Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO)

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO)

BACKGROUND: In industrialized countries a considerable and increasing proportion of strokes occur at younger ages. Stroke at young age causes marked disability at worst and thus long-standing socioeconomic consequences and exposes survivors for 4-fold risk of premature death compared with background population. Up to 50% of young patients with ischemic stroke remain without definitive etiology for their disease despite extensive modern diagnostic work-up (i.e. cryptogenic stroke). The group of cryptogenic strokes includes those with patent foramen ovale (PFO) or other abnormalities in the atrial septum in the heart as the only or concomitant finding. Population prevalence of PFO is high, 25%, and the mechanisms how PFO would be associated causally with ischemic stroke remain to be clarified. Moreover, there are only scarce data on clinical outcome, long-term risk of new vascular events, and prevention of such events in these patients.

DESIGN: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO) is an international prospective multicenter case-control study of young adults (age 18-49) presenting with an imaging-positive first-ever ischemic stroke of undetermined etiology (aim N=2000). Patients are included after standardized diagnostic procedures (brain MRI, imaging of intracranial and extracranial vessels, cardiac imaging, and screening for coagulopathies) and age- and sex-matched to healthy controls in a 1:1 fashion. Up to 45 study sites worldwide will be needed to recruit the planned participant population during a 3-year period. Neurovascular imaging and echocardiography studies, and ECGs will be read centrally.

AIMS: SECRETO involves five principal fields of investigation: (1) Stroke triggers and clinical risk factors; (2) Long-term prognosis (new vascular events, functional and psychosocial outcomes); (3) Abnormalities of thrombosis and hemostasis; (4) Biomarkers of e.g. inflammation, atherogenesis, endothelial function, thrombosis, platelet activation, and hemodynamic stress to characterize postulated cryptogenic stroke mechanisms; and (5) genetic study, including genome-wide association and candidate gene studies as well as next-generation sequencing approach. All analyses consider cardiac functional and interatrial structural properties as a possible mediator. Furthermore, SECRETO Family Study (substudy) aims at collecting extensive family history of thrombotic events from informative patients being screened for SECRETO main study and collect genetic samples from all consenting family members for whole-genome sequencing.

SIGNIFICANCE: SECRETO will provide novel information on clinical and subclinical risk factors, both transient and chronic, predisposing to cryptogenic ischemic stroke in young adults. This study also reveals long-term prognosis of this understudied patient population and may discover new genetic background underlying the disease mechanism and provide potential targets for drug development.

Study Overview

• Status: Recruiting
• Conditions: Ischemic Stroke; Thrombosis; Brain Infarction; Foramen Ovale, Patent

• Study Type: Observational
• Enrollment (Estimated): 1200

Contacts and Locations

• Study Contact: Name: Jukka Putaala, A/Prof.; Phone Number: +35894711; Email: jukka.putaala@hus.fi
• Study Contact Backup: Name: Anu Eräkanto; Phone Number: +35894711; Email: anu.erakanto@hus.fi

Study Locations

• Estonia
  • Tartu, Estonia
    • Completed
    • Tartu University Hospital
• Finland
  • Helsinki, Finland, FI-00029
    • Completed
    • Helsinki University Central Hospital
  • Kuopio, Finland, 70029
    • Completed
    • Kuopio University Hospital
  • Oulu, Finland
    • Completed
    • Oulu University Hospital
  • Tampere, Finland
    • Completed
    • Tampere University Hospital
  • Turku, Finland
    • Completed
    • Turku University Central Hospital
• Germany
  • Greifswald, Germany
    • Completed
    • Ernst-Moritz-Arndt University Medicine
• Greece
  • Athens, Greece
    • Suspended
    • "Attikon" Hospital, University of Athens, School of Medicine
• Italy
  • Brescia, Italy, 25123
    • Completed
    • University of Brescia
  • Reggio Emilia, Italy
    • Recruiting
    • Arcispedale S. Maria Nuova
    • Contact: Marialuisa Zedde, MD, PhD; Email: Marialuisa.Zedde@asmn.re.it
    • Principal Investigator: Marialuisa Zedde, MD, PhD
• Lithuania
  • Vilnius, Lithuania
    • Completed
    • Vilnius University Hospital Santariskiu Klinikos
• Netherlands
  • Nijmegen, Netherlands, 6500 HB
    • Completed
    • Radboud University Nijmegen Medical Centre
• Norway
  • Bergen, Norway, 5021
    • Completed
    • Haukeland University Hospital
• Portugal
  • Lisboa, Portugal, 1649-035
    • Completed
    • Hospital Santa Maria
• Spain
  • Almería, Spain
    • Completed
    • Torrecárdenas University Hospital
• Sweden
  • Gothenburg, Sweden
    • Completed
    • Sahlgrenska University Hospital
• Turkey
  • Istanbul, Turkey
    • Completed
    • Istanbul University Istanbul Faculty of Medecine
• United Kingdom
  • Peterborough, United Kingdom
    • Completed
    • Peterborough City Hospital
  • Stoke-on-Trent, United Kingdom
    • Completed
    • Royal Stoke University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 47 years (Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

