The Japanese Aggrenox (Extended-Release Dipyridamole plus Aspirin) Stroke Prevention versus Aspirin Programme (JASAP) Study: A Randomized, Double-Blind, Controlled Trial

Abstract

Background: Despite improvements in treatment, stroke still carries a high death toll and disability in Asia. Extended-release dipyridamole (ER-DP) plus acetylsalicylic acid (ASA) has consistently been shown to be superior over conventional platelet inhibition by ASA. ER-DP plus ASA is well established in the secondary prevention of stroke in a lot of countries including the USA and Europe. DP has an established benefit in the treatment of heart disease in Japan; however, for the prevention of stroke, the fixed-dose combination of ER-DP plus ASA has only been investigated in a small number of patients in Japan. Methods: The aim of this double-blind, randomized clinical trial was to investigate the efficacy and safety of ER-DP plus ASA versus 81 mg ASA over 1 year. The primary end point of this study was the event rate of recurrent ischemic stroke (fatal or nonfatal) using the Kaplan-Meier method and Cox regression analysis. Results: Of the 1,294 enrolled patients, the primary end point was analyzed in 652 patients in the ER-DP plus ASA group and 639 in the ASA group. The incidence of ischemic stroke was 6.9% for ER-DP plus ASA and 5.0% for ASA with a hazard ratio of 1.47 (95% confidence interval 0.93–2.31) for the primary end point. The ASA treatment group was found to have a lower than expected yearly event rate, compared to other studies in Japanese stroke patients. Noninferiority of ER-DP plus ASA versus ASA could not be shown. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group. Conclusions: The results of the study are inconclusive. Noninferiority of ER-DP plus ASA versus ASA could not be established, a difference between treatments could not be shown for the primary end point. Possible reasons for this result include a small sample size, low event rates and too short a treatment duration (ClinicalTrials. gov number, NCT00311402).

Impact of Non-Vitamin K Antagonist Oral Anticoagulants on Intracranial Bleeding in Asian Patients With Non-Valvular Atrial Fibrillation

“…19- 24 The annual incidence of intracranial bleeding during aspirin treatment for secondary prevention of stroke in Japan has been reported as 0.84-1.50%/year, much higher than the 0.13-0.35%/year reported from Western countries. [19][20][21][22][23] Interestingly, no such ethnic differences have been found with clopidogrel treatment for the secondary prevention of stroke. 19, [25][26][27] In an important study, Shen et al identified 18,867 qualifying AF hospitalizations (78.5% white, 8% black, 9.5% Hispanic, 3.9% Asian) and 173 qualifying intracranial bleeding events over 3.3 years of follow-up and found that warfarin was associated with increased intracranial bleeding risk in all races.…”

Clopidogrel alone is safer than clopidogrel and aspirin for secondary prevention of acute ischemic stroke

“…This recommendation was supported by four citations [1][2][3][4] , which included a systematic review and meta-analysis; this was used as the starting point for our PubMed search. 4 The meta-analysis focused on seven randomized, controlled studies 1,[5][6][7][8][9][10] ; that included patients with recent history of stroke or transient ischemic attack (TIA); and that compared DPT versus monotherapy. The meta-analysis indicated that DPT was superior to aspirin alone, but not to clopidogrel alone, and that dual anti-platelet therapy was more harmful than clopidogrel.…”

Cost-Effectiveness of Proton Pump Inhibitor Co-Therapy in Patients Taking Aspirin for Secondary Prevention of Ischemic Stroke

“…Having reviewed relevant clinical trials of patients with a history of ischemic stroke and taking ASA for secondary prevention of ischemic stroke [5,[22][23][24], we applied the transition probabilities for ASA treatment of stroke patients (27.5 per 1000 patient-years for ischemic stroke, 9.7 per 1000 patient-years for hemorrhagic stroke) from the CSPS2 (Cilostazol for Prevention of Secondary Stroke) trial and the transition probabilities for treatment without ASA (57.8 per 1000 patient-years for ischemic stroke, 7.2 per 1000 patient-years for hemorrhagic stroke) from the CSPS (Cilostazol Stroke Prevention Study) [22,23]. Transition probabilities were taken from these two studies because (1) there are no clinical trials directly comparing a placebo arm with an ASA arm; (2) a placebo arm was included only in the CSPS; (3) subjects targeted in the CSPS were similar to those in CSPS2, which also included an ASA arm; and (4) many sites in Japan participated in these trials (183 in CSPS and 278 in CSPS2).…”