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Original Investigation
July 8, 2020

Effect of C-Reactive Protein on Lipoprotein(a)-Associated Cardiovascular Risk in Optimally Treated Patients With High-Risk Vascular Disease: A Prespecified Secondary Analysis of the ACCELERATE Trial

Author Affiliations
  • 1Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
  • 2Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, Ohio
  • 3Québec Heart & Lung Institute, Université de Laval, Québec, Québec, Canada
  • 4Eli Lilly, Indianapolis, Indiana
  • 5MonashHeart, Department of Cardiology, Monash University, Clayton, Victoria, Australia
JAMA Cardiol. 2020;5(10):1136-1143. doi:10.1001/jamacardio.2020.2413
Key Points

Question  Can inflammation modulate lipoprotein(a)–associated cardiovascular risk during secondary prevention in optimally treated patients with high-risk vascular disease?

Findings  In a prespecified post hoc secondary analysis of the ACCELERATE trial, in patients with established vascular disease who were optimally treated, increasing lipoprotein(a) levels (assessed as either quintiles or continuous logarithmic transformed levels) during treatment were significantly associated with cardiovascular death, myocardial infarction, and stroke only in individuals with high-sensitivity C-reactive protein levels of 2 mg/L or higher during treatment, but not in those with levels less than 2 mg/L. Similar significant associations were identified in time-to-first event rates and survival curves, as well as specifically in the placebo-treated group.

Meaning  There is likely to be incremental benefit in lowering lipoprotein(a) levels in optimally treated patients with high-risk vascular disease, which appears to be optimized in patients with concomitant high-sensitivity C-reactive protein levels of 2 mg/L or more.


Importance  Although lipoprotein(a) (Lp[a]) is a causal genetic risk factor for atherosclerotic cardiovascular disease, it remains unclear which patients with established atherosclerotic cardiovascular disease stand to benefit the most from Lp(a) lowering. Whether inflammation can modulate Lp(a)-associated cardiovascular (CV) risk during secondary prevention is unknown.

Objective  To examine whether Lp(a)-associated CV risk is modulated by systemic inflammation in optimally treated patients at high risk of CV disease.

Design, Setting, and Participants  A prespecified secondary post hoc analysis of the double-blind, multicenter randomized clinical Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial was conducted between October 1, 2012, and December 31, 2013; the study was terminated October 12, 2015. The study was conducted at 543 academic and community hospitals in 36 countries among 12 092 patients at high risk of CV disease (acute coronary syndrome, stroke, peripheral arterial disease, or type 2 diabetes with coronary artery disease) with measurable Lp(a) and high-sensitivity C-reactive protein (hsCRP) levels during treatment. Statistical analysis for this post hoc analysis was performed from September 26, 2018, to March 28, 2020.

Interventions  Participants received evacetrapib, 130 mg/d, or matching placebo.

Main Outcomes and Measures  The ACCELERATE trial found no significant benefit or harm of evacetrapib on 30-month major adverse cardiovascular events (CV death, myocardial infarction [MI], stroke, coronary revascularization, or hospitalization for unstable angina). This secondary analysis evaluated rates of CV death, MI, and stroke across levels of Lp(a).

Results  High-sensitivity C-reactive protein and Lp(a) levels were measured in 10 503 patients (8135 men; 8561 white; 10 134 received concurrent statins; mean [SD] age, 64.6 [9.4] years). In fully adjusted analyses, in patients with hsCRP of 2 mg/L or more but not less than 2 mg/L, increasing quintiles of Lp(a) were significantly associated with greater rates of death, MI, and stroke (P = .006 for interaction). Each unit increase in log Lp(a) levels was associated with a 13% increased risk of CV death, nonfatal MI, or stroke only in those with hsCRP levels of 2 mg/L or more (P = .008 for interaction). There was also a significant stepwise relationship between increasing Lp(a) quintiles and time to first CV death, MI, or stroke (log-rank P < .001) when hsCRP levels were 2 mg/L or more but not less than 2 mg/L. Sensitivity analyses in the ACCELERATE placebo-treated group yielded similar significant associations exclusively in the group with hsCRP of 2 mg/L or more.

Conclusions and Relevance  Elevated Lp(a) levels during treatment are related to CV death, MI, and stroke when hsCRP levels are 2 mg/L or more but not less than 2mg/L. This finding suggests a potential benefit of lowering Lp(a) in patients with residual systemic inflammation despite receipt of optimal medical therapy.

Trial Registration  ClinicalTrials.gov Identifier: NCT01687998