In patients with cryptogenic stroke, up to 4 randomized trials and subsequent meta-analyses have recently shown a significant reduction in recurrent ischemic stroke events following percutaneous closure of patent foramen ovale (PFO).1–6 All randomized trials but one excluded patients older than 60 years, and a mean patient age of about 50 years was reported in the single randomized trial including older patients.3 Thus, whereas PFO closure has been established as the new gold-standard therapy in young patients with cryptogenic stroke and PFO, there are no definite recommendations on the management of patients older than 60 years.7–9 Some studies have shown that older patients with cryptogenic stroke exhibit a much higher prevalence of PFO (compared with patients with stroke of known cause), similar to that in younger populations,10,11 but scarce data exist on acute and mid-term clinical outcomes of older patients undergoing PFO closure.12–16 In addition, no studies to date have specifically focused on the long-term outcomes of patients older than 60 years.

The objective of our study was to evaluate long-term clinical outcomes following transcatheter PFO closure in older (> 60 years) patients with cryptogenic embolism.

A total of 475 consecutive patients who underwent PFO closure between 2001 and 2018 because of cryptogenic embolism (stroke, transient ischemic attack [TIA], peripheral embolism) were included. A presumptive diagnostic of paradoxical embolism was established by a neurologist after screening including brain magnetic resonance imaging and/or brain computed tomography, 24-hour Holter monitoring, transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), and transcarotid Doppler. The diagnosis of PFO was established on the basis of a right to left shunt during TEE examination with agitated saline contrast test with and without Valsalva maneuver. The shunt was classified as small, moderate or large, with or without atrial septal aneurysm.17

The type and size of the implanted device were left to the criteria of the physician performing the procedure. Postprocedural TTE was performed in all patients prior to hospital discharge, typically a few hours after the procedure to confirm device position, evaluate residual shunt, and exclude pericardial effusion. Medical therapy at discharge was (usually) aspirin (indefinitely), and clopidogrel was added in some patients (for 6 months) according to the preference of the physician performing the procedure. Anticoagulation was prescribed in the presence of other medical reasons requiring anticoagulation therapy (pulmonary embolism, deep venous thrombosis). At 1- to 6-months postprocedure, patients had a clinical visit and an echocardiographic (TTE and/or TEE) examination. All procedural and 1- to 6-month follow-up data were prospectively entered into a dedicated database.

Follow-up was ensured by the referral neurologist/cardiologist or the physician performing the PFO closure along with the family physician responsible for the patient, but there was no pre-established timing for the clinical visits during the follow-up period after the 1-year follow-up. The medical records of all patients were reviewed and data on all clinical events and current medications were collected. In addition, a systematic clinical visit or telephone call was conducted in all patients with no follow-up data. Each patient was asked about recurrences of stroke, TIA or peripheral embolism, new hospitalizations (and reason), bleeding, arrhythmias and cardiac events, migraine, and current medications. When an event was suspected on the basis of the questionnaire, the complete medical file of the center taking care of the patient was consulted. The patient's primary care physician and cardiologist/neurologist responsible for the patient were consulted if any further information was needed.

All neurological events (stroke, TIA) were diagnosed by a neurologist and defined according to TOAST criteria.18 All bleeding events were recorded and classified according to the BARC criteria.19

The main results of our study can be summarized as follows: a) older patients with cryptogenic embolism and PFO exhibited a higher burden of cardiovascular risk factors; b) PFO closure was safe in older patients, with no differences in periprocedural complications compared with younger patients; c) at long-term (median of 8 years) follow-up post-PFO closure, the global mortality rate was higher among older patients, but differences were driven by noncardiovascular mortality (mainly cancer), and d) the rate of recurrent stroke/TIA was low (much lower than that predicted by the RoPE score), but there was a tendency toward a higher incidence of recurrent stroke/TIA among older patients, which appeared to be partially related to cardiovascular risk factor burden (no differences in recurrent ischemic event rate were observed after adjustment for baseline differences in cardiovascular risk factors between groups).

