cardiovascular events, overall and by quartile of baseline lipoprotein(a). The rates of total vascular events per 100 patient-years of follow-up are shown for the alirocumab and placebo groups stratified by baseline quartile of lipoprotein(a) and for the overall population. The forest plots depict relative and absolute risk reduction with alirocumab compared with placebo. For relative risk reduction, there was a significant linear trend in the log hazard ratios across baseline quartiles, with point estimates progressively further below 1.00 for higher quartiles. CI, confidence interval; HR, hazard ratio.
Take home figure
Take home figure
Relationship between reduction in lipoprotein(a) (Lp(a)) from baseline to Month 4 and total cardiovascular events after Month 4 in the alirocumab group, overall and by quartile of baseline lipoprotein(a). The percentages represent the predicted risk reduction attributable to the median reduction in lipoprotein(a) within each quartile or overall as a percentage of the joint predicted risk reduction by median decreases in lipoprotein(a) and low-density lipoprotein cholesterol corrected for lipoprotein(a) cholesterol. Lipoprotein(a) did not contribute to the joint predicted risk reduction in Quartile 1 (
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7724642/bin/ehaa649f3.jpg

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