STOCKHOLM (EGMN) – The selective and reversible platelet inhibitor elinogrel will advance to a 24,000-patient, phase III megatrial on the strength of its encouraging performance in the phase II trial INNOVATE-PCI and other studies.

The phase III trial, due to start in the first quarter of 2011, will focus on patients with chronic coronary heart disease who are on background aspirin after an acute MI that occurred 6 months to 5 years before enrollment. They will be randomized to low- or high-dose oral elinogrel or placebo for roughly 29 months, with a primary efficacy end point comprising cardiovascular death, MI, or stroke, Dr. Sunil Rao announced while presenting the INNOVATE-PCI results at the annual congress of the European Society of Cardiology.

Elinogrel is the only competitive and reversible P2Y₁₂ receptor antagonist. It has a 12-hour half-life. Other available P2Y₁₂ inhibitors include clopidogrel – the standard workhorse in dual antiplatelet therapy – as well as prasugrel and ticlopidine. (Ticagrelor, an investigational oral antiplatelet that is also reversible and has a 12-hour half-life, is under review by the U.S. Food and Drug Administration, with a decision expected by the end of the year.)

A major potential advantage for elinogrel is that it can be used in both intravenous and oral preparations. The intravenous form provides near-maximal platelet inhibition within 15 minutes – hours faster than oral antiplatelet drugs – which would be of great benefit in acute coronary syndromes and for percutaneous coronary interventions. The patient could then be smoothly transferred to the oral version of the same platelet inhibitor for long-term therapy, explained Dr. Rao of Duke University, Durham, North Carolina.

Clopidogrel elicits highly variable patient responses and is ineffective in some patients. That’s not the case for elinogrel. And unlike clopidogrel, elinogrel is reversible, so it may reduce PCI-associated bleeding problems, although this has yet to be established, added Dr. Rao, coprincipal investigator of INNOVATE-PCI.

INNOVATE-PCI was a randomized, double-blind trial in which 652 patients who were undergoing nonurgent PCI were assigned to elinogrel or clopidogrel and followed for 120 days. The main elinogrel regimen consisted of a 120-mg intravenous bolus dose that was administered immediately before balloon inflation, followed by 100 mg or 150 mg of oral elinogrel twice daily for the remainder of the 4-month study. The clopidogrel regimen consisted of a 300-mg or 600-mg oral loading dose that was given up to 12 hours prior to PCI, followed by 75 mg/day.

Both intravenous and oral elinogrel resulted in faster and stronger platelet inhibition than did clopidogrel during acute and chronic therapy. There was no difference between the elinogrel and clopidogrel groups in rates of TIMI (Thrombolysis in Myocardial Infarction) major or minor bleeding or clinically relevant bleeding at either the 24-hour or 120-day assessments.

The elinogrel group did show a dose-dependent increase in less-severe bleeding requiring medical attention. These events mainly consisted of periprocedural hematomas at the vascular access site. But only about one-quarter of study participants underwent PCI using the radial approach, which is known to greatly reduce the frequency of such bleeding. As the radial approach grows in popularity – it was utilized in a clear majority of PCI patients in several other studies presented at the Stockholm congress – mild bleeding problems at the vascular access site will arise markedly less often than when femoral access was the rule, the cardiologist predicted.

Dyspnea occurred in 4.3% of the clopidogrel group during 120 days of follow-up, and was roughly threefold more common with elinogrel. The dyspnea was generally mild and transient, and seldom led to treatment discontinuation.

Elevated liver enzymes (greater than three times the upper limit of normal) occurred in 1% of the clopidogrel group and in 4.0% and 4.8% of the elinogrel 100-mg and 150-mg twice daily arms, respectively. Most cases occurred within the first 60 days, none involved serious hepatotoxicity, and all resolved even though treatment continued.

