Percutaneous Closure of Patent Foramen Ovale Versus Medical Treatment in Patients With Cryptogenic Embolism - PC

Description:

Numerous observational studies have suggested a beneficial effect of patent foramen ovale (PFO) closure on recurrent stroke in patients with cryptogenic stroke and PFO. However, the only randomized controlled trial on this topic, CLOSURE I, failed to show a benefit with PFO closure using the STARFlex device over routine medical management with anticoagulant/antiplatelet agents. The PC trial sought to compare outcomes after PFO closure with the Amplatzer PFO Occluder over medical therapy in patients with cryptogenic stroke and evidence of a PFO.

Hypothesis:

Among patients with cryptogenic stroke and peripheral embolism, percutaneous closure of PFO using the Amplatzer PFO Occluder would be superior to medical treatment with antiplatelet agents or vitamin K antagonists for secondary prevention of thromboembolism.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Age <60 years
  • Presence of PFO (with or without atrial septal aneurysm)
  • Clinically and neuro-radiologically verified ischemic stroke or TIA with documented corresponding intracranial ischemic lesion or clinically and radiologically verified extracranial peripheral thromboembolism
  • Sufficient recovery from the thromboembolic index event to allow independent daily activities

    Number of enrollees: 414
    Duration of follow-up: 4 years (median)
    Mean age: 44.5 years
    Percentage female: 50%

Exclusions:

  • Cause for thromboembolic event other than PFO
    - Cardiac (mural thrombus, dilated cardiomyopathy, atrial fibrillation, prosthetic heart valves)
    - Cerebral (significant intracranial disease, relevant atherosclerosis, dissection of intra- or extracranial arteries)
    - Vascular (arteritis, vasculitis, collagen vascular disease)
    - Hematological (hyperviscosity syndrome, hypercoagulable state)
  • Contraindication for chronic antithrombotic treatment
  • Clinical indication other than PFO for chronic antithrombotic treatment
  • Previous surgical or percutaneous PFO closure
  • Central nervous system disease such as seizure disorder, disability from previous stroke, etc.

Primary Endpoints:

  • Composite of death from any cause, nonfatal stroke, TIA, and peripheral embolism

Secondary Endpoints:

  • Myocardial infarction and peripheral thromboembolism
  • New arrhythmia (atrial fibrillation)
  • Re-hospitalization related to PFO or its treatment
  • Device-related problems (dislodgement, structural failure, infection, thrombosis)

Drug/Procedures Used:

Patients with a documented PFO and evidence of cryptogenic stroke were randomized to either percutaneous closure with the Amplatzer PFO Occluder or medical management (oral anticoagulation or antiplatelet therapy at the discretion of the neurologist). Patients with PFO closure received aspirin 100-325 mg and ticlopidine 250-500 mg/clopidogrel 75 mg daily.

Principal Findings:

A total of 414 patients were randomized at 29 sites in Europe, Canada, Brazil, and Australia, 204 to PFO closure and 210 to medical management. Baseline characteristics were fairly similar between the two arms. Approximately 3% had diabetes, and 54% were age ≥45 years. Qualifying event was stroke in 79% of the patients, and 37% had experienced >1 prior cerebrovascular event. An atrial septal aneurysm was noted in approximately one-fourth of the patients, whereas approximately 22% had evidence of a large right-to-left shunt.

Among the 204 patients in the PFO closure arm, device implantation was attempted in 196, and completed in 191 patients. Procedural complication occurred in 1.5% of patients. Follow-up transesophageal echocardiography information was available for approximately three-fourth of the patients; effective closure of the PFO was noted in 96% of the patients.

Over a median duration of follow-up of 4 years, the primary composite endpoint of all-cause mortality, nonfatal stroke, transient ischemic attack (TIA), and peripheral embolism was similar between the PFO closure and medical management arms (3.4% vs. 5.4%; hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.24-1.62; p = 0.34). Per-protocol analysis resulted in a similar hazard ratio. Other outcomes including stroke (0.5% vs. 2.4%; p = 0.14), TIA (2.5% vs. 3.3%, p = 0.56); myocardial infarction (HR, 2.04; 95% CI, 0.19-22.5; p = 0.56), and PFO-related hospitalizations (6.4% vs. 6.2%; p = 0.95) were also similar between the two arms. Overall bleeding (3.9% vs. 5.7%, p = 0.40) and atrial fibrillation (2.9% vs. 1.0%, p=0.17) were similar between the two arms.

Interpretation:

The results of the PC trial indicate that PFO closure (with the Amplatzer PFO Occluder) is not superior to medical management in reducing recurrent embolic episodes including cerebrovascular accident in patients with cryptogenic stroke and evidence of a PFO. These results are similar to those noted in the CLOSURE I trial with the STARFlex device. Similar to the CLOSURE I trial, the PC trial also experienced slow enrollment with a prolonged recruitment duration. However, contrary to the CLOSURE I trial, where the trial was negative due to a higher event rate in the PFO closure arm, the PC trial is negative due to a lower than expected event rate in the medical management arm.

Similarly, in the RESPECT trial with the Amplatzer PFO Occluder, there was no difference between the device and medical therapy arms in stroke reduction, although they were numerically lower in the device arm. These data argue against routine PFO closure in patients with cryptogenic stroke and PFO. It is unclear if there might be a benefit in select subgroups such as younger patients, those with complete obliteration of right-to-left shunt with closure, and those with large septal aneuryms. Pooled analyses of the PC and RESPECT trial areĀ planned and are awaited. Results of ongoing trials including REDUCE and CLOSE areĀ also awaited.

References:

Meier B, Kalesan B, Mattle HP, et al., on behalf of the PC Trial Investigators. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013;368:1083-91.

Presented by Dr. Stephan Windecker at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2012), Miami, FL, October 25, 2012.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Noninvasive Imaging, Congenital Heart Disease, CHD and Pediatrics and Imaging, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Echocardiography/Ultrasound

Keywords: Vitamin K, Myocardial Infarction, Stroke, Ischemic Attack, Transient, Follow-Up Studies, Platelet Aggregation Inhibitors, Ticlopidine, Foramen Ovale, Patent, Purinergic P2Y Receptor Antagonists, Thromboembolism, Confidence Intervals, Echocardiography, Transesophageal, Diabetes Mellitus


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