CADISS
(Cervical Artery Dissection In Stroke Study)
First results
The CADISS Investigators
1
Presenter Disclosure Information
CADISS : funded by the
FINANCIAL DISCLOSURE:
No other relevant financial relationship exists
Carotid and vertebral dissection
• 10-25 % of stroke in young and middle aged
patients
• Associated with risk of recurrent stroke
• Stroke mechanism believed to be primarily
embolic
• Antiplatelets and anticoagulants widely
prescribed to prevent recurrent stroke
• Physicians have widely differing practices but no
RCT data to inform choice
Early Recurrent Stroke Risk in some…
2 weeks post-dissection
1 week post-dissection
Beletsky et al., 2003 Stroke
Biousse et al., 1995 Stroke
But not in all studies
Eg. Touzé E, et al. Neurology 2003
1% - 10-15%
Kennedy et al. Neurology 2012: 79:686
Antiplatelets
Anticoagulants
496
1131
P = 0.79
5
CADISS
Cervical Artery Dissection In Stroke Study
Aim: To determine whether antiplatelet agents or
anticoagulation are more effective at preventing stroke in
acute (<1 week) cervical dissection
Initial feasibility phase (N=250) to allow power calculations
for a definitive study
Secondary aim : How frequent is recurrent stroke in this
population?
Inclusion Criteria
• Clinical
– Symptom onset within 7 days
• Ipsilateral TIA or stroke
• Ipsilateral Horner’s syndrome, neck pain or headache
– Patients with TIA or stroke within last 7 days
eligible even if history of local symptoms > 7days
– Extracranial dissection only
– No contraindication to either antiplatelets or
anticoagulants
• Imaging
– evidence on MRI/MRA, CTA, DSA
Study Design
• Randomisation between:
– Antiplatelet agents: Aspirin, dipyridamole or
clopidogrel alone or in dual combination
– Anticoagulation: Heparin (LMWH) followed by
warfarin
•
•
•
•
Open treatment
Blinded adjudication of endpoints
Trial treatment until 3 months
Follow-up to 3 months with repeat MRA/CTA
• Primary endpoint: ipsilateral stroke and death at 3/12
Recruitment
N=250
Active centres: 39 UK, 7 Australian,
70
60
50
40
30
20
10
0
2006
2007
2008
2009
2010
2011
2012
2013
Baseline characteristics
Results : Endpoints
•
•
•
4 strokes, all ipsilateral
All in patients presenting with stroke
Recurrent stroke rate 1.6% (2.1% in those presenting
with stroke/TIA)
•
1 major bleed – SAH
•
No deaths
Results : Endpoints
Results : Analysis by treatment
Protocol defined Per Protocol Analysis
Imaging non-confirmation N = 52
Due to two factors.
• Imaging poor quality - impossible to be sure if the diagnosis
was dissection.
• Central imaging review suggested alternative diagnosis
- atherosclerosis
- atretic rather than dissected vertebral artery
- narrowed artery without any definite evidence of
dissection
- adherent thrombus without clear evidence of dissection
(N=1)
Other causes N=1
Randomisation on day 9
Endpoints
Per-protocol analysis
Power calculations for a
definitive trial
• Per-protocol endpoint of Stroke, death or major
bleeding: 3/101 v 2/96
• Power of 0·8 and significance level of 0·05
• Would require total sample size of 9752
- but wide CIs due to low number of endpoints
Conclusions
• Recurrent stroke rate low: 1.6% ITT; 2.0% PPP
• This is lower than reported in some
observational studies
• No difference between two treatment arms
• Showing a difference would require approx
10000 patients
• 20% of dissections not confirmed on central
imaging review suggesting diagnostic criteria not
always applied in practice
Acknowledgements
Trial Managers: Jennifer Peycke, Melina
Willson, Cara Hicks, Elizabeth Hayter
Clinical fellows and telephone follow-up:
Ranjith Menon; Fiona Kennedy; Usman
Khan.
Statistical Analysis: Adina Feldman, Matt
Hollocks, Hugh Markus
Imaging review: Alice King, Jeremy
Madigan
Steering committee
Hugh Markus, John Norris, Ahamed Hassan,
Graham Venables, Sally Kerry Chris Levi
DMC
Gary Ford (chair), Philip Bath, Chris Weir
Study neuroradiologists: , Andy Clifton
Jeremy Madigan
Adjudication committee
Lalit Kalra (chair), Denis Briley, Ajay Bhalla.
