prasugrel vs氯吡格雷：减少冠脉支架术后缺血事件

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Intensive antiplatelet therapy reduces ischemia, stent thrombosis risk in TRITON-TIMI 38

30 March 2008

MedWire News: Intensive antiplatelet therapy with prasugrel lowers the risk for ischemic events after coronary stenting compared with standard clopidogrel treatment, a TRITON-TIMI 38 substudy shows.

Moreover, prasugrel therapy resulted in reductions in both early and late stent thrombosis, irrespective of stent type and in patients with a broad range of clinical and procedural characteristics. However, bleeding rates were slightly higher among patients receiving prasugrel.

Lead investigator Stephen Wiviott (Brigham and Women’s Hospital, Boston, Massachusetts, USA) presented the findings at the ongoing American College of Cardiology Annual Scientific Sessions, being held in Chicago, Illinois. The results have been simultaneously released in an advance online publication by The Lancet.

The main TRITON-TIMI 38 trial results showed that treatment with prasugrel, which has a more rapid onset of action and greater antiplatelet activity than clopidogrel, significantly reduced the primary endpoint of cardiovascular death, myocardial infarction (MI), or stroke in comparison with clopidogrel in acute coronary syndrome patients undergoing planned percutaneous coronary intervention (PCI).

For the current study, the investigators compared outcomes with each treatment in the 12,844 patients in TRITON-TIMI 38 who received at least one coronary stent when undergoing the index procedure. Of these patients, 47% received bare-metal stents (BMS) only, 42% drug-eluting stents (DES) only, and 5% received both BMS and DES.

Patients randomly assigned to receive prasugrel received a 60-mg loading dose before the procedure, followed by 10 mg daily. Those assigned to clopidogrel received a 300-mg loading dose before PCI, followed by a maintenance dose of 75 mg daily. Treatment was continued for a minimum of 6 months and a maximum of 15 months, and event rates were recorded for the duration of treatment.

Patients who received prasugrel therapy had significantly lower rates of the primary composite endpoint (cardiovascular [CV] death, nonfatal MI, or nonfatal stroke) than those given clopidogrel, at 9.7% versus 11.9%, respectively (hazard ratio [HR]=0.81, p=0.0001).

Similar reductions in the primary endpoint were seen with prasugrel versus clopidogrel among patients who received DES, at 9.0% versus 11.1% (HR=0.82, p=0.19) and those with BMS, at 10.0% versus 12.2% (HR=0.80, p=0.003).

Thrombolysis in MI (TIMI) major bleeding unrelated to coronary artery bypass grafting (CABG) was slightly higher in prasugrel-treated patients, but did not reach significance (2.4 vs 1.9%, HR=1.27;p=0.06). Overall, the net clinical benefit, defined as the composite of all- cause death, nonfatal MI, nonfatal stroke, and nonfatal TIMI major bleeding unrelated to CABG, favored prasugrel (12.0 vs 13.7%, HR=0.86; p=0.002).

Definite or probable stent thrombosis, as defined by Academic Research Consortium Criteria, was reduced with prasugrel overall (1.13% vs 2.35, HR=0.48; p<0.0001) and in patients with DES (0.84 vs 2.31%, HR=0.36; p<0.0001) and BMS (1.27 vs 2.41%, HR=0.52; p=0.0009) only. Further analysis showed that prasugrel reduced the relative risk for both early-stent thrombosis, by 59%, and late-stent thrombosis, by 40%, compared with clopidogrel.

Moreover, reductions in stent thrombosis with prasugrel were significant when analyzed by alternative definitions, and irrespective of baseline (acute coronary syndrome presentation, renal function, presence of diabetes, age, gender, and CV disease history) and treatment (stent length and type, use of bifurcation stenting, and use of glycoprotein IIb/IIIa inhibitors) characteristics.

Wiviott noted that the data represent a reduction of 12 stent thrombosis events and 15 primary ischemic endpoint events per 1000 patients treated with prasugrel, at a cost of five additional major bleeding events.

Highlighting that stent thrombosis was related to substantially increased mortality in the trial, he concluded: “Our data indicate that an agent with more rapid, consistent, and greater inhibition of platelet aggregation (prasugrel) results in major reductions (around 50%) in stent thrombosis across a broad array of clinical procedural characteristics.”

