1
Stroke in the young
9th International Congress of Internal Medicine
Athens, Greece09 March 2017
Jukka Putaala, MD, PhD, MSc(Stroke), Associate Prof.Department of Neurology
Helsinki University HospitalFinland
Disclosures• Significant research grant
Finnish Medical Foundation, Helsinki and Uusimaa Hospital District, Academy of Finland, Finnish Funding Agency for Innovation, St. Jude Medical
• Research collaboration
Nokia Technologies, Mega EMG, BcB Medical, Bayer, Vital Signum
• Speaker’s honorary
Orion Pharma, Boehringer-Ingelheim, BMS-Pfizer, Bayer, St. Jude Medical
• Advisory board
BMS-Pfizer, Medtronic, Allergan, Boehringer-Ingelheim
• Other
ESO Guideline Work Group: Post-stroke hyperglycemia, Secondaryprevention in patients with AF
Finnish Duodecim Society and Stroke Society Guideline Work Group:Ischemic stroke and TIA
CONTENTS
1. Current epidemiology2. Risk factors
3. Stroke mechanisms4. Cardiovascular prognosis5. Evidence for prevention
1. Current epidemiology
1.3 million young people suffer ischemic stroke annually.Globally increasing incidence of ischemic stroke at younger ages:
USA, Sweden, Denmark, Norway, UK, France…
Rosengren et al. Stroke 2013; George et al. Ann Neurol 2011; Vangen-Lønne et al. Stroke 2015; Kissela et al. Neurology 2012; Béjot et al. J Neurol Neurosurg Psychiatry 2014; Tibæk et al. JAHA 2016
Men: Increase of 1.3% / yearWomen: Increase of 1.6% / year
Some possible factors contributing to increasingincidence at younger ages
• Improved diagnostic accuracy (MRI, higher Teslas)
• Increasing awareness in the population
• Increasing prevalence of sedentary lifestyle, physically non-demanding work tasks
• Increasing prevalence of obesity, diabetes, metabolic syndrome
• Increasing use of alcohol, illicit drugs
• 24/7 society-syndrome: long work hours, shift work, long-haulflights, online life, information overload... Increasing burden of chronic stress, sleep deprivation, junk food consumption.
• Increasing exposure to air pollution
2. Risk factors
Sex-specific clustering of traditional vascular risk factorswith age in young stroke patients
Men
Women
von Sarnowski et al. Stroke 2013; Putaala et al. Stroke 2009; Putaala et al. Stroke 2012
High waist circumference(men ≥94 cm, women ≥80 cm): The most prevalent risk factor(69%)
Early-onset type 2 diabetes carries a 10-fold hazard for stroke compared with usual onset type 2 diabetes
Hillier et Pedula. Diabetes Care 2003
Studies of early-onset forms of common diseases with stroke
endpoint are warranted.
Maaijwee et al. Nat Rev Neurol 2014; Spector et al. Am J Med 2010; Shürks et al. BMJ 2009; Kurth et al. JAMA 2006; MacClellan et al Stroke2007; Alsheikh-Ali et al. Stroke 2009; Davis et al. Neuroepidemiology 2013; Urbanus et al. Lancet Neurol 2009; Brey J Thromb Haemost 2005;
Roach et al. Cochrane 2015; Rumalla et al. J Neurol Sci 2016
RISK FACTOR PREVALENCE IN PATIENTS
STRENGTH OF ASSOCIATION
COMMENT
Migraine with aura 20-27% OR ≈2.0 Stronger association for women, smokers, COC users, active migraine, and cryptogenic stroke.
Patent foramen ovale 25-50% OR 5.1 for age <55 y N.S. in population-based studies
Oral contraceptives 10-40% in women OR ≈2.0 Mixed results; Association strongerfor COCs with high-dose estrogen.
Lupus anticoagulant 10-17% OR 2.2-43.1 (women) Mixed results; stronger association for smokers and COC users.
F5 Leiden mutationF2 mutationAT 3 deficiencyProtein C deficiencyProtein S deficiency
3.0-7.5%2-6%5-8%4-11%6-23%
OR 1.0-2.0OR 1.5Not reportedNot reportedNot reported
Mixed and inconclusive results for young adult stroke; Associationsfound in selected cohorts, mostconclusively for F2 mutation.
