Cerebral Microbleeds During NOACs or Warfarin Therapy in NVAF Patients With Acute Ischemic Stroke (CMB-NOW) (CMB-NOW)

Introduction Anticoagulants are generally recognized as a necessary therapy to prevent the recurrence of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF), but in some patients they also cause bleedings, particularly intracranial hemorrhage (including intracerebral hemorrhage). One of the independent predictors of intracerebral hemorrhage is the presence of cerebral microbleeds (CMBs); a high incidence of intracerebral hemorrhage is reported in patients with multiple CMBs (Soo et al, J Neurol, 2008; Lee et al, Neurology, 2009) Also, the rate and absolute number of CMBs increase in proportion to CHADS2 score in patients with cerebral infarction accompanying NVAF (Song et al, Eur J Neurol, 2013). Among CMB-positive patients, a high incidence of intracranial hemorrhage associated with oral anticoagulation therapy has been reported (Song et al, Eur J Neurol, 2013); suggesting a relationship between the occurrence or absolute number of CMBs and the development of intracranial hemorrhage during oral anticoagulation therapy. Imaizumi et al. (J Stroke Cerebrovasc Dis, 2013) found that warfarin alone did not increase the incidence of intracerebral hemorrhage in all subjects with CMBs, but subjects with 3 or more deep CMBs did show an increased incidence. Also, a meta-analysis conducted by Lovelock et al. (Stroke, 2010) demonstrated a higher incidence of CMBs in patients with intracerebral hemorrhage receiving warfarin than in patients with intracerebral hemorrhage not receiving antithrombotic therapy. Recently, Orken et al (Clin Neurol Neurosurg, 2013) suggested that patients who had CMBs at baseline developed more new CMBs after 2 years (26%), compared with patients (12%) who did not have CMBs at baseline (p=0.03). However, there has been no study on the progression of CMBs in patients receiving so-called novel oral anticoagulants (NOACs).

NOACs, including dabigatran (Hart et al, Stroke 2012), rivaroxaban (Patel et al, N Engl J Med 2011), apixaban (Granger CB et al, N Engl J Med 2011), and edoxaban (Giugliano et al, N Engl J Med 2013), are superior to warfarin in preventing stroke or systemic embolism in patients with NVAF, and have been reported to significantly reduce the incidence of hemorrhagic stroke. Therefore, this study was designed to evaluate and compare the absolute number of CMBs in patients with at least one CMB at baseline, who receive anticoagulant therapy with NOACs and with warfarin. The correlation between CMBs and intracranial hemorrhage, as well as the status of CMBs before commencement of treatment and their progression during treatment, will be evaluated to determine whether there are differences between the two groups.

The feature of this study Japan has a very high availability of MRI facilities, and thus CMBs can be readily evaluated in multiple patients using T2*WI. As of January 1, 2013, the total population of Kanagawa Prefecture was 9.07 million, of whom the elderly (≥65 years) comprised 1.95 million; therefore, a clinical observational study covering this prefecture that revealed a significant difference between NOACs and warfarin should have a substantial impact on drug-prescribing practice.

CMBs found on T2*-weighted gradient-echo MRI 1.5 Tesla should be evaluated. The imaging data will be evaluated by the Cerebral Microbleeds Evaluation Committee using the assessment scale of Gregoire et al. under a blinded condition.

Study design This study tests the hypothesis that the incidence of hemorrhagic stroke is lower in patients receiving NOACs than in those receiving warfarin, and this difference reflects the difference in the effects of warfarin and NOACs on the progression of CMBs in patients with at least one CMB.

This study is an observational study, and the numbers of patients in the NOACs and warfarin groups were not predetermined, though the total number of patients for the study was limited to 200 for practical reasons. Primary endpoint is the proportion of subjects with an increased number of CMBs at Month 12 of treatment with NOACs or warfarin. If the results of this study support the efficacy of NOACs in preventing increase of CMBs, this would be of great interest to domestic and overseas clinicians, in view of the potential therapeutic impact, including that for primary prevention of ischemic stroke.

For quality assurance, data validation and registry procedures including any plans for site monitoring and auditing is performed.