TARDIS
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
Year of Publication: 2018
Authors: Philip M Bath, Lisa J Woodhouse, Jason P Appleton, ..., Nikola Sprigg
Journal: The Lancet
Citation: Lancet 2018; 391:850-59
Link: http://dx.doi.org/10.1016/S0140-6736(17)32849-0
PDF: https://www.thelancet.com/action/showPdf...%2817%2932849-0
PDF: Clinical Question
Is intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) more effective and safer than guideline-based antiplatelet therapy for preventing recurrent events in patients with acute cerebral ischaemia?
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).
Design
Study Type: International, prospective, randomised, open-label, blinded-endpoint, phase 3 superiority trial
Randomization: 1
Blinding: Assessor-masked to treatment allocation for final follow-up and adjudication of outcomes.
Enrollment Period: April 7, 2009, and March 18, 2016
Follow-up Duration: 90 days
Centers: 106
Countries: Denmark, Georgia, New Zealand, UK
Sample Size: 3096
Analysis: Intention-to-treat; ordinal logistic regression for primary efficacy and main safety outcomes, adjusted for stratification and minimization factors; Cox regression for composite outcomes and death; multiple linear regression for other outcomes.
Inclusion Criteria
- Adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 hours of onset.
- Non-cardioembolic ischaemic stroke with limb weakness, dysphasia, or neuroimaging-positive hemianopia, or a non-cardioembolic TIA with at least 10 min of limb weakness or isolated dysphasia.
- Participants who received intravenous thrombolysis could be randomly assigned after 24 hours had elapsed from treatment, provided post-treatment neuroimaging excluded secondary cerebral bleeding.
Exclusion Criteria
- Age younger than 50 years
- Isolated sensory symptoms, facial weakness, or vertigo or dizziness
- Presumed cardioembolic stroke or TIA
- Parenchymal haemorrhage or other intracranial haemorrhage
- Non-ischaemic cause for symptoms
- Definite need for, or contraindication to, aspirin, clopidogrel, or dipyridamole
- Definite need for full-dose anticoagulation
- Premorbid dependency
- Severe hypertension
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age, years | 68.9 (10.3) | 69.1 (9.9) |
| Sex - Male | 963 (63%) | 982 (63%) |
| Sex - Female | 577 (37%) | 574 (37%) |
| Geographical region - UK | 1473 (96%) | 1482 (95%) |
| Geographical region - Denmark | 25 (2%) | 26 (2%) |
| Geographical region - Georgia | 38 (2%) | 45 (3%) |
| Geographical region - New Zealand | 4 (<1%) | 3 (<1%) |
| Medical history - Previous antiplatelet agents - Aspirin | 404 (26%) | 412 (26%) |
| Medical history - Previous antiplatelet agents - Aspirin and dipyridamole | 42 (3%) | 43 (3%) |
| Medical history - Previous antiplatelet agents - Clopidogrel | 73 (5%) | 89 (6%) |
| Medical history - Previous antiplatelet agents - Other | 4 (<1%) | 13 (1%) |
| Medical history - Previous heparin | 5 (<1%) | 2 (<1%) |
| Medical history - Hypertension | 894 (58%) | 930 (60%) |
| Medical history - Hyperlipidaemia | 662/1477 (45%) | 655/1496 (44%) |
| Medical history - Atrial fibrillation | 1 (<1%) | 0 |
| Medical history - Stroke | 159 (10%) | 189 (12%) |
| Medical history - Ischaemic heart disease | 207 (13%) | 196 (13%) |
| Medical history - Peripheral artery disease | 30 (2%) | 40 (3%) |
| Medical history - Current smoker | 380 (25%) | 404 (26%) |
| Qualifying event - Ischaemic stroke | 1099 (71%) | 1121 (72%) |
| Qualifying event - TIA | 425 (28%) | 413 (27%) |
| Qualifying event - Crescendo (TIA) | 83/385 (22%) | 72/388 (19%) |
| Qualifying event - Patients on dual antiplatelet therapy before having their TIA | 13 (3%) | 23 (6%) |
| Qualifying event - Non-ischaemic stroke or TIA | 16 (1%) | 22 (1%) |
| Weakness | 1397 (91%) | 1392 (89%) |
| Sensory loss | 555 (36%) | 511 (33%) |
| Dysphasia | 485 (31%) | 522 (34%) |
| Isolated | 72 (5%) | 88 (6%) |
| Neglect | 177 (11%) | 154 (10%) |
| Hemianopia | 158 (10%) | 146 (9%) |
| Isolated hemianopia | 10 (1%) | 16 (1%) |
| NIHSS (out of 42) | 2.7 (3.5) | 2.8 (3.6) |
| ABCD2 score (out of 7) | 5.0 (5.0-6.0) | 5.0 (5.0-6.0) |
