RE start or ST op A ntithrombotics R andomised T rial (RESTART)

1. Insert your hospital logo here REstart or STop Antithrombotics Randomised Trial (RESTART) Insert your name here on behalf of the RESTART collaboration

2. One of Edinburgh’s Stroke Trials:

3. The question the trial will answer: In the past… Now… Should I start or avoid antiplatelet drug(s)? Vaso-occlusive disease or AF • On antithrombotic drug(s) • Antiplatelet, and/or • Anticoagulant

4. It would be good to know what to do, but there aren’t any trials… Cardiovasc Ther 2010;28:177-84

5. Observational studies haven’t solved this therapeutic dilemma • NS = no significant association with aspirin use • ↑ = significant increase with aspirin use • ↓ = significant decrease with aspirin use Stroke 2010;41:2606-11 Neurology 2010;75:693-8 Thromb Haemost 2012;107:241-7

6. Do MR biomarkers of small vessel disease modify treatment effect? • Criteria for microbleeds • Black lesions on gradient echo (GRE) MRI • Round or ovoid • Blooming on GRE MRI • No signal hyperintensity on T1 or T2 MRI • At least half of lesion surrounded by brain parenchyma • Deep (GRE MRI) • Lobar (GRE MRI) Lancet Neurol 2009;8:165-74

7. Microbleeds are associated with future ischaemic stroke and ICH • Meta-analysis of TIA/ischaemic stroke cohorts: • Similar for people without stroke • Inconclusive for people with ICH ± anti-platelets Lancet Neurol 2009;8:165-74

8. So, let’s randomise! On antithrombotics for vaso-occlusive disease prevention + spontaneous ICH Pre-randomisation: brain MRI (optional sub-study) Randomisation (central) 1:1 360 START antiplatelet drugs* 360 AVOID antiplatelet drugs Follow-up for ≥2 years (central via GP, after local hospital discharge) * Aspirin or clopidogrel or dipyridamole

9. Eligibility criteria • Inclusion criteria • Age ≥18 years • Spontaneous primary or secondary ICH • Took antithrombotic drugs to prevent vaso-occlusive disease before ICH • Anytime ≥24 hrs after ICH onset (so prevalent patients can be recruited) • Exclusion criteria • ICH due to preceding trauma or haemorrhagic transformation of ischaemic stroke • Intention to use anticoagulant drugs after randomisation

10. We’re one of 112 hospitals in the trial February 2016 • Scotland: 12 • Northern Ireland: 5 • Wales: 4 • England: 91

11. RESTART is as easy as possible • Online training, teleconference site initiation • Research nurse recruitment (doctor confirms eligibility and PI implements prescribing policy) • Prescribing policy, so no specific drug • Only two forms: randomisation and discharge • Minimal adverse event reporting • Central follow-up

12. Example of a suitable patient • 83 year-old man • Ischaemic heart disease, aspirin • Mild left hemiparesis (NIHSS=4) • Admitted to acute stroke unit • Day 2 – patient information leaflet • Day 4 – consent • Day 5 – MRI, randomised

13. We can recruit as part of our clinical routine…

14. Recruit on the stroke unit… • ICH growth happens early in the first 24 hours • Recruitment is allowed >24 hours after onset • ICH recurrence does not seem to be higher early vs. later after ICH (ballpark 2%/year) • Ischaemic events can occur soon after ICH • Half of randomisations so far are inpatients

15. Recruit in outpatients… • Invite prevalent patients, flag inpatients • Confirm eligibility before clinic • Obtain consent • Perform MRI as inpatient, or before clinic • Recruit, randomise +/- prescribe in clinic • Complete clinic discharge form

16. Our most recent participant • Insert your patient’s • Presenting complaint • Past medical history • Antithrombotic drug use • Clinical stroke type Insert a slice of your patient’s anonymised diagnostic brain imaging

17. ‘Reasons to randomise’ • Extra care for participants • Extra reimbursed brain MRI • Extra follow-up for at least 2 years • Drugs’ effects monitored • Fair test of treatment • Randomisation is the fairest test of treatment • Fairest way to see if microbleeds alter drug effects

18. We can ‘consent with confidence’ • The observational studies don’t clearly show hazard from restarting. One found benefit! • 4 DMC reviews recommended continuation • By February 2016 • 112 hospitals had joined the collaboration • 280 patients had consented • Remember the reasons to randomise

19. Resources to help patients understand the benefits of trials • Visit our website • www.RESTARTtrial.org/patient.html • Compendium of information about trials for patients

20. Help us to answer this question by recruiting more participants!

21. Hit a six like the toprecruiters (at February 2016)

22. The gains for us • Addresses dilemma in everyday clinical practice • We can resolve this dilemma for future patients! • The trial will be submitted to The Lancet • The trials’ results will be accessible to all • All active collaborators will be listed in PubMed • BHF funds modest reimbursement per patient

23. David Werring Professor of clinical neurology, University College London “Many patients with ICH, including either lobar or deep hemorrhages, are eligible and should be encouraged to take part. RESTART will also show how cerebral microbleeds affect outcomes in ICH.” Pippa Tyrrell Prof of stroke medicine, University of Manchester “Avoiding antiplatelet agents after brain haemorrhage might feel like the “safe” thing to do. But are we putting people at more risk by not preventing ischaemic events? The only way to find out is the RESTART trial!” Nikola Sprigg Associate Prof, University of Nottingham “TICH-2 submitted a protocol amendment to allow participants to be co-enrolled into RESTART as I think this it is vital that we prevent the burden of further strokes. The stroke survivors working on TICH-2 were fully supportive of this approach.” Tom Robinson Prof of stroke medicine, University of Leicester “As the NIHR National Specialty Lead for Stroke, I would strongly encourage clinicians to approach their local NIHR CRN Stroke Leads to seek participation in this vitally important trial.” Gary Ford Prof of clinical pharmacology, University of Oxford “RESTART will provide high quality evidence to answer a problem frequently faced by patients with stroke due to cerebral haemorrhage and their stroke physicians.” Peter Langhorne Prof of Stroke Care, University of Glasgow “RESTART is important because this kind of clinical question will never be reliably answered by any approach other than a randomised controlled trial” Christine Roffe Professor of stroke medicine, Keele University “Practice varies widely between individuals. There is no good evidence to support decision making. I think the RESTART trial is very important and timely.” Keith Muir SINAPSE Prof of clinical imaging & consultant neurologist, University of Glasgow “RESTART addresses a scenario for which we lack good quality evidence to guide treatment decisions. Randomising in the trial offers the best opportunity to address an important clinical question.” Eivind Berge Stroke physician, Oslo University Hospital “RESTART will answer a question which is common and very important in daily clinical practice.” Graeme Hankey Prof of neurology, University of Western Australia “RESTART is important because it promises to resolve continuing uncertainty about antiplatelet therapy among survivors of intracerebral haemorrhage who had been taking an antithrombotic drug.”

24. www.RESTARTtrial.orgRESTART.trial@ed.ac.uk