About The Trial

Table of Contents

Rationale

Cervical artery dissection (CAD) is the leading cause of stroke in the young. Despite its clinical importance, the optimal antithrombotic treatment for stroke prevention remains uncertain. The CADISS trial showed no difference in efficacy or safety between antiplatelet therapy (mainly aspirin) and anticoagulation (mainly vitamin K antagonists) (1). The subsequent TREAT-CAD trial, designed to demonstrate non-inferiority of aspirin, failed to confirm that aspirin is non-inferior to anticoagulation, without demonstrating superiority of either strategy (2).

An individual patient data meta-analysis combining CADISS and TREAT-CAD did not show superiority of either treatment. However, it suggested a possible benefit of anticoagulation in reducing major adverse events at 90 days (3). Similarly, the large observational STOP-CAD study found no significant difference between treatment strategies, although a non-significant trend toward fewer ischemic strokes with anticoagulation was observed (4).

These studies indicate that the risk of recurrent ischemia is highest in the early phase after CAD, with events clustering within the first weeks, highlighting the importance of rapidly effective treatment. However, low event rates, limited sample sizes, and heterogeneity in treatment approaches restrict the ability of conventional trial designs to demonstrate superiority or non-inferiority. Therefore, future studies should prioritize precise comparative effectiveness between antiplatelet and anticoagulation strategies rather than relying solely on traditional hypothesis testing.

In addition to aspirin and vitamin K antagonists, current guidelines also allow the use of direct oral anticoagulants and dual antiplatelet therapy, although evidence for these approaches remains limited (5).

Trial design

TREAT-CAD 2 is an international, multicenter, open-label, blinded endpoint, pragmatic trial. 550 patients will have been randomized to the anticoagulation treatment strategy and 550 patients to the antiplatelet treatment strategy.

Randomization

The trial is designed as a randomized, parallel group controlled trial. Allocation of patients will be done once the patient fulfills all inclusion and exclusion criteria. Patients will be randomly assigned in a ratio of 1:1 to one of two treatment arms:

  1. Antiplatelet treatment strategy
  2. Anticoagulation treatment strategy

Outcomes

The primary endpoint is a composite outcome at 90 days (± 2 weeks) after randomization, defined as the occurrence of recurrent ischemic stroke, major bleeding (extracranial or intracranial), or vascular death.

Secondary endopoints at 90 days (± 2 weeks) after randomization include the occurrence of each individual component of the primary composite outcome, functional neurological outcome measured by the modified Rankin Scale (mRS) including absolute differences and shift analysis in favorable outcome (defined as mRS ≤ 2), all-cause mortality, recurrence of coronary artery disease, and patient-reported outcomes assessed by PROMIS-10 and the EuroQol 5D Visual Analog Scale.

Inclusion and exclusion criteria

Inclusion criteria

  • Written informed consent (according to requirements by national legislation)
  • Onset/visualization of acute cerebral ischemia (≤ 3 days prior to randomization) attributable to CAD (either)
    • CLINICAL ISCHEMIA: onset of acute ischemic stroke (including retinal infarct) or transient ischemic attack (including amaurosis fugax) attributable to CAD OR
    • ISCHEMIA WITHOUT CORRESPONDING SYMPTOMS: visualization of acute ischemic lesion on diffusion weighted imaging attributable to CAD
  • Clinical MRI with suitable sequences for CAD diagnosis 
    • available OR
    • scheduled to be performed before discharge (if not performed before enrolment) 
  • Diagnosis of CAD (i.e. extracranial carotid and/or vertebral artery) by MRI/A or CTA based on the presence of the following criteria (at least one)   
    • Mural hematoma OR 
    • Long tapering stenosis OR 
    • Intimal flap OR 
    • Double lumen OR 
    • Flame-like occlusion of the dissected artery

Exclusion criteria

  • Contraindications to either antiplatelets or oral anticoagulation therapy
  • Other indication than CAD for full dose oral anticoagulation
  • Contraindications for performance of MRI
  • Age < 18 years
  • Female patients who are either pregnant or breastfeeding (pregnancy testing prior to start of treatment will follow the standard operating procedures of clinical routine at participating sites)  

Thrombolysis and/or endovascular treatment is/are not considered an exclusion criterion.

Trial structure

Steering Committee

  • Prof. Dr. med. Alessandro Pezzini (national coordinator Italy)
  • Prof. Dr. med. Anne Hege Aamodt (national coordinator Norway)
  • Prof. Dr. med. Christian H. Nolte (national coordinator Germany)
  • Dr. med. Cristina Duque (national coordinator Portugal)
  • Prof. Dr. med. Daniel Strbian & Prof. Dr. med. Jelle Demeestere (national coordinator Finland)
  • Prof. Dr. med. Hanne Christensen (national coordinator Denmark)
  • Prof. Dr. med. Henrik Gensicke (national coordinator Switzerland)
  • Prof. Dr. med. Janika Kõrv (national coordinator Estonia)
  • Dr. med. Josefin Kaufmann, PhD (Junior Member)
  • Prof. Dr. med. Lars Hemkens MPH (Trial Methodology)
  • Dr. med. Dr. phil. Lukas S. Enz (Lead Trial Statistician)
  • Prof. Dr. med. Paul Nederkoorn (national coordinator Netherlands)
  • Prof. Dr. med. Robin Lemmens (national coordinator Belgium)
  • Sabine Schädelin, MSc (Senior Trial Statistician)
  • Prof. Dr. med. Thomas Gattringer (national coordinator Austria)
  • Dr. Sandra Kohlmeier (PPI Responsible)

Data Safety Monitoring Board

TBA

Literature

  1. CADISS trial investigators, Markus HS, Hayter E, et al. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015; 14: 361–367.
  2. Engelter ST, Traenka C, Gensicke H, et al. Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial. Lancet Neurol 2021; 20: 341–350.
  3. Kaufmann JE, Harshfield EL, Gensicke H, et al. Antithrombotic Treatment for Cervical Artery Dissection: A Systematic Review and Individual Patient Data Meta-Analysis. JAMA Neurol 2024; 81: 630–637.
  4. Yaghi S, Shu L, Mandel D, et al. Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection: The STOP-CAD Study. Stroke 2024; 55: 908–918.
  5. Debette S, Mazighi M, Bijlenga P, et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J 2021; 6: XXXIX–LXXXVIII.