1. REstart or STop Antithrombotics Randomised Trial (RESTART)
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
Study
Patients
Intervention /
Comparator
Outcome associations with aspirin use
ICH
Ischaemic stroke
Acute coronary syndrome
All serious vascular events
Flynn et al. 2010
Scotland
PICH
120 Aspirin NS
297 none
Biffi et al. 2010
USA
Lobar CAA-ICH
16 Aspirin
88 none
Chong et al. 2012
Hong Kong
PICH, SAH, SDH
56 Aspirin ↑ ↓
384 none
NS = no significant association with aspirin use
↑ = significant increase with aspirin use
↓ = significant decrease with aspirin use
Stroke 2010;41:
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! Randomisation (central)
360 START antiplatelet drugs*
360 AVOID antiplatelet drugs
1:1
Pre-randomisation: brain MRI (optional sub-study)
Follow-up for ≥2 years (central via GP, after local hospital discharge)
On antithrombotics for vaso-occlusive disease prevention + spontaneous ICH
* Aspirin or clopidogrel or dipyridamole

9. Eligibility criteria Inclusion criteria Exclusion 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 116 hospitals in the trial
October 2015
Scotland: 12
Northern Ireland: 5
Wales: 5
England: 94

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 October 2015
116 hospitals had joined the collaboration
226 patients had consented
Remember the reasons to randomise

19. Resources to help patients understand the benefits of trials
Visit our website
Compendium of information about trials for patients

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

21. Join the rising tide in 2015…

22. Hit a six like the top recruiters (at October 2015)
Hospital MRI sub-study Overall
Royal Infirmary, Edinburgh
Southend, Westcliff-on-Sea 6 11
Royal Hallamshire, Sheffield 9 9
Guy’s and St Thomas’, London 1 7
Torbay DGH, Torquay 0 7
Monklands, Airdrie 6 6
Western General, Edinburgh 6 6
Royal Devon & Exeter, Exeter 5 6
Salford Royal, Manchester 5 6
Royal Preston, Preston 3 6

23. 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

24. Professor of stroke medicine, Keele University
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.”
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.”
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.”
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”
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.”
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.”
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.”
Eivind Berge
Stroke physician, Oslo University Hospital
“RESTART will answer a question which is common and very important in daily clinical practice.”

25. www.RESTARTtrial.org RESTART.trial@ed.ac.uk