TARDIS

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Bath PM, Woodhouse LJ, Appleton JP, Beridze M, Christensen H, Dineen RA, Duley L, England TJ, Flaherty K, Havard D, Heptinstall S, James M, Krishnan K, Markus HS, Montgomery AA, Pocock SJ, Randall M, Ranta A, Robinson TG, Scutt P, Venables GS, Sprigg N; TARDIS Investigators. "Triple antiplatelets for reducing dependency after ischaemic stroke". The Lancet. 2018. 391(10123):850-859.
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Clinical Question

In patients with acute non-cardioembolic ischaemic stroke or transient ischaemic attack, is intensive antiplatelet therapy with three drugs versus guideline antiplatelet therapy reduce the risk and severity of recurrent stroke?

Bottom Line

Triple antiplatelet therapy does not reduce the risk and severity of recurrent stroke, and is associated with more, and more severe, bleeding.

Major Points

Dual antiplatelet is superior to mono antiplatelet therapy in reducing the risk of recurrence after acute stroke and TIA. TARDIS tested more intensive treatment with three antiplatelets but found that triple antiplatelet therapy did not reduce the risk and severity of recurrent stroke, and was associated with more, and more severe, bleeding.

Guidelines

No guidelines have incorporated these findings to date.

Design

  • Multicenter, open-label, parallel-group, randomised, controlled trial
  • N=3,096
    • Intensive (n=1,556)
    • Guideline (n=1,540)
  • Setting: 106 centres in United Kingdom, Denmark, Georgia and New Zealand
  • Enrollment: April 2009 to March 2016
  • Mean follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome: Stroke recurrence and its severity

Population

Inclusion Criteria

  • Non-cardioembolic ischaemic stroke or transient ischaemic attack
  • Age >=50 years
  • IS: Limb weakness, dysphasia and/or neuroimaging-positive hemianopia
  • TIA: >=10 minutes with limb weakness and/or dysphasia
  • Symptom onset <=48 hours
  • Written consent or proxy consent

Exclusion Criteria

  • Isolated sensory symptoms, facial weakness or vertigo/dizziness
  • Parenchymal haemorrhage or other intracranial haemorrhage
  • Contraindication to aspirin, clopidogrel and/or dipyridamole
  • Definitie need for full dose anticoagulation
  • Pre-morbid dependency

Baseline Characteristics

  • Mean age: 69 years
  • Sex, male: 62.8%
  • UK: 95.4%
  • Ischaemic stroke: 71.7%
  • Transient ischaemic attack: 27.1%
  • National Institutes of Health Stroke Scale: 2.8
  • ABCD2 score: 5.0

Interventions

  • Randomised to intensive or guideline antiplatelet therapy

    • Intensive antiplatelet therapy
 group received combined aspirin, clopidogrel and dipyridamole
    • Guideline antiplatelet therapy
 group received combined aspirin and dipyridamole, or clopidogrel alone
  • Thrombolysis allowed at least 24 hours prior to randomisation

Outcomes

Comparisons are intensive vs. guideline antiplatelet therapy. All outcomes are at 90 days.

Primary Outcome

Stroke and its severity (based on modified Rankin Scale
acOR 0.90 (95% CI 0.67-1.20, p=0.47)

Secondary Outcomes

Stroke or transient ischaemic attack
aHR 0.87 (95% CI 0.66-1.16, p=0.34)
Transient ischaemic attack
aHR 0.63 (95% CI 0.41-0.97, p=0.034)

Subgroup Analysis

There was no interaction for the primary endpoint for geographical region, age, sex, stroke vs. TIA, LACS vs. POCS vs. PACS vs. TACS, ABCD2 score, NIHSS, time to randomisation, thrombolysis, gastroprotection, small vessel disease, carotid stenosis

Adverse Events

Death
1.7% vs. 1.8% (aHR 0.89, 95% CI 0.51 to 1.55, p=0.69)
Bleeding and its severity
acOR 2.54 (95% CI 2.05-3.16, p<0.0001)
Serious adverse events
acOR 1.02 (95% CI 0.86-1.22, p=0.80)

Net risk : benefit balance

Stroke or fatal and major bleeding
aHR 1.24 (95% CI 0.90 to 1.70, p=0.19)
Death, stroke, myocardial infarction or fatal and major haemorrhage
aHR 1.02 (95% CI 0.77 to 1.35, p=0.88)

Criticisms

  • Change of guidelines required that clopidogrel alone be added to combined aspirin and dipyridamole
  • Trial stopped early on advice of Data Monitoring Committee
  • See Amarenco Commentary below

Funding

British Heart Foundation; National Institute of Health Research Health Technology Assessment programme

Further Reading