Treating Combined High Lipoprotein, Inflammation Reduces MACE Risks

Rishi Puri, MBBS, PhD

New secondary findings from the ACCELERATE Trial suggest lowering lipoprotein(a) (Lp[a]) in particular patients at high risk of cardiovascular disease may provide benefits including reduced risk of death, myocardial infarction, and stroke.

The assessment, authored by a team of Cleveland Clinic investigators and international contributors, benefited the understanding of modulated Lp(a) levels among patients at high risk for vascular events and conditions.

Investigators, led by Rishi Puri, MBBS, PhD, of the Cleveland Clinic Department of Cardiovascular Medicine, conducted the prespecified secondary post hoc analysis of the 12,000-plus trial assessing evacetrapib in patients at high vascular outcome risk.

The ACCELERATE Trial, was terminated in October 2015 after there was no observed benefit of the cholesteryl ester transfer protein inhibitor on 30-month major adverse cardiovascular events (MACE).

Though the reduction of low-density lipoprotein cholesterol (LDL-C) remains the clinical target most associated with decreased atherosclerotic cardiovascular disease (ASCVD) in at-risk patients, genetically-mediated Lp(a) has emerged as another target for reduced ASCVD risk.

The team gauged in their post hoc analysis whether Lp(a)-associated ASCVD risk could be modulated by residual systemic inflammation levels among the optimally-treated patients with high-risk vascular disease in ACCELERATE.

Their patient population included 10,503 of the 12,092 ACCELERATE participants with high cardiovascular disease risk from 543 hospitals across 36 countries. All patients observed in the post hoc analysis had measurable Lp(a) and high-sensitivity C-reactive protein (hsCRP) levels during the original trial period.

Patients were prominently male (77.4%) and white (81.5%); mean patient age was 64.6 years old. Nearly all (96.5%) received concurrent statins.

Patients with hsCRP of ≥2 mg/L versus <2 mg/L had greater mean body mass index (BMI), a more frequent cluster of common cardiovascular risk factors, and were actually less likely to be receiving statins.

A total of 714 MACEs (6.8% of patients) were observed in the analysis population.

Puri and colleagues observed a significantly greater risk of MACE among patients with higher hsCRP levels versus lower levels (HR, 1.59; 95% CI, 1.37-1.86; P <.001). Greater Lp(a) levels during treatment were not associated with significantly greater MACE risk (HR, 1.03; 95% CI, 0.88-1.20; P = .72).

But when stratifying the overall population based on hsCRP levels <2 mg/L versus ≥2 mg/L and quintiles of Lp(a) levels, investigators noted greater Lp(a) levels were significantly associated with MACE only when hsCRP levels were ≥2 mg/L. Relative to the first quintile, the hazard ratio for MACE of the second quintile was 1.31; 1.42 for the third quintile; 1.50 for the fourth quintile; and 1.70 for the fifth quintile.

No association between increasing Lp(a) levels and MACE was observed among patients with hsCRP levels <2 mg/L.

The data shed new understanding of the interdependence between Lp(a) and systemic inflammation, 2 previously known mediators of primary and residual ASCVD risk.

“We demonstrate for the first time, to our knowledge, that Lp(a)-mediated ASCVD risk appears to be mediated by concomitant hsCRP levels during treatment in a large, contemporary, cohort with high-risk vascular disease ubiquitously treated with statins,” investigators wrote.

The post hoc analysis findings may most particularly benefit the progression of Lp(a)-lowering therapy assessments, which recently have shown ability to safely reduce MACE-risk patients’ levels by 70% to 90%.

As pivotal randomized, controlled trials come to assess the association between modulated Lp(a) levels and ASCVD, clinicians will need to navigate emerging options for care. At the least, this secondary ACCELERATE assessment helps target the appropriate patient groups.

“These findings, while shedding further insight into the mechanisms underlying Lp(a)-associated ASCVD risk, may prove useful for identifying individuals who might benefit the most from novel Lp(a)-lowering therapies,” they concluded.

The study, “Effect of C-Reactive Protein on Lipoprotein(a)-Associated Cardiovascular Risk in Optimally Treated Patients With High-Risk Vascular Disease,” was published online in JAMA Cardiology.