Elevated Lp(a) levels associated with increased risk of MACE when hsCRP ≥2 mg/L
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
Introduction and methods
Early phase clinical trials in humans have demonstrated substantial 70% to 90% reductions in circulating lipoprotein(a) (Lp(a)) levels with antisense oligonucleotides directed against hepatocytes . However, it remains unclear which patients would benefit most from Lp(a) reducing therapies [2,3]. Data from translational and clinical studies have suggested a synergism between systemic inflammation and proatherosclerotic effects of Lp(a) [4,5]. This exploratory post hoc analysis of the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial investigated whether systemic inflammation can modulate Lp(a)-associated CV risk in optimally treated patients with high-risk vascular disease.
ACCELERATE was a randomized, double-blind, multicenter, placebo-controlled phase 3 trial that randomized 12,092 patients with high risk vascular disease (ACS within previous 30-365 days, cerebrovascular atherosclerotic disease, peripheral arterial disease, or T2DM with coronary artery disease) to either the cholesteryl ester transfer protein inhibitor evacetrapib or placebo, in addition to standard medical therapy. The primary efficacy outcome was the first occurrence of any component of the composite of CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina pectoris. An interim analysis for futility was conducted and data showed that evacetrapib conferred neither benefit nor harm. The trial was stopped early. The current analysis pooled the ACCELERATE trial population and enrolled patients that had Lp(a) and high-sensitivity C-reactive protein (hsCRP) levels measured during follow up (n=10,503).
The primary endpoint of the present analysis was major adverse CV events (MACE), defined as CV death, MI or stroke. Median follow-up period was 28 months.
- In the overall population, hsCRP levels of 2 mg/L or higher during treatment were associated with a significantly greater risk of MACE, compared to hsCRP levels lower than 2 mg/L in a fully adjusted multivariable model (HR 1.59, 95%CI 1.37-1.86, P<0.001).
- Lp(a) levels (≥ median vs. < median) during treatment were not associated with risk of MACE in the overall population (HR 1.03, 95%CI 0.88-1.20, P=0.72). However, when the population was stratified according to hsCRP levels (≥2 mg/L vs. <2 mg/L) and quintiles of Lp(a) levels, a significant association was found between higher Lp(a) levels and MACE, but only in when hsCRP levels were ≥2 mg/L (relative to quintile 1 [Q1], HR for MACE of Q2: 1.31, 95%CI 0.94-1.84; Q3: HR 1.42, 95%CI 1.02-1.98; Q4: HR 1.50, 95%CI 1.08-2.09, Q5: HR 1.70, 95%CI 1.23-2.36). A significant interaction for MACE between Lp(a) quintile and hsCRP dichotomy was observed (P=0.006 for interaction).
- No significant interaction between higher Lp(a) and risk of MACE was found in when hsCRP levels were <2 mg/L during treatment.
- When looking at the association between hsCRP and continuous Lp(a) levels with MACE in a fully adjusted multivariable model, each unit increase in the logarithm of Lp(a) was associated with a 13% increase in risk of MACE in those with hsCRP levels ≥2 mg/L (HR 1.13, 95%CI 1.05-1.22, P=0.002). No significant association between hsCRP and continuous Lp(a) levels with MACE was found in patients with hsCRP levels <2 mg/L (HR 0.95, 95%CI 0.87-1.05, P=0.32). A significant interaction for MACE between continuous Lp(a) and hsCRP dichotomy was observed (P=0.008 for interaction).
- Increasing quintiles of Lp(a) levels were associated with higher cumulative incidence of MACE over time in a stepwise manner in patients with hsCRP levels ≥2 mg/L (P<0.001 for trend). Increasing quintiles of Lp(a) levels were not associated with a higher cumulative incidence of MACE over time in patients with hsCRP levels <2 mg/L (P=0.44 for trend).
This exploratory post hoc analysis of data from the ACCELERATE trial showed a significant association between higher Lp(a) levels and MACE in optimally treated patients with high-risk vascular disease with hsCRP levels ≥2 mg/L. No significant association was found between higher Lp(a) levels and risk of MACE in those with hsCRP levels <2 mg/L.