Commentator George Dangas (Columbia University Medical Center, New York, USA) said the key question now is whether it is possible “to distinguish those patients at increased risk for stent thrombosis versus those at increased risk for bleeding and treat both accordingly.”

American College of Cardiology Annual Scientific Sessions; Chicago, Illinois: 29 March – 1 April 2008
TRITON-TIMI 38研究发现，强化抗血小板治疗可以降低局部缺血和支架内血栓形成的风险******
MedWire新闻：一项TRITON-TIMI 38研究结果显示，与标准的氯吡格雷疗法相比，以普拉格雷为基础的强化抗血小板治疗可减少冠脉支架术后局部缺血事件的发生率。此外，不论支架类型，在具有广泛临床特征和手术特性的病人中，普拉格雷疗法都能够降低早期和晚期的支架血栓形成。然而，病人的出血风险有所增加。
正在伊利诺州芝加哥市举行的美国心脏病学会科学年会上，主要研究者Stephen Wiviott公布了这一研究结果。该结果同时提前发表在柳叶刀杂志的网络版上。主要研究结果显示，在经皮冠脉介入治疗（PCI）的急性冠脉综合症病人中，应用普拉格雷治疗比氯吡格雷起效更快，抗凝效应更强，可显著降低心血管死亡的主要终点、心肌梗死（MI）或中风事件。
对于当前的研究，研究者对比了12844例参与TRITON-TIMI 38研究且至少接受过一种冠脉支架术治疗的患者的治疗结果。这些病人当中，47%仅接受普通金属支架治疗(BMS)，42%仅接受药物洗脱支架治疗(DES)，另5%接受了BMS和 DES两种支架治疗。病人被随机安排给予普拉格雷，术前60mg负载量，之后每天10mg。被安排给予氯吡格雷的患者，在PCI前的负载量为300mg，之后的维持剂量为每天75mg。疗程最短6个月，最长则15个月，治疗期间的事件发生率被记录在案。普拉格雷组的主要复合终点（心血管（CV）死亡，非致命性心肌梗塞或非致命性中风）较氯吡格雷组明显降低，分别为9.7%和11.9%(危险率 [HR]=0.81, p=0.0001).同样的下降在接受DES治疗的患者和接受BMS治疗的患者中也可以观察到，普拉格雷组的主要终点VS氯吡格雷组的主要终点分别为9.0% vs11.1% (HR=0.82, p=0.19)和10.0% vs 12.2% (HR=0.80, p=0.003).
心肌梗塞溶栓治疗（TIMI）中非冠状动脉旁路移植术(CABG)相关的大出血情形在接受普拉格雷治疗的患者中略有升高，但并没有显著性差异（2.4 vs1.9%， HR=1.27;p=0.06)。以致命、非致命性MI、非致命性中风和非致命性TIMI与CABG不相关的大出血结合在一起定义临床净获益率，总的说来，普拉格雷更优(12.0 vs 13.7%, HR=0.86; p=0.002).按照学术研究联合会标准，给予普拉格雷，肯定的或可能的支架内血栓形成率总体下降(1.13% vs 2.35, HR=0.48; p<0.0001)，仅接受DES治疗的为(0.84 vs 2.31%, HR=0.36; p<0.0001)，仅接受BMS治疗的为(1.27 vs 2.41%, HR=0.52; p=0.0009)。进一步的分析表明，与氯吡格雷相比，普拉格雷不仅能使早期的支架血栓形成率下降59%，还能使晚期的支架血栓形成率下降40%。
此外，当采用另一种定义分析时，不论基线水平（急性冠脉综合症表现、肾功能、糖尿病、年龄、性别和心血管（CV）病史）和支架治疗（支架长度和类型，分叉支架的使用以及糖蛋白IIb/IIIa抑制剂的使用）特点，普拉格雷都能明显降低支架血栓形成率。
Wiviott指出，数据表明每一千例接受普拉格雷治疗的患者中，可减少12起支架血栓事件和15起主要缺血性终点事件，代价是额外增加5起大出血事件。
他强调指出，支架血栓与试验中的死亡率增加有关。各阶段的临床过程特性的数据表明，一种快速、持续并且有效抑制血小板聚集的药物（普拉格雷）可导致支架血栓形成率大幅下降（约50%）。
评论家George Dangas（哥伦比亚大学医学中心，纽约，USA）说，现在关键的问题是“识别面临支架血栓风险的病人与面临出血风险的病人以及处理二者”是否是可能的。