Preventing recurrent ischemic stroke: A 3-step plan
To prevent recurrent stroke, address the patient’s risk factors, clear stenosis, and thin the blood
The applicability of the CURE trial findings to a stroke population is questionable, however. This trial addressed neither the efficacy nor the safety of this combination in a stroke population. Results were recently reported by the Management of Atherothrombosis with Clopidogrel in High Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial, which compared clopidogrel alone with clopidogrel plus aspirin in a population of patients with recent stroke or TIA plus 1 vascular risk factor.51
Researchers reported no significant difference in prevention of a combined vascular outcome or in preventing ischemic stroke alone. They did find a significant increase in life-threatening bleeding and major bleeding using the combination of aspirin and clopidogrel. Unfortunately, this trial did not address the issue of safety or efficacy of the combination of aspirin plus clopidogrel versus aspirin alone. The Stroke Prevention in Small Subcortical Strokes (SPS3) trial, an NINDS-funded study, will address this question, but the results of that trial are several years away.
Lau and colleagues52 report that the platelet inhibition activity of clopidogrel was attenuated in patients undergoing coronary artery stent implantation and who were being treated with 10 to 40 mg of atorvastatin. Antiplatelet activity was significantly attenuated for up to 8 days after stent implantation in these patients, compared with clopidogrel alone.
Based on the data, clopidogrel is the first-line drug of choice for secondary stroke prevention for patients unable to take aspirin. The combination of aspirin and clopidogrel has increased risk without increasing efficacy and, therefore, is not a reasonable first-line choice for secondary stroke prevention.
Aspirin plus extended-release dipyridamole (ER-DP). Dipyridamole reversibly inhibits platelet activity by inhibiting both platelet phosphodiesterase and the uptake of adenosine. For the standard release formulation, the time to peak concentration varies from 34 to 75 minutes.53 Standard-release dipyridamole falls below its therapeutic level about 6 to 8 hours after the last dose. And because its inhibition of platelet function is reversible, 3 to 4 daily doses of the drug are necessary to maintain the desired antiplatelet effect.54 ER-DP reportedly requires twice daily dosing and achieves a therapeutic steady state after approximately 48 hours. Combining aspirin with ER-DP has the potential for taking advantage of the inhibition of the platelet cyclooxygenase and phosphodiesterase plus the platelet uptake of adenosine.
The second European Stroke Prevention Study (ESPS-2) investigated, in a population at high risk for stroke, the safety and efficacy of 4 antiplatelet strategies: (1) aspirin 25 mg twice daily; (2) extended-release dipyridamole 200 mg twice daily; (3) combination aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily; (4) and placebo.55
Compared with placebo, aspirin alone reduced stroke risk by 18.1% (P=.013) , dipyridamole alone by 16.3% (P=.039), and the combination agent by 37.0% (P<.001). The relative risk reductions for the combined end point of stroke or death were 13.2% (P=.016) with aspirin, 15.4% (P=.015) with dipyridamole, and 24.4% (P<.001) with the combination agent.
Headache and gastrointestinal disturbances were common adverse events in all treatment groups, but bleeding episodes were more frequent and severe only in the regimens that contained aspirin.55 In the aspirin group, 8.2% of patients reported bleeding, while in the aspirin plus ER-DP group, 8.7% reported bleeding.
This was the first trial to demonstrate that very-low-dose aspirin is effective in preventing secondary stroke.55 Efficacy was also found for extended-release dipyridamole as a single agent. The risk reduction achieved with the combination agent was approximately double that of either component alone.55 Aspirin plus ER-DP reduced stroke risk by 23% over aspirin alone.56
In progress now are trials validating ESPS2, comparing clopidogrel plus aspirin with aspirin alone, and comparing combination aspirin plus ER-DP with clopidogrel.
Applying the evidence. Until these trials are complete, reasonable first-line choices for secondary stroke prevention are aspirin alone or in combination with ER-DP. For patients unable to take aspirin, consider giving clopidogrel alone.
CORRESPONDENCE
Stanley N. Cohen, MD, 8700 Beverly Blvd, Suite 4127, Los Angeles, CA 90048. E-mail: Stanley.Cohen@cshs.org
