Dual‐center experiences with interventional closure of patent foramen ovale: A medium‐term follow‐up study comparing two patient groups aged under and over 60 years

Abstract Background Current guidelines recommend interventional closure of patent foramen ovale (PFO) in patients with cryptogenic ischemic stroke who are under 60 years of age. Hypothesis The hypothesis of this study was to compare follow‐up results of PFO closure in patients over 60 years of age to those of patients under 60 years of age in order to determine whether the procedure is safe and effective for both age groups. Methods We included 293 patients who had a cryptogenic ischemic stroke and a PFO confirmed by transesophageal echocardiography (TEE) and who were scheduled for percutaneous closure of the PFO between 2014 and 2019. The device implantation was completed in all patients using an Amplatzer™, Occlutec™, or Cardia Ultrasept PFO occluder. Results Follow‐up TEE examinations were performed at intervals of 1, 3, and 6 months after implantation. Patients were followed for a median of 3.6 ± 1.2 years. Recurrent ischemic stroke or transient ischemic attack, cardiac death, arrhythmias, and residual shunt were reported equally in both groups. Conclusions Interventional closure of PFO can be as safe and effective in patients over 60 years of age as it is in patients under 60 years of age regardless of the device used. In this older patient group, rigorous discussion and a case‐by‐case decision‐making process including cardiologists and neurologists is warranted to ensure optimal procedure selection.

However, the latest trials conducted with long-term follow-up of patients who received PFO closure successfully prove a significant reduction in the recurrence of cryptogenic stroke in patients under 60 years of age. 1112-14 Following these results, guidelines of the German Societies of Cardiology and Neurology strongly recommended interventional closure for these patients. Furthermore, additional studies report a strong association between the presence of a PFO and cryptogenic stroke. [15][16][17] Thus, paradoxical embolism through a PFO may be an important cause of otherwise unexplained ischemic cerebral events. 18,19 Current literature and studies covering the subject matter often fail to include elderly patients. 4,20,21 Theoretically, patients face increasingly competing sources for embolic stroke with increasing age such as rhythm disturbances like atrial fibrillation or severe cerebrovascular disease.
The role of PFO closure in preventing stroke recurrence in patients older than 60 years remains uncertain particularly after exclusion of these concurrent pathways. PFO is still a potential cause of cryptogenic stroke in both older and younger populations. 22 Thus, the present dual-center study was undertaken to retrospectively evaluate the medium-term clinical results after percutaneous closure using three well-established occlusion devices in older patients.

| Patient population
This study was approved by the local ethical committee. From 2014 to 2019, 293 consecutive patients with a PFO, at least one documented presumed paradoxical thromboembolic event and a scheduled percutaneous closure of the PFO defect were considered for this study. Patients were divided into two groups: patients under 60 years in age (Group A) and patients over 60 years in age (Group B) and signed informed consent forms. All data were analyzed retrospectively. An ischemic stroke was defined as an acute focal neurologic deficit, presumably due to ischemia, that either resulted in clinical symptoms lasting 24 hours or more or was associated with evidence of relevant infarction on magnetic resonance imaging (MRI) or, if MRI could not be performed, by computed tomography (CT) of the brain. All evidence was confirmed by a neurologist where the symptomatic patient first presented. In all cases, a PFO was identified by transesophageal echocardiography (TEE) and other thromboembolic risk factors were excluded, such as, (a) large vessel arteriopathy, (b) an intracardiac thrombus, masses and valve vegetations, (c) intrinsic small vessel disease, (d) cardiac arrhythmias (through 3-day electrocardiography), and (e) a hypercoagulable state (protein C and S, antithrombin III, antiphospholopid antibodies, and activated protein C resistance).
Post-intervention bleeding was defined as a decrease of hemoglobin count ≥2 g/dL.

| Echocardiography
TEE (iE33, Philips or E90, GE) was performed within 3 ± 2 weeks prior to device implantation (baseline) and at 3-months and 6-months follow-up. Atrial septal aneurysm (ASA) was diagnosed on the basis of a septum primum excursion greater than 10 mm as identified on transesophageal echocardiography. Shunts were defined by the appearance of microbubbles in the left atrium within three cardiac cycles after opacification of the right atrium at rest or during Valsalva maneuver. The degree of shunt was graded into three groups: 1-9 bubbles as ''small,'' up to 30 bubbles as ''moderate,'' and more than 30 bubbles as ''large''. The results of PFO closure were assessed with the use of contrast echocardiography. Furthermore, device position and absence of thrombotic formations were evaluated.

| Post-implantation treatment
After implantation, patients continued to receive 100 mg of aspirin and 75 mg of clopidogrel daily for 3 months, followed by aspirin monotherapy for up to 6 months. Before hospital discharge, a transthoracic echocardiography was performed to confirm correct device position. Prophylaxis of infectious endocarditis was performed for the first 6 months. Clinical follow-ups were performed after 3 and 6 months by TEE. Additionally, telephone contact based on a centrally recorded database was conducted on an annual basis. All verification of database recordings and interviews was performed by an experienced nurse or physician. During this interview, the patient or a family member was queried for the occurrence of cardiac events, such as, (a) cardiovascular death, defined as any death with a demonstrable cardiovascular cause or any death that was not clearly attributable to a non-cardiovascular cause or (b) hospitalization for recurrent neurological or peripheral thromboembolic events. If such an event was identified, the referring general practitioner was contacted for detailed information. No loss of follow-up occurred. The mean followup period was 3.6 ± 1.2 years, the median monitoring interval was 3.2 years.

| Statistics
Continuous data are expressed as mean values ± SD and compared using Student's t test or ANOVA as appropriate. Ordinal data were compared using the chi-square test. A p-value of <.05 was considered statistically significant. Analysis was conducted using SAS.  Table 1. The demographic and clinical characteristics of the two groups were generally well balanced (Table 1).

| Implantation procedure and complication
In the 293 study patients, device implantation failed in none (0) of the patients. Mean procedural time was 29 ± 6 minutes with a mean fluoroscopy time of 2 ± 1 minutes. The number of periprocedural complications was 8 (4%) in Group A and 5 (5%) in Group B with no significant differences between these groups (p = 0.772), see Table 2. One patient in Group A suffered from a severe air embolism, most likely due to a damaged delivery system, with need for hyperbaric oxygen therapy.

| Endpoints during follow-up period
Two patients in Group B were lost due to non-cardiac death (breast cancer, N = 1 and thrombotic thrombocytopenic purpura, N = 1).   Our study has a few limitations, specifically that it is a small nonrandomized observational study. Furthermore, follow-ups were performed by TEE examinations after 3 and 6 months and through telephone contact with the patient and the practitioner regarding cardiovascular or neurological events. However, there may be a recall bias and an opportunity to miss or to over-interpret clinical events.

| CONCLUSION
In cases of patent foramen ovale following cryptogenic ischemic stroke, patients over 60 years of age could also be considered suitable candidates to receive interventional closure of the PFO in order to substantially reduce the risk of a recurrent stroke, and age alone should not be considered a limiting factor. Based on the results of this study, interventional closure of patent foramen ovale could be as safe and effective in patients over 60 years of age as it is in patients under 60 years of age. In order to determine the best treatment options, the patient's cardiologist and neurologist are tasked with deciding on the optimal course of action based on the individual patient's medical history and current physical condition. Since it is linked to the increasing life expectancy and improved quality of life of the population, this topic will occupy us doctors more in the future. For this purpose, in order to make a strong definitive statement, we need multi-center randomized large studies.