Patent Foramen Ovale and Recurrent Stroke: Closure is the Best Option: Yes
Patent foramen ovale (PFO), a common congenital cardiac anomaly in the general population, is more prevalent among patients with stroke <50 years of age, especially patients with “cryptogenic” stroke. That a PFO can serve as a conduit for brain emboli is not in dispute. Right-to-left shunting is easily demonstrated on echocardiography with agitated saline. If the bubbles (ie, emboli) can get from the right heart to the left heart, they can get to the brain.
Although warfarin has been the “conventional” medical therapy for patients with PFO and transient ischemic attack (TIA) or stroke, there are few data to support its routine use and associated risk of bleeding. In a French study,1 the 2-year risk of stroke or TIA was not increased in patients with cryptogenic stroke and a PFO alone treated with aspirin, but was increased from 4.7% to 8.0% in patients with PFO and atrial septal aneurysm. In the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS),2 PFO was more prevalent among patients with cryptogenic stroke, but there was no significant difference in the 2-year rate of stroke and death in patients with or without PFO (14.3% versus 12.7%). There was also no significant difference whether PFO patients were treated with warfarin or aspirin. Unfortunately, while suggesting that the risk of recurrent stroke in patients with cryptogenic stroke and PFO is low even with aspirin, except perhaps in patients with atrial septal aneurysm, definitive conclusions cannot be drawn from available studies because the patient numbers are too small.
The advent of percutaneous devices has made PFO closure an increasingly attractive alternative option.3–5 Open-heart surgery is now done infrequently for simple PFO closure. At the Cleveland Clinic we have closed 300 PFOs percutaneously in the past 2 years and about 10 000 have been closed worldwide. Percutaneous PFO closure has a very low serious complication rate (<1%). Long-term durability of available devices also appears excellent, with a 5-year failure rate of <1%.
One of the persuasive arguments for PFO closure is the avoidance of long-term warfarin. Warfarin carries a 1% per year risk of significant hemorrhage, no small consideration especially in younger patients. Of course, the issue of long-term warfarin risk becomes moot if aspirin works just as well. After percutaneous PFO closure, patients are treated with aspirin indefinitely and with clopidogrel usually for 6 months.
In the United States, percutaneous PFO closure is permitted under an FDA Humanitarian Device Exemption (HDE). The specific HDE wording for the CardioSEAL® device is instructive:
“The CardioSEAL Septal Occlusion System is indicated for the closure of a patent foramen ovale (PFO) in patients with recurrent cryptogenic stroke due to presumed paradoxical embolism through a patent foramen ovale and who have failed conventional drug therapy. Cryptogenic stroke is defined as a stroke occurring in the absence of potential phanerogenic cardiac, pulmonary, vascular or neurological sources. Conventional drug therapy is defined as a therapeutic INR on oral anticoagulants.”6
Aside from the word phanerogenic, the HDE poses 2 dilemmas: first, how to define “recurrent cryptogenic stroke,” and, second, defining warfarin as the “conventional drug therapy.” Both concepts may be outdated. The modern definition of stroke includes diffusion-weighted MRI-positive TIA—as many as 75% of clinical TIA lasting >1 hour have an abnormal diffusion-weighted MRI.7 A recurrent true TIA also poses a treatment dilemma since that is how many patients with a PFO end up on long-term warfarin in the first place. If a TIA warrants warfarin, why not close the PFO? A TIA simply signifies that the paradoxical embolism lysed; what about the next time?
Many patients are psychologically crippled by their PFO and prefer simply to have it closed. Certainly patients who meet the HDE criteria should undergo percutaneous PFO closure. However, the HDE definition of “recurrent stroke” should include MR-positive TIA. Personally, I would also close the PFO for a recurrent TIA. Percutaneous PFO closure should also be considered as the initial treatment in patients with cryptogenic stroke or TIA requiring long-term warfarin. On the basis of available data, this would include patients with a brisk right-to-left shunt and patients with an atrial septal aneurysm. The truth is, however, that whether percutaneous PFO closure is worse than, equivalent to, or superior to warfarin or aspirin alone (to say nothing of combination therapy or other agents) in patients with cryptogenic stroke and PFO is unknown. That is why 2 FDA-approved multicenter trials of percutaneous PFO closure versus medical therapy alone are about to get under way. For patients with first TIA or first stroke presumably due to a PFO, I therefore confidently recommend percutaneous PFO closure but only if the patient is randomized to the device arm within one of these clinical trials. Otherwise, a “hole” will always remain in our stroke prevention knowledge base.
Section Editors: Geoffrey A. Donnan, MD, FRACP, and Stephen M. Davis, MD, FRACP
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
Mas JL, Zuber M, for the French Study Group on Patent Foramen Ovale and Atrial Septal Aneurysm. Recurrent cerebrovascular events in patients with patent foramen ovale or atrial septal aneurysm, or both and cryptogenic stroke or TIA. Am Heart J. 1995; 140: 1083–1088.
Homma S, Sacco RL, DiTullio MR, Sciacca RR, Mohr JP, for the PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale: Patent Foramen Ovale in Cryptogenic Stroke Study. Circulation. 2002; 105: 2625–2631.
Windecker S, Wahl A, Chatterjee T, et al. Percutaneous closure of patent foramen ovale in patients with paradoxical embolism: long-term risk of recurrent thromboembolic events. Circulation. 2000; 101: 893–898.
US Food and Drug Administration. Humanitarian Device Exemption. HDE #H990011 February 2000.