Triple Antiplatelets for Reducing Dependency After Ischaemic Stroke - TARDIS
Contribution To Literature:
The TARDIS trial shows that among patients with acute, non-cardioembolic ischemic stroke or TIA, a regimen of intensive antiplatelet therapy for 30 days (aspirin, clopidogrel, and dipyridamole) does not reduce stroke recurrence, but significantly increases bleeding compared with guideline-directed antiplatelet therapy (dual therapy with aspirin/dipyridamole or clopidogrel).
The goal of the trial was to compare the role of triple antiplatelet therapy with low-dose aspirin, clopidogrel, and dipyridamole to standard of care treatment based on current guidelines (either low-dose aspirin and dipyridamole, or clopidogrel monotherapy).
Patients at risk for recurrent stroke (non-cardioembolic cerebrovascular accident [CVA]/transient ischemic attack [TIA]) were randomized in a 1:1 fashion to either triple therapy (n = 1,556) or standard of care antiplatelet therapy (n = 1,540). Participants randomly assigned to triple therapy received combined aspirin (300 mg load then 50-150 mg daily, typically 75 mg), clopidogrel (300 mg load then 75 mg daily), and dipyridamole (200 mg twice daily modified release, or 100 mg three or four times daily).
Those randomly assigned to standard of care antiplatelet therapy received either combined aspirin and dipyridamole, or clopidogrel alone using the same loading and maintenance doses as in the intervention group. Randomly assigned antiplatelet drugs were given for 30 days, after which participants were treated according to local guidelines, typically with clopidogrel alone or combined aspirin and dipyridamole.
- Total number of enrollees: 3,096
- Duration of follow-up: 90 days
- Mean patient age: 69 years
- Percentage female: 37%
- At risk for recurrent ischemic stroke
- Presentation with nonembolic CVA or TIA
- Randomization within 48 hours of symptom onset
- If thrombolytics were given, patients could be enrolled after 24 hours of drug completion and without evidence of cerebral bleeding
- Age <50 years
- Isolated sensory symptoms, facial weakness, or vertigo or dizziness
- Presumed cardioembolic stroke or TIA
- Parenchymal hemorrhage or other intracranial hemorrhage
- Nonischemic cause for symptoms
- Definite need for, or contraindication to, aspirin, clopidogrel, or dipyridamole
- Definite need for full-dose anticoagulation
- Premorbid dependency
- Severe hypertension
Other salient features/characteristics:
- Qualifying event of ischemic stroke: 72%, ischemic TIA: 27%
- Baseline National Institutes of Health Stroke Scale (NIHSS) score: 2.9
- Use of thrombolytics: 11%
- Evidence of ischemic stroke on imaging: 45%, normal or no lesion: 50%
The TARDIS study stopped early due to safety concerns. The primary efficacy outcome of ordinal stroke or TIA, for triple antiplatelet therapy vs. standard of care antiplatelet therapy, was 6% vs. 7%, p = 0.47. Functional independence at 90 days was 49% vs. 13%, post probability > 0.999.
- For triple antiplatelet therapy vs. standard of care antiplatelet therapy
- Death: 1% vs. <1%, p = 0.17
- Ordinal bleeding: 20% vs. 9%, p < 0.0001
- Fatal bleeding: 1% vs. <1%, p = 0.07
- Intracranial hemorrhage: 1% vs. <1%, p = 0.026
- Extracranial bleeding: 19% vs. 9%, p < 0.0001
Among patients with acute, non-cardioembolic ischemic stroke or TIA, a regimen of intensive antiplatelet therapy for 30 days did not reduce stroke recurrence or its severity when compared with guideline antiplatelet therapy with either clopidogrel alone or combined aspirin and dipyridamole; the more aggressive strategy resulted in significantly higher and more severe bleeding rates.
Bath PM, Woodhouse LJ, Appleton JP, et al. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Lancet 2017;Dec 20:[Epub ahead of print].
Keywords: Aspirin, Brain Ischemia, Dipyridamole, Intracranial Hemorrhages, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Primary Prevention, Standard of Care, Stroke, Ticlopidine, Vascular Diseases, Aneurysm
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