Prognosis of Cryptogenic Stroke With Patent Foramen Ovale at Older Ages and Implications for Trials

Key Points Question Is the prognosis of cryptogenic transient ischemic attack and stroke in patients receiving medical treatment alone associated with the presence of patent foramen ovale and age? Findings In this population-based study, risk of recurrent ischemic stroke (2.05 per 100 patient-years) was consistent with the pooled estimate from a systematic review and meta-analysis (2 per 100 patient-years). Risk increased with mean cohort age, and only in patients with cryptogenic transient ischemic attack and stroke aged 65 years or older was patent foramen ovale vs no patent foramen ovale associated with a higher risk of recurrent ischemic stroke. Meaning The findings of this study suggest that a higher risk of stroke recurrence at older ages in patients with patent foramen ovale warrants trials of patent foramen ovale closure in older patients.


A daily (weekdays only)
, urgent open-access "TIA clinic" to which participating general practitioners (GPs) and the local accident and emergency department (A&E) send all individuals with suspected TIA or stroke whom they would not normally admit to hospital, with alternative on-call review provision at weekends. Patients too frail to attend are assessed at their residence by a study nurse or doctor. 2. Daily searches and case note review of admissions to the Emergency Assessment Unit, Medical Short Stay Unit, Coronary Care Unit and Cardiothoracic Critical Care Unit, Cardiology, Cardiothoracic, and Vascular Surgery wards, Acute Stroke Unit, Neurology ward and all other general wards when indicated. 3. Daily searches of the local A&E and eye hospital attendance registers. 4. Daily identification via the Bereavement Office of patients dead on arrival at hospital or who died soon after. 5. Daily searches of lists of all patients from the study population in whom a troponin-I level had been requested. 6. Daily assessment of all patients undergoing diagnostic coronary, carotid and peripheral angiography, angioplasty, stenting or vascular surgical procedures in any territory to identify both total burden of vascular invention and any potential missed prior acute events.
Cold pursuit procedures were: 1. Frequent visits to the study practices and monthly searches of practice diagnostic codes. 2. Monthly practice-specific list of all patients admitted to all acute and community NHS hospitals. 3. Monthly listings of all referrals for brain or carotid imaging studies performed in local hospitals. 4. Monthly reviews of all death certificates and coroners reports to review out-of-hospital deaths. 5. Practice-specific listings of all ICD-10 death codes from the local Department of Public Health.
Patients found on GP practice searches who have an event whilst temporarily out of Oxfordshire are included, but visitors who were not registered with one of the study practices are excluded. A study clinician assessed patients as soon as possible after the event in the hospital or at home. Informed consent was sought, if possible, or assent was obtained from a relative.
Data are collected using event-specific forms, for TIA and stroke, acute coronary syndrome or acute peripheral vascular events. Standardised clinical history and cardiovascular examination are recorded. Information recorded from the patient, their hospital records and their general practice records includes details of the clinical event, medication, past medical history, all investigations relevant to their admission (including blood results, electrocardiography, brain imaging and vascular imaging-duplex ultrasonography, CT-angiography, MRangiography or DSA) and all interventions occurring subsequent to the event.
If a patient died before assessment, we obtained an eyewitness account of the clinical event and reviewed any relevant records. If death occurred outside the hospital or before investigation, the autopsy result was reviewed. Clinical details are sought from primary care physicians or other clinicians on all deaths of possible vascular aetiology.
All surviving TIA and stroke patients are followed-up face-to-face at 1, 6, 12, 60 and 120 months after the initial event by a research nurse or physician and all recurrent vascular events were recorded together with the relevant clinical details and investigations. If face-to-face follow up is not possible, telephone follow-up is performed or enabled via the general practitioner. All recurrent vascular events that presented to medical attention would also be identified acutely by ongoing daily case ascertainment within OXVASC. If a recurrent vascular event was suspected at a follow-up visit or referred by the GPs to clinic or admitted, the patient was re-assessed and investigated by a study physician.

Definitions of events
Although new definitions for stroke and TIA have been suggested recently, 4,5 in order to enable comparison with previous studies, the classic definitions of TIA and stroke are used throughout. 6 A stroke is defined as rapidly developing clinical symptoms and/or signs of focal, and at time global (applied to patients in deep coma and to those with subarachnoid haemorrhage), loss of brain function, with symptoms lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin. 6 A TIA is an acute loss of focal brain or monocular function with symptoms lasting less than 24 hours and which is thought to be caused by inadequate cerebral or ocular blood supply as a result of arterial thrombosis, low flow or embolism associated with arterial, cardiac or haematological disease. 4 All diagnoses were reviewed by a senior neurologist (PMR). With the high rate (97%) of imaging or autopsy in OXVASC, strokes of unknown type were coded as ischaemic.

eResults: Characteristics of studies included in the Systematic Review
Of 577 potentially eligible records found by the systematic review, we identified 28 eligible papers reporting on 23 studies (nine trials and 14 observational studies) including 4889 patients with cryptogenic stroke/TIA and PFO on medical treatment alone (PRISMA Flow Chart, Figure I in the Supplement). Non-eligible studies included: observational studies S8-S13 and one randomised trial (47 patients with cryptogenic stroke/TIA randomised to either warfarin or aspirin) S14 with a population below the threshold for inclusion (<100 cryptogenic stroke/TIA patients enrolled); observational studies on an unsuitable population (mostly retrospective studies selecting patients on the basis of echocardiographic finding of a PFO, where the analysis included non-stroke patients as well, or stroke/TIA patients with both cryptogenic and non-cryptogenic stroke/TIA); S15-S23 secondary publications of an included study; S24,S25 and one paper that reported only composite outcomes of stroke/TIA and peripheral embolism. S26 We contacted eight authors and obtained unpublished data from four. S6,S27-S30 In the studies reporting data for the population with PFO (