TARDIS

In Review

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.
PubMed • Full text • PDF

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

• Krishnan K et al. Safety and efficacy of intensive vs. guideline antiplatelet therapy in high-risk patients with recent ischemic stroke or transient ischemic attack: rationale and design of the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial (ISRCTN47823388). Int J Stroke 2015. 10:1159-65.
• Bath PM et al. Statistical analysis plan for the 'Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke' (TARDIS) trial. Int J Stroke 2015. 10:449-51.
• Bath PM et al. Baseline characteristics of the 3096 patients recruited into the 'Triple Antiplatelets for Reducing Dependency after Ischemic Stroke' trial. Int J Stroke 2017. 12:524-538.
• Bath PM et al. Remote Assessment of Platelet Function in Patients with Acute Stroke or Transient Ischaemic Attack. Stroke Res Treat 2017. 2017:7365684.
• Amarenco P Learning from TARDIS: time for more focused trials in stroke prevention. Lancet 2018. 391:819-821.