WASHINGTON (EGMN) – Treatment with the investigational antiplatelet agent atopaxar did not significantly increase bleeding in patients with acute coronary syndromes in a randomized trial, making protease-activated receptor-1 blockade “a promising target” for ACS treatment, the trial’s lead investigator reported.
Drugs that inhibit platelet activation, such as aspirin and P2Y12 inhibitors (clopidogrel, for instance), are the mainstay of therapy for patients with ACS, but these drugs do not inhibit the thrombin receptor as atopaxar does. “Thrombin is known to be the most potent platelet agonist,” explained Dr. Michelle O’Donoghue of Brigham and Women’s Hospital in Boston.
Thrombin acts primarily via the PAR-1 receptor, which has led investigators to wonder whether PAR-1 receptor blockage – in addition to the current antiplatelet therapy – can move clinicians closer to the goal of reducing major adverse cardiac events without increasing the incidence of clinically significant bleeding.
Results from the LANCELOT ACS trial show that the PAR-1 antagonist atopaxar “achieves potent and rapid platelet inhibition ... without a significant increase in bleeding in patients with ACS,” Dr. O’Donoghue reported at the Transcatheter Cardiovascular Therapeutics 2010 meeting, which was sponsored by the Cardiovascular Research Foundation.
In the multicenter, double-blind study, 603 patients with unstable angina or non–ST-elevation myocardial infarction (NSTEMI) were randomized within 72 hours of symptom onset to receive either placebo or a 400-mg loading dose of atopaxar followed by a daily maintenance dose of 50 mg, 100 mg, or 200 mg for 12 weeks. The patients were followed for 4 weeks and, with few exceptions, were treated with aspirin or dual antiplatelet therapy in addition to atopaxar or the placebo drug.
The average rate of bleeding across the three atopaxar groups was 3.1% according to the CURE bleeding classification (1.8% CURE major and 1.3% CURE minor), compared with 2.2% in placebo group (all CURE minor). There was “no evidence of any dose-dependent trend,” Dr. O’Donoghue said.
The study, funded by Eisai Inc., was not powered for efficacy – the primary objective was to establish safety and tolerability – but “numerically, there was a lower incidence of cardiovascular death, MI, or stroke in the active combined group as compared with placebo,” Dr. O’Donoghue said. This difference was not statistically significant, but it shows “favorable trends for efficacy,” she said.
The incidence of Holter-detected ischemia at 48 hours following a 400-mg loading dose also was significantly lower in the atopaxar groups, compared with placebo.
“There was a significant 33% relative risk reduction [in the atopaxar groups combined],” she said. “This is the first time an oral antiplatelet drug was shown to reduce Holter-detected ischemia.”
Overall, the drug was well tolerated, but dose-dependent transaminitis and relative QTc prolongation were observed with the higher doses of atopaxar.
A platelet function substudy showed there was significant inhibition of platelet aggregation 1-3 hours after the loading dose. Platelet inhibition increased further at 3-6 hours to levels that were maintained until the first maintenance dose. Once maintenance doses began, “there was some evidence of a dose-dependent trend, with greater inhibition of platelet aggregation at the higher doses,” said Dr. O’Donoghue.
Dr. David J. Moliterno, who moderated a discussion of the trial, said that atopaxar is “only the second drug to be studied in this class in a phase II fashion.”
“Should we be concerned by the increase [in the rate of major bleeds], from 0 to 1.8%?” said Dr. Moliterno, chief of cardiology at the University of Kentucky, Lexington. “I don’t think we should be discouraged. ... It was a small trial ... and there was no clear dose effect.”
Similar outcomes of treatment with the new agent were reported this year for the J-LANCELOT trial, which tested atopaxar in patients with ACS and high-risk coronary artery disease in Japan (Eur. Heart J. 2010 [doi:10.1093/eurheartj/ehq320]).
The study was funded by Eisai Inc. Dr. O’Donoghue disclosed that she has received research support from Eisai and GlaxoSmithKline, and that she is a consultant for Eli Lilly & Co. and Daiichi Sankyo.
Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
华盛顿(EGMN)——波士顿布里格姆与妇科医院的Michelle O’Donoghue博士在由心血管研究基金会资助的经导管心血管治疗2010学术年会上报告，他们开展的LANCELOT ACS研究发现，对于急性冠脉综合征(ACS)患者，试验药抗血小板制剂atopaxar并未增加患者出血风险，这使得阻断蛋白酶活化受体1(PAR-1)成为ACS治疗充满希望的靶点。
抑制血小板活性的药物，如阿司匹林和P2Y12抑制剂(如氯吡格雷)是ACS患者的主要治疗药物，但这些药物并无抑制凝血酶受体的功效，而atopaxar有这种功效。凝血酶是已知最为强效的血小板拮抗剂，主要通过PAR-1受体起效。为阐释目前的抗血小板疗法联合阻断PAR-1受体能否更好地减少严重心血管不良事件同时不增加临床严重出血的发生率，研究者们进行了此研究。
此项多中心双盲研究中，603例不稳定型心绞痛或非ST段抬高的心肌梗死(NSTEMI)患者在症状出现72 h内被随机分配接受安慰剂或atopaxar治疗(起始剂量400 mg，其后每日50 mg、100 mg或200 mg维持，共12周)，他们在接受atopaxar或安慰剂治疗的同时还接受阿司匹林或双重抗血小板治疗，仅少数患者例外。随访时间为4周。
参照CURE出血分级，三个atopaxar治疗组的平均出血率为3.1%(CURE大出血率为1.8%，CURE小出血率为1.3%)，而相比之下，安慰剂组为2.2%，且均为CURE小出血，其中未发现剂量依赖关系。与安慰剂组相比，atopaxar治疗组的心血管死亡率、心肌梗死率或卒中率均较低，此差异不具统计学意义，但数据显示其效果确实更优。另外，与安慰剂组相比，动态心电监测发现atopaxar治疗组在给予初始剂量(400 mg)48 h后的局部缺血发生率明显更低。atopaxar治疗组的相对风险下降达33%，这是首次发现一种抗血小板药物可降低动态心电监测发现的局部缺血的发生率。此外，一项有关血小板功能的亚组研究发现，一旦开始维持用药，即可发现剂量效应趋势，亦即剂量越高其对血小板的抑制作用越强。
总体上，该药的耐受性很好，大剂量atopaxar治疗组会出现剂量依赖性转氨酶升高和QT间期相对延长的现象。 PAR-1拮抗剂atopaxar“获得了有力而快速的血小板抑制作用，并未显著增加ACS患者的出血事件”。本年度J-LANCELOT研究也报告了有关这种新药的与本研究相似的治疗结果(Eur. Heart J. 2010 [doi:10.1093/eurheartj/ehq320])。
LANCELOT ACS研究由卫材公司资助。研究者声明接受多家医药公司经济资助。
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