1. Patients aged 18 to 49 hospitalized due to first-ever imaging-positive ischemic stroke of undetermined etiology;
2. Age-, gender- and race-ethnicity-matched stroke-free control subjects

Description

PATIENTS:

Inclusion Criteria:

1. Age 18 to 49 at stroke onset
2. Patient hospitalized due to first-ever imaging-positive ischemic stroke of undetermined etiology after complete timely diagnostic testing.

Exclusion Criteria:

1. Baseline mandatory tests not obtained in the first week following stroke onset, including:

   • Brain MRI
   • Routine blood tests, including complete blood count, CRP, fasting glucose, creatinine, aPTT, INR, total cholesterol, LDL-cholesterol, HDL-cholesterol, HbA1C, hemoglobin electrophoresis in individuals of African origin

2. Other baseline mandatory tests not obtained within the first two weeks following stroke onset, including:

   • Imaging of cervicocephalic arteries by CTA, MRA, or DSA
   • Transesophageal (highly recommended) or transthoracic echocardiography
   • 24-hour Holter monitoring or continuous in-hospital ECG monitoring with automated arrhythmia detection for at least 24 hours
   • Screening for thrombophilia, including antiphospholipid antibodies and other coagulopathies (any abnormal finding must be retested at mandatory 3-month follow-up visit >12 weeks from initial testing or >4 weeks after cessation of anticoagulation at any later time point); mandatory tests include anticardiolipin antibodies, lupus anticoagulant, anti-β2-glycoprotein antibodies, factor V mutation (or aPC resistency ruled out), factor II mutation, homocysteine, antithrombin III, protein C, and protein S
3. No evidence of current brain ischemia
4. Current stroke due to cerebral venous thrombosis or as a complication of subarachnoid hemorrhage, angiography, or cardiac surgery
5. Patient otherwise not eligible for the study or adherent for follow-up (eg nonresident) or has concurrent disease affecting outcome (eg multiple sclerosis, cancer)
6. Informed consent not obtained from the patient or a proxy.

CONTROL SUBJECTS:

Inclusion Criteria:

1. Age 18 to 49 years
2. Absence of prior ischemic stroke as ascertained using the Questionnaire for Verifying Stroke-Free Status

Exclusion Criterion:

1. Informed consent not obtained

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Patients w/ cryptogenic ischemic stroke; Patients aged 15 to 49 years with unexplained first-ever ischemic stroke
Stroke-free control subjects; Stroke-free subjects age- and gender-matched to patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nonfatal or fatal recurrent ischemic cerebrovascular event	Ischemic stroke or transient ischemic attack	10 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Composite of noncerebrovascular arterial or venous thrombotic events, or cerebral venous thrombosis	10 years
Death from any cause	10 years
New-onset atrial fibrillation	10 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale	Functional outcome will be assessed with modified Rankin Scale at mandatory 3-month visit and at annual follow-up contacts from year 1 to year 10.	10 years
Vocational outcome	Vocational status will be assessed at each follow-up contact with Poststroke Working Activity Questionnaire and a set of questions designed for the study.	10 years
Cognitive outcome	Cognition will be assessed at mandatory 3-month follow-up visit (Montreal Cognitive Assessment).	3 months
Anxiety and depression	Poststroke anxiety and depression will be evaluated at 3-month visit, 1-year, 5-year, and 10-year follow-up contacts with Hospital Anxiety and Depression Scale.	10 years
Quality of life	Quality of life will be assessed at 3-month visit, 1-year, 5-year, and 10-year follow-up contacts with EuroQol questionnaire.	10 years
Caregiver burden	Poststroke burden to caregiver will be assessed at 3-month visit with Expanded Caregiver Strain Index Questionnaire.	3 months
Barthel Index	Functional outcome will be assessed with Barthel Index at mandatory 3-month visit and at annual follow-up contacts from year 1 to year 10.	10 years

