Learning from TARDIS: time for more focused trials in stroke prevention
Authors: Pierre Amarenco
Journal: The Lancet (2017)

Antithrombotic therapy immediately following stroke is important to minimise the risk of recurrence, but the optimum choice and number of drugs to use are unclear, and efficacy in preventing thrombosis needs to be weighed against bleeding risk. In The Lancet, the TARDIS investigators report findings from a randomised trial1Bath PM Woodhouse LJ Appleton JP et al.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.Lancet. 2017; (published online Dec 20.)http://dx.doi.org/10.1016/S0140-6736(17)32849-0Google Scholar that tested intensive antiplatelet therapy with three agents (aspirin, clopidogrel, and dipyridamole) against therapy based on current UK guidelines2Royal College of PhysiciansNational clinical guidelines for stroke (fifth edition).https://www.strokeaudit.org/SupportFiles/Documents/Guidelines/2016-National-Clinical-Guideline-for-Stroke-5t-(1).aspxDate: 2016Google Scholar (either clopidogrel, or aspirin plus dipyridamole) for 30 days in patients with transient ischaemic attack (TIA) or ischaemic stroke. Patients were randomly assigned within the first 48 h after symptom onset, and the investigators used an innovative primary endpoint at 90 days that captured both incidence and severity of recurrent stroke and TIA. However, after 3096 patients were randomly assigned (more than 70% of the target sample size of 4200 patients), the data monitoring committee recommended that the trial be stopped for futility (for the primary endpoint, adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47) and because of an increased risk of bleeding, particularly fatal bleeding, in the intensive therapy group (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). If bleeding excess could be anticipated, how could triple therapy be futile in terms of efficacy when dual therapy seemed very efficacious in the CHANCE trial3Wang Y Wang Y Zhao X et al.Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.N Engl J Med. 2013; 369: 11-19Crossref PubMed Scopus (1074) Google Scholar (32% relative reduction in stroke compared with aspirin alone, and 49% in non-carriers of the CYP2C19 loss-of-function allele, who metabolise clopidogrel normally)?4Wang Y Zhao X Lin J et al.Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischeyamic attack.JAMA. 2016; 316: 70-78Crossref PubMed Scopus (208) Google Scholar First, TARDIS included not only patients with TIA (about a third of the study population), but also those with ischaemic stroke of various severities. About 11% of the study population had severe strokes (National Institutes of Health Stroke Scale NIHSS>6) and another 10% had undergone thrombolysis before randomisation. These patients have increased risk of bleeding complications, particularly intracerebral haemorrhage or haemorrhagic transformation, and indeed in the TARDIS trial there was a significant treatment-by-thrombolysis subgroup interaction for bleeding. Inclusion of severe strokes can only yield harm from an antithrombotic strategy, with no substantial benefit, because little or no remaining cerebral tissue in the hemisphere of the brain infarction can be preserved from a potential recurrent stroke; the choice to include these severe strokes in TARDIS might have contributed to the futility of its findings. Second, 80 (40%) of the 198 recurrent events included in the primary endpoint were recurrent TIAs. Inclusion of an endpoint such as TIA is questionable because of the high risk of misdiagnosis (ie, TIA mimic), even by neurologists. Third, 70% of patients were included 24–48 h after symptom onset, a time window with the highest risk of acute damage to the blood–brain barrier due to ischaemia, and in which a loading dose of clopidogrel and aspirin could also increase the risk of bleeding complications. It would be interesting to learn in further analysis of the TARDIS data whether haemorrhagic cerebral complications clustered during the first days of treatment in patients randomly assigned beyond 24 h. Fourth, the duration of the triple therapy was the first 30 days after randomisation, rather than the entire 90 days of trial duration. Although this choice minimised exposure to bleeding complications, it might also have affected the efficacy outcome at 3 months and thereby futility. Conversely, most of the risk of recurrence in the CHANCE3Wang Y Wang Y Zhao X et al.Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.N Engl J Med. 2013; 369: 11-19Crossref PubMed Scopus (1074) Google Scholar and SOCRATES5Johnston SC Amarenco P Albers GW et al.Ticagrelor versus aspirin in acute stroke or transient ischemic attack.N Engl J Med. 2016; 375: 35-43Crossref PubMed Scopus (355) Google Scholar trials and in the TIAregistry.org6Amarenco P Lavallee PC Labreuche J et al.One-year risk of stroke after transient ischemic attack or minor stroke.N Engl J Med. 2016; 374: 1533-1542Crossref PubMed Scopus (361) Google Scholar occurred during the first 8–10 days, so an 8–10-day duration of triple antiplatelet therapy (instead of 30 days as in the TARDIS trial) might have reduced intracerebral and extracerebral bleeding without sacrificing too much efficacy. Fifth, the choice of dipyridamole as the third antiplatelet treatment might have been inappropriate because findings from trials such as ESPRIT7The ESPRIT Study GroupMedium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a randomised controlled trial.Lancet Neurol. 