Safety and Efficacy of Intensive Versus Guideline Antiplatelet Therapy in High Risk Patients With Recent Ischaemic Stroke or Transient Ischaemic Attack: a Randomised Controlled Trial
Overview
- Phase
- Phase 3
- Intervention
- Aspirin, Dipyradimole, Clopidogrel
- Conditions
- Stroke
- Sponsor
- University of Nottingham
- Enrollment
- 3096
- Locations
- 1
- Primary Endpoint
- The primary outcome is ordinal stroke severity at 90 days
- Status
- Terminated
- Last Updated
- 7 years ago
Overview
Brief Summary
The risk of recurrence is greatest immediately after stroke or Transient Ischaemic Attack (TIA). Existing prevention strategies (antithrombotic, lipid/blood pressure lowering, endarterectomy) reduce, not abolish, further events. Dual antiplatelet therapy - aspirin & clopidogrel (AC) for IHD, aspirin & dipyridamole (AD) for stroke, is superior to aspirin monotherapy. The investigators hypothesise that triple antiplatelet therapy (ACD) will be superior to AD in patients at high-risk of recurrence, providing bleeding does not become excessive.
Design: TARDIS is a multicentre, parallel-group, prospective, randomised, open-label, blinded-endpoint, controlled trial. In the start-up phase, the investigators will assess over 3 years the safety, tolerability and feasibility of intensive therapy (ACD) versus guideline therapy (AD) given for 1 month in 750 patients with acute stroke/TIA. The main phase will then assess the safety and efficacy of ACD in up to 3500 patients. The primary outcome is ordinal stroke (fatal/severe non-fatal/mild/TIA/none) at 90 days. Secondary outcomes include death, MI, vascular events, function, bleeding, serious adverse events; sub-studies will assess cerebral emboli and platelet function.
Detailed Description
2.1 Purpose To perform a randomised trial assessing the efficacy, safety and tolerability of intensive antiplatelet therapy (Asp+Dip+Clop) versus guideline antiplatelet therapy (Asp+Dip or Clop) in patients with recent ischaemic stroke or TIA and who are at high risk of recurrence. 2.2 Primary Objective To assess ordinal stroke severity at 90 days after short-term administration (1 month) of intensive antiplatelet therapy versus guideline therapy in patients with very recent ischaemic stroke or TIA. 2.3 Secondary Objectives 1. To assess the safety of short-term administration (1 month) of intensive antiplatelet therapy versus guideline therapy in patients with very recent ischaemic stroke or TIA. 2. To further assess, in high risk patients with stroke/TIA, whether: ii. it is feasible to administer intensive therapy acutely and is tolerable to take for 1 month, iii. intensive therapy is superior in respect of surrogate markers such as platelet function. iv. intensive therapy improves functional outcome
Investigators
Eligibility Criteria
Inclusion Criteria
- •Adults at high risk of recurrent ischaemic stroke:
- •Age ≥ 50 years
- •Within 48 hours of ictus (24-48 hours if thrombolysed)
- •TIA with limb weakness and/or dysphasia lasting between 10 minutes and \< 24 hours with no residual symptoms and presenting with any of the following
- •ABCD2 score \> 4, or
- •Crescendo TIA or
- •Already on dual antiplatelet therapy
- •Note: Neuroimaging is not necessary for transient ischaemic attack. Crescendo TIA is \> 1 TIA in one week and the onset time of last TIA is taken as time of ictus.
- •Ischaemic non cardioembolic stroke presenting with any of the following
- •Ongoing limb weakness and/or dysphasia of more than one hour duration
Exclusion Criteria
- •Isolated sensory symptoms or vertigo/dizziness or facial weakness
- •Isolated hemianopia without positive neuroimaging evidence
- •Intracranial haemorrhage
- •Baseline neuroimaging showing parenchymal haemorrhagic transformation (PH I/II) of infarct, subarachnoid haemorrhage or other non ischaemic cause for symptoms
- •Presumed cardioembolic stroke (e.g. history or current AF, myocardial infarction within 3 months)
- •Participants with contraindications to, or intolerance of, aspirin, clopidogrel or dipyridamole.
- •Participants with definite need for treatment with aspirin, clopidogrel or dipyridamole individually or in combination (e.g. aspirin and clopidogrel for recent MI/acute coronary syndrome)
- •Participant has taken clopidogrel or dipyridamole after the index event but prior to randomisation (aspirin is allowed between ictus onset and randomisation)
- •Definite need for full dose oral (e.g. warfarin, dabigatran) or medium to high dose parenteral (e.g. heparin) anti-coagulation. NB Low dose heparin for DVT prophylaxis is allowed
- •Definite need for glycoprotein IIb-IIIa inhibitors
Arms & Interventions
Intensive antiplatelet therapy
Participants in the intensive antiplatelet group will receive Aspirin+Dipyridamole+Clopidogrel triple therapy for 28-30 days (to cover the period of maximum risk of recurrence) along with standard 'best care' (including lifestyle advice, BP and lipid lowering). Clop will be given as a loading dose of 300 mg,12 then 75 mg daily, Asp as a loading dose of 300 mg,22 then 75 mg daily, and Dip modified release 200 mg twice daily 9 for 28-30 days.
Intervention: Aspirin, Dipyradimole, Clopidogrel
Outcomes
Primary Outcomes
The primary outcome is ordinal stroke severity at 90 days
Time Frame: 90 days
5-level ordinal stroke and TIA scale with stroke ordered by its severity using the modified Rankin Scale (mRS): fatal stroke / severe non-fatal stroke (mRS 2-5) / mild stroke (mRS 0,1) / TIA / no stroke-TIA, measured at 90 days.; this approach allows for smaller sample sizes compared to binary outcomes such as stroke/no stroke
Secondary Outcomes
- Death(90 days)
- Platelet function.(90 Days)
- Safety(90 days)
- Serious adverse events(90 Days)