[ACC 2009]ACTIVE-A:Clopidogrel与阿斯匹灵降低心房纤维颤动之心血管事件


  March 31, 2009 (佛州奥兰多) —无法服用warfarin的心房纤维颤动(AF)病患中,与安慰剂相较,并用clopidogrel (Plavix,Bristol-Myers Squibb/Sanofi-Aventis药厂)和阿斯匹灵,可减少严重血管事件,特别是中风,但代价是可能增加严重出血。
  
  主要研究者、McMaster大学人口健康研究中心的Stuart J. Connolly医师向与会听众表示,虽然warfarin和维他命K拮抗剂是中风风险高之AF病患的治疗首选,有多达50%因为被医师视为不适用或者因为仅使用阿斯匹灵而未善加治疗,相当不符合医疗需求。
  
  Connolly医师结论表示,ACTIVE-A这个有关心房纤维颤动抗血栓治疗的最大型试验,中风病例数是其它任何试验的三倍以上,清楚显示clopidogrel减少严重血管事件,主要是因为中风比率降低了,而就大出血这点看来还属可以接受。整体而言,clopidogrel在一个可接受的风险下提供大部份病患一个重要的帮助。
  
  他发表的风险利益分析显示,在1,000名治疗三年的AF病患中,预防了28件中风,其中17件可能是致命或失能的、6件心肌梗塞(MIs),在20件非中风严重出血的案例中,3件致命;总住院天数降低,从大约34,000天降到30,000天。
  
  这项结果在线登载于3月31日的新英格兰医学期刊,与他们在美国心脏学会第58届年度科学会议中发表的一致,研究结果将于5月14日的期刊出版。
  
  【ACTIVE-A】
  Connolly医师表示,心房纤维颤动中,已知维他命K拮抗剂比起阿斯匹灵更能降低中风风险,可达38%,所以在各种指引中列为中风预防的建议。不过,这些病患有一大部份因为某些因素被视为不适用而未接受warfarin;例如,他们的国际标准凝血时间比(INR)控制不佳,有出血顾虑,药物交互作用,或者病患的用药习性,其中多数发现有治疗监控之需要。
  
  Connolly医师表示,阿斯匹灵对AF之抗血小板活性的抑制可减少中风约22%;加入clopidogrel与阿斯匹灵并用后,可进一步减少血小板活性,显示能在可接受的出血风险下,降低急性冠状症状者的血管事件。
  
  在「Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE)」试验计画中,心房纤维颤动且有一个以上其它中风风险因素之病患被纳入两个试验之一。如果他们被视为适合warfarin治疗,就纳入 ACTIVE-W试验,比较warfarin与并用clopidogrel及阿斯匹灵。ACTIVE-W的结果之前被提出报告,显示使用维他命K拮抗剂比并用clopidogrel和阿斯匹灵更降低中风风险,可达42%(ACTIVE Writing Group of the ACTIVE Investigators. Lancet 2006;367:1903-1912)。
  
  那些被视为不适用warfarin治疗者被纳入ACTIVE-A,于阿斯匹灵背景治疗下,随机分派接受clopidogrel (75 mg/天)或安慰剂。被视为不适用维他命K拮抗剂治疗但纳入ACTIVE-A的原因包括:23%出现特定出血风险因素,50%被医师评估视为不适合,而有26%是因为病患不愿意接受维他命K拮抗剂而纳入ACTIVE-A。
  
  初级结果包括严重血管事件,如中风、MI、非中枢神经系统(CNS)栓塞、血管原因死亡。总共有来自33个国家、580个中心的7,554名病患。平均追踪3.6年。
  
  Connolly医师报告指出,并用clopidogrel和阿斯匹灵可降低初级结果达11%,统计上相当显著。此一降低有一大部份是因为中风显著减少、达28%,这在统计上也是相当显著的降低。
  
  MI也有减少趋势,但统计上不显著。血管原因死亡以及非中枢神经系统栓塞都没有减少。
  
  【表1. ACTIVE-A:治疗组的心血管终点】

终点

Clopidogrel, n (%/y)

安慰剂, n (%/y)

相关风险 (95% CI)

P

严重血管事件

832 (6.8)

924 (7.6)

0.89 (0.81 – 0.98)

.014

中风

296 (2.4)

4.8 (3.3)

0.72 (0.62 – 0.83)

< .001

心肌梗塞

90 (0.7)

115 (0.9)

0.77 (0.59 – 1.02)

.067


  缺血性中风或者未知原因中风显著减少,出血性中风增加,但并不显著。
  
  【表2. ACTIVE-A:治疗组的中风】

终点

Clopidogrel, n (%/y)

安慰剂, n (%/y)

相关风险 (95% CI)

P

全部的中风

297 (2.4)

