Protocol Dabigatran following acute transient ischemic attack and minor stroke II (DATAS II) International Journal of Stroke 2017, Vol. 12(8) 910 914! 2017 World Stroke Organization Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: 10.1177/1747493017711947 journals.sagepub.com/home/wso Kuan H Ng 1, Mukul Sharma 1, Oscar Benavente 2, Laura Gioia 3, Thalia S Field 2, Michael D Hill 4, Shelagh B Coutts 4, and Kenneth Butcher 5 ; for the DATAS-2 Investigators Abstract Rationale: Patients with transient ischemic attack or minor stroke are at high risk of early recurrent cerebrovascular events. Anticoagulation with heparin or warfarin acutely after ischemic stroke is at least as efficacious as aspirin for preventing recurrent events but is associated with an increased risk of clinical worsening due to hemorrhagic transformation. Aim and hypothesis: We aim to demonstrate the safety of early anticoagulation with dabigatran, an oral direct thrombin inhibitor, in acute cerebrovascular syndrome patients. The primary hypothesis is that symptomatic hemorrhagic transformation rates in dabigatran and aspirin-treated patients will be similar. Sample size estimates: At least 136 participants in two groups required to demonstrate an absolute between-group difference in the rate of hemorrhagic transformation of 5.6% with 80% power, assuming alpha ¼ 5%. Methods and design: A randomized, multicenter open-label clinical trial (NCT02295826). Three-hundred participants with a transient ischemic attack/ischemic stroke (National Institutes of Health Stroke Scale 9) will undergo magnetic resonance imaging within 72 h of symptom onset and will be randomized to aspirin 81 mg daily or dabigatran 150 mg twice daily for 30 days. Participants undergo repeat magnetic resonance imaging at 30 days and clinical assessment to 90 days. Study outcomes: The primary outcome is the symptomatic hemorrhagic transformation rate. Secondary outcomes include recurrent stroke and new ischemic lesions on repeat magnetic resonance imaging. Discussion: This study will determine the safety of early anticoagulation with dabigatran in patients with acute transient ischemic attack/ischemic stroke and will inform the design of a phase III randomized trial aimed at demonstrating reduced recurrent early ischemic events after acute transient ischemic attack/stroke. Keywords Stroke, ischemic stroke, magnetic resonance imaging, anticoagulation, hemorrhage Received: 1 February 2017; accepted: 11 April 2017 Introduction and rationale The risk of recurrent cerebrovascular events following a minor ischemic stroke or transient ischemic attack (TIA) is as high as 17% in the first three months with most events occurring early in this interval. 1 The period shortly following TIA/minor stroke represents an opportunity for high-impact intervention. Antiplatelet agents are recommended immediately after TIA/minor stroke. 2 Although short-term combination antiplatelet therapy has been shown to reduce early recurrent stroke, it has not become standard of care owing to 1 McMaster University, Hamilton, Canada 2 University of British Columbia, Vancouver, Canada 3 University of Montreal, Montreal, Canada 4 University of Calgary, Calgary, Canada 5 University of Alberta, Edmonton, Canada Corresponding author: Kenneth Butcher, 7-132D Clinical Sciences Building, University of Alberta, 11350-83 Ave, Edmonton, Alberta T6G 2G3, Canada. Email: ken.butcher@ualberta.ca
Ng et al. 911 unique features of the population in a single trial and a second large trial is ongoing. 3 Early parenteral anticoagulant use in this population is associated with reduced early recurrent stroke rates, but greater risk of symptomatic hemorrhagic transformation (HT). 4,5 Current guidelines recommend against routine anticoagulation in acute ischemic stroke. 2 Dabigatran, a direct oral anticoagulant (DOAC), is a thrombin inhibitor that has been approved for the prevention of ischemic stroke in patients with atrial fibrillation (AF). Dabigatran is associated with a substantially lower risk of intracranial hemorrhage than warfarin, with absolute rates of hemorrhage that approximate those seen with aspirin (ASA) treatment. 6 Dabigatran inhibits both clot-bound and free thrombin, which may make it particularly effective at reducing early recurrent events in patients with unstable thrombus and/or thrombogenic vascular lesions. In addition, dabigatran is likely to be more efficacious than ASA in preventing recurrent cardioembolic stroke in patients with covert AF. A recently completed single-arm, open-label trial demonstrated the feasibility and safety of treating patients with TIA/minor stroke with dabigatran within 24 h of onset. 