Stefan T Engelter1, Christopher Traenka2, Henrik Gensicke2, Sabine A Schaedelin3, Andreas R Luft4, Barbara Goeggel Simonetti5, Urs Fischer6, Patrik Michel7, Gaia Sirimarco7, Georg Kägi8, Jochen Vehoff8, Krassen Nedeltchev9, Timo Kahles9, Lars Kellert10, Sverre Rosenbaum11, Regina von Rennenberg12, Roman Sztajzel13, Stephen L Leib14, Simon Jung6, Jan Gralla15, Nicole Bruni3, David Seiffge16, Katharina Feil17, Alexandros A Polymeris18, Levke Steiner19, Janne Hamann19, Leo H Bonati18, Alex Brehm20, Gian Marco De Marchis16, Nils Peters2, Christoph Stippich21, Christian H Nolte12, Hanne Christensen11, Susanne Wegener19, Marios-Nikos Psychogios20, Marcel Arnold6, Philippe Lyrer18. 1. Department of Neurology and Stroke Centre, University Hospital Basel and University of Basel, Basel, Switzerland; Neurology and Neurorehabilitation, University Hospital for Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland. Electronic address: stefan.engelter@felixplatter.ch. 2. Department of Neurology and Stroke Centre, University Hospital Basel and University of Basel, Basel, Switzerland; Neurology and Neurorehabilitation, University Hospital for Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland. 3. Department of Clinical Research and Clinical Trial Unit, University Hospital Basel and University of Basel, Basel, Switzerland. 4. Division of Vascular Neurology and Neurorehabilitation, Department of Neurology, University Hospital of Zurich and University of Zurich, Zurich, Switzerland; Cereneo, Centre for Neurology and Rehabilitation, Vitznau, Switzerland. 5. Department of Neurology, University Hospital Bern, University of Bern, Bern, Switzerland; Department of Neuropaediatrics, Institute of Paediatrics of Southern Switzerland, San Giovanni Hospital, Bellinzona, Switzerland. 6. Department of Neurology, University Hospital Bern, University of Bern, Bern, Switzerland. 7. Stroke Centre and Neurology Service, Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. 8. Department of Neurology and Stroke Centre, Cantonal Hospital St Gallen, St Gallen, Switzerland. 9. Department of Neurology and Stroke Centre, Cantonal Hospital Aarau, Aarau, Switzerland. 10. Department of Neurology, Ludwig Maximilian University, Munich, Germany; Institute for Stroke and Dementia Research, University Hospital LMU Munich, Munich, Germany. 11. Department of Neurology, Bispebjerg Hospital and University of Copenhagen, Copenhagen, Denmark. 12. Klinik und Hochschulambulanz für Neurologie and Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany; Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany. 13. Department of Neurology and Stroke Centre, University Hospital Geneva and Medical School, Geneva, Switzerland. 14. Institute for Infectious Diseases, University Hospital Bern, University of Bern, Bern, Switzerland. 15. Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, University of Bern, Bern, Switzerland. 16. Department of Neurology and Stroke Centre, University Hospital Basel and University of Basel, Basel, Switzerland; Department of Neurology, University Hospital Bern, University of Bern, Bern, Switzerland. 17. Department of Neurology, Ludwig Maximilian University, Munich, Germany. 18. Department of Neurology and Stroke Centre, University Hospital Basel and University of Basel, Basel, Switzerland. 19. Division of Vascular Neurology and Neurorehabilitation, Department of Neurology, University Hospital of Zurich and University of Zurich, Zurich, Switzerland. 20. Department of Neuroradiology, Clinic of Radiology and Nuclear Medicine, University Hospital Basel and University of Basel, Basel, Switzerland. 21. Department of Neuroradiology, University Hospital of Zurich and University of Zurich, Zurich, Switzerland.
