贝匹地酸在他汀类药物不耐受患者中的心血管结局。

Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients.

机构信息

From the Cleveland Clinic, Cleveland (S.E.N., A.M.L., D.B., D.M., L.C., V.M., J.M., D.D.); Imperial College London, London (K.K.R.); University of Amsterdam Academic Medical Center, Amsterdam (J.J.P.K.), and University Medical Center Utrecht, Utrecht (D.E.G.) - both in the Netherlands; Hartford Hospital, Hartford, CT (P.D.T.); Brigham and Women's Hospital, Harvard Medical School, Boston (P.L., J.P.); Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); University of Kansas Medical Center, Kansas City (P.M.M.); Esperion Therapeutics, Ann Arbor, MI (M.J.L., C.-F.C., N.L., L.B., P.R., M.H., W.J.S.); Centro de Investigación Cardiovascular y Metabólica, Tijuana, Mexico (P.F.-C.); General Hospital Sveti Luka, Smederevo, Serbia (P.P.); Center of Clinical and Preclinical Research Medipark, Pavol Jozef Šafárik University, Košice, Slovakia (J.F.); Medicome, Oświęcim, Poland (W.Z.); Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia (Y.L.); and Victorian Heart Institute, Monash University, Melbourne, VIC, Australia (S.J.N.).

出版信息

N Engl J Med. 2023 Apr 13;388(15):1353-1364. doi: 10.1056/NEJMoa2215024. Epub 2023 Mar 4.

DOI:10.1056/NEJMoa2215024

PMID:36876740

Abstract

BACKGROUND

Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain.

METHODS

We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.

RESULTS

A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.

CONCLUSIONS

Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).

摘要

背景

依折麦布，一种三磷酸腺苷柠檬酸裂解酶抑制剂，可降低低密度脂蛋白（LDL）胆固醇水平，且肌肉相关不良事件的发生率较低；其对心血管结局的影响仍不确定。

方法

我们进行了一项双盲、随机、安慰剂对照试验，纳入了因不良反应不可接受（“他汀类不耐受”患者）而无法或不愿服用他汀类药物且患有或有心血管疾病高风险的患者。患者被分配接受口服苯扎贝特酸，每日 180mg，或安慰剂。主要终点是主要不良心血管事件的四项综合指标，定义为心血管原因死亡、非致死性心肌梗死、非致死性卒中和冠状动脉血运重建。

结果

共有 13970 名患者接受随机分组；6992 名患者被分配至苯扎贝特酸组，6978 名患者被分配至安慰剂组。中位随访时间为 40.6 个月。两组患者的基线 LDL 胆固醇水平均为 139.0mg/分升，6 个月后，苯扎贝特酸组 LDL 胆固醇水平下降幅度大于安慰剂组 29.2mg/分升；苯扎贝特酸组降幅百分比高出 21.1 个百分点。苯扎贝特酸组主要终点事件的发生率明显低于安慰剂组（819 例患者[11.7%]与 927 例患者[13.3%]；风险比，0.87；95%置信区间[CI]，0.79 至 0.96；P=0.004），心血管原因死亡、非致死性卒中和非致死性心肌梗死复合终点的发生率也是如此（575 例患者[8.2%]与 663 例患者[9.5%]；风险比，0.85；95%CI，0.76 至 0.96；P=0.006）；致命或非致命性心肌梗死（261 例患者[3.7%]与 334 例患者[4.8%]；风险比，0.77；95%CI，0.66 至 0.91；P=0.002）；以及冠状动脉血运重建（435 例患者[6.2%]与 529 例患者[7.6%]；风险比，0.81；95%CI，0.72 至 0.92；P=0.001）。苯扎贝特酸对致命性或非致命性卒中和心血管原因死亡以及任何原因导致的死亡没有显著影响。苯扎贝特酸组的痛风和胆石症发生率高于安慰剂组（3.1%比 2.1%和 2.2%比 1.2%），血清肌酐、尿酸和肝酶水平的小幅度升高发生率也更高。