Addition of clopidogrel to aspirin reduces stroke rate after TIA or minor strokeLiterature - Wang Y, Wang Y, Zhao X, et al. CHANCE Investigators - N Engl J Med. 2013 Jul 4;369(1):11-9
Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.
Wang Y, Wang Y, Zhao X, et al. CHANCE Investigators
N Engl J Med. 2013 Jul 4;369(1):11-9. doi: 10.1056/NEJMoa1215340
BackgroundThe risk of having another stroke after having had a transient ischemic attack (TIA) or minor stroke is high; for 10-20% of patients this happens within 3 months after the index event, most of these strokes even occur within the first 2 days [1-4]. Although the role of antiplatelet therapy for secondary stroke prevention is well established, only the use of aspirin has been studied in the acute phase of stroke, during which its benefit is modest [5,6].
Aspirin and clopidogrel synergistically inhibit platelet aggregation [7,8]. Trials of secondary prevention of ischemic events after stroke have not shown a benefit of use of this dual therapy [9-11], but these trials did not study the early, high-risk period after stroke.
The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial was set up to test the hypothesis that 3 months of treatment with a combination of clopidogrel and aspirin would reduce the risk of recurrent stroke, as compared to aspirin alone, among patients with acute high-risk TIA or minor ischemic stroke. CHANCE was a randomised, double-blind placebo-controlled clinical trial conducted in 114 clinical centres in China, involving 5170 patients .
- Stroke occurred in 212 (8.2%) patients in the dual treatment group, as compared with 303 (11.7%) in the aspirin group (HR: 0.68, 95%CI: 0.57-0.81, P<0.001). Fatal or disabling stroke also occurred less often in the clopidogrel-aspirin group, as compared to aspiring group (5.2% vs. 6.8%, HR: 0.75, 95%CI: 0.60-0.94, P=0.01). Ischemic stroke occurred in 7.9% of patients on dual therapy vs. 11.4% of patients on aspirin (HR: 0.67, 95%CI: 0.56-0.81, P<0.001), whereas the occurrence of hemorrhagic stroke did not differ between the study groups (0.3%).
- The composite secondary outcome of vascular events occurred in 216 (8.4%) in the clopidogrel-aspirin group, as compared to 307 (11.9%) patients in the aspirin group (HR: 0.69, 95%CI: 0.58-0.82, P<0.001).
- Moderate or severe bleeding occurred to a similar extent in the dual therapy (n=7) and the aspirin group (n=8, in both groups 0.3%, P=0.73). The rate of any bleeding event was 2.3% in the clopidogrel-aspirin group as compared with 1.6% on aspirin alone (HR: 1.41, 95%CI: 0.95-2.10, P=0.09).
- The reduction in rate of stroke and combined secondary vascular events with addition of clopidogrel to aspirin was consistent across all major subgroups.
- Adverse event rates were similar in the two groups (5.8% vs. 5.0%), as well as serious adverse event rates (1.0% vs. 0.8%).
ConclusionAddition of clopidogrel to aspirin within 24 hours after symptom onset reduced the risk of subsequent stroke by about 30%, in Chinese patients with high-risk TIA or minor ischemic stroke, as compared to aspirin alone. Event rates were very high; number needed to treat was 29 patients to prevent one stroke with clopidogrel and aspirin in a period of 90 days. Dual treatment was not associated with more severe bleeding, although a trend towards more overall bleeding was seen.
Due to differences in clinical practice and presentation (including different prevalence of genetic polymorphisms that affect the metabolism of clopidogrel) between China and for instance Europe and the United States, these result may not apply to other patient populations.
Editorial comment This scientifically rigorous trial proves the concept that dual antiplatelet therapy can be more effective than single antiplatelet therapy in preventing early recurrent stroke in patients with actue symptomatic atherothrombosis of the brain. Dual antiplatelet therapy can be given without excess harm, provided that patients have a low risk of hemorrhagic transformation.
Patients with major ischemic stroke were excluded, thus the results cannot be generalised to most patients. Patients at lower risk for recurrent stroke and those with access to effective secondary stroke prevention may not benefit of the observed advantage of adding clopidogrel to aspirin. Furthermore, the results may not apply to non-Chinese patients, due to different forms of underlying arterial disease and drug-metabolising enzymes, and beyond 90 days after ischemic stroke.
1. Kleindorfer D, Panagos P, Pancioli A, et al. Incidence and short-term prognosis of transient ischemic attack in a population-based study. Stroke 2005;36:720-3.
2. Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ
3. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000;284:2901-6.
4. Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 2004;62:569-73.
5. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997;349:1641-9.
6. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke. Lancet 1997;349:1569-81.
7. Herbert JM, Dol F, Bernat A, et al. The antiaggregating and antithrombotic activity of clopidogrel is
potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost 1998;80:512-8.
8. Makkar RR, Eigler NL, Kaul S, et al. Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis. Eur Heart J 1998;19:1538-46.
9. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17.
10. The SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012;367:817-25.
11. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH):
randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331-7.
12. Wang Y, Johnston SC. Rationale and design of a randomized, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk
patients with acute nondisabling cerebrovascular event. Am Heart J 2010;160(3):380.e1-386.e1.
13. Hankey GJ. Dual antiplatelet therapy in acute transient ischemic attack and minor stroke. N Engl J Med. 369:1