Illicit drug use 9-20% OR 2.0 for cocaineOR 2.2 for amphetamineOR 2.3 for cannabis
Stronger associations for temporallypromixal use and certain routes (e.g. crack cocaine)
Examples of unconventional or less well documentedrisk factors, some of that may be young-age specific
Siegerink et al. Circulation 2010; Grau et al. Stroke 2004; Capuccio et al. Eur Heart J 2011; von Sarnowski et al. Stroke 2013; Vyas et al. BMJ 2012; Jood et al. BMC Medicine 2009; Sade et al. Stroke 2015
RISK FACTOR PREVALENCE IN PATIENTS
STRENGTH OF ASSOCIATION
COMMENT
Activated Intrinsic coagulation proteins
(=activated protein-inhibitor complexes for C1 esterase inhibitors)
≈50% (women) Pooled OR ≈2.5FXIIa-C1-INH: OR 2.1FXIa-C1-INH: OR 2.8FXIa-AT-INH: OR 2.3 Kallikrein-C1: OR 4.3
Studied in young women (mean age 39 yrs).Increasing risk with oral contraceptive use.
Pregnancy/puerperium 7.5% in women RR 8.7 during puerperium No association for pregnancy; mixedresults
Chronic infections(example: periodontitis)
? OR 6.1 for >6 mm attachment loss
N.S. for older patients (≥60 yrs)Stronger association for cryptogenicstroke
Short or long sleepduration
18% for sleep <6 hours
RR 1.15 for shortRR 1.65 for long
RR for all stroke, association notstudied exclusively in young patients
Shift work ? RR 1.05
Psychological stress ≈29% OR 3.5 Mean age of patients 56 yrs
Air pollution N.A. OR 1.11 for particulatematter <10 μm for age <55 yrs
N.S. for age ≥55 yrs
More examples of unconventional and much less welldocumented risk factors
Family history of stroke frequently positive: 37-47%Studies of genetic variants predisposing to young stroke
• Promising to investigate, since genetic effect might be stronger for young-onset stroke.
• Known rare variants of monogenetic diseases each explain only a smallfraction of young strokes: e.g. Fabry disease, CADASIL, CARASIL, MELAS...
• Limitations thus far: inconclusive results, small sample sizes, inconsistentphenotyping, studies not focusing particularly on young-onset cases.
• The studied risk-factor candidate genes can be grouped into:
1) Genes involved in coagulation and fibrinolytic system
eg, F5, F2, FGA, and FGB
or genes encoding platelet glycoproteins
eg, ITGB3 and ITGA2
2) Genes in the homocysteine metabolism
eg, MTHFR
3) Genes involved with lipid metabolism
eg, APOE
4) Genes regulating inflammation
Thijs et al. Stroke 2015; Ilinca et al. Eur J Neurol 2015; Cheng et al. Circ Cardiovasc Genetics 2014; Cheng et al. Stroke 2016
- Only now sufficient number of cases are being reached for GWAS
of early-onset stroke as a result of international collaboration and
data pooling.
- Genetics of Early-Onset Stroke (GEOS) consortium:
GWAS of 4505 cases and 21 968 controls identifies susceptibility locus at
10q25; a secondary analysis identifies 2 SNPs associated with plasma
factor VII-activating protease levels, a product of HABP2 gene.
- Next-gen sequencing of large patient cohorts behind the corner
3. Stroke mechanisms
The younger the patient, the larger the proportion of cryptogenic stroke
Yesilot Barlas et al. Eur J Neurol 2013; Putaala Eur Stroke J 2016
Etiological diagnosis of young stroke is a multidisciplinary challenge
Ferro et al Lancet Neurol 2010
Ferro et al Lancet Neurol 2010
ESUS: The first serious attempt to creatediagnostic criteria for cryptogenic strokes
Hart et al. Lancet Neurol 2014
Textbook examples of embolic infarctions
ESUS prevalence
• Athens Stroke Registry (1992-2011; n=2735): 10%– 13% other cryptogenic (non-embolic or incomplete
evaluation)
• Oxford Vascular Study (2002-14; n=2555): 7%– 24% other cryptogenic (non-embolic or incomplete
evaluation)
• ESUS Global Registry (2013-14; n=2144): 16%– 95% CI 15-18%– 14% with incomplete work-up
• Portugese study (2010-14; n=100): 42%– Age 22-55 years– 9% other cryptogenic; ESUS 82% of all cryptogenic strokes.
Ntaios et al. Stroke 2015; Li et al. Lancet Neurol 2015; Ladeira et al. Int J Stroke 2015
Searching for Explanations for Cryptogenic ischemic stroke in the young: Revealing the Etiology, Triggers, and Outcome
• Multicenter observational case-control study
• Participants
– (1) patients 18-49 years with recent cryptogenic ischemic stroke
– (2) age- and gender-matched stroke-free controls
• Standardized timely diagnostic procedures
– Brain MRI Central reading
– MRA or CTA of cervicocephalic arteries Central reading
– Standardized echocardiography (TTE + TEE) and ECG Central reading
– Lab (routine and coagulopathy screen)
– Questionnaires for triggers, comorbidites, lifestyle, family history etc.
