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ESPRIT: Protocol Change

To increase the current accrual rate, ESPRIT now offers the option of split randomization. Preferably, a patient should be randomized according to the protocol shown in table 1 (3 arms, scheme A), but if a patient does not meet the inclusion criteria of age or leukoaraiosis, if a patient refuses to participate because he/she does not want to use oral anticoagulants, if the neurologist has special difficulties in prescribing oral anticoagulation, or if no dipyridamole is available in a country, the patient can be randomized via two alternative schemes, each with two treatment arms: (B) aspirin in combination with dipyridamole versus aspirin alone and (C) oral anticoagulation versus aspirin alone. Split randomization will have the following consequences for the originally planned primary analyses: For each of these comparisons, the original sample size calculation applies, i.e., 4,500 patient-years per treatment arm (equivalent to 1,500 patients followed for a mean of 3 years). The first comparison will consist of groups A1 + C1 versus groups A3 + C2, the second of groups A2 + B1 versus groups A3 + B2 (see table 1). Because the groups will be assigned to their study treatment at random, the internal validity of the trial is not compromised by the altered design. In fact, a similar approach has been used before in the European Atrial Fibrillation Trial [2]. The generalizability of the trial results might be a point of concern, particularly the aspirin plus dipyridamole versus aspirin alone comparison. Patients could enter either via scheme A or scheme B, with the latter scheme having less stringent inclusion criteria. For this an a priori subgroup analysis according to the randomizing scheme (A versus B) has been specified for this treatment comparison. If no important differences are observed in the relative risk between the two subgroups, our results are generally applicable. Such a concern hardly plays a role in the anticoagulation versus aspirin comparison, because for both scheme A and scheme C the strict exclusion criteria for anticoagulation apply.