CHANCE: Short-term antiplatelet combo beneficial poststroke

July 03, 2013

Boston, MA - Final results of the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study, suggesting that a short course of dual antiplatelet therapy appears to be beneficial poststroke or transient ischemic attack (TIA), has now been published online June 26, 2013 in the New England Journal of Medicine[1].

The study, which was first presented at the International Stroke Conference 2013, found that the combination of aspirin and clopidogrel given for 21 days, with clopidogrel alone continued up to day 90, was more effective than aspirin alone in preventing recurrent strokes in Chinese patients who had suffered a minor stroke or TIA.

Results showed a 3.5% absolute reduction in the occurrence of stroke at 90 days in the aspirin/clopidogrel group, with a similar rate of moderate or severe hemorrhage in both groups. The number need to treat was just 29 to prevent one stroke over 90 days.

CHANCE: Major outcomes


End point
Combination (%)
Aspirin alone (%)
HR (95% CI)
p
Stroke (primary end point)
8.2
11.7
0.68 (0.57-0.81)
<0.001
Strok e/MI/CV death
8.4
11.9
0.69 (0.58-0.82)
<0.001
Hemorrhagic stroke
0.3
0.3
1.01 (0.38-2.70 )
0.98
Severe bleeding
0.2
0.2
0.94 (0.24-3.79)
0.94
Moderate bleeding
0.1
0.2
0.73 (0.16-3.26)
0.68
Mild bleeding
1.2
0.7
1.57 (0.88-2.79)
0.12

In their report, the authors, led by Dr Yongjun Wang (Beijing Tiantan Hospital, China), point out that they have achieved a successful result with dual antiplatelet therapy poststroke where many other trails have failed. They suggest that this may be because they targeted patients very early on after their stroke/TIA, when the risk of recurrence is the highest, with treatment started within 24 hours of symptom onset. They also excluded patients with severe stroke who may be at a higher bleeding risk.

They note that the primary-end-point curves diverged very early (within the first few days) and then remained parallel, showing the importance of early aggressive treatment.

"In clinical practice, treatment with aspirin and clopidogrel as soon as possible after symptom onset is likely to produce the greatest absolute benefit, since ischemic event rates are highest in the initial hours after symptoms appear," they write.

Results not generalizable to most patients

In an accompanying editorial [2], Dr Graeme J Hankey (University of Western Australia, Perth) says the results show that dual antiplatelet therapy is possible without excess harm in patients with acute focal brain ischemia, provided that patients have a low risk of hemorrhagic transformation—no fresh brain infarction (TIA) or a very small volume of fresh brain infarction (minor ischemic stroke).

He notes that the CHANCE investigators had to screen more than 40 000 patients to find 5000 appropriate for inclusion, so the results cannot be generalized to most patients. He also questions whether the results can be generalized to non-Chinese patients, who generally have a different stroke profile.

But there won't be too long to wait for results in a Western population. A similar trial, the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) study, sponsored by the National Institutes of Health, is ongoing and will involve predominantly North American patients. The POINT trial is evaluating a higher loading dose of clopidogrel and a narrower time window, starting treatment within 12 hours of symptom onset.

Commenting on the study, Dr Ralph Sacco (University of Miami, FL) described CHANCE as "a large, well-conducted study that shows impressive results with short-term treatment with aspirin plus clopidogrel in the acute phase after a minor stroke or TIA."

He explained that it is already established that a combination of aspirin plus clopidogrel is beneficial in unstable angina, but this has not been shown definitively in stroke before. "The problem in stroke patients appears to be that they are more sensitive to bleeding than cardiac patients and that bleeding can occur more often in the brain, which can be catastrophic."

Early short-term treatment the key

Other studies have looked at the clopidogrel/aspirin combination after stroke but have not found any benefit over monotherapy and have shown an increased risk of bleeding. Sacco pointed out that the major difference with the CHANCE study was that it looked just at short-term treatment. "The combination of the two drugs was given only for 21 days. Then clopidogrel alone was continued up to 90 days. This regimen was compared with aspirin monotherapy and found to be better."

He added: "So the key appears to be to only use dual antiplatelet therapy for a relatively short time. The bleeding risk appears to increase over the longer term, but in this study they have minimized the bleeding risk by short-term treatment and they have maximized the benefit by starting early when the risk of recurrence is at its highest. "

He believes that getting the drugs on board early is crucial. "A key difference from other studies is that treatment was started within 24 hours in CHANCE and both antiplatelet agents were loaded up front. This early phase has been a gap in our knowledge until now."

Sacco explained that at present, patients who have had a stroke are recommended to take long-term antiplatelet therapy with aspirin, clopidogrel, or extended-release dipyridamole. "But normally this isn't started until after 24 hours of stroke onset. Mostly aspirin is used."

In this study after the initial three weeks of aspirin plus clopidogrel, clopidogrel was used alone up to day 90. Clopidogrel is a more potent antiplatelet than aspirin, so this regimen is a more aggressive approach. Asked what he would do after day 90, Sacco replied: "It would make sense to leave them on clopidogrel monotherapy, or you could switch back to aspirin. Clopidogrel is not as well tested in TIA patients as aspirin."

He also believes the results are difficult to extrapolate to Western populations. "The Chinese are different; they have an increased risk of intracranial atherosclerosis," he explained. "These are higher-risk strokes and could benefit from dual antiplatelet [therapy] more. For this reason, I feel I need further data in non-Chinese populations. But I may consider this regimen now for patients with intracranial atherosclerosis, based on this study as well as the SAMMPRIS trial, which showed the aspirin/clopidogrel combination to be better than angioplasty and stenting in this group."

Sacco also pointed out that thrombolysis was not used in this study. "Thrombolysis is not indicated in TIA, and you wouldn't use antiplatelets at same time as thrombolysis."

CHANCE was funded by the Ministry of Science and Technology (MST) , People's Republic of China. Wang's institution has received grants, Support for travel to meetings for the study or other purposes , and f ees for participation in review a ctivities from MST. Disclosures for the coauthors are available at http://www.nejm.org .

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