The article by Roth and Alli in this issue describes in depth more than 10 years of research that addresses the question, Should we close a patent foramen ovale (PFO) to prevent recurrent cryptogenic stroke?
There is no longer any doubt that PFO can be the pathway for thrombus from the venous circulation to go from the right atrium to the left atrium, bypassing the pulmonary capillary filtration bed, and entering the arterial side to produce a stroke, myocardial infarction, or peripheral embolus. Two questions remain: What should we do to prevent another episode? And is percutaneous closure of a PFO with the current devices preferable to medical therapy?
How much do we know about the risks and benefits of closure of PFO? I maintain that we know a great deal about interatrial shunt and paradoxical embolism as a cause of cryptogenic stroke. Prospective randomized clinical trials now give us data with which we can provide appropriate direction to our patients. Percutaneous closure is no longer an “experimental procedure,” as insurance companies claim. The experiment has been done, and the only issue is how one interprets the data from the randomized clinical trials.
The review by Roth and Alli comprehensively describes the observational studies, as well as the three randomized clinical trials done to determine whether PFO closure is preferable to medical therapy to prevent recurrent stroke in patients who have already had one cryptogenic stroke. If we understand some of the subtleties and differences between the trials, we can reach an appropriate conclusion as to what to recommend to our patients.
A review of 10 reports of transcatheter closure of PFO vs six reports of medical therapy for cryptogenic stroke showed a range of rates of recurrent stroke at 1 year—between 0% and 4.9% for transcatheter closure, and between 3.8% and 12% for medical therapy.1
These numbers are important because they were used to estimate the number of patients that would be necessary to study in a randomized clinical trial to demonstrate a benefit of PFO closure vs medical therapy. Unlike most studies of new devices, the PFO closure trials were done in an environment in which patients could get their PFO closed with other devices that were already approved by the US Food and Drug Administration (FDA) for closure of an atrial septal defect. This ability of patients to obtain PFO closure outside of the trial with an off-label device meant that the patients who agreed to be randomized tended to have lower risk for recurrence than patients studied in the observational populations. From a practical standpoint, this meant that the event rate in the patients who participated in the randomized clinical trials (1.7% per year) was lower than predicted from the observational studies.2,3
Another way of saying this is that the randomized clinical trials were underpowered to answer the question. A common way of dealing with this problem is to combine the results of different studies in a meta-analysis. This makes sense if the studies are assessing the same thing. This is not the case with the PFO closure trials. Although the topic of percutaneous PFO closure vs medical therapy was the same, the devices used were different.
In the CLOSURE trial (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale),3 the device used was the STARFlex, which is no longer produced—and for good reasons. It is not as effective as the Amplatzer or Helex devices in completely closing the right-to-left shunt produced by a PFO. In addition, the CardioSEAL or STARFlex device increases the risk of atrial fibrillation, which was seen in 6% of the treated patients.3 This was the major cause of recurrent stroke in the CLOSURE trial. The CardioSEAL STARFlex device was also more thrombogenic.