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)

Abstract

RationaleThe risk of recurrence following a stroke or transient ischemic attack is high, especially immediately after the event.HypothesisBecause two antiplatelet agents are superior to one in patients with non‐cardioembolic events, more intensive treatment might be even more effective.Sample size estimatesThe sample size of 4100 patients will allow a shift to less recurrence, and less severe recurrence, to be detected (odds ratio 0·68) with 90% power at 5% significance.Methods and design Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (ISRCTN47823388) is comparing the safety and efficacy of intensive (combined aspirin, clopidogrel, and dipyridamole) vs. guideline antiplatelet therapy, both given for one‐month. This international collaborative parallel‐group prospective randomized open‐label blinded‐end‐point phase III trial plans to recruit 4100 patients with acute ischemic stroke or transient ischemic attack. Randomization and data collection are performed over a secure Internet site with real‐time data validation and concealment of allocation. Outcomes, serious adverse events, and neuroimaging are adjudicated centrally with blinding to treatment allocation.Study outcomeThe primary outcome is stroke recurrence and its severity (‘ordinal recurrence’ based on modified Rankin Scale) at 90 days, with masked assessment centrally by telephone. Secondary outcomes include vascular events, functional measures (disability, mood, cognition, quality of life), and safety (bleeding, death, serious adverse events).DiscussionThe trial has recruited more than 50% of its target sample size (latest number: 2399) and is running in 104 sites in 4 countries. One‐third of patients presented with a transient ischemic attack.

Remote Assessment of Platelet Function in Patients with Acute Stroke or Transient Ischaemic Attack

“…Of these, 689 (22.3%) patients from 23 recruiting sites (21.7%) had a P-selectin expression measurement at baseline; one patient was not included in subsequent analyses having presented on triple antiplatelets ( n = 1, a protocol violation [34]). The characteristics of the patients are shown in Table 1.…”

“…Importantly the data come from a large high-fidelity trial with prospective data collection [34, 35]. However, the study has several caveats.…”

Triple versus guideline antiplatelet therapy to prevent recurrence after acute ischaemic stroke or transient ischaemic attack: the TARDIS RCT

“…The timing of 90 days was chosen to emulate the usual follow-up period in acute stroke trials. Severity of recurrent stroke was assessment of the mRS, a six-level ordered categorical scale: 76,77 fatal stroke, non-fatal severe stroke (mRS score of 4-5), moderate stroke (mRS score of 2-3), mild stroke (mRS score of 0-1), TIA and no stroke or TIA. 77 The primary outcome was a balance of ischaemic stroke (potential benefit if reduced) and intracerebral haemorrhage (potential harm if increased).…”

“…more death and less impairment), an extreme value for death was added to the other outcome scales: EQ-VAS = -1, t-MMSE = -1, SSS = -1, TICS-M = -1, verbal fluency = -1, and ZDS = 102.5. 77,87 Including death in these secondary outcome scores has the additional advantage of increasing statistical power and of anchoring the scales to one another.…”

Recent advances in the management of transient ischemic attacks

“…Patients with large artery atherosclerosis 8 have been shown by several studies to benefit from double antiplatelet therapy 118 , 122 , 123 . That said, more is not necessarily better, and the recently reported (not yet published) Triple Antiplatelets for Reducing Dependency after Ischemic Stroke (TARDIS) study failed to show a benefit of adding dipyridamole to aspirin and clopidogrel for stroke risk reduction 124 , 125 . The results of TARDIS are not surprising since, although shown to be beneficial in combination with low-dose aspirin 126 , 127 , dipyridamole has not been found to be superior to clopidogrel in reducing the risk of stroke 128 .…”