Table 3: Studies in secondary prevention of ischemic stroke.

ESPS-2
The European Stroke Prevention Study 2
Follow up during 2 years of 6602 patients prior TIA or stroke.Aspirin (25 mg twice daily) alone, Extended release dipyridamole (ER-DP) (200 mg twice daily) alone, Aspirin combined with ER-DP, Placebo.The combination of aspirin and ER-DP was reported to be twice as effective for stroke prevention as either drug alone.

ATC
Antiplatelet Trialists’ Collaboration
10404 patients with preexisting symptomatic atherosclerotic disease from 25 trials.Aspirin (75–150 mg daily) combined with dipyridamole versus aspirin alone.Nonsignificant 6% risk reduction in serious vascular events (nonfatal stroke, MI, vascular deaths). The apparent reduction in nonfatal stroke was derived mainly from the ESPS-2 study and was not consistent with the findings for nonfatal stroke or nonfatal MI or vascular death in other studies.

ESPRIT
European/Australasian Stroke Prevention in Reversible Ischemia Trial
2739 patients with minor ischemic stroke or TIA were randomized and followed for a mean of 3.5 years.Oral anticoagulation (INR 2.0 to 3.0) Dipyridamole (400 mg daily) plus ASA (30–325 mg/day). ASA only (same dose).The results were “positive” for the specified primary outcome constellation of stroke, myocardial infarct, vascular death, or major hemorrhage, but the reduction in ischemic stroke was not statistically significant.

ESPRIT- 2
European Stroke Prevention Study-2 randomized double-blind trial
3299 participants followed for two years with 363 stroke events.Dipyridamole (200 mg twice daily). Low-dose aspirin (25 mg twice daily).Reported reduction of recurrent stroke in 23% of patients with initial TIA/stroke relative to aspirin alone. Methodological fails led to skepticism on the part of some about the incremental value of extended-release dipyridamole plus aspirin over aspirin alone for secondary stroke prevention.

Subanalysis ESPRIT-2
De Schryver et al.
Randomized trials of individuals who were within 6 months after presentation of arterial vascular disease and who were treated for at least 1 month.Starting therapy consisted of dipyridamole (in any dose) alone or added to another antiplatelet drug compared with placebo or antiplatelet drug(s) other than dipyridamole.Dipyridamole alone or in combination with another antiplatelet agent compared with placebo reduced vascular events such as nonfatal stroke or nonfatal MI. There was no evidence that dipyridamole alone was more efficacious than aspirin.

PRoFESS
Prevention Regimen for Effectively avoiding Second Strokes
20,332 patients (mean age was 66 years, 64% were men) with recent (<120 days) ischemic stroke were randomized.Dipyridamole (200 mg)/low-dose aspirin (25 mg) twice daily. Clopidogrel 75 mg once daily in a double-blind was also randomized to receive telmistartan versus. placebo added to usual blood pressure care.The recurrent stroke rate was 3.6% per year for those assigned extended-release dipyridamole plus aspirin and 3.5% per year for those assigned clopidogrel.There were fewer major hemorrhages in those assigned clopidogrel (P = 0.05): about 1 fewer major hemorrhage per year for every 200 treated patients.
No difference for recurrent stroke or for major vascular events between clopidogrel and extended-release dipyridamole plus low-dose aspirin, with a narrow confidence interval around the hazard ratio that excludes a clinically important difference. Trends favor clopidogrel regarding fewer major hemorrhages and better tolerance, but absolute differences are small.

CAPRIE
Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events trial
Long-term prevention of recurrent atherothrombotic vascular events in 19185 patients, including 6431 with prior ischemic stroke.Clopidogrel (75 mg/d). Aspirin (325 mg/d).Among all patients, clopidogrel reduced the risk of stroke, MI, or vascular death by 8.7%. For the subgroup of patients with prior ischemic stroke, the relative risk reduction (RRR) was similar and not statistically different from the overall result. The safety profile of clopidogrel was comparable with that of aspirin.

MATCH
Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke randomized trial
7599 patients with recent TIA or ischemic stroke.Aspirin (75 mg) added to clopidogrel (75 mg) was compared with clopidogrel alone.The combination of aspirin and clopidogrel did not significantly lower the incidence of ischemic strokes, MI, or vascular death but was associated with an increase in the risk of major and lifethreatening bleeding absolute risk increase.

CHARISMA and MATCH Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management, and Avoidance randomized and double-blind trial15,603 patients with stable cardiovascular disease or multiple cardiovascular risk factors during 2.3 years mean followup.The combination of clopidogrel 75 mg/day plus aspirin (dosage range 75 mg to 162 mg daily) was compared with aspirin alone.Among the 3645 participants who had a prior ischemic stroke a mean of 3 months before study entry, the primary event constellation was reduced by 22%, but beware of accepting positive exploratory subgroup analyses from overall negative trials.