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1 Stroke in the young 9 th International Congress of Internal Medicine Athens, Greece 09 March 2017 Jukka Putaala, MD, PhD, MSc(Stroke), Associate Prof. Department of Neurology Helsinki University Hospital Finland

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Page 1: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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

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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

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CONTENTS

1. Current epidemiology2. Risk factors

3. Stroke mechanisms4. Cardiovascular prognosis5. Evidence for prevention

Page 4: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

1. Current epidemiology

Page 5: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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

Page 6: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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

Page 7: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

2. Risk factors

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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%)

Page 9: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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.

Page 10: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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

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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

Page 12: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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

Page 13: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

3. Stroke mechanisms

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The younger the patient, the larger the proportion of cryptogenic stroke

Yesilot Barlas et al. Eur J Neurol 2013; Putaala Eur Stroke J 2016

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Etiological diagnosis of young stroke is a multidisciplinary challenge

Ferro et al Lancet Neurol 2010

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Ferro et al Lancet Neurol 2010

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ESUS: The first serious attempt to creatediagnostic criteria for cryptogenic strokes

Hart et al. Lancet Neurol 2014

Page 18: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

Textbook examples of embolic infarctions

Page 19: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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

Page 20: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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

Page 21: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

4. Cardiovascular prognosis

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Mortality 4-fold compared to background population, irrespective of age and sex

Rutten-Jacobs et al. JAMA 2013

Page 23: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

Recurrent vascular events

Aarnio et al. Neurology 2016

~19% ~21% ~7%

~36%

~11%

~34%

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Recurrent vascular events: High-risk subgroups

Aarnio et al. Neurology 2016

=PFO

Page 25: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

5. Evidence for prevention

Page 26: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;
Page 27: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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

Page 28: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

Ongoing trials: CLOSE, REDUCE, DEFENSE-PFO

Page 29: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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

Page 30: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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)

Page 31: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

ATTICUS

Page 32: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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.

Page 33: Athens, Greece - Livemedia.gr · Athens, Greece 09 March 2017 Jukka Putaala ... Grau et al . Stroke 2004 ... ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source;

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?