409 (3.3)

0.72 (0.62 – 0.84)

< .0001

缺血性中风

236 (1.9)

343 (2.8)

0.68 (0.58 – 0.80)

< .0001

出血性中风

30 (0.23)

22 (0.17)

1.37 (0.79 – 2.37)

.26


  当根据治疗分析中风严重度时,使用clopidogrel在失能中风且致命和非失能中风上有相似的效果;失能中风占ACTIVE-A之所有中风的约65%。
  
  整体来说,使用clopidogrel在致命缺血性中风上减少了26件,但是致命的出血性中风多了3件,Connolly医师表示,整体致命中风减少23件。
  
  不过,治疗组严重出血比率显著增加,从每年1.3%增加到2.0%,致命出血也有增加倾向,但未达统计上的显著意义。颅内与颅外出血也显著增加。
  
  【表3. ACTIVE-A:治疗组的严重出血】

终点

Clopidogrel, n (%/y)

安慰剂, n (%/y)

相关风险 (95% CI)

P

严重出血

251 (2.0)

162 (1.3)

1.57 (1.29 – 1.92)

< .001

致命出血

41 (0.3)

28 (0.2)

1.47 (0.91 – 2.38)

.12


  在报告中,研究者指出,于ACTIVE-W试验中,维他命K拮抗剂治疗比并用clopidogrel和阿斯匹灵更能降低中风风险,可达42%,与warfarin和单用阿斯匹灵之试验的后设分析显示的降低38%相似;这一点也在记者会中被提出。
  
  Connolly医师表示,ACTIVE-A清楚显示并用clopidogrel和阿斯匹灵降低中风风险达28%,那么,我们如何证明这些结果和ACTIVE-A的结果一致呢?他推测,差异可能存在于ACTIVE-W,多数病患已经使用warfarin超过两年。
  
  他表示,我们和已经使用warfarin、曾经使用warfarin的人,比较并用clopidogrel和阿斯匹灵,而造成排除对warfarin有问题之病患的事实。
  
  如果你着眼于ACTIVE-W试验中,于研究开始时未使用warfarin的病患,并用clopidogrel和阿斯匹灵,相较于warfarin的结果,与ACTIVE-A的结果更一致,因此,我们认为, ACTIVE-W的结果有部份高估了warfarin相较于并用clopidogrel和阿斯匹灵的利益。
  
  【还不能改变?】
  讨论时,来自克里夫兰大学医院的Albert L. Waldo医师提出有关ACTIVE-A试验病患筛选的问题,如果病患表示「我不要服用杀老鼠的毒药」,理由是否充分?我担心,因为warfarin看来这么好,人们可能会对服用此药太乐观。
  
  Connolly医师同意,warfarin对那些可以服用者来说是很好的药物,也指出对于这些病患,进入ACTIVE-W 试验是选项之一。医师根据他们对个别病患的了解、知识,做出清楚判断病患是否适用warfarin。再者,这与他们以前的决定一致,因为我们发现在一开始就使用维他命K拮抗剂

ACC 2009: ACTIVE-A: Clopidogrel and Aspirin Reduce CV Events in Atrial Fibrillation

By Susan Jeffrey
Medscape Medical News

March 31, 2009 (Orlando, Florida) — In patients with atrial fibrillation (AF) who cannot take warfarin, the combination of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and aspirin reduced major vascular events, particularly stroke, compared with placebo, although at the expense of an increase in major bleeding.

Although warfarin and vitamin-K antagonists are the treatment of choice for AF patients at high risk for stroke, up to 50% are not treated with either because they are judged as unsuitable candidates by their physician, and for these patients who are treated only with aspirin, "there is a major unmet medical need," lead author Stuart J. Connolly, MD, from McMaster University Population Health Research Institute, in Hamilton, Ontario told the meeting here.

"The results of ACTIVE-A, which is the largest trial ever performed of an antithrombotic therapy in atrial fibrillation, with more than 3 times as many strokes as any other trial, have clearly shown that clopidogrel reduces major vascular events, primarily due to a reduction in stroke," Dr. Connolly concluded. "This occurs at a cost that is acceptable in terms of major bleeding. Overall, clopidogrel provides an important benefit to a majority of patients at an acceptable risk."

He presented a risk/benefit analysis suggesting that in 1000 of AF patients treated for 3 years, 28 strokes would be prevented, 17 of which would be fatal or disabling, and 6 myocardial infarctions (MIs), at the cost of 20 nonstroke major bleeds, 3 of which would be fatal. Total days in the hospital would also be reduced, from about 34,000 to just over 30,000 total days, he noted.

The results are published online March 31 in the New England Journal of Medicine to coincide with their presentation here at the American College of Cardiology 58th Annual Scientific Session. They will appear in the May 14 issue of the Journal.

