Beneficial effects of PCSK9i on CV events depend on both hsCRP and Lp(a) levels

Elevated C-Reactive Protein Amplifies Association of Lipoprotein(a) With Cardiovascular Risk and Clinical Benefit of Alirocumab

Literature - Schwartz GG, Szarek M, Zeiher A, et al., - J Am Coll Cardiol. 2022 Dec 13;80(24):2356-2359. doi: 10.1016/j.jacc.2022.09.035.

Introduction and methods


C-reactive protein (CRP) binds to oxidized phospholipids on lipoproteins and therefore may interact with Lp(a). CRP binding to oxidized phospholipids promotes macrophage clearance and the formation of foam cells [1], which has unfavorable effects on atherosclerosis progression and CV events (CVE). The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial previously showed that the PCSK9i alirocumab reduced Lp(a), LDL-c, and the risk for CVE in patients with ACS [2-4].

Aim of the study

The current post hoc analysis of the ODYSSEY OUTCOMES trial determined whether Lp(a)-associated risk of total CVE and reduction in that risk with alirocumab are modified by high-sensitivity CRP (hsCRP) levels.


The ODYSSEY OUTCOMES trial was a multicenter, double-blind, placebo-controlled phase 3 RCT with patients with recent ACS (1-12 months prior to randomization) and hyperlipidemia despite high-intensity or maximum-tolerated statin therapy. Patients were randomized to 75 mg subcutaneous injections of alirocumab twice monthly (9,462 patients) or placebo (9,462 patients), and followed for a median of 2.8 years (IQR: 2.3-3.4 years). In the current analysis, 5,555 CVE in 18,290 patients were included (10,323 patients with baseline hsCRP<2 mg/L and 7,967 patients with baseline hsCRP ≥2 mg/L). Patients were categorized in quartiles according to baseline Lp(a) concentration; Q1: <6.7 mg/dL, Q2: 6.7 to <21.2 mg/dL, Q3: 21.2 to <59.6 mg/dL, Q4: ≥59.6 mg/dL.


Primary outcomes were major CVE, which included CHD death, nonfatal MI, fatal and nonfatal ischemic stroke or unstable angina (UA) requiring hospitalization.

Main results

  • Lp(a)-associated risk of total CVE is modified by hsCRP levels. In patients with baseline hsCRP <2 mg/L, the CVE rate was modestly increased in patients with the highest baseline Lp(a) quartile (HR of Q2: 0.96; 95%CI: 0.81-1.14; HR of Q3: 0.93; 95%CI: 0.78-1.10; HR of Q4: 1.19; 95%CI: 1.02-1.40; Ptrend=0.059). In contrast, in patients with baseline hsCRP ≥2 mg/L, the CVE rate increased monotonically across baseline Lp(a) quartiles (HR of Q2: 1.06; 95%CI: 0.90-1.25; HR of Q3: 1.33; 95%CI: 1.13-1.55; HR of Q4: 1.72; 95%CI: 1.48-2.00; Ptrend<0.0001).
  • Alirocumab modestly reduced the risk for CVE in patients with baseline hsCRP<2 mg/L and in the highest baseline Lp(a) quartile (HR: 0.87; 95%CI: 0.74-1.02). The incidence of CVE in patients with baseline hsCRP <2 mg/L and in the other Lp(a) quartiles was relatively comparable between the alirocumab and placebo group (HR of Q1: 0.94; 95%CI: 0.80-1.12; HR of Q2: 0.97; 95%CI: 0.81-1.15; HR of Q3: 0.89; 95%CI: 0.74-1.07; overall treatment HR: 0.91; 95%CI: 0.84-0.99; Ptrend=0.38).
  • The incidence of CVE in patients with baseline hsCRP ≥2 mg/L was monotonically reduced in patients that received alirocumab compared to placebo across all baseline Lp(a) quartiles (HR of Q1: 0.99; 95%CI: 0.84-1.17; HR of Q2: 0.91; 95%CI: 0.77-1.07; HR of Q3: 0.88; 95%CI: 0.75-1.02; HR of Q4: 0.65; 95%CI: 0.56-0.75; overall treatment HR: 0.82; 95%CI: 0.76-0.89; Ptrend=0.0003).


This post hoc analysis of the ODYSSEY OUTCOMES trial demonstrated that elevated hsCRP amplifies the relationship of Lp(a) with CVE risk after ACS. The clinical beneficial effects of alirocumab on CVE are dependent on both hsCRP and Lp(a) levels.


1. Van Tits L, de Graaf J, Toenhake H, et al. C-reactive protein and annexin A5 bind to distinct sites of negatively charged phospholipids present in oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):717-722.

2. Szarek M, White HD, Schwartz GG, et al. Alirocumab reduces total nonfatal cardiovascular and fatal events: The ODYSSEY OUTCOMES Trial. J Am Coll Cardiol. 2019 Feb 5;73(4):387-396.

3. Szarek M, Bittner VA, Aylward P, et al. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J. 2020 Nov 21;41(44):4245-4255.

4. Bittner VA, Szarek M, Aylward PE, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol. 2020 Jan 21;75(2):133-144.

Find this article online at J Am Coll Cardiol.

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