To assess the feasibility of a phase 3 trial, we did power calculations with the per-protocol data, and the composite outcome of stroke, death, or major bleeding (2·08%, 95% CI 0·25–7·32 in the anticoagulant group and 2·97%, 0·62–8·44 in the antiplatelet group). We calculated that a study with a power of 0·8 and signifi cance level of 0·05 would require a sample size of 4876 in each group.
Discussion The results of our study, to our knowledge the fi rst randomised trial of antiplatelet treatment compared with anticoagulant treatment for extracranial carotid and vertebral artery dissection (panel), show that recurrent stroke at 3 months is rare, with no signifi cant diff erence between the two treatments. Although more strokes occurred in the antiplatelet group than in the anticoagulant group, this diff erence was counterbalanced by one major subarachnoid haemorrhage in the anticoagulant group. The risk of recurrent events was lower than that reported in some observational studies. One of the fi rst studies,2 which included 80 patients with carotid dissection (29 retrospectively and 51 prospectively recruited) reported recurrences in 17 (41%) of 41 patients presenting with transient ischaemic attack. In a prospective multicentre Canadian study,3 in which follow-up data were available for 105 individuals, nine patients had stroke after presentation with either carotid or vertebral dissection, although fi ve recurrences were before study enrolment; the time between enrolment and onset of symptoms was not documented. By contrast, a retrospective analysis15 of data from 298 patients with carotid dissection, all treated with either antiplatelet or anticoagulant drugs, reported fewer recurrences: 0·3% had ischaemic stroke, 3·4% had transient ischaemic attack, and 1·0% had retinal ischaemia. New ischaemic events were signifi cantly more common in patients with ischaemic events at onset (6·2%) than in patients with local symptoms or asymptomatic patients (1·1%). The results from the non- randomised part of CADISS6 reported a similarly low proportion: two (2%) recurrent strokes occurred during 3-month follow-up of 87 individuals with both carotid and vertebral artery dissection; however, mean time from symptom onset was 10·8 days (SD 7·0, range 1–31). In a trial setting, patients might have been recruited after they had already had their recurrent stroke; however, few patients in our study had such symptoms, suggesting this eff ect was not the reason for the diff erence in recurrence of stroke in CADISS compared with previous observational studies. Because recurrences were rare, any defi nitive study examining this question is likely to need a very large sample size. Power calculations based on the per-protocol data and using the endpoint of stroke, death, or major bleeding gave a required total sample size of almost 10 000 participants, which will be diffi cult to recruit.
However, because the outcomes were rare, the 95% CIs for the endpoints were large and therefore the number of participants needed according to our calculation should be considered a rough estimate. Diagnosis of dissection could not be centrally confi rmed on imaging review in about a fi fth of participants, despite evidence of dissection on angio graphic imaging or cross- sectional imaging through the vessel wall. The failure to confi rm diagnosis was mainly caused by two factors. First, imaging was of poor quality for some participants and it was impossible to be sure of the diagnosis. Second, central review of imaging suggested an alternative diagnosis in some patients for whom imaging was of adequate quality. The most common alternative diagnoses were atherosclerosis, an atretic rather than dissected vertebral artery, a narrowed artery without any defi nite evidence of dissection and, in one case, adherent thrombus without clear evidence of dissection. Several radiographic features suggest dissection, including appearance of a fl ap, tapering stenosis or pseudoaneurysm on angiography, and imaging of the arterial wall showing intramural blood. The diffi culties associated with diagnosis of dissection have been well- documented.16 For imaging of the vessel, diffi culties include limited spatial resolution, the tortuous course of arteries, variability in normal vessel calibre, presence of a thick bone covering, and adjacent veins. Imaging the vertebral arteries is more diffi cult than imaging the carotid arteries because of their smaller size, the fact that one is often atretic, and because fl ow-related enhancement of the vertebral plexus surrounding the artery can mimic intramural blood.16 This greater diffi culty in diagnosis of vertebral dissection was shown by the lower proportion of confi rmed diagnoses for vertebral artery dissection (100 of 132) versus carotid dissection (98 of 118). However, the low proportion of confi rmed diagnoses and variations between recruitment sites suggest that training and quality control need to be improved. We did not use prespecifi ed imaging criteria; doing so might have improved the accuracy of diagnosis. CADISS was designed as a pragmatic trial and therefore the choice of antiplatelet drugs was at the discretion of the clinician. Prescription of dual antiplatelet treatment for all patients might have improved effi cacy. Another limitation is that many patients did not have imaging confi rmation after central review; however, this shortcoming provides important information about routine clinical practice in the real world and a strength of the study was central review of imaging for all patients. Disease heterogeneity—eg, carotid versus vertebral dissection, or recent stroke versus local symptoms only— might have caused diff erent groups to respond diff erently to treatments. Endpoints were too rare to assess such subgroups, but all recurrent strokes occurred in patients who had presented with stroke, consistent with previous data from observ ational studies,15 suggesting this group are at the highest risk of recurrent event..