Standard therapy for cryptogenic stroke in the setting of patent foramen ovale (PFO) includes antiplatelet medications and long-term anticoagulation with warfarin. Oral anticoagulation increases the risk of bleeding complications and may not prevent recurrent ischemic neurological events.1 Therapy for recurrent cryptogenic stroke with PFO includes surgical closure or percutaneous transcatheter closure of the PFO. Surgical closure is associated with significant morbidity with no proven benefits.2 Since the first report of percutaneous PFO closure,3 advances in device design have led to facilitated delivery and improved PFO occlusion rates. Recent studies report success rates of deployment with complete closure, as assessed by transesophageal echocardiography (TEE), of more than 90% six months after device implantation.4–17 Most reports of transcatheter PFO closure have been from Europe4,6,8,9,12–17 or from United States centers involved in pre-FDA approval trials of PFO closure devices.5,10,11 Reports from the United States since FDA approval have involved large, high-volume interventional centers.7,18 Under current practice guidelines and indications, transcatheter PFO closure is offered to few PFO patients with cryptogenic stroke. It is unclear whether safe and effective PFO closure can be performed with relative rarity at interventional centers that do not do high procedure volumes. We assessed the safety and efficacy of transcatheter PFO closures performed with low frequency at a rural, moderate-volume interventional institution. Methods Program development. Procedures were performed at a moderate-volume interventional cardiology center (1,000 coronary angioplasties/year) located in rural central Pennsylvania. The first 8 procedures were performed by an experienced moderate-volume interventionist (200 interventions/year). Pre-initiation training included didactic conferences, review of instructional CDs, participation in 2 cases with an expert operator at an outside institution, and proctoring during the first several cases by clinical specialists from the company supplying the devices. A second experienced moderate-volume interventionist (200 interventions/year) assisted with these procedures and performed the subsequent 44 procedures after the first interventionist left the institution. All procedures were performed with the assistance of an interventional cardiology fellow, and often an additional interventionist helped. Patient selection. In June 2001, percutaneous closure of PFO was first performed, and by December 2004, 52 patients had undergone the procedure. All were included in this study. Data were obtained and recorded prospectively. Approval was given by the local institutional review board. Informed, written consent was obtained from all patients contacted for follow up. All patients undergoing PFO closure were referred either by primary care physicians or by neurologists after TEE showed a PFO. Patients referred by primary care physicians without imaging evidence of stroke were seen by a neurologist. These patients were further considered for PFO closure only if the procedure was unequivocally recommended by the neurologist. Patients without magnetic resonance imaging evidence of stroke or definite diagnosis by a neurologist of stroke or transient ischemic attack were excluded from further consideration for PFO closure. All patients underwent evaluation for sources of cerebral embolization including carotid duplex studies, brain computed tomography, brain magnetic resonance imaging and angiography, telemetry or Holter monitoring, lower extremity venous duplex studies and evaluation for coagulation disorders. Patients with obvious sources of embolic stroke (e.g., atrial fibrillation, severe carotid stenosis) were excluded from further consideration for PFO closure. All patients were advised of the experimental nature of transcatheter PFO closure, current Food and Drug Administration recommendations regarding transcatheter PFO closure, and standard medical and surgical alternatives. All patients were offered an option of medical therapy with reevaluation after the results of clinical trials were available. Patients with questionable indications and older individuals were advised to continue with conservative medical therapy. All patients undergoing PFO closure unequivocally requested the procedure on at least two different occasions. Implantation procedure. PFO closure was performed with three types of devices: CardioSEAL® (NMT Medical, Boston, Massachusetts), Amplatzer® PFO Occluder (AGA Medical, Minneapolis, Minnesota), or Cardia Star™ (Cardia, Inc., Burnsville, Minnesota). The CardioSEAL was used in patients #1–22. When the Amplatzer became available, its simpler implantation technique and smaller delivery sheath