Collaborators and Investigators

• Sponsor: SECRETO Study Consortium
• Collaborators: Sahlgrenska University Hospital, Sweden; Academy of Finland; Hospital District of Helsinki and Uusimaa; Hospital District of Southwestern Finland; Finnish Medical Foundation; Pirkanmaa Hospital District; Hospital District of North Ostrobothnia; Northern Savo Hospital District
• Investigators: Principal Investigator: Jukka Putaala, A/Prof., Helsinki University Central Hospital; Principal Investigator: Steven Kittner, Prof., University of Maryland Hospital

Publications and helpful links

General Publications

• Kuusisto JK, Poyhonen PAK, Pirinen J, Lehmonen LJ, Raty HP, Martinez-Majander N, Putaala J, Sinisalo J, Jarvinen V. Revisiting left atrial volumetry by magnetic resonance imaging: the role of atrial shape and 3D angle between left ventricular and left atrial axis. BMC Med Imaging. 2021 Nov 9;21(1):167. doi: 10.1186/s12880-021-00701-5.
• Poyhonen P, Kuusisto J, Jarvinen V, Pirinen J, Raty H, Lehmonen L, Paakkanen R, Martinez-Majander N, Putaala J, Sinisalo J. Left ventricular non-compaction as a potential source for cryptogenic ischemic stroke in the young: A case-control study. PLoS One. 2020 Aug 14;15(8):e0237228. doi: 10.1371/journal.pone.0237228. eCollection 2020.
• Pirinen J, Jarvinen V, Martinez-Majander N, Sinisalo J, Poyhonen P, Putaala J. Left Atrial Dynamics Is Altered in Young Adults With Cryptogenic Ischemic Stroke: A Case-Control Study Utilizing Advanced Echocardiography. J Am Heart Assoc. 2020 Apr 7;9(7):e014578. doi: 10.1161/JAHA.119.014578. Epub 2020 Mar 25.
• Martinez Majander N, Sinisalo J, Sundararajan S, Strbian D, Putaala J. Cryptic Loss of Consciousness in a 36-Year-Old Woman. Stroke. 2015 Jul;46(7):e164-6. doi: 10.1161/STROKEAHA.115.009405. Epub 2015 May 12. No abstract available.
• Poyhonen P, Kuusisto J, Pirinen J, Raty H, Lehmonen L, Paakkanen R, Martinez-Majander N, Gerdts E, Putaala J, Sinisalo J, Jarvinen V. Right atrium and cryptogenic ischaemic stroke in the young: a case-control study. Open Heart. 2021 May;8(1):e001596. doi: 10.1136/openhrt-2021-001596.

Helpful Links

• Study website

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2013
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2031

Study Registration Dates

• First Submitted: August 29, 2013
• First Submitted That Met QC Criteria: August 29, 2013
• First Posted (Estimated): September 4, 2013

Study Record Updates

• Last Update Posted (Estimated): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 21, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Prognosis; Deep Vein Thrombosis; Patent Foramen Ovale; Subarachnoid Hemorrhage; Ischemic Stroke; Myocardial Infarction; Databases, Genetic; Pulmonary Embolism; Brain Infarction; Stroke in the Young; Cerebral Venous Thrombosis
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Congenital Abnormalities; Embolism and Thrombosis; Brain Ischemia; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Septal Defects, Atrial; Heart Septal Defects; Infarction; Stroke; Ischemic Stroke; Thrombosis; Foramen Ovale, Patent; Brain Infarction
• Other Study ID Numbers: SECRETO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED