Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score

Abstract

Background: The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established. Methods: We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27–single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years. Results: After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events ( P trend =0.005) and major coronary events ( P trend <0.0001). Individuals with intermediate and high genetic risk scores had 1.23- and 1.65-fold increased hazard for major coronary events, respectively. Elevated genetic risk was additive to major atherosclerotic risk factors and identified patients more likely to benefit from evolocumab. There was no benefit for major vascular events in patients without multiple clinical risk factors or high genetic risk (hazard ratio [HR], 1.02; absolute risk reduction [ARR], −0.2%, P =0.86). In contrast, there was a 13% relative risk reduction (HR, 0.87 [0.75–0.998], P =0.047) and a 1.4% ARR in patients with multiple clinical risk factors but without high genetic risk and a 31% relative risk reduction (HR, 0.69 [0.55–0.86], P =0.0012), and 4.0% ARR in patients with high genetic risk, irrespective of clinical risk ( P trend for HR=0.017, ARR P trend =0.004). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk. Conclusion: Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest relative and absolute benefit from evolocumab, which mitigated this risk.

Polygenic modulation of lipoprotein(a)-associated cardiovascular risk

“…Our study suggests that the CAD GRS may be useful for identifying high risk patients that are likely to benefit most from lipoprotein(a)-lowering therapy, or other therapies that reduce cardiovascular risk among individuals with elevated lipoprotein(a). In support of this hypothesis, previous studies have shown that individuals with high genetic risk for CAD demonstrate greater absolute risk reduction of cardiovascular events from statins 24,45 or PCSK9 inhibitors 46 relative to individuals at lower genetic risk. In addition, the data presented here suggest that a GRS may be useful to de-risk patients with isolated elevated lipoprotein(a), as we observed that a low GRS in such individuals was associated with a risk of myocardial infarction that was similar to, or lower than, that of individuals with non-elevated lipoprotein(a) and a median GRS.…”

<p>Cardiovascular Outcomes and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: Current Data and Future Prospects</p>

“…Polygenic risk scores for coronary artery disease have been shown to identify higher-risk individuals, independently of baseline LDL-C and other known risk factors, who may derive greater clinical benefit from statin and/or PCSK9 inhibitors. 109,110 In post-ACS and ASCVD patients, a high polygenic risk score for coronary artery disease was associated with an elevated risk for recurrent MACE and larger ARR and RRR with alirocumab 109 and evolocumab, 110 respectively, providing an independent tool that may be used for risk stratification and early targeted therapy.…”

An update on genetic risk scores for coronary artery disease: are they useful for predicting disease risk and guiding clinical decisions?

“…On a parallel note, two recently published studies suggest that the efficacy of PCSK9 inhibition might be modified by an individual's genetic susceptibility to CAD [14,23,24]. Within the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial and the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, post-hoc analyses suggested that those individuals with the highest genetic risk burden had the highest absolute and relative risk reductions upon treatment with PCSK9 inhibitors [23,24]. The two studies used GRS consisting of more than 6 Million SNPs and 27 SNPs, respectively [23,24].…”

“…Within the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial and the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, post-hoc analyses suggested that those individuals with the highest genetic risk burden had the highest absolute and relative risk reductions upon treatment with PCSK9 inhibitors [23,24]. The two studies used GRS consisting of more than 6 Million SNPs and 27 SNPs, respectively [23,24]. However, in a case-control study nested within the ACCELERATE secondary prevention trial, there was no evidence that the efficacy of evacetrapib (a cholesteryl ester transfer protein inhibitor) treatment in reducing major CVD was modified by a GRS consisting of 6.6 Million SNPs [25]; there was no association between evacetrapib treatment and CVD events across GRS quintiles [25].…”