Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial.
Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial.
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DOI：
10.1161/circulationaha.119.043805
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发表时间：
2020-02-25
期刊：
影响因子：
37.8
通讯作者：
Ruff CT
中科院分区：
文献类型：
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作者：
Marston NA;Kamanu FK;Nordio F;Gurmu Y;Roselli C;Sever PS;Pedersen TR;Keech AC;Wang H;Lira Pineda A;Giugliano RP;Lubitz SA;Ellinor PT;Sabatine MS;Ruff CT
尚未确定遗传风险评分预测已确定心血管疾病风险的能力，并确定从PCSK 9（前蛋白转化酶枯草杆菌蛋白酶/kexin 9型）抑制中获得更大益处的个体。我们研究了FOURIER试验（高风险受试者中PCSK 9抑制的进一步心血管结局研究）中的14298例动脉粥样硬化性心血管疾病患者。27个单核苷酸多态性遗传风险评分定义低（五分位1），中等（五分位2-4）和高（五分位5）遗传风险。还根据主要动脉粥样硬化风险因素对患者进行分类，包括糖尿病、高血压、低密度脂蛋白胆固醇≥100 mg/dl和吸烟;多个（≥2个）风险因素被视为高临床风险。结局包括主要冠状动脉事件（冠心病死亡、心肌梗死或冠状动脉血运重建）和主要血管事件（主要冠状动脉事件和卒中）。中位随访时间为2.3年。在我们调整了临床因素后，遗传风险评分与主要血管事件（P趋势=0.005）和主要冠状动脉事件（P趋势<0.0001）的风险相关。具有中等和高遗传风险评分的个体发生主要冠状动脉事件的风险分别增加1.23倍和1.65倍。升高的遗传风险是主要动脉粥样硬化风险因素的附加因素，并确定患者更可能从依洛尤单抗中获益。在没有多种临床风险因素或高遗传风险的患者中，主要血管事件没有获益（风险比[HR]，1.02;绝对风险降低[ARR]，-0.2%，P=0.86）。相比之下，（HR，0.87 [0.75-0.998]，P=0.047）和1.4%的ARR患者有多种临床风险因素，但没有高遗传风险和31%的相对风险降低（HR，0.69 [0.55-0.86]，P=0.0012），高遗传风险患者的ARR为4.0%，与临床风险无关（HR的P趋势=0.017，ARR的P趋势=0.004）。接受evoloclavin治疗的高遗传风险患者的事件发生率与遗传和临床风险均较低的患者相似。没有多种临床风险因素或高遗传风险的患者的事件发生率较低，并且在2.3年内似乎没有从evolocumab中获益。相反，具有多种临床风险因素但没有高遗传风险的患者具有中等风险和中等风险降低。无论临床风险如何，具有高遗传风险的患者的事件发生率都很高，并且从evolocumab中获得了最大的相对和绝对获益，从而减轻了这种风险。
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. 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 stroke). Median follow-up was 2.3 years. After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events (Ptrend=0.005) and major coronary events (Ptrend<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 (Ptrend for HR=0.017, ARR Ptrend=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. 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.