PDF: TARDIS
(2018)Objective
Triple antiplatelet therapy (aspirin, clopidogrel, dipyridamole) versus guideline-based antiplatelet therapy in patients with acute non-cardioembolic ischemic stroke or TIA.
Study Summary
Intervention
Multicenter, international, open-label, blinded-endpoint RCT. N=3,096 patients randomized within 48 hours of non-cardioembolic stroke or TIA onset to either: - Intensive therapy: aspirin (75 mg), clopidogrel (75 mg), dipyridamole (200 mg BID) for 30 days - Guideline therapy: clopidogrel alone or aspirin + dipyridamole (standard practice) Follow-up at day 90. Primary outcome: ordinal scale of recurrent stroke/TIA severity.
Study Design
Arms: Array
Outcome
• Major or fatal bleeding: higher with intensive therapy (3% vs 1%, HR 2.23; 95% CI 1.25–3.96; p=0.006)
• Intracranial hemorrhage: 1% vs <1% (HR 3.14; p=0.026)
• Composite of stroke or major bleeding: HR 1.24; p=0.19
• No difference in death, MI, or serious adverse events
• Trial stopped early due to futility and harm
Bottom Line
Intensive antiplatelet therapy with three agents did not reduce the incidence and severity of recurrent stroke or TIA, but significantly increased the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice for secondary prevention after acute cerebral ischaemia.
Major Points
- The trial was stopped early on the recommendation of the data monitoring committee due to futility and increased bleeding.
- The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0.90, 95% CI 0.67–1.20, p=0.47).
- Intensive antiplatelet therapy was associated with significantly more, and more severe, bleeding (adjusted cOR 2.54, 95% CI 2.05–3.16, p<0.0001).
- Combined fatal and major intracranial bleeding was increased with intensive antiplatelet therapy (adjusted HR 3.84, 95% CI 1.26–11.63, p=0.018).
- There was no significant difference in all-cause mortality between the groups (2% in both groups; adjusted HR 0.89, 95% CI 0.51–1.55, p=0.69).
Study Design
- Study Type
- International, prospective, randomised, open-label, blinded-endpoint, phase 3 superiority trial
- Randomization
- Yes
- Blinding
- Assessor-masked to treatment allocation for final follow-up and adjudication of outcomes.
- Sample Size
- 3096
- Follow-up
- 90 days
- Centers
- 106
- Countries
- Denmark, Georgia, New Zealand, UK
Primary Outcome
Definition: Combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 105 (7%) participants had a recurrent event | 93 (6%) participants had a recurrent event | - (0.67-1.20) | 0.47 |
Limitations & Criticisms
- The broad population might have included groups more likely to either respond (e.g., those with minor stroke or TIA, or atherosclerotic disease) or have a major bleed (e.g., those receiving thrombolysis, or having small vessel disease), which might explain the neutral results; future trials might need to be more specific.
- The antiplatelet agents were administered in an open-label design, and participants knew their treatment, which could have driven the reporting of known adverse events like headache with dipyridamole and bleeding with intensive antiplatelet therapy. However, outcomes were assessed centrally and masked to treatment assignment to reduce bias.
- The comparator group involved different antiplatelet agents (clopidogrel alone or combined aspirin and dipyridamole), reflecting changes in guidelines.
- Randomly assigned treatments were given for 30 days, which might have been too long in view of the identified haemorrhage risk.
- The trial was stopped early, and results could represent a false neutral finding related to lower-than-planned statistical power, though post-hoc power remained high (85%).
Citation
Lancet 2018; 391:850-59