Clinical trial NCT01934725: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome
Official title: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO)
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Brain Infarction
Ischemic Stroke
Thrombosis
Foramen Ovale, Patent
Keywords: Ischemic Stroke
Brain Infarction
Patent Foramen Ovale
Stroke in the Young
Myocardial Infarction
Cerebral Venous Thrombosis
Pulmonary Embolism
Deep Vein Thrombosis
Subarachnoid Hemorrhage
Prognosis
Databases, Genetic
Lead sponsor: SECRETO Study Consortium
Sponsor class: OTHER
Collaborators: name: Finnish Medical Foundation
name: Academy of Finland
name: Hospital District of Helsinki and Uusimaa
name: Hospital District of Southwestern Finland
name: Pirkanmaa Hospital District
name: Hospital District of North Ostrobothnia
name: Northern Savo Hospital District
name: Sahlgrenska University Hospital
name: Sigrid Jusélius Foundation
First posted: 2013-09-04
Enrollment: 1200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 49
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Nonfatal or fatal recurrent ischemic cerebrovascular event
timeFrame: 10 years
Secondary outcomes:
measure: Composite of noncerebrovascular arterial or venous thrombotic events, or cerebral venous thrombosis
timeFrame: 10 years
measure: Death from any cause
timeFrame: 10 years
measure: New-onset atrial fibrillation
timeFrame: 10 years
Other outcomes:
measure: Modified Rankin Scale
timeFrame: 10 years
measure: Vocational outcome
timeFrame: 10 years
measure: Cognitive outcome
timeFrame: 3 months
measure: Anxiety and depression
timeFrame: 10 years
measure: Quality of life
timeFrame: 10 years
measure: Caregiver burden
timeFrame: 3 months
measure: Barthel Index
timeFrame: 10 years
Locations:
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Oulu
country: Finland
facility: Oulu University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Central Hospital
city: Greifswald
country: Germany
facility: Ernst-Moritz-Arndt University Medicine
city: Athens
country: Greece
facility: "Attikon" Hospital, University of Athens, School of Medicine
city: Brescia
country: Italy
facility: University of Brescia
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santariskiu klinikos
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Lisboa
country: Portugal
facility: Hospital Santa Maria
city: Almería
country: Spain
facility: Torrecárdenas University Hospital
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul Faculty of Medecine
city: Peterborough
country: United Kingdom
facility: Peterborough City Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
Study officials:
affiliation: Helsinki University Central Hospital
name: Jukka Putaala, A/Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Maryland Hospital
name: Steven Kittner, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.