Medical Treatment With or Without Transcatheter Patent Foramen Ovale Closure

Study Overview
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Brief Summary
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Patent foramen ovale PFO closure has been shown to reduce the risk of stroke in patients with recurrent stroke. However, the majority of existing clinical studies in this field excluded patients over the age of 60 years. Data in older patients is limited and since the population ages and stroke remains a major cause of death and morbidity, randomized clinical trials are needed to better assess the benefit of PFO closure in this elderly population. Therefore, this study proposal sought to determine the efficacy of PFO closure for the prevention of recurrent stroke in older patients with PFO and cryptogenic stroke.

Detailed Description
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Background and importance Consistent with studies performed in younger patient cohorts, older patients suffering a cryptogenic stroke exhibit a much higher prevalence of patent foramen ovale (PFO) compared to their stroke of known origin counterparts. Several studies have provided promising preliminary data regarding PFO closure in older patients with cryptogenic stroke, with very low stroke recurrence rates at mid- to long-term follow-up. Several randomized trials have shown the beneficial effects of PFO closure vs. medical treatment in patients younger than 60 years with cryptogenic stroke and PFO. Current observational data suggest similar or even more marked effects on stroke recurrence prevention of PFO closure in older patients and would support the design of a randomized trial to provide definite evidence in this field. Therefore, the objective of the present study is to evaluate the efficacy of transcatheter PFO closure for preventing recurrent ischemic stroke (nonlacunar) events in patients >60 years diagnosed with a cryptogenic stroke and PFO.

Official Title
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Medical Treatment With or Without Transcatheter Patent Foramen Ovale CloSure for Older Patients With CrypTogenic StrOke and Patent Foramen Ovale. The STOP Trial

Conditions
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Patent Foramen Ovale, Cryptogenic Stroke, Older Patients, Medical Treatment, Recurrent Stroke

Intervention / Treatment
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* Procedure: Transcatheter PFO closure
* Drug: Optimal medical treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cryptogenic stroke Age >60 years Right-to-left shunt as evaluated by echocardiography (TEE). Exclusion Criteria: -≤60 year-old Lacunar (small vessel) stroke. Permanent or paroxysmal atrial fibrillation/flutter (clinically apparent or detected by continuous ECG monitoring). Need for chronic anticoagulation therapy. Any contraindication for antiplatelet therapy (aspirin, clopidogrel, ticagrelor). Presence of extracranial or intracranial atherosclerosis causing ≥50% luminal --stenosis in arteries supplying the area of ischemia. Presence of complex atheroma plaques at the ascending aorta-aortic arch (≥4-mm-thick, ulcerated or containing mobile thrombi) as evaluated by TEE. Presence of intracardiac thrombus as evaluated by TEE. Uncontrolled hypertension (systemic pressure values >160/90 mmHg despite optimal medical treatment). History of myocardial infarction or coronary intervention. (percutaneous coronary intervention, coronary artery bypass graft). History of prior valve surgery or transcatheter valve repair. Presence of deep venous thrombosis at the time of index stroke as evaluated by Doppler ultrasonography. Left ventricular ejection fraction <50% as evaluated by TTE. Significant (moderate or severe) valvular disease as evaluated by echocardiography. History of congestive heart failure. Severe chronic kidney dysfunction defined an estimated glomerular filtration rate <30 ml/min/m2 or need for dialysis. Isolated ASD or ASD associated with PFO but with a hemodynamically significant left-to-right shunt requiring closure. Other specific cause of stroke identified (eg, arteritis, dissection, migraine/vasospasm, and drug abuse). Prior surgical or endovascular treatments of PFO or ASD. Rheumatic heart disease. Left atrial enlargement defined as a left atrial diameter >41 mm in men and ≥39 mm in women. Presence of high burden of premature atrial contractions (>500 per 24 hrs) as evaluated by continuous ECG monitoring. Follow-up impossible or expected poor compliance. Active cancer. Presence of an inferior vena cava filter. Severe pulmonary artery hypertension (systolic pulmonary pressure >60 mmHg). Functional dependency as measured by a modified Rankin Scale score >3 (unable to attend to own bodily needs without assistance and unable to walk unassisted). Any medical condition determining a life expectancy <2 years. Participation in another randomized study. Failure to provide signed informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial comparing transcatheter PFO closure + medical treatment vs. medical treatment alone.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: transcatheter PFO closure + optimal medical treatment<br>Patients will undergoes transcatheter PFO closure (+ optimal medical treatment). Patients will receive antithrombotic agents (single antiplatelet treatment ), and modifiable vascular risk factors (dyslipidemia, hypertension, diabetes) according to stroke prevention guidelines. The type of antithrombotic therapy will be left to the discretion of the physician responsible for the patient. | Procedure: Transcatheter PFO closure<br>* Transcatheter PFO closure procedure will be performed according to the standards and experience of each participating center. Any approved PFO occluder device will be allowed in the study. Patients will also receive antithrombotic agents (single antiplatelet treatment ), and modifiable vascular risk factors (dyslipidemia, hypertension, diabetes) according to stroke prevention guidelines. The type of antithrombotic therapy will be left to the discretion of the physician responsible for the patient.<br>Drug: Optimal medical treatment<br>* Patients will receive antithrombotic agents (single antiplatelet treatment ), and modifiable vascular risk factors (dyslipidemia, hypertension, diabetes) according to stroke prevention guidelines. The type of antithrombotic therapy will be left to the discretion of the physician responsible for the patient.<br>|
| Experimental: Optimal medical treatment<br>Patients will receive antithrombotic agents (single antiplatelet treatment ), and modifiable vascular risk factors (dyslipidemia, hypertension, diabetes) according to stroke prevention guidelines. The type of antithrombotic therapy will be left to the discretion of the physician responsible for the patient. | Drug: Optimal medical treatment<br>* Patients will receive antithrombotic agents (single antiplatelet treatment ), and modifiable vascular risk factors (dyslipidemia, hypertension, diabetes) according to stroke prevention guidelines. The type of antithrombotic therapy will be left to the discretion of the physician responsible for the patient.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of ischemic events | New ischemic non-lacunar stroke events | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of stroke events | All new non-lacunar stroke events | 12 months | 
| Rate of mortality | All cause mortality | 10 year follow-up | 
| Rate of cardiovascular mortality | Cardiovascular death | 10 year follow-up | 
| Incidence of cerebral hemorrhage | Cerebral bleeding | 10 year follow-up | 
| Rate of new-onset atrial fibrillation | All new onset atrial fibrillation episodes | 10 year follow-up | 
| Rate of bleeding | Major/life-threatening bleeding | 10 year follow-up | 
| Health-related quality of life | Evaluated by the EQ-5D-5L questionnaire | 10 year follow-up | 
| Neurocognitive assessment | Evaluated by the MoCA questionnaire | 10 year follow-up |