Informing Strategies for Stroke Prevention
Martin O’Donnell MB PhD MRCPI
HRB Conference, Feb 26 2015
Director, HRB-Clinical Research Facility, NUI Galway and Saolta
Associate Professor, Translational Medicine, NUI Galway
Disclosures
• Principal Investigator
• INTERSTROKE (McMaster University, S Yusuf) (CIHR, CSN, ERC, HSFC)
• SLEPT trial (HRB)
• STICK trial (HRB)
• COSIP (ERC)
• Steering Committee
• EMBRACE trial
• AVERROES trial (Apixaban)
• COMPASS trial (Rivaroxaban)
• ESUS-Navigate (Rivaroxaban)
• Global Burden of Disease (Stroke Committee)
• Honoraria (BMS, Pfizer, BI and Sanofi Aventis)
OVERVIEW
• Importance of stroke
• INTERSTROKE study
• Salt intake and Stroke (and CVD)
• Highlight the required infrastructure/resources to complete
clinical research programme
• Comments on evolution of Stroke research in Ireland
Global Burden of Stroke
Global Burden of Stroke
• Leading cause of death and a leading cause of disability (85% occur in LMICs)
Modifiable Risk Factors for Stroke
• INTERHEART 90% of PAR due to 9 potentially modifiable risk factors
Yusuf et al INTERHEART Lancet 2001
Feigin et al Global Burden of Disease Lancet 2014
GLOBAL BURDEN OF STROKE
Stroke Prevalence
Stroke Incidence
800
300
250
200
278
246 251 250
281
256
221
700
258
217
500
546
400
150
300
100
715
676
600
502
490
435
360
387
393
1990
2005
2010
200
50
100
0
0
1990
2005
2010
Stroke Mortality
140
120
Age –adjusted per
100,000 patients years
131
117
100
80
115
105
99
96.5
60
72.3
88
61
40
20
0
1990
High income
2005
Low/Middle Income
2010
Globally
Feigin et al Lancet 2014
INTERSTROKE (FULL-SCALE STUDY)
• International standardized case-control study (Coordinated: PHRI, McMaster
University, Canada)
• Shared methodology with INTERHEART
• 32 countries Mar 07-Aug 14 (n=26,508)
• N America/Europe: Australia, Canada, Croatia, Denmark, Germany, Ireland,
Poland, Russia, Turkey, UK
• S America: Argentina, Brazil, Chile, Colombia, Ecuador, Peru
• Asia: China, India, Pakistan, Philippines, Malaysia, Thailand
• Africa: Mozambique, Nigeria, South Africa, Sudan, Uganda
• Middle East: Iran, Kuwait, Saudi Arabia, UEA
• Case: First stroke admitted within 5 days of symptom onset
• Proxy respondents for patients unable to complete Qs
• Control: No history of stroke (Matched for age and gender)
• Community and hospital-based controls
INTERSTROKE- OBJECTIVES
• Informing strategies for stroke prevention, globally and within regions
• Determine estimates of strength of association between vascular risk
factors and stroke
• All stroke (global)
• Within stroke subtypes
• Within risk factors
• Determine regional variations in the importance of risk factors for
stroke
• Importance of regional variations in developing prevention
programs
• Determine the importance of emerging risk factors, particularly the
role of genetics
INTERSTROKE (PHASE I: 6,000 FROM 22 COUNTRIES)
POPULATION ATTRIBUTABLE RISK (ALL STROKE)
60
50
40
30
20
10
52
10 RISK FACTORS ASSOCIATED WITH 90% OF RISK
(ALL STROKE)
28
26
24
19
18
7
5
5
4
0
O’Donnell et al INTERSTROKE Lancet 2010
PAR FOR ALL RISK FACTORS FOR ALL STROKE BY REGION
Region
Western Europe
PAR
88.9
99% CI
81.5 - 93.6
Eastern/central Europe
Middle east
Africa
South Asia*
80.4
88.8
84.7
85.0
61.5 - 91.3
47.9 - 98.6
62.2 - 94.9
75.8 - 91.1
China
South East Asia
South America
94.5
96.8
92.4
91.4 - 96.5
89.1 - 99.1
84.6 - 96.5
North America/Australia
90.0
76.3 - 96.2
*Excluding apolipoproteins
BY REGION (ISCHEMIC STROKE) INTERSTROKE STUDY
30
25
24
23.5
23
71% OF CARDIAC CAUSES
20
NORTH DUBLIN: 31.3%
15.3
15
12.6
10
8.2
8.1
5
5.1
4.8
India
China
0
N America Europe Australia S America SE Asia
M East
Africa
N=11,124 PATIENTS WITH STROKE IN 30 COUNTRIES
INTERSTROKE Lancet 2010, with unpublished data
Kelly P et al Stroke 2012 Hannon Stroke 2013
Challenging Existing Recommendations
WHO Guideline: Sodium Intake < 2g/day
Systolic BP
Evidence to
Support
Guideline
• Cross-sectional Studies
and Small Clinical Trials
• Blood Pressure
• Short-term Follow-up
Mozaffarin et al GBD NEJM 2014
INTERSALT BMJ 1988
CV Events
Evidence
Against
Guideline
• Prospective Cohort
Studies
• CVD Events and Death
• Effect on CV Surrogates
Graudal et al AJH 2014
O’Donnell et al JAMA 2011
O’Donnell et al NEJM 2014
< 3g/day
Clarifying Optimal Sodium Intake in Populations
COSIP
Overview
Epidemiology
Genetics
Experimental
(Clinical Trials)
Epidemiology
PURE Cohort
(N=101,975)
≈ 10,000 events
INTERSTROKE
(N=27,204)
17 Countries
Fasting urines
32 Countries
Fasting and Random Urines
Stroke (Subtypes)
Death, MI, Stroke Heart Failure
•
•
•
•
Who is at risk from high and low sodium intake?