size led to its adoption for patients #23–52 except for patients #41, #44, and #47, who received the Cardia Star device under an experimental protocol. TEE, under general anesthesia, was utilized as an adjunctive imaging modality in the first 25 patients. Two patients underwent closure with both TEE and by intracardiac echocardiography (ICE) guidance, then all subsequent patients underwent closure with ICE guidance only. ICE was adopted as the preferred imaging modality in our center, as in most centers performing PFO closure, to avoid the cost and complexity of coordinating anesthesiologists, anesthetists, and TEE operators in the catheterization laboratory. A sizing balloon was inflated across the defect. Stretched-balloon diameter in the defect was assessed by TEE or ICE and by fluoroscopic quantitative analysis of the inflated sizing balloon. All patients received intravenous heparin to achieve activated clotting times of 200–250 seconds. Intravenous antibiotics (cephalosporin or vancomycin) were given during the procedure. Patients were routinely discharged on the day after the procedure. Postprocedure medications included aspirin (in all patients), warfarin anticoagulation for 6 months or longer at the recommendation of a neurologist (n = 32 patients) and clopidogrel for 1–6 months (n = 20 patients). Follow-up protocol. On the morning after the procedure, electrocardiography, chest radiograph and transthoracic echocardiography (TTE) with bubble injection and Doppler evaluation were performed. At discharge, patients were educated about late complications and instructed to call the interventionist if any occurred. Transthoracic echocardiography was performed at 1 month and 6 months, with a clinical evaluation at 6 months. All patients with suspected recurrent neurologic events were evaluated by a neurologist with additional imaging as needed. Statistical methods. Demographic and procedural parameters are reported with descriptive statistics. Continuous variables were expressed as mean ± standard deviation (SD). Results Patient demographics. From June 2001 to December 2004, 140 persons with PFO documented by transesophageal echocardiography were screened for possible PFO closure and 52 of these underwent percutaneous PFO closure at our institution. Patient demographics are summarized in Table 1. Prior neurologic events included transient ischemic attack in 25 patients (47%) and stroke in 27 patients (53%). Mild or moderate aortic atherosclerosis was present in 28 patients (54%). Hypercoagulability disorders included methyl tetrahydrofolate reductase mutation in 27 (52%), all with normal homocysteine, low protein S in 2 (4%) and anticardiolipin antibodies in 6 (12%). Baseline TEE showed moderate, small and no right-to-left shunts in 30 (59%), 20 (38%) and 2 (3%) of patients, respectively. An atrial septal aneurysm was present in 17 (33%) patients. Mean PFO tunnel length measured by TEE was 18 ± 5 mm. Balloon-stretched PFO size ranged from 6–25 mm. Twenty-two patients (42%) had migraine headache and 12 (24%) of these had aura. Procedural results. The occluder devices including CardioSEAL (n = 28, 54%), Amplatzer (n = 21, 41%) and Cardia Star (n = 3, 5%) were implanted successfully in all 52 patients. Diameter of devices ranged from 16–40 mm. In all patients with atrial septal aneurysms, the device partially covered the hyper-mobile portions of the septum and greatly reduced their mobility. All patients were discharged on the day after the procedure. Discharge medical regimen included aspirin + clopidogrel (10, 19%), aspirin + warfarin (32, 63%), aspirin + clopidogrel + warfarin (7, 13%), or clopidogrel + warfarin (3, 5%). Complications. There were no immediate major complications during the procedure. Two patients suffered pharyngeal laceration during TEE and were sutured without serious sequelae. Two patients had retroperitoneal bleeding treated with transfusion and fluids. Two additional patients had minor hematomas not requiring transfusion or prolonged hospital stay. Transient arrhythmias were seen in 3 patients (1 paroxysmal atrial fibrillation, 1 nonsustained ventricular tachycardia, 1 bradycardia). Ten (19%) patients had trivial/small residual shunt on echocardiography with bubble injection on the day after the procedure. Follow up. All patients returned for clinical follow up. Follow-up data were collected from hospital records (n = 52) and telephone interviews (n = 50). There were no incidents of cardiac perforation, device embolization or malposition, thrombus formation, significant arrhythmia, infective endocarditis or other comorbidity during follow up (28 ± 12 months, range [3,46]). Four patients (7%) reported spells of uncertain etiology, but neurologic evaluation excluded neurologic events in all of them. One patient