ACTIVE-A

In atrial fibrillation, vitamin-K antagonists have been shown to reduce the risk for stroke by 38% over aspirin therapy and so are recommended for stroke prevention by all guidelines, Dr. Connolly said. However, a substantial proportion of these patients do not receive warfarin because they are considered unsuitable for 1 of a number of reasons; among these, that they have poor international normalized ratio (INR) control, concern about bleeding, drug interactions, or the preference of the patient, many of whom find the need for monitoring of this therapy onerous.

Suppression of antiplatelet activity in AF with aspirin reduces stroke by about 22%; the addition of clopidogrel to aspirin reduces platelet activity further and has been shown to reduce vascular events in the setting of acute coronary syndromes with an "acceptable bleeding risk," Dr. Connolly said.

In the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) trial program, patients with atrial fibrillation and 1 or more additional risk factors for stroke were enrolled 1 of 2 trials. If they were considered suitable candidates for warfarin therapy, they were enrolled in ACTIVE-W, a comparison of warfarin with the combination of clopidogrel and aspirin. The results of ACTIVE-W were reported previously and showed that use of a vitamin-K antagonist reduced the risk for stroke by 42% over clopidogrel and aspirin (ACTIVE Writing Group of the ACTIVE Investigators. Lancet 2006;367:1903-1912).

Those considered unsuitable for warfarin therapy were enrolled in ACTIVE-A and randomized to receive clopidogrel (75 mg/day) or placebo on a background of aspirin therapy. The reasons patients were not considered suitable for vitamin-K–antagonist therapy and enrollment in ACTIVE-W included the presence of a specific risk factor for bleeding in 23%, a physician assessment that the patient was inappropriate in 50%, and in 26%, he said, "the only reason given for enrollment in ACTIVE-A was a patient preference not to receive a vitamin-K antagonist."

The primary outcome was a composite of major vascular events, including stroke, MI, non–central-nervous-system (CNS) systemic embolism, or death from vascular causes. A total of 7554 patients were enrolled from 580 centers in 33 countries. Median follow-up was 3.6 years.

The primary outcome was reduced by 11% with the combination of clopidogrel and aspirin, a highly statistically significant reduction, Dr. Connolly reported. "This reduction was in large part due to a substantial reduction in the outcome of stroke, which was reduced by 28%, a result that is also highly statistically significant."

There was a trend to a reduction in MI, but this was not statistically significant. There was no reduction in vascular death and no reduction in non-CNS systemic embolism.

Table 1. ACTIVE-A: Cardiovascular End Points by Treatment Group
End Point Clopidogrel, n (%/y) Placebo, n (%/y) Relative Risk (95% CI) P
Major vascular events 832 (6.8) 924 (7.6) 0.89 (0.81 – 0.98) .014
Stroke 296 (2.4) 4.8 (3.3) 0.72 (0.62 – 0.83) < .001
MI 90 (0.7) 115 (0.9) 0.77 (0.59 – 1.02) .067

Strokes of ischemic or unknown origin were reduced significantly, and hemorrhagic stroke was increased, although not significantly.

Table 2. ACTIVE-A: Strokes by Treatment Group
End Point Clopidogrel, n (%/y) Placebo, n (%/y) Relative Risk (95% CI) P
All strokes 297 (2.4) 409 (3.3) 0.72 (0.62 – 0.84) < .0001
Ischemic stroke 236 (1.9) 343 (2.8) 0.68 (0.58 – 0.80) < .0001
Hemorrhagic stroke 30 (0.23) 22 (0.17) 1.37 (0.79 – 2.37) .26

When they looked at stroke severity by treatment, there was a similar effect on both disabling and fatal vs nondisabling strokes with clopidogrel; disabling strokes accounted for about 65% of all strokes in ACTIVE-A.

Overall, there were 26 fewer fatal ischemic strokes and 3 more fatal hemorrhagic strokes with clopidogrel, "for a net reduction of fatal strokes of 23," Dr. Connolly said.

However, the rate of major bleeding was significantly increased, from 1.3% to 2.0% per year, with treatment, and there was a trend to increased fatal bleeding that did not reach statistical significance. There were also significant increases in intracranial and extracranial bleeding.

Table 3. ACTIVE-A: Major Bleeding by Treatment Group
End point Clopidogrel, n (%/y) Placebo, n (%/y) Relative Risk (95% CI) P
Major bleeding 251 (2.0) 162 (1.3) 1.57 (1.29 – 1.92) < .001
Fatal hemorrhage 41 (0.3) 28 (0.2) 1.47 (0.91 – 2.38) .12

In the paper, the researchers point out that in ACTIVE-W, vitamin-K–antagonist therapy reduced stroke by 42%

    
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