7 DATAS II is aimed at determining the safety of early anticoagulation with dabigatran compared with aspirin in acute cerebrovascular syndrome patients without diagnosed AF. The design includes serial magnetic resonance imaging (MRI) to identify the frequencies and predictors of both symptomatic and asymptomatic HT associated with acute dabigatran and aspirin treatment. Methods Study design This is a randomized, open label blinded endpoint trial registered with clinicaltrials.gov (NCT02295826). Patients with TIA/minor ischemic stroke (National Institutes of Health Stroke Scale (NIHSS) 9) within 72 h of symptom onset are randomized 1:1 to dabigatran 150 mg BID for 30 days or ASA 81 mg for 30 days (Figure 1). Patient population Three hundred patients from six Canadian stroke centers will be enrolled. Eligible patients are randomized within 72 h of symptom onset after baseline MRI with diffusion-weighted images (DWIs), carotid imaging, and electrocardiograph. Detailed inclusion and exclusion criteria are shown in Table 1. Large DWI lesions (25 ml) are excluded due to an increased risk of HT. 8 Enrolled patients will continue to have stroke investigations as per best practice recommendations. Randomization Eligible patients are randomized 1:1 to open label dabigatran or ASA via a secure web client (https://rome. phri.ca/files/idatafax/). A permuted-block design with variable block size is utilized. Treatment ASA group. Participants randomized to aspirin are loaded with 325 mg of ASA, followed by 81 mg/day. Study ASA is provided to patients. Adherence is assessed at study visits by pill counts. Dabigatran group. Participants randomized to dabigatran are treated with 150 mg twice daily for 30 days. The dose is reduced to 110 mg twice daily in participants 80 years of age and/or an estimated GFR of 30 50 ml/min (calculated using a weight-based equation). After 30 days, participants are treated with ASA 81 mg daily unless an indication for anticoagulation is established (e.g. AF). Primary outcome The primary outcome is the rate of symptomatic HT, defined as a parenchymal hematoma associated with- 4-point increase in NIHSS score within five weeks of treatment initiation. Secondary outcomes Secondary outcomes include the rate of asymptomatic HT, recurrent ischemic stroke, and progression/recurrence of DWI lesions seen on the day 30 study MRI sequence on follow-up MRI (supplementary Table 1). All images will be read by central readers blinded to treatment allocation. Data Monitoring Committee (DMC) An independent DMC meets after every 50 patients randomized (supplementary Table 2). No interim analyses are planned. The DMC may recommend that the trial be halted or the protocol amended at any point. Sample size estimates The frequency of symptomatic HT in patients treated with antiplatelet agents has been found in previous studies to be <1%. 9 The maximum acceptable rate of symptomatic HT associated with an acute therapy should not
912 International Journal of Stroke 12(8) Figure 1. Overview of entry and follow-up procedures. exceed that of tpa (6.4%). 9 A sample size of 136 participants per group is required to demonstrate an absolute between-group difference in the rate of total HT of 5.6% with 80% power, assuming alpha ¼ 5%. A total trial size of 272 participants is therefore required. The sample size was inflated to 300 (150 patients per group) to account for participants lost to follow up or nonadherent to treatment allocation. Statistical analyses One-tailed t-test will be used to demonstrate if there is an absolute difference between intervention groups as it is unlikely that ASA will have a higher rate of HT than dabigatran. Univariate linear regression and logistic regression analyses will be used to test the relationship between imaging endpoints, hypothesized clinical factors, and risk of all forms of HT. Study organization and funding The trial Coordinating Centre is the University of Alberta, where clinical, regulatory, and budgetary activities of the trial are overseen. Site monitoring is conducted by the Department of Quality Management in Clinical Research at the University of
