Schwartz Gregory G, Szarek Michael, Bhatt Deepak L, Bittner Vera A, Bujas-Bobanovic Maja, Diaz Rafael, Fazio Sergio, Fras Zlatko, Goodman Shaun G, Harrington Robert A, Jukema J Wouter, Manvelian Garen, Pordy Robert, Ray Kausik K, Scemama Michel, White Harvey D, Steg Ph Gabriel
Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA.
CPC Clinical Research, Aurora, CO, USA.
Eur Heart J. 2023 Mar 5;44(16):1408-17. doi: 10.1093/eurheartj/ehad144.
Long-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects follow a short period of very low low-density lipoprotein cholesterol (LDL-C) levels achieved with statin plus PCSK9 inhibitor.
In 18,924 patients post-acute coronary syndrome, the ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab with placebo, each added to high-intensity or maximum-tolerated statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL) on alirocumab had blinded placebo substitution for the remainder of the trial with continued statin treatment. In post hoc analyses, major adverse cardiovascular events (MACE) in these patients were compared to MACE in propensity score-matched patients from the placebo group with similar baseline characteristics and study medication adherence. In the alirocumab group, 730 patients had blinded placebo substitution at a median 8.3 months from randomization, after a median 6.0 months with LDL-C < 0.39 mmol/L. They were matched to 1460 placebo patients. Both groups had lower baseline LDL-C and lipoprotein(a) and better study medication adherence than the overall cohort. Over a median follow-up of 2.8 years, MACE occurred in 47 (6.4%) alirocumab patients with limited-duration, very low achieved LDL-C versus 122 (8.4%) matched placebo patients (treatment hazard ratio 0.72; 95% confidence interval 0.51, 0.997; P = 0.047).
A short period of LDL-C levels <0.39 mmol/L achieved with statin and alirocumab, followed by statin monotherapy, was associated with lower risk of MACE than statin monotherapy throughout the observation period. Clinical benefit persisted for several years.
ClinicalTrials.gov NCT01663402.
长期的、安慰剂对照的降胆固醇试验已证明存在遗留效应（试验结束后持续存在或出现的临床益处）。目前尚不清楚，在使用他汀类药物加前蛋白转化酶枯草溶菌素9（PCSK9）抑制剂使低密度脂蛋白胆固醇（LDL-C）水平短期内极低之后，是否会出现遗留效应。
在18924例急性冠状动脉综合征后患者中，ODYSSEY OUTCOMES试验将PCSK9抑制剂阿利西尤单抗与安慰剂进行了比较，二者均添加至高强度或最大耐受剂量的他汀类药物治疗中。接受阿利西尤单抗治疗且连续两次LDL-C水平<0.39 mmol/L（15 mg/dL）的患者，在试验剩余时间内接受盲法安慰剂替代，并继续接受他汀类药物治疗。在事后分析中，将这些患者的主要不良心血管事件（MACE）与安慰剂组中倾向评分匹配的、具有相似基线特征且研究药物依从性相似的患者的MACE进行了比较。在阿利西尤单抗组中，730例患者在随机分组后中位8.3个月时接受了盲法安慰剂替代，此时LDL-C<0.39 mmol/L的中位时间为6.0个月。他们与1460例安慰剂组患者进行了匹配。两组的基线LDL-C和脂蛋白(a)水平均较低，且研究药物依从性均优于总体队列。在中位随访2.8年期间，47例（6.4%）接受阿利西尤单抗治疗、LDL-C达到极低水平且持续时间有限的患者发生了MACE，而匹配的安慰剂组患者中有122例（8.4%）发生了MACE（治疗风险比0.72；95%置信区间0.51, 0.997；P = 0.047）。
在观察期内，使用他汀类药物和阿利西尤单抗使LDL-C水平在短期内<0.39 mmol/L，随后采用他汀类药物单药治疗，与单独使用他汀类药物单药治疗相比，MACE风险更低。临床益处持续了数年。
ClinicalTrials.gov NCT01663402。
