Low-density lipoprotein cholesterol &lt;50 mg/dL is an appropriate target after acute coronary syndrome: propensity score-matched analysis of the ODYSSEY OUTCOMES trial
Authors: Schwartz G.G , Szarek M , Bhatt D.L , Bittner V.A , Diaz R , Goodman S.G , Harrington R.A , Jukema J.W , Kim Y.U , Li Q.H , Manvelian G , White H.D , Zeiher A.M , Steg P.G 
Published: November 2020

Abstract

Background
New ESC/EAS guidelines advise a low-density lipoprotein cholesterol (LDL-C) target level &lt;55 mg/dL for patients with acute coronary syndromes (ACS), and a level &lt;40 mg/dL for those with recurrent events. Previous analyses of clinical trials have sought to define an optimal LDL-C target range to prevent major adverse cardiovascular events (MACE). However, those analyses are limited because patients who achieve lower versus higher LDL-C levels on lipid-lowering therapy differ in other characteristics that are prognostic for MACE, including baseline LDL-C, lipoprotein(a), and medication adherence.

Aim
To overcome these limitations, we performed a propensity score-matching (PSM) analysis of the ODYSSEY OUTCOMES trial, which compared the PCSK9 inhibitor alirocumab with placebo in 18,924 patients with recent ACS.

Methods
Patients on alirocumab were classified in 1 of 3 pre-specified categories according to Month 4 LDL-C &lt;25 (n=3357), 25–50 (n=3692) or &gt;50 mg/dL (n=2197). Within each category, MACE after Month 4 was compared with patients on placebo using 1:1 PSM on demographic, clinical, and adherence variables. Because the trial design involved blinded substitution of placebo for alirocumab when consecutive LDL-C levels were &lt;15 mg/dL on alirocumab, we also evaluated MACE in those patients (n=730) in comparison with patients chosen from the placebo group by 1:3 PSM.

Results
Patients in the three achieved LDL-C categories of the alirocumab group differed by baseline age, sex, geographic region; history of diabetes, smoking, peripheral artery disease, cerebrovascular disease, coronary revascularization, heart failure, obstructive pulmonary disease, or malignancy; type of index ACS event; baseline LDL-C, lipoprotein(a), estimated glomerular filtration rate, body mass index, systolic blood pressure; use of intensive statin therapy; and adherence with study medication. After PSM, patients in each LDL-C category on alirocumab were well matched to patients on placebo for these characteristics. Treatment hazard ratios (HRs) for MACE (Figure) were similar in those with achieved LDL-C &lt;25 mg/dL or 25–50 mg/dL. Patients with achieved LDL-C &gt;50 mg/dL achieved less benefit. Patients who achieved consecutive LDL-C levels &lt;15 mg/dL and were switched to placebo nonetheless had a robust HR (0.71, 95% CI 0.52–0.98) and thus did not dilute efficacy of alirocumab among those in the &lt;25 mg/dL achieved LDL-C category.

Conclusion
After accounting for differences in baseline characteristics and adherence, reduction in risk of MACE with alirocumab was similar in patients who achieved LDL-C &lt;25 or 25–50 mg/dL. These data suggest that an LDL-C target of less than 50 mg/dL may be reasonable after ACS and is essentially congruent with new ESC/EAS guidelines.

Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): Sanofi and Regeneron Pharmaceuticals, Inc