Does optimal intake vary by population?
How important are other dietary factors?
Sodium intake and other vascular-related outcomes
Genetics
INTERSTROKE
(n≈ 5,000)
17 Countries
Fasting urines
Death,
MI, Stroke Heart
Failure
SNPs associated
with:
•
•
•
•
•
Blood pressure
Renal Sodium Transportation
RAAS
Uromodulin
Salt sensitivity
Experimental
(Randomised Controlled Trial)
Effect of Sustained Low Sodium Intake On Cardiorenal Biomarkers
Sodium Intake
2-7g/day
Phase IIb
(n=286)
Sodium Intake
<2.0g/day
Sodium Intake
2.0-5.0g/day
Outcomes
CV/Renal Biomarkers
(e.g. PRA, Aldosterone)
24-ABPM
Funded by HRB
Experimental
(Randomised Controlled Trial)
Effect of ‘Evening Bolus’ versus Basal Pattern on 24-Hr ABPM
Usual Diet
Basal
Sodium
Bolus
Sodium
Bolus
Sodium
Basal
Sodium
Cross-over Trial (n=38)
4 X 2 Week Periods
Primary Outcome
24-Hour ABPM
Informing Novel Targets
SLEPT Trial
Effect of Sleep Behaviour Intervention on
Blood Pressure and CV Biomarkers
Hypertension
Sleep
Intervention
(Mild)
24-ABPM
CV Biomarkers
Control
Phase IIb
McGrath et al Trials 2014
Funded by HRB
Ireland, a Research Leader in Stroke: What is Required?
Collaborations
Infrastructure
Expertise
Funding
Collaborations
National
HRB
Institutions/Other
North Dublin Stroke Study
RCTs (ESCAPE)
HRB-Stroke Trials Network
International
(PHRI, McMaster)
Research Studies
Education/Training
Funding
Expertise
Prof Peter Kelly
Prof Joe Harbison
Prof David Williams
Prof Des Kelly
Dr Ronain Collins
Industry
Collaborations
National
International
(PHRI, McMaster)
HRB
Institutions/Other
North Dublin Stroke Study
RCTs (ESCAPE)
HRB-Stroke Trials Network
HRB-CCRC
Research Studies
Education/Training
Funding
Expertise
Prof Peter Kelly
Prof Joe Harbison
Prof David Williams
Prof Des Kelly
Dr Ronain Collins
Industry
Infrastructure
Clinical Research Facilities
• Dublin (James’, Vincent’s, Beaumont, Mater)
• Cork
• Limerick
• HRB-Clinical Research Coordinating Centre
HRB-Clinical Research Facility-Galway
Healthcare
• Hospital Networks
• General Practice/Community (Prof A Murphy)
2007: Capital funding for the HRB Clinical
Projected commencement date is Sept 2013
Completion projected March 2015
Health Research Board
Multidisciplinary Expertise
Regulation
Research
Methodology
Biostatistics
Research
Nursing
Monitoring
Audit
Engine
Health
Economics
Other
Research
Coordination
PM
IT/DM
Expertise: Health Research Methodology
Training (MSc in Clinical Research)
Recruitment and retention of highly trained staff
HRB-Clinical Research Facility Galway
Caroline Whiriskey Áine Keogh Emma Deenihan Alice Power Veronica McInerney Heather Kelly Linda Duane Laura McCormack
Alice Power Gráinne MacNamara Máiread Waldron Emma Hawkins Clodagh Raleigh Patrick Hayes
Martin O’Donnell Mary Bourke Michael Faherty Alberto Alvarez Iglasias Patricia Gunning Sharon Conway
Lisa Daly John Newell Caroline Kelly Michelle Kehoe Howard Foye Aideen O’Doherty Collette Kirwan Leona Moylan Elaine Faulkner
Methodology and Biostatistics
No, n=1s?
The science of how we do clinical research
•
•
•
•
Insufficient number
Competing job opportunities
Career path
Research Enablement vs
Researcher
STROKE RESEARCH AND HRB
• North Dublin Stroke Study (Prof P Kelly)
• TILDA study (Prof RA Kenny)
• Clinical Research Infrastructure
• Enabling competitive European Research Awards
• HRB-Stroke Clinical Trials Network
• Lead international clinical trials in stroke
• Next Generation of Stroke Researchers
• HRB-Research Fellowships
• Investigator support
• Early career support (key target)
• Thematic priority in Population Health
• Invest in Research Methodology and Biostatistics