REstart or STop Antithrombotics Randomised Trial (RESTART)

Insert your name hereon behalf of the RESTART

collaboration

Insert your hospital logo here

One of Edinburgh’s Stroke Trials:

The question the trial will answer:

In the past… Now…

Vaso-occlusivedisease or AF

On antithrombotic drug(s)•Antiplatelet, and/or•Anticoagulant

Should I start or avoid

antiplatelet drug(s)?

It would be good to know what to do, but there aren’t any trials…

Cardiovasc Ther 2010;28:177-84

Observational studies haven’t solved this therapeutic dilemmaStudy Patients Intervention /

ComparatorOutcome associations with aspirin use

ICH Ischaemic stroke

Acute coronary syndrome

All serious vascular events

Flynn et al. 2010Scotland

PICH1994-2005

120 Aspirin NS NS NS NS

297 none

Biffi et al. 2010USA

Lobar CAA-ICH1994-2006

16 Aspirin NS NS NS NS

88 none

Chong et al. 2012Hong Kong

PICH, SAH, SDH1996-2010

56 Aspirin NS ↑ ↓ ↓384 none

Stroke 2010;41:2606-11Neurology 2010;75:693-8Thromb Haemost 2012;107:241-7

NS = no significant association with aspirin use↑ = significant increase with aspirin use

↓ = significant decrease with aspirin use

Do MR biomarkers of small vessel disease modify treatment effect?

Lancet Neurol 2009;8:165-74

Deep (GRE MRI) Lobar (GRE MRI)

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

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

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

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

We’re one of 116 hospitals in the trial

• Scotland: 12• Northern Ireland: 5• Wales: 5• England: 94

October 2015

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

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

We can recruit as part of our clinical routine…

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

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

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

Insert a slice of your patient’s anonymised

diagnostic brain imaging

‘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

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

Resources to help patients understand the benefits of trials

• Visit our website• www.RESTARTtrial.org/patient.html

• Compendium of information about trials for patients

Help us to answer this question by recruiting more participants!

Join the rising tide in 2015…

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Hit a six like the toprecruiters (at October 2015)Hospital MRI sub-study Overall

Royal Infirmary, Edinburgh 10 15

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

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

Tom RobinsonProf 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.”

Peter LanghorneProf 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”

Pippa TyrrellProf 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 SpriggAssociate 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.”

David WerringProfessor 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.”

Keith MuirSINAPSE 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.”

Christine RoffeProfessor 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.”

Eivind BergeStroke physician, Oslo University Hospital

“RESTART will answer a question which is common and very important in daily clinical practice.”

Graeme HankeyProf 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.”

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