• Investigational blood samples x 2: baseline and @ 3-months
• Follow-up: 10 years
www.secretostudy.net NCT0193472
4. Cardiovascular prognosis
Mortality 4-fold compared to background population, irrespective of age and sex
Rutten-Jacobs et al. JAMA 2013
Recurrent vascular events
Aarnio et al. Neurology 2016
~19% ~21% ~7%
~36%
~11%
~34%
Recurrent vascular events: High-risk subgroups
Aarnio et al. Neurology 2016
=PFO
5. Evidence for prevention
Warfarin vs. aspirin in cryptogenic stroke Subcohort of PICSS (WARSS substudy)
Warfarin Aspirin HR (95% CI)
PICSS, entire cohort with TEE (n=601)
PFO + (n=203) 16.5% 13.2% 1.29 (0.63-2.64)
PFO – (n=398) 13.4% 17.4% 0.80 (0.49-1.33)
PICSS, cryptogenic strokes with TEE (n=250)
PFO + (n=98) 9.5% 17.9% 0.52 (0.16-1.67)
PFO – (n=152) 8.3% 16.3% 0.50 (0.19-1.31)
Homma S et al. Circulation 2002
Warfarin-Aspirin Recurrent Stroke Study (WARSS): Warfarin (INR 1.4-2.8) vs. aspirin (325 mg/day); n=2206, age 59.0 ± 12.2 years; follow-up 24 months
Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS): n=601 patients who underwent TEE, including 250 with cryptogenic stroke
Primary endpoint: Recurrent stroke or death
Ongoing trials: CLOSE, REDUCE, DEFENSE-PFO
30 days
Safety
Follow-up
Rivaroxaban 15 mg od
ASA 100 mg odEfficacy
Cut-off DateStudy End
Event-driven study
NAVIGATE ESUS
Embolic Stroke of Undetermined Source Study
Official study title: Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in
Patients With Recent Embolic Stroke of Undetermined Source (ESUS)
www.clinicaltrials.gov/ct2/show/NCT02313909
R
N~7,000
1:1
Day 1
Population: Patients with recent embolic stroke of undetermined source;Age ≥50 years
Total study duration: ~3 years
Mean treatment duration per patient: ~2 years
Short design: Multicentre, randomized, double-blind,
double-dummy, active-comparator, event-driven,
superiority study
Indication: Secondary stroke prevention in ESUS
Start: Q4 2014
LPLV: Q4 2017
Objective: Efficacy of rivaroxaban in reducing the risk of recurrent stroke and systemic embolism in patients with a recent Embolic Stroke of Undetermined Source (ESUS)
Back to O
verv
iew
30
Mar 2016
*mRS ≤3, age ≥60, or 18–59 years with additional risk factors; †All patients receive dabigatran 150 mg BID, unless
≥75 years or creatinine clearance 30–50 mL/min. These patients receive dabigatran 110 mg BID; ‡0 days–6 months in
patients aged >60 years with additional risk factors.
ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source; mRS, modified Rankin score
1. Boehringer Ingelheim Clinical Trial Protocol, Trial No. 1160.189; 2. Diener HC et al. Int J Stroke 2015
RE-SPECT ESUS™: design
Primary endpoint: any stroke
30-day
follow-up0 days–3 months‡ 0.5–3 years
n=3000
n=3000
End of treatment
Assess with MRI/CT to
rule out lacunae;
vascular imaging and
≥24-hr rhythm monitoring
to rule out AF
Dabigatran (150 or 110 mg BID)†
ASA (100 mg OD)
Placebo (matching dabigatran)
Placebo (matching ASA)Index ischaemic
stroke (ESUS)*
An estimated 6000 patients and observation period of ~3 years will be
necessary to achieve sufficient observed events for required statistical power
(actual number and duration will be adjusted as needed)
ATTICUS
Statins in cryptogenic stroke in the young: What are we observing here?
Putaala et al. Neurology 2011
Adjusted for age, sex, dyslipidemia, hypertension, antihypertensive medication, stroke year, and
propensity score, patients on a statin at any time during follow-up were less likely to experience
outcome events, hazard ratio 0.23, 95% confidence interval 0.08-0.66; p = 0.006.
Summary & open questions & challenges
1. Reasons for the increasing incidence?
2. Heavy load of traditional risk factors in early midlife –targeting primary prevention?
3. Early forms of vascular risk factors – are they different?
4. In up to half of young adults strokes remain cryptogenic• Too simplistic thinking (e.g. PFO)? Unconventional environmental
risk factors, genetic influence, risk-factor interactions?
5. Multiple studies show (phenotype-dependent) considerablerisks of death and future cardiovascular events in youngstroke patients – new approaches needed for organizingsecondary prevention and follow-up of young patients?
6. Limited evidence guides secondary prevention choices. Doesgeneral RCT evidence hold true for the young? Need to teste.g. statins and aspirin vs. NOAC separately in this group?