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

Abstract

IMPORTANCE Patent foramen ovale (PFO) closure may prevent recurrent stroke after cryptogenic transient ischemic attack (TIA) or stroke (TIA/stroke) in patients aged 60 years or younger. Patent foramen ovale is associated with cryptogenic stroke in the older population, but risk of recurrence is unknown. Data on prognosis of patients receiving medical treatment at older ages (Ն60 years) are essential to justify trials of PFO closure. OBJECTIVE To examine the age-specific risk of recurrence in patients with cryptogenic TIA/stroke with PFO. DESIGN, SETTING, AND PARTICIPANTS A prospective study was nested in the population-based Oxford Vascular Study between September 1, 2014, and March 31, 2019, with face-to-face follow-up for 5 years. A total of 416 consecutive patients with a diagnosis of cryptogenic TIA or nondisabling stroke, screened for PFO at a rapid-access TIA/stroke clinic, were included. A systematic review and meta-analysis of cohort studies reporting on ischemic stroke recurrence after cryptogenic TIA/stroke in patients with PFO who were receiving medical therapy alone, or with PFO vs no-PFO was conducted. Sample size calculation for future trials on PFO closure was performed for patients aged 60 years or older. EXPOSURES Patent foramen ovale and age as modifiers of risk of recurrent stroke after cryptogenic TIA/stroke in patients receiving only medical therapy. MAIN OUTCOMES AND MEASURES Risk of ischemic stroke recurrence in patients with cryptogenic TIA/stroke and PFO receiving medical therapy only, and in patients with vs without PFO, stratified by age (<65 vs Ն65 years), as well as sample-size calculation for future trials of PFO closure in patients aged 60 years or older. RESULTS Among the 153 Oxford Vascular Study patients with PFO (mean [SD] age, 66.7 [13.7] years; 80 [52.3%] men), recurrent ischemic stroke risk (2.05 per 100 patient-years) was similar to the pooled estimate from a systematic review of 23 other studies (9 trials and 14 observational studies) (2.00 per 100 patient-years; 95% CI, 1.55-2.58). However, there was heterogeneity between studies (P < .001 for heterogeneity), owing mainly to risk increasing with mean cohort age (meta-regression: R 2 = 0.31; P = .003). In the pooled analysis of 4 studies including patients with or without PFO, increased risk of stroke recurrence with PFO was seen only at age 65 years or older (odds ratio, 2.5; 95% CI, 1.4-4.2; P = .001 for difference; P = .39 for heterogeneity). The pooled ischemic stroke risk was 3.27 per 100 patient-years (95% CI, 2.59-4.13) in 4 cohorts with mean age 60 years or older. Assuming the more conservative 2.0 per 100 patient-years ischemic stroke risk in the PFO nonclosure arms of future trials in patients aged 60 years or older, projected sample sizes were 1080 per arm for 80% power to detect a 33% relative risk reduction. CONCLUSIONS AND RELEVANCE The findings of this study suggest that age is a determinant of risk of ischemic stroke after cryptogenic TIA/stroke in patients with PFO, such that trials of PFO closure at older ...

Non-stenotic Carotid Plaques in Embolic Stroke of Unknown Source

“…The ongoing Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA, NCT03192215) ( 101 ), Apixaban for Treatment of Embolic Stroke of Undetermined Source (ATTICUS, NCT02427126), and A Study on BMS-986177 (oral factor XIa inhibitor) for the Prevention of a Stroke in Patients Receiving Aspirin and Clopidogrel (AXIOMATIC-SSP, NCT03766581) trials will, hopefully, provide conclusive results to guide patient care. Likewise, in the Oxford Vascular Study, a large patent foramen ovale is present in 36% of patients with a cryptogenic stroke aged >60 years ( 119 ) and associated with a 2.5 times higher risk of recurrent ischemic stroke ( 120 ), thus suggesting it might be worth trialing PFO closure or anticoagulation in elderly patients with a large PFO. However, the causal relationship between the PFO and the recurrent stroke was not formally established and the prevalence of ipsilateral non-stenotic carotid plaque not reported.…”

Transesophageal echocardiogram in the evaluation of acute ischemic stroke of young adults

“…These associated findings are crucial in risk stratification of PFO in cryptogenic AIS and help in further secondary stroke prevention strategies. [ 38 47 48 ] Recent clinical trials reported that cryptogenic AIS patients with PFO along with structural abnormalities such as ASA are at higher risk of paradoxical emboli and might benefit from PFO closure resulting in lower recurrence rate. [ 39 ] Our study confirms that TEE was able to detect ASA associated with PFO in 2.3% of cases.…”

Heart–Brain Relationship in Stroke

“…However, this is in recognition that the annualized risk reduction is relatively low, at roughly 0.6%, but that the cumulative risk over time for a relatively young patient can be viewed as substantial. It has been pointed out that TIA and stroke can be seen in older subjects in association with TIA [ 63 , 64 ] and that the pathological mechanism might actually be enhanced in this older population, related to higher incidence of venous thrombosis with age, increased pulmonary pathology which could increase right-sided heart pressure and facilitate a right-to-left shunt as well the potential for an increase in PFO size with age [ 65 ]. These authors report on a pooled analysis of four studies of recurrent stroke, in subjects with and without PFO, and identified an enhanced risk of stroke recurrence with PFO only at age ≥65 years with an odds ratio of 2.5.…”