UK
Aberdeen Royal Infirmary, Aberdeen
Aintree University Hospital, Liverpool
Airedale General Hospital, Keighley,
Brighton and Sussex University Hospital, Brighton
Charing Cross Hospital, London
Cheltenham General and Gloucester Royal Hospitals, Derriford Hospital, Frenchay Hospital, Bristol
Guy’s and St Thomas’
Heartlands Hospital, Birmingham
Hope Hospital, Salford
Kent and Canterbury Hospital, Canterbury
King's College Hospital, London
Leeds General Hospital, Leeds
Musgrove Park Hospital, Taunton
Newcastle Hospitals Trust, Newcastle upon Tyne
Ninewells Hospital, Dundee Northwick Park, Harrow Pinderfields General Hospital, Wakefield
Queen Elizabeth Hospital, Gateshead,
Queen Elizabeth Queen Mother Hospital, Margate,
Royal Bournemouth Hospital, Bournemouth,
Royal Cornwall Hospitals NHS Trust, Truro,
Royal Devon and Exeter Hospital, Exeter,
Royal Hallamshire Hospital, Sheffield,
Royal Hampshire Hospital, Winchester,
Royal Preston Hospital, Preston,
Royal United Hospital, Bath,
Southampton General Hospital, Southampton,
Southend Hospital, Southend,
Southern General Hospital, Glasgow,
St George’s Hospital, London,
Royal London Hospital,
Torbay Hospital, Torbay,
University Hospital North Staffordshire, Stoke-on Trent University Hospital Wales, Cardiff,
University Hospitals of Leicester,
William Harvey Hospital, Ashford,
Yeovil District Hospital
Frimley Park Hospital, Frimley,
Watford General Hospital, Watford
Australia
Austin Hospital, Melbourne,
Gosford Hospital, Gosford,
John Hunter Hospital, New Lambton,
Royal Adelaide Hospital, Adelaide,
Royal Brisbane and Women’s Hospital, Brisbane
Royal Melbourne Hospital, Melbourne,
Royal Prince Alfred Hospital.
Acknowledgements
Trial Managers: Jennifer Peycke, Melina
Willson, Cara Hicks, Elizabeth Hayter
Clinical fellows and telephone follow-up:
Ranjith Menon; Fiona Kennedy; Usman
Khan.
Statistical Analysis: Adina Feldman, Matt
Hollocks, Hugh Markus
Imaging review: Alice King, Jeremy
Madigan
Steering committee
Hugh Markus, John Norris, Ahamed Hassan,
Graham Venables, Sally Kerry Chris Levi
DMC
Gary Ford (chair), Philip Bath, Chris Weir
Study neuroradiologists: , Andy Clifton
Jeremy Madigan
Adjudication committee
Lalit Kalra (chair), Denis Briley, Ajay Bhalla.
UK
Aberdeen Royal Infirmary, Aberdeen
Aintree University Hospital, Liverpool
Airedale General Hospital, Keighley,
Brighton and Sussex University Hospital, Brighton
Charing Cross Hospital, London
Cheltenham General and Gloucester Royal Hospitals, Derriford Hospital, Frenchay Hospital, Bristol
Guy’s and St Thomas’
Heartlands Hospital, Birmingham
Hope Hospital, Salford
Kent and Canterbury Hospital, Canterbury
King's College Hospital, London
Leeds General Hospital, Leeds
Musgrove Park Hospital, Taunton
Newcastle Hospitals Trust, Newcastle upon Tyne
Ninewells Hospital, Dundee Northwick Park, Harrow Pinderfields General Hospital, Wakefield
Queen Elizabeth Hospital, Gateshead,
Queen Elizabeth Queen Mother Hospital, Margate,
Royal Bournemouth Hospital, Bournemouth,
Royal Cornwall Hospitals NHS Trust, Truro,
Royal Devon and Exeter Hospital, Exeter,
Royal Hallamshire Hospital, Sheffield,
Royal Hampshire Hospital, Winchester,
Royal Preston Hospital, Preston,
Royal United Hospital, Bath,
Southampton General Hospital, Southampton,
Southend Hospital, Southend,
Southern General Hospital, Glasgow,
St George’s Hospital, London,
Royal London Hospital,
Torbay Hospital, Torbay,
University Hospital North Staffordshire, Stoke-on Trent University Hospital Wales, Cardiff,
University Hospitals of Leicester,
William Harvey Hospital, Ashford,
Yeovil District Hospital
Frimley Park Hospital, Frimley,
Watford General Hospital, Watford
Australia
Austin Hospital, Melbourne,
Gosford Hospital, Gosford,
John Hunter Hospital, New Lambton,
Royal Adelaide Hospital, Adelaide,
Royal Brisbane and Women’s Hospital, Brisbane
Royal Melbourne Hospital, Melbourne,
Royal Prince Alfred Hospital.
Events prior to Randomisation
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•
•
•
To determine whether recurrent events may have occurred
before recruitment and randomization, cases presenting with
stroke in whom previous TIA or minor stroke had occurred
were recorded.
Premonitory symptoms occurred in 19 (7.6%) (9 AC, 10 AP)
of cases in the ITT analysis, and 14 (7.1%) (7 AC, 7 AP) of
cases in the PP analysis.
The mean (SD, range) time between these symptoms and
subsequent stroke was 3.39 (SD 5.50, range 0.04-21,
median (IQR) 1 (3.75)) days in the ITT cohort, and in the PP
cases 3.94 (SD 6.31, range 0.13-21, median (IQR) 1 (5.46))
days.