Kastelein John J P, Kereiakes Dean J, Cannon Christopher P, Bays Harold E, Minini Pascal, Lee L Veronica, Maroni Jaman, Farnier Michel
aDepartment of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands bThe Christ Hospital, Heart and Vascular Center/The Lindner Research Center, Cincinnati, Ohio cHarvard Clinical Research Institute, Boston, Massachusetts dLouisville Metabolic and Atherosclerosis Research Center (L-MARC), Louisville, Kentucky eSanofi, Bridgewater, New Jersey fRegeneron Pharmaceuticals Inc., Tarrytown, New York, USA gBiostatistics and Programming, Sanofi, Chilly-Mazarin hPoint Médical, Dijon, France.
Coron Artery Dis. 2017 May;28(3):190-197. doi: 10.1097/MCA.0000000000000438.
The objective of this study is to report the dose response in ODYSSEY phase 3 clinical trials of proprotein convertase subtilisin kexin type 9 inhibition with alirocumab in patients not at prespecified lipid goals who received a per-protocol dose increase from 75 every 2 weeks (Q2W) to 150 mg Q2W.
Patients (n=2181) receiving statins were enrolled in six phase 3 randomized, double-blind, double-dummy trials (24-104 weeks): alirocumab versus placebo or ezetimibe 10 mg/day. The 75 mg subcutaneous Q2W dose was increased to 150 mg at week 12 if week 8 LDL cholesterol (LDL-C) was greater than or equal to 70 mg/dl (>100 mg/dl in OPTIONS studies for patients without previous coronary heart disease, but with other risk factors). LDL-C percentage reductions from baseline (on-treatment data, n=1291) were compared at week 12 versus week 24.
Most patients (n=951; 73.7%) with 75 mg Q2W dose plus background statin achieved LDL-C less than 70 or less than 100 mg/dl at week 8. In 340 (26.3%) patients, alirocumab dose was increased to 150 mg Q2W at week 12, and 60.9% of these patients achieved LDL-C goals at week 24, with an additional 14.2% reduction in LDL-C from week 12 to week 24. Adverse event rates were comparable in patients with versus without a dose increase (72.4 vs. 71.8% in placebo-controlled trials; 67.0 vs. 67.6% in ezetimibe-controlled trials).
Most patients achieved LDL-C goals with alirocumab 75 mg Q2W plus statins. Of those (26.3%) receiving a dose increase, 60.9% achieved LDL-C goals at week 24 with an additional 14.2% reduction in LDL-C.
本研究的目的是报告在ODYSSEY 3期临床试验中，对于未达到预先设定血脂目标的患者，使用阿利西尤单抗抑制前蛋白转化酶枯草溶菌素9型，并将每2周一次的按方案给药剂量从75mg增加至150mg时的剂量反应。
接受他汀类药物治疗的患者（n = 2181）被纳入6项3期随机、双盲、双模拟试验（24 - 104周）：阿利西尤单抗与安慰剂或10mg/天依折麦布对比。如果第8周的低密度脂蛋白胆固醇（LDL-C）大于或等于70mg/dl（在无既往冠心病但有其他危险因素的患者的OPTIONS研究中为>100mg/dl），则在第12周将每2周一次皮下注射75mg的剂量增加至150mg。比较第12周和第24周时LDL-C较基线的百分比降低情况（治疗期数据，n = 1291）。
大多数接受每2周一次75mg剂量加用背景他汀类药物治疗的患者（n = 951；73.7%）在第8周时LDL-C低于70mg/dl或低于100mg/dl。在340例（26.3%）患者中，阿利西尤单抗剂量在第12周增加至每2周一次150mg，这些患者中有60.9%在第24周时达到LDL-C目标，从第12周到第24周LDL-C又额外降低了14.2%。有剂量增加和无剂量增加的患者不良事件发生率相当（安慰剂对照试验中分别为72.4%和71.8%；依折麦布对照试验中分别为67.0%和67.6%）。
大多数患者使用每2周一次75mg阿利西尤单抗加用他汀类药物可实现LDL-C目标。在那些接受剂量增加的患者（26.3%）中，60.9%在第24周时达到LDL-C目标，且LDL-C又额外降低了14.2%。
