Reducing Risk of Stroke in Patients with TIA

Results of a randomized, double-blind, placebo-controlled, multicenter trial [N Engl J Med. 2013;doi:10.1056/NEJMoa1215340] show that the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke among patients with transient ischemic attack (TIA) without increasing the risk of hemorrhage when used within 24 hours after the onset of symptoms.

Patients who experience a TIA are at increased risk of stroke during the first weeks after the TIA or minor ischemic stroke. Prior studies on the efficacy of combined clopidogrel and aspirin have not shown a benefit over aspirin alone in this setting; however, according to researchers, the earlier studies did not look at the benefit when used early after TIA when patients are at highest risk of stroke.

To evaluate the efficacy and safety of combination clopidogrel and aspirin in reducing the risk of recurrent stroke in patients with acute high-risk TIA, investigators randomized 5170 patients with stroke or TIA to combination clopidogrel and aspirin (n=2584) (clopidogrel was given at an initial dose of 300 mg followed by 75 mg per day for 90 days plus 75 mg per day of aspirin for 21 days) or to placebo plus aspirin (n=2586; 75 mg per day for 90 days) within 24 hours after the onset of minor ischemic stroke or high-risk TIA.

Minor ischemic stroke was defined by a score of ≤3 at the time of randomization on the National Institutes of Health Stroke Scale and high-risk TIA was defined as a focal brain ischemia with resolution of symptoms within 24 hours after onset plus a moderate-to-high risk of stroke recurrence. Patients were randomized between October 2009 and July 2012.

Patients included in the study were at least 40 years of age and were able to start the study drug within 24 hours of symptom onset. Patients with image-detected hemorrhage or other conditions such as major nonischemic brain disease, along with women of childbearing age not using contraception, were excluded. No patients enrolled in the study received treatment with thrombolysis around the time of randomization.

Patients were similar between the 2 groups, with a median age of 62 years, and 33.8% were female. Most patients had a history of hypertension (65.7%), had diabetes (21.1%), and were current or former smokers (43.0%).

The primary efficacy outcome of the study was the occurrence of stroke during 90 days of follow-up. The primary safety outcome was a moderate-to-severe bleeding event.

Based on an intention-to-treat analysis, the study found a significant reduction in stroke in patients treated with combined clopidogrel and aspirin compared to aspirin alone (8.2% vs 11.7%). The hazard ratio [HR] was 0.68 (95% confidence interval, 0.57-0.81, P<.001).

No difference was found in the rate of moderate or severe hemorrhage between the combined clopidogrel and aspirin group and aspirin-alone group (0.3% each, P=.73).

According to the authors, the superior benefit of clopidogrel and aspirin in this study compared to prior studies that found no benefit may be due to the patient population in the current study that included patients who were at particularly high risk for recurrent ischemia and at low risk of hemorrhage.

The authors also noted that the survival curves for patients free of stroke were particularly steep in the first few days, after which the rates of strokes between the 2 treatment groups were similar.

Based on this, the authors stated, “Treatment with clopidogrel and aspirin 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.”