Abstract
BACKGROUND:Cervical artery dissection is a major cause of stroke in young people (aged <50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K antagonists for patients with cervical artery dissection, although some current guidelines-based on available evidence from mostly observational studies-suggest using aspirin. If proven to be non-inferior to vitamin K antagonists, aspirin might be preferable, due to its ease of use and lower cost. We aimed to test the non-inferiority of aspirin to vitamin K antagonists in patients with cervical artery dissection. METHODS: We did a multicentre, randomised, open-label, non-inferiority trial in ten stroke centres across Switzerland, Germany, and Denmark. We randomly assigned (1:1) patients aged older than 18 years who had symptomatic, MRI-verified, cervical artery dissection within 2 weeks before enrolment, to receive either aspirin 300 mg once daily or a vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target international normalised ratio [INR] 2·0-3·0) for 90 days. Randomisation was computer-generated using an interactive web response system, with stratification according to participating site. Independent imaging core laboratory adjudicators were masked to treatment allocation, but investigators, patients, and clinical event adjudicators were aware of treatment allocation. The primary endpoint was a composite of clinical outcomes (stroke, major haemorrhage, or death) and MRI outcomes (new ischaemic or haemorrhagic brain lesions) in the per-protocol population, assessed at 14 days (clinical and MRI outcomes) and 90 days (clinical outcomes only) after commencing treatment. Non-inferiority of aspirin would be shown if the upper limit of the two-sided 95% CI of the absolute risk difference between groups was less than 12% (non-inferiority margin). This trial is registered with ClinicalTrials.gov, NCT02046460. FINDINGS:Between Sept 11, 2013, and Dec 21, 2018, we enrolled 194 patients; 100 (52%) were assigned to the aspirin group and 94 (48%) were assigned to the vitamin K antagonist group. The per-protocol population included 173 patients; 91 (53%) in the aspirin group and 82 (47%) in the vitamin K antagonist group. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI -4 to 21], non-inferiority p=0·55). Thus, non-inferiority of aspirin was not shown. Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischaemic strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial haemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group, and 26 in the vitamin K antagonist group. INTERPRETATION: Our findings did not show that aspirin was non-inferior to vitamin K antagonists in the treatment of cervical artery dissection. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Stroke Funds Basel, University Hospital Basel, University of Basel, Academic Society Basel.
RCT Entities:
BACKGROUND: Cervical artery dissection is a major cause of stroke in young people (aged <50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K antagonists for patients with cervical artery dissection, although some current guidelines-based on available evidence from mostly observational studies-suggest using aspirin. If proven to be non-inferior to vitamin K antagonists, aspirin might be preferable, due to its ease of use and lower cost. We aimed to test the non-inferiority of aspirin to vitamin K antagonists in patients with cervical artery dissection. METHODS: We did a multicentre, randomised, open-label, non-inferiority trial in ten stroke centres across Switzerland, Germany, and Denmark. We randomly assigned (1:1) patients aged older than 18 years who had symptomatic, MRI-verified, cervical artery dissection within 2 weeks before enrolment, to receive either aspirin 300 mg once daily or a vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target international normalised ratio [INR] 2·0-3·0) for 90 days. Randomisation was computer-generated using an interactive web response system, with stratification according to participating site. Independent imaging core laboratory adjudicators were masked to treatment allocation, but investigators, patients, and clinical event adjudicators were aware of treatment allocation. The primary endpoint was a composite of clinical outcomes (stroke, major haemorrhage, or death) and MRI outcomes (new ischaemic or haemorrhagic brain lesions) in the per-protocol population, assessed at 14 days (clinical and MRI outcomes) and 90 days (clinical outcomes only) after commencing treatment. Non-inferiority of aspirin would be shown if the upper limit of the two-sided 95% CI of the absolute risk difference between groups was less than 12% (non-inferiority margin). This trial is registered with ClinicalTrials.gov, NCT02046460. FINDINGS: Between Sept 11, 2013, and Dec 21, 2018, we enrolled 194 patients; 100 (52%) were assigned to the aspirin group and 94 (48%) were assigned to the vitamin K antagonist group. The per-protocol population included 173 patients; 91 (53%) in the aspirin group and 82 (47%) in the vitamin K antagonist group. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI -4 to 21], non-inferiority p=0·55). Thus, non-inferiority of aspirin was not shown. Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischaemic strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial haemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group, and 26 in the vitamin K antagonist group. INTERPRETATION: Our findings did not show that aspirin was non-inferior to vitamin K antagonists in the treatment of cervical artery dissection. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Stroke Funds Basel, University Hospital Basel, University of Basel, Academic Society Basel.
Authors: Ei Zune The; Ne Naing Lin; Ching Jocelyn Chan; Jason Cher Wei Loon; Benjamin Yong-Qiang Tan; Chee Seong Raymond Seet; Hock Luen Teoh; Joy Vijayan; Leong Litt Leonard Yeo Journal: Neurol Res Pract Date: 2022-06-13