| OCSP classification - Total anterior | 95 (6%) | 86 (6%) |
| OCSP classification - Partial anterior | 698 (45%) | 714 (46%) |
| OCSP classification - Lacunar | 642 (42%) | 646 (42%) |
| OCSP classification - Posterior | 103 (7%) | 110 (7%) |
| TOAST - Cardioembolic | 69 (4%) | 65 (4%) |
| TOAST - Large vessel | 222 (15%) | 268 (17%) |
| TOAST - Small vessel | 603 (40%) | 621 (40%) |
| TOAST - Mixed | 14 (1%) | 8 (1%) |
| TOAST - Other/undetermined | 613 (40%) | 569 (37%) |
| Blood pressure - Systolic, mm Hg | 143.6 (18.5) | 143.5 (18.2) |
| Blood pressure - Diastolic, mm Hg | 79.6 (11.5) | 79.4 (11.3) |
| Brain imaging - Normal or no lesion | 780 (51%) | 770 (50%) |
| Brain imaging - Ischaemic stroke | 688 (45%) | 702 (45%) |
| Brain imaging - Non-stroke lesion | 2 (<1%) | 6 (<1%) |
| Brain imaging - No brain scan | 67 (4%) | 79 (5%) |
| Time from onset to randomisation, h - Ischaemic stroke | 32.0 (24.8-41.0) | 29.3 (21.7-39.7) |
| Time from onset to randomisation, h - TIA | 24.2 (17.5-30.0) | 24.3 (17.5-29.5) |
| Time from onset to randomisation - ≤12 h | 167 (11%) | 147 (9%) |
| Time from onset to randomisation - 13-24 h | 309 (20%) | 342 (22%) |
| Time from onset to randomisation - >24 h | 1064 (69%) | 1067 (69%) |
| Thrombolysis | 172 (11%) | 169 (11%) |
Arms
| Field | Intensive antiplatelet therapy | Control |
|---|---|---|
| Intervention | Loading doses and then 30 days of combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily (modified release or 100 mg three or four times daily). | Loading doses and then 30 days of either clopidogrel alone (75 mg daily) or combined aspirin (75 mg daily) and dipyridamole (200 mg twice daily modified release or 100 mg three or four times daily). |
| Duration | 30 days | 30 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| 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. | Primary | 105 (7%) participants had a recurrent event | 93 (6%) participants had a recurrent event | 1.00% | 0.47 |
| Death (mRS 6) | Secondary | 7 (<1%) | 13 (1%) | 1.92 | 0.17 |
| TIA | Secondary | 54/1530 (4%) | 34/1540 (2%) | 0.63 | 0.034 |
| Ischaemic stroke | Secondary | 50/1530 (3%) | 46/1540 (3%) | 0.89 | 0.56 |
| Haemorrhagic stroke | Secondary | 5/1530 (<1%) | 14/1540 (1%) | 2.77 | 0.052 |
| Overall death | Secondary | 28/1535 (2%) | 26/1556 (2%) | 0.89 | 0.69 |
| Composite: Any stroke or major haemorrhage | Secondary | 69 (5%) | 87 (6%) | 1.24 | 0.19 |
| Composite: Death, stroke, myocardial infarction, or major haemorrhage | Secondary | 98 (6%) | 102 (7%) | 1.02 | 0.88 |
| Overall bleeding (ordinal scale: fatal, major, moderate, mild, none) | Adverse | 139/1531 (9%) had bleeding of any severity | 305/1541 (20%) had bleeding of any severity | 2.54 | <0.0001 |
| Fatal or major haemorrhage | Adverse | 17/1530 (1%) | 39/1540 (3%) | 2.23 | 0.0063 |
| Intracranial bleeding (fatal or major) | Adverse | 4/1530 (<1%) | 15/1540 (1%) | 3.84 | 0.018 |
| Extracranial bleeding (fatal or major) | Adverse | 13/1530 (1%) | 26/1540 (2%) | 1.89 | 0.064 |
| Serious adverse events (excluding primary outcome and bleeding events) | Adverse | 327/1531 (21%) | 335/1543 (22%) | 1.02 | 0.80 |
| Fatal serious adverse events | Adverse | 22/1531 (1%) | 13/1543 (1%) | 0.52 | 0.070 |
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%).
Subgroup Analysis
No significant interactions between the primary outcome and treatment were present in prespecified subgroups. However, for bleeding, a statistically significant interaction was found: intensive treatment was associated with more bleeding when compared with aspirin and dipyridamole than when compared with clopidogrel. An interaction was also seen for patients who received thrombolysis; intensive antiplatelet therapy was associated with more bleeding in those who received thrombolysis than those who did not.
Funding
National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.
Based on: TARDIS (The Lancet, 2018)
Authors: Philip M Bath, Lisa J Woodhouse, Jason P Appleton, ..., Nikola Sprigg
Citation: Lancet 2018; 391:850-59
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