INNOVATE-PCI was not sufficiently powered to look at efficacy end points. This will happen in future studies of elinogrel in the setting of acute coronary syndrome and PCI. But the first phase III clinical trial of elinogrel will focus on chronic coronary heart disease patients because they are a population with a very high event rate and few treatment options.

“This is an indication that sorely needs new agents,” Dr. Rao emphasized.

Discussant Dr. Steen Dalby Kristensen said INNOVATE-PCI showed “quite convincingly” that elinogrel works faster and is a more efficient platelet inhibitor than clopidogrel, a drug with known disadvantages.

The elinogrel-induced liver enzyme elevations could be a matter of concern, however. Only further studies can resolve this issue, added Dr. Kristensen of Aarhus (Denmark) University.

Dr. Rao is a consultant to Novartis, which is developing elinogrel. Dr. Kristensen disclosed that he has received research grants from and serves as a consultant to numerous pharmaceutical companies that have an interest in platelet-inhibiting drugs.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

斯德哥尔摩(EGMN)——依诺格雷在Ⅱ期临床研究INNOVATE-PCI及其他研究中的表现较好，其疗效将在一项纳入24,000例患者的Ⅲ期临床试验中得以进一步验证。

 

依诺格雷是惟一一种竞争性和可逆性的P2Y12受体拮抗剂，其半衰期为12 h。其他P2Y12抑制剂包括氯吡格雷、普拉格雷(正接受FDA审查)和噻氯匹定。

 

这项Ⅲ期临床研究将集中纳入接受阿司匹林治疗的入组前6个月～5年发生急性心肌梗死的慢性冠状动脉心脏病患者。受试者将被随机分配接受低剂量或高剂量依诺格雷或安慰剂口服治疗近29个月，研究的主要疗效终点包括心血管原因死亡、心肌梗死、卒中。

 

Ⅱ期临床研究INNOVATE-PCI是一项随机双盲临床研究，纳入了652例接受非急诊PCI治疗的患者，患者被随机分配接受依诺格雷或氯吡格雷治疗，随访120天。依诺格雷治疗方案包括在球囊扩张前静脉接受单次剂量120 mg，其后4个月内每日100 mg或150 mg两次口服。氯吡格雷方案包括PCI治疗12 h前口服负荷剂量为300 mg或600 mg的氯吡格雷，其后每日口服75 mg。

 

研究结果显示，静脉应用或口服依诺格雷对血小板抑制作用的起效比氯吡格雷更快，效力更强。在用药24 h或120天后，依诺格雷组和氯吡格雷组在心肌梗死溶栓出血率或临床相关出血率方面无差异。另外，依诺格雷治疗组需要临床处理的不严重出血的发生率具有剂量相关性，例如治疗期间血管开口处血肿。此外，随访期间，氯吡格雷组呼吸困难的发生率为4.3%，依诺格雷组发生率几乎是它的1/3。其呼吸困难多较轻微，常为一过性的，极少导致中断治疗。氯吡格雷组肝酶升高(高于正常值高限的3倍)的发生率为1%，依诺格雷 100 mg和150 mg每日两次治疗组分别为4.0%和4.8%，大多发生在治疗最初的60天内，无一例导致严重的肝毒性，并且所有患者均在治疗期间缓解。

 

依诺格雷既可静脉用药也可口服应用。静脉应用时，可在15 min内发挥接近最大的抗血小板效能，比口服抗血小板药物起效快数小时，这对于急性冠状动脉综合征和接受经皮冠状动脉介入(PCI)治疗的患者非常有益。但INNOVATE-PCI研究还不足以对依诺格雷的疗效终点进行评价，还有赖于将来依诺格雷应用于急性冠状动脉综合征和接受PCI治疗的患者的研究。

 

INNOVATE-PCI研究显示有力地说明了依诺格雷起效迅速，是一种比氯吡格雷更有效的血小板抑制剂。但其引起的肝酶升高应加以关注，只有进一步的研究才能解决这个问题。

 

研究者声明其是依诺格雷的开发商诺华公司的顾问。

 

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