had one episode of atrial fibrillation. There were no transient ischemic attacks or strokes. One patient died of renal failure and sepsis unrelated to PFO closure. Echocardiography at 6 months was performed in 51 patients (98%). Four patients (8%) had trivial/small residual shunt on echocardiography with bubble injection. In all cases, the PFO device was correctly positioned and the septum was thickened by the device and overgrowing epithelial tissue. In all patients who had atrial septal aneurysms preclosure, the septum postclosure was immobile. Of the 22 patients with migraine, 8 (36%) had complete relief of migraine and 8 (36%) had partial relief. There was a cumulative reduction in the frequency of migraine attacks from 3.06 episodes/patient/month to 0.05 episodes/patient/month. Outcomes and complications in early versus late patients. There was no evidence of a learning curve that affected complications or outcomes. All procedures were technically successful. Complications were related to imaging techniques (TEE or ICE), not to order in the sequence of patients. (Two pharyngeal lacerations were caused by TEE used in patients #1–25. Both retroperitoneal bleeds were at the access site for the 10 Fr ICE imaging catheter, which was used for patients #26–52.) Echocardiographic assessment at 6 months revealed an incidence of residual leak of 8% in the first 26 patients, and 8% in the last 26 patients. Discussion The results of this study suggest that PFO closure can be performed infrequently at a moderate-volume interventional center with high success rates. Complications that did occur were mostly related to TEE (now no longer used), or venous access. They did not delay discharge and were similar in frequency to those reported by other investigators.7,9,11 Most reports of transcatheter PFO closure have been from Europe4,6,8,9,12–17 or from United States centers involved in pre-FDA-approval trials of PFO closure devices.5,10,11 Reports from the United States since FDA approval have been from large, high-volume interventional centers.7,18 Under current practice guidelines and indications, transcatheter PFO closure in the United States is offered to a few patients. In the United States, the FDA indication is for cryptogenic stroke occurring despite adequate anticoagulation following a first cryptogenic stroke. The FDA has granted Investigational Device Exemption to only two companies, and each is allowed only 4,000 devices per year for implantation. Thus, with over a million coronary interventions per year performed in the United States, transcatheter PFO closure constitutes less than 1% of cardiac interventions. At institutions offering transcatheter PFO closure, it is generally a low-volume procedure. The number of PFO closure procedures may decline in 2007 as device manufacturers limit their use to patients enrolled in registries with strict entry criteria. In an era where high volume is equated with high quality,19,20 it is unclear whether procedures can be performed safely and effectively in low volumes. For coronary artery interventions, there are abundant data21-28 that operator and institutional volumes correlate with quality of outcomes. However, other studies have found no correlation between volumes and outcomes.29-32 Lack of correlation may be due to wider confidence limits in outcome data for low-volume operators,33 selection of low-risk cases by low-volume operators,34 oversight of low-volume operators by high-volume operators,30 institutional systems that keep low-volume operators “out of trouble,”35 operator expertise in routine interventions that carries over into low-volume procedures,37 or true absence of a volume-outcome correlation. In the case of PFO closure, most institutions perform 2 to 4 procedures monthly (Table 2). PFO closure at our institution is performed less frequently, about once per month, but with the same excellent outcomes as those achieved by high-volume centers. The excellent outcomes, despite low volume at our institution, may reflect the simplicity of the procedure, experience of the interventionist with other percutaneous cardiac procedures, good fortune, or a combination of these. In any case, our results demonstrate that an experienced operator can obtain good results performing PFO closure infrequently. Study limitations. There are several limitations to this study. The patient population is a selected cohort referred to our center for percutaneous PFO closure and may differ from other published series. Patients who were asymptomatic did not undergo neurologic follow up after the procedure. The results obtained in this series may be operator-dependent and there is no guarantee that its results could be extended to all centers and operators.
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