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Insert your hospital logo here
REstart or STop Antithrombotics
Randomised Trial (RESTART)
Insert your name here
on behalf of the RESTART
collaboration
One of Edinburgh’s Stroke Trials:
The question the trial will answer:
In the past…
Vaso-occlusive
disease or AF
On antithrombotic drug(s)
•
•
Antiplatelet, and/or
Anticoagulant
Now…
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 dilemma
Study
Patients
Intervention /
Comparator
Flynn et al. 2010
Scotland
PICH
1994-2005
120 Aspirin
Biffi et al. 2010
USA
Lobar CAA-ICH
1994-2006
16 Aspirin
Chong et al. 2012
Hong Kong
PICH, SAH, SDH
1996-2010
56 Aspirin
Outcome associations with aspirin use
ICH
NS
Ischaemic Acute
stroke
coronary
syndrome
NS
NS
All serious
vascular
events
NS
NS
NS
NS
NS
NS
↑
↓
↓
297 none
88 none
384 none
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
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)
Lancet Neurol 2009;8:165-74
Lobar (GRE MRI)
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!
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
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 112 hospitals in the
trial
February 2016
•
•
•
•
Scotland: 12
Northern Ireland: 5
Wales: 4
England: 91
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
‘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 February 2016
– 112 hospitals had joined the collaboration
– 280 patients had consented
• Remember the reasons to randomise
Resources to help patients
understand the benefits of trials
• Visit our website
• www.RESTARTtrial.org/p
atient.html
• Compendium of
information about trials
for patients
Help us to answer this question
by recruiting more participants!
Hit a six like the top
recruiters (at February 2016)
HOSPITAL
MRI
TOTAL
Edinburgh Royal Infirmary
12
17
Southend University Hospital
6
Royal Hallamshire, Sheffield
HOSPITAL (cont.)
MRI
TOTAL
Torbay District General Hospital
0
7
11
Western General, Edinburgh
6
6
9
9
South Glasgow Uni Hospital
5
6
Salford Royal , Manchester
8
9
Royal Devon & Exeter Hospital
5
6
Guys and St Thomas, London
2
8
North Middlesex Uni Hospital
3
6
Monklands Hospital, Airdrie
7
7
City Hospital, Nottingham
3
6
Morriston Hospital, Swansea
4
7
Royal Preston Hospital
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
David
Nikola
Pippa
Tyrrell
Sprigg
KeithWerring
Muir
Graeme
Hankey
Tom
Gary
Robinson
Ford
Peter
Langhorne
Professor
of
clinical
neurology,
Associate
Profofof
stroke
Prof,
University
medicine,
of
University
Nottingham
of
Christine
Roffe
SINAPSE
Prof
of
clinical
imaging
&University
consultant
Prof
neurology,
University
of
Western
Prof
Prof
of of
stroke
clinical
medicine,
pharmacology,
University
University
Leicester
of
Prof
of
Stroke
Care,
ofof
Glasgow
EivindUniversity
Berge
College
London
“TICH-2
submitted
Manchester
a protocol
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to
Professor
of stroke
medicine,
Keele
University
neurologist,
University
of
Glasgow
Australia
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NIHR National
Oxford
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www.RESTARTtrial.org
[email protected]