Patent foramen ovale in patients ≥60 with cryptogenic stroke—not a bystander: why diagnosis and closure matter?

Stroke is the leading cause of death and disability, accounting for one in six cardiovascular-related deaths globally in 2021. In the USA, a stroke occurs every 40 s, and every 3 min and 14 s, a stroke leads to death.1 Approximately one-third of ischaemic strokes are cryptogenic, indicating an unknown cause.2 According to the TOAST criteria, cryptogenic stroke (or stroke of undetermined aetiology) refers to brain infarction that cannot be attributed to a clear cause, such as cardioembolism, large artery atherosclerosis, or small artery disease, despite thorough vascular, cardiac, and serologic workups.2 Embolic stroke of undetermined source (ESUS) accounts for about half of cryptogenic strokes and is defined as a stroke with an unclear aetiology despite recommended diagnostic evaluations. While both terms indicate an unknown cause, cryptogenic stroke may not necessarily be embolic and can result from incomplete or inconclusive diagnostics.2 Among these cryptogenic strokes, a significant portion is suspected to stem from paradoxical embolism attributed to a patent foramen ovale (PFO).2 Patent foramen ovale is a congenital heart defect present in ∼30% of adults and 40% of cryptogenic stroke patients that can facilitate the passage of an embolus from the right to the left side of the heart, reaching the cerebral circulation and potentially causing an embolic stroke.2 In patients over 55, the prevalence of PFO is significantly higher in those with cryptogenic strokes (28.3%) compared with those with a known cause (11.9%), with moderate to large PFOs found in up to 35% of patients aged ≥65.3 Additionally, patients over 60 experience a higher recurrence rate of cryptogenic strokes following an initial PFO-related event (12.5%) compared with younger patients (5.6%). These findings emphasize the importance of preventive strategies, such as PFO closure, in older patients at higher risk of recurrence. This article examines the reasons for considering PFO closure in patients aged 60 and older with cryptogenic stroke. Research shows that percutaneous PFO closure (PPFOC) significantly reduces clinical events, leading to its recommendation in current guidelines. For younger patients aged 18–60 with a history of non-lacunar ESUS and high-risk PFO features, PFO closure with a transcatheter device and long-term antiplatelet therapy is preferred over antithrombotic therapy alone.4 Supporting evidence from six randomized controlled trials (RCTs), including the CLOSE and Gore REDUCE trials, confirms this approach.4 However, determining the appropriate candidates for PFO closure still remains ambiguous. Despite promising outcomes in younger patients, there is insufficient evidence to ascertain whether device closure effectively prevents recurrent ischaemic strokes in patients > 60 years with PFO and cryptogenic stroke. This uncertainty stems from the current lack of high-quality evidence, which limits the endorsement of device closure to individuals under 60.4 Moreover, most RCTs have exclusively enrolled patients aged <60 years, resulting in a limited presence of older participants > 60 years in these studies. One of the latest cohort studies examining PFO closure in patients with cryptogenic stroke or transient ischemic attack (TIA) found that patients > 60 years (45.1%) who underwent PFO closure had a reduced risk of recurrent ischaemic events, lower all-cause mortality, and better functional outcomes at 180 days, as indicated by a lower Modified Ranking Scale score (0–2), compared with those without PFO closure.5 Further supporting these findings, another cohort study on PPFOC in cryptogenic stroke patients over 60 years demonstrated a significant reduction in the risk of ischaemic stroke or TIA (Hazard ratio [HR]: 0.40; P = 0.006) in high-risk PFO patients after a median follow-up of 3.9 years.6 Combining results from available observational studies, the number needed to treat for PFO closure to prevent one recurrent stroke or TIA is ∼21 for patients over 60, compared with 69 for those aged 18–60.7–10 This means that for every 21 patients over 60 treated, one recurrent stroke or TIA is prevented, whereas in the younger population (18–60), 69 patients need to be treated to prevent one event. These findings provide further evidence supporting the hypothesis that PFO closure may offer greater benefit to older patients with cryptogenic stroke. However, the observational nature of these studies and lack of randomization may introduce selection bias, so these findings should be considered exploratory and hypothesis generating. Table 1 summarizes key observational studies comparing PFO closure outcomes in patients over 60 (older) vs. those under 60 (younger). Comparison of patent foramen ovale closure outcomes in patients aged ≥60 vs. <60 years AF, atrial fibrillation; mRS, Modified Ranking Scale; PFO, patent foramen ovale; TIA, transient ischemic attack. Despite promising results from observational studies, RCT evidence supporting PFO closure in patients over 60 is limited. In the DEFENSE-PFO trial, only a small proportion of patients over 60 were included, and subgroup analysis showed that PFO closure was more effective in preventing recurrent ischaemic stroke or TIA in patients aged ≥60 (34 patients) compared with those aged <60 (86 patients).11 Currently, the only ongoing trial exclusively including patients over 60 is the CLOSE-2 trial (NCT05387954), which focuses on patients with a large PFO shunt (>20 microbubbles) or atrial septal aneurysm (ASA > 10 mm) and unexplained ischaemic stroke. It is expected to be completed in 2030.12 Another challenge is determining appropriate candidates for PFO closure in patients over 60, as the risk of paradoxical embolism (RoPE) score, which is useful for those aged 18–60, tends to be lower in older patients.2 With increasing age, the RoPE score becomes less reliable due to a higher prevalence of vascular risk factors that can independently contribute to stroke, limiting its accuracy in older cohorts. In this group, morphologic features such as a large PFO (septum primum–septum secundum separation > 2–3 mm), long tunnel (>10 mm), ASA, significant shunt size, and a prominent Eustachian valve are more reliable indicators of stroke risk. Observational studies suggest that these high-risk anatomical features, more common in older patients, may offer greater benefit from PFO closure.2 This calls for further research to better guide treatment decisions for patients over 60. Given the aging population and the growing recognition of PFO as a potential cause of cryptogenic stroke in older adults, there is a clear need for practice recommendations tailored to patients > 60. Older patients often have comorbidities such as atrial fibrillation (AF), carotid artery disease, and valvular heart disease, complicating diagnosis and treatment. Some studies suggest nearly double the procedural complication risk in those over 60 undergoing PFO closure, but due to the observational nature of these studies, further RCTs are needed to assess the risks and benefits. Future recommendations should consider frailty, comorbidities, life expectancy, bleeding risk, and functional status to guide PFO closure decisions. Involving neurocardiology teams in evaluation may improve decision-making through a comprehensive assessment of cerebrovascular and cardiological factors. RCTs specifically including patients over 60 are essential to assess the safety and long-term efficacy of PFO closure, focusing on outcomes like recurrent ischaemic strokes, new-onset AF, all-cause mortality, functional recovery, and quality of life, ultimately refining treatment guidelines for older patients. J.L.D.: Conceptualization, writing—original draft, and writing—review and editing. S.A.S.: Conceptualization and design, statistical analysis, writing—original draft, and writing—review and editing. H.P.: Writing—review and editing. J.T.M.: Writing—review and editing. V.R.D.: Writing—review and editing. All gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors confirm that the data supporting the findings of this study are available within the manuscript.