Ng et al. 913 Table 1. Study inclusion and exclusion criteria Inclusion criteria: 1. Male/female patients 18 years of age 2. TIA/ischemic stroke (NIHSS score 9) 3. Symptom onset 72 h prior to enrollment 4. Informed consent 5. MRI including DWI performed prior to randomization 6. DWI lesion volume < 25 ml Exclusion criteria: 1. Contraindication to MRI 2. Glomerular filtration rate (GFR) < 30 ml/min calculated using Cockcroft Gault formula 3. Patients deemed, as attending stroke physician, to have any ongoing bleeding risks or unsuitable for dabigatran therapy 4. Patients with MRI demonstrated additional pathology including arteriovenous malformations, intracranial aneurysms, tumors, or abscess, which potentially increase the rise of bleed 5. Individuals with small incidental lesions, at low risk of bleed such as meningiomas may be included at the discretion of the investigator 6. Pregnant or breast feeding women 7. Severe dysphagia necessitating nasogastric (NG) feeding (dabigatran cannot be delivered via NG tube 8. Planned thrombolysis or endovascular intervention for the index event 9. Thrombolysis for ischemic stroke within the preceding seven days 10. Planned carotid endarterectomy/carotid artery stent within 30 days. Note: Carotid investigations will be completed prior to enrolment. Patients with symptomatic stenosis and a planned carotid procedure will be excluded 11. Any history of spontaneous intracranial bleeding 12. Clear indication for anticoagulation, including atrial fibrillation, mechanical cardiac valves, deep venous thrombosis, pulmonary embolism or known hypercoagulable state 13. Comorbid illness with expected life expectancy of <90 days DWI: diffusion-weighted image; MRI: magnetic resonance imaging; NIHSS: National Institutes of Health Stroke Scale; TIA: transient ischemic attack. Alberta. The imaging core laboratory is also located at the University of Alberta, where all images are assessed centrally. The Statistical Center, located in the Population Health Research Institute (PHRI) at McMaster University houses the randomization web portal, electronic Case Report Form and databases (https://rome.phri.ca/files/idatafax/). All data quality checks, statistical analyses, and reports are completed by PHRI staff. DATAS II is supported by grant-in-aid funding from the Canadian Institutes for Health Research (G327075). Additional support is provided by a Clinical Research Initiative Organization grant from Alberta Innovates Health Solutions, the Canada Research Chair Program and PHRI grant. Discussion This randomized trial is the first step in advancing acute prevention in the TIA/stroke population beyond antiplatelet therapy. DOACs have shown promise in stroke prevention outside of AF. 10 If it can be demonstrated that short-term dabigatran is not associated with an increased frequency of symptomatic HT relative to aspirin in ischemic stroke defined as NIHSS 9, it will be reasonable to assess its efficacy in acute prevention of early recurrent ischemic events in this high-risk population. Irrespective of dabigatran as a novel strategy in undifferentiated acute cerebrovascular syndrome patients, it is a proven secondary prevention strategy
914 International Journal of Stroke 12(8) in AF patients. The risk of recurrent stroke is front loaded but the lack of data with respect to the timing of initiation of dabigatran, or any other DOAC, within 14 days of a cerebrovascular event precludes any evidence-based recommendations. This trial enrolling acute ischemic strokes with NIHSS 9 is a necessary first step toward achieving that goal. Summary and conclusions This is the first randomized study of a novel anticoagulant in the acute TIA/stroke population. Demonstrating the safety of short-term dabigatran therapy will facilitate the design of subsequent potential trials to assess efficacy for prevention of early recurrent brain ischemia. Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. References 1. Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ and Ghali WA. Early risk of stroke after transient ischemic attack: a systematic review and meta-analysis. Arch Intern Med 2007; 167: 2417 2422. 2. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44: 870 947. 3. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369: 11 19. 4. Immediate anticoagulation of embolic stroke: a randomized trial. Cerebral Embolism Study Group. Stroke 1983; 14: 668 676. 5. Berge E, Abdelnoor M, Nakstad PH and Sandset PM. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute Embolic Stroke Trial. Lancet 2000; 355: 1205 1210. 6. Hart RG, Diener HC, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke 2012; 43: 1511 1517. 7. Kate M, Gioia L, Buck B, et al. Dabigatran therapy in acute ischemic stroke patients without atrial fibrillation. Stroke 2015; 46: 2685 2687. 8. Butcher K, Christensen S, Parsons M, et al. Postthrombolysis blood pressure elevation is associated with hemorrhagic transformation. Stroke 2010; 41: 72 77. 9. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group. N Engl J Med 1995; 333: 1581 1587. 10. Gibson CM, Chi G, Halaby R, et al. Extended-duration betrixaban reduces the risk of stroke versus standarddose enoxaparin among hospitalized medically Ill patients: an APEX trial substudy (acute medically ill venous thromboembolism prevention with extended duration betrixaban). Circulation 2017; 135: 648 655.