2007; 6: 115-124Summary Full Text Full Text PDF PubMed Scopus (200) Google Scholar and meta-analyses8Rothwell PM Algra A Chen Z Diener HC Norrving B Mehta Z Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials.Lancet. 2016; 388: 365-375Summary Full Text Full Text PDF PubMed Scopus (273) Google Scholar have shown that dipyridamole was not associated with an early benefit as opposed to aspirin. Sixth, as correctly pointed out by the authors, 40% of patients had small vessel disease as the mechanism of their stroke (it normally represents less than 20% of ischaemic strokes9Sirimarco G Lavallée PC Labreuche J et al.Overlap of diseases underlying ischemic stroke—The ASCOD phenotyping.Stroke. 2013; 44: 2427-2433Crossref PubMed Scopus (31) Google Scholar), and only 16% of strokes were due to large vessel atherosclerotic disease (any ipsilateral stenosis usually represents 60% of ischaemic strokes9Sirimarco G Lavallée PC Labreuche J et al.Overlap of diseases underlying ischemic stroke—The ASCOD phenotyping.Stroke. 2013; 44: 2427-2433Crossref PubMed Scopus (31) Google Scholar) according to TOAST classification. Dual or triple antiplatelet therapy addresses clot formation on a ruptured plaque, which is a common complication of atherosclerotic stenosis, whereas in (mostly hypertensive) small vessel disease the mechanism underlying stroke is far less clear. For example, in the SOCRATES trial10Amarenco P Albers GW Denison H et al.Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subrgoup analysis of SOCRATES, a randomised, double-blind, controlled trial.Lancet Neurol. 2017; 16: 301-310Summary Full Text Full Text PDF PubMed Scopus (136) Google Scholar the difference between ticagrelor and aspirin was observed almost entirely in the 3081 (23%) of 13 199 patients with ipsilateral atherosclerotic disease, with absolutely no difference in the 10 118 patients without stenosis (including 3839 [29%] patients with lacunar stroke or stroke of unknown cause). There was a significant interaction between treatment and atherosclerotic stenosis, with a 31% relative risk reduction of the primary endpoint compared with aspirin in this specific aetiological group. Seventh, compared with SOCRATES,5Johnston SC Amarenco P Albers GW et al.Ticagrelor versus aspirin in acute stroke or transient ischemic attack.N Engl J Med. 2016; 375: 35-43Crossref PubMed Scopus (355) Google Scholar which had a similar superiority hypothesis, the sample size in TARDIS was less than a quarter of the size. Had the sample size been 13 000 patients in TARDIS, with no inclusion of severe strokes (and no randomisation beyond 24 h), the trial might not have been stopped for futility after 3096 patients were randomised. I do not think that the TARDIS trial provides a definitive answer about the safety or efficacy of triple antithrombotic therapy in patients with TIA or minor stroke of atherosclerotic origin. It is time that stroke researchers recognise that the disease has multiple and very different underlying aetiologies and that a single treatment strategy cannot fit all. Around the world, patients with stroke or TIA now have immediate brain and arterial imaging when they are admitted to the stroke unit,6Amarenco P Lavallee PC Labreuche J et al.One-year risk of stroke after transient ischemic attack or minor stroke.N Engl J Med. 2016; 374: 1533-1542Crossref PubMed Scopus (361) Google Scholar meaning that targeting of atherosclerotic stenosis in clinical trials that randomly assign patients within 24 h is highly feasible, and could be cost-effective by reducing the sample size needed to verify the trial hypothesis. I am part of the RIGHT-2 steering committee led by Philip Bath (main author of the TARDIS trial), and I am co-Chair of the Executive Committee of the SOCRATES and THALES trials, both testing ticagrelor in secondary prevention of stroke. I also report research grant support and lecture fees from Pfizer, Sanofi (antithrombotic treatment), Bristol-Myers Squibb (antithrombotic treatment), Merck, AstraZeneca (antithrombotic treatment), and Boston Scientific; consultancy fees from Pfizer, Bristol-Myers Squibb, Merck, Boehringer Ingelheim (antithrombotic treatment), AstraZeneca (antithrombotic treatment), Bayer (antithrombotic treatment), Daiichi-Sankyo (antithrombotic treatment), Lundbeck, Edwards, Boston Scientific, Kowa, GlaxoSmithKline, and Fibrogen; lecture fees from Bayer, Boston Scientific, and St-Jude Medical; and research grants from the French Government. 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 trialAmong patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. Full-Text PDF Open Access