Download this article's Factoid (PDF & PPT for Gold Subscribers

In patients who present early with minor ischemic stroke or high-risk transient ischemic attack (TIA), treatment with dual antiplatelet therapy (DAPT) for 21 days, followed by clopidogrel alone out to 90 days, reduces the risk of recurrent stroke by 32% compared with aspirin alone, with no increase in moderate-to-severe bleeding. The findings were published online June 26, 2013, ahead of print in the New England Journal of Medicine.

For the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial, a team led by Yongjun Wang, MD, of Beijing Tiantan Hospital (Beijing, China), enrolled 5,170 patients who presented to 114 Chinese centers with acute minor ischemic stroke or high-risk TIA (27.9%). After receiving open-label aspirin (75 mg to 300 mg) on day 1, participants were randomized to clopidogrel (initial dose of 300 mg followed by 75 mg daily on days 2 through 90) plus aspirin (75 mg daily on days 2 through 21; n = 2,584) or placebo (for 90 days) plus aspirin (75 mg daily on days 2 through 90; n = 2,586).

DAPT Improves Vascular Outcomes

At 90-day follow-up, stroke, the primary efficacy endpoint, was less frequent in the combination-therapy group compared with the aspirin-alone group, as were composite vascular events (ischemic or hemorrhagic stroke, MI, or vascular death) and ischemic stroke. Rates of hemorrhagic stroke, death from vascular causes, and TIA were similar between arms (table 1).

Table 1. Efficacy Outcomes at 90 Days

No difference was seen between groups in rates of GUSTO-defined moderate-to-severe hemorrhage, the primary safety endpoint. However, a trend emerged toward increased rates of any bleeding in the DAPT arm (table 2).

Table 2. Safety Outcomes at 90 Days

The reduction in stroke risk imparted by DAPT was consistent across 11 predefined subgroups, including those based on age (threshold, 65 years), sex, type of index event (minor stroke vs. TIA), ABCD² stroke risk score (4 vs. > 4), or previous stroke/TIA. There were no interactions with treatment effect in any of the subgroups (P > 0.10 for all comparisons).

Rates of adverse events were similar between the DAPT and aspirin-alone groups (5.8% and 5.0%, respectively). Serious adverse events also occurred at similar rates in both treatment arms (1.0% and 0.8%, respectively).

Strongest Protection in First Few Days 

The authors observe that the advantage of DAPT over aspirin alone for stroke-free survival was dramatic in the first few days after the index event, suggesting that treatment should be initiated as soon as possible after symptom onset to reap the greatest absolute benefit.

In an accompanying editorial, Graeme J. Hankey, MD, of the Royal Perth Hospital (Perth, Australia), says the trial shows that DAPT can be given without excess harm to patients with a low risk of hemorrhagic transformation, ie, no (TIA) or a very small volume (minor ischemic stroke) of new brain infarction. But, he points out, because only 12.4% of patients screened for the trial fit those categories, the results cannot be generalized to most patients.

In particular, they may not apply to non-Chinese patients, who tend to have different forms of underlying arterial disease and different prevalences of genetic polymorphisms for enzymes that activate clopidogrel, Dr. Hankey points out. The authors acknowledge the limitation, noting that a similar trial of DAPT called POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) is currently enrolling patients primarily at sites in the United States.

Moreover, the CHANCE results may not apply beyond 90 days, when the cumulative risks of bleeding with DAPT vs. aspirin alone may outweigh the benefits, Dr. Hankey cautions.

Going forward, he urges that DAPT research be broadened to test new antiplatelet agents such as prasugrel and ticagrelor and new anticoagulants such as rivaroxaban that are effective for acute coronary syndromes in patients with acute TIA and minor ischemic stroke due to thromboembolism. 

1. Wang, Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;Epub ahead of print.

2. Hankey GJ. Dual antiplatelet therapy in acute transient ischemic attack and minor stroke [editorial]. N Engl J Med. 2013;Epub ahead of print.