Several studies have shown that transcatheter PFO closure is a safe procedure in young (< 60 years) patients. However, scarce and controversial data exist on periprocedural complications in older patients. Merkler et al.21 showed a higher risk of in-hospital complications among older patients undergoing PFO closure, with a periprocedural complication rate double that observed in patients aged <60 years. In contrast, similar to the results of our study, Wahl et al.15 showed the absence of an increased periprocedural risk in older patients undergoing PFO closure. These data are reassuring and important, particularly considering the lack of randomized data and specific guideline recommendations on PFO closure in older patients.7,8

Our study is the first to provide long-term data following PFO closure in patients older than 60 years. A mean difference in age of approximately 20 years was observed between younger (< 60 years) and older patients and, not surprisingly, the long-term mortality rate among older patients was much higher than that observed in the younger population. Of note, all deaths following PFO closure were of noncardiovascular origin (with cancer as the most frequent cause of death), and the death rate observed in older patients was similar to that reported by the Institut de la Statistique du Québec for the Quebec Canadian population of the same age and sex (6.6% probability of death in the 5 years following the 65th birthday in men and 4.4% for women).22 Thus, the mortality difference observed between younger and older patients in this study seems to be driven by the higher risk of dying in older people.

The rate of recurrent thromboembolic events at long-term follow-up post-PFO closure in older patients was low, with only 2 strokes and 3 TIA episodes occurring during the follow-up period. This represents a rate of 0.3 strokes per 100 person-years and 0.8 stroke/TIA per 100 person-years, which is much lower than the incidence estimated by the RoPE score, suggesting that the beneficial effects of PFO closure may extend beyond the limit of 60 years. Previous studies have shown a low incidence of ischemic events at 1 to 3 years following PFO closure in older patients13–15 and the results of our study extend these positive findings to the long-term (> 5 years) follow-up of these patients. However, we observed a tendency toward a higher incidence of cerebrovascular events (stroke/TIA) in older (vs younger) patients. The fact that this tendency disappeared after adjustment for cardiovascular risk factors suggests a potential role of atherosclerotic burden in some of the ischemic events observed in older patients.

It is well-known that the prevalence of cardiovascular risk factors (particularly hypertension and diabetes) steadily increases with age, and the prevalence observed in our population of older patients is similar to that reported in the Canadian population of the same age range.23 However, the prevalence of risk factors such as dyslipidemia (35.6%), hypertension (48.9%) or diabetes (10%) was much higher than that observed in younger patients. In addition, Alsheikh-Ali et al.24 reported that in patients with cryptogenic stroke, 20% (16% to 25%) and 48% (34% to 66%) of PFOs are likely to be incidental in younger and older patients, respectively. Interestingly, these rates decrease to 9% (4% to 18%) in younger patients and to 26% (12% to 56%) in older patients when a concomitant atrial septal aneurysm is detected. This highlights the need for careful patient evaluation by an interdisciplinary team including neurologists, cardiologists, and the patient's own point of view, as described in recent guidelines.7,8 In addition, a higher incidence of AF episodes was observed among older patients in the years following PFO closure, further stressing the importance of AF screening in these patients before PFO closure. Moreover, these data raise the question about the use of longer term cardiac monitoring or even consideration of insertable cardiac monitors in some of these patients.25

The limitations of this study include those inherent to retrospective studies. Although the number of patients lost to follow-up was very low (particularly considering the long-term follow-up), we cannot completely exclude the possibility of missing some adverse events. However, this would be highly unlikely with regard to major events and those requiring rehospitalization. Also, medical records were reviewed to obtain data on patient hospitalizations over time. Finally, the referral cardiologist/neurologist, family physicians and pharmacists were also contacted if there were doubts regarding events and/or medication. The echo data were site reported and not analyzed in a central echocardiographic laboratory.

This study shows that PFO closure in patients older than 60 years is safe and associated with a low event rate at long-term follow-up. These results emphasize the need for the design of future randomized trials involving older patients with PFO and cryptogenic embolism. Meanwhile, this study suggests that PFO closure may be considered in older patients with cryptogenic embolism. However, the presence and number of cardiovascular risk factors favoring the atherothrombotic origin of cerebrovascular events should be taken into account in the clinical decision-making process in such patients. In addition, careful screening for arrhythmic events (particularly FA) should be undertaken in the workup before PFO closure.

J. Rodés-Cabau holds the Research Chair Fondation Famille Jacques Larivière for the Development of Structural Heart Disease Interventions. J. Wintzer-Wehekind was supported by a grant from the Association de Recherche Cardio-vasculaire des Alpes”. A. Alperi and D. del Val were supported by a grant from the Fundación Alfonso Martín Escudero, Madrid, Spain.

None declared.