What do we know thus far from the clinical trials about the efficacy and safety of patent foramen ovale (PFO) closure for cryptogenic stroke? The CLOSURE I trial results were presented at the 2010 AHA Scientific Sessions and then presented again with more detail at the 2011 International Stroke Conference. The full data have not yet been formally published, but according to the results presented, PFO closure with the STARFlex septal closure device was no better than medical therapy alone with aspirin or warfarin. Thus, there is currently no clear evidence that PFO closure is better than medical therapy alone — and since PFO closure is an invasive procedure that poses an up-front risk, and the long-term risks of having a device like this in place for 20 to 30 years are not yet known, it is very difficult to advocate PFO closure in clinical practice. However, this trial has a number of design and patient selection issues that leave open the possibility that PFO closure is a good strategy, just not with this particular device. One of the issues involves the device arm of the CLOSURE I trial in which many of the strokes were attributable to the device itself, either because of clot forming on the device or because of atrial fibrillation caused by the device. A different PFO closure device that was less likely to cause clot formation or atrial fibrillation would still offer a promising approach. The other problem with CLOSURE I is that it was designed over a decade ago, and when it started, patients were enrolled if they had a transient ischemic attack (TIA) or a stroke and a PFO, and the goal was to enroll patients with cryptogenic stroke or TIA. However, it seems likely, based on the data presented, that there were in fact patients enrolled in the trial — and the number may have been large — who had another explanation for their stroke, but who just happened to have a PFO as an “innocent bystander”. We know that one out of four people has a PFO, thus on average, one out of four people with a stroke will have a PFO, but that does not necessarily make it the cause of the stroke. In the CLOSURE I trial, many of the recurrent strokes in both arms of the trial were due to atherosclerotic disease, small-vessel disease, other cardiac disease, which PFO closure would not be expected to fix. Thus, a thorough evaluation of these patients is needed to rule out other causes of their stroke before enrolling them in such a trial, which brings us to the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) and REDUCE (Gore HELEX™ Septal Occluder for Patent Foramen Ovale Closure in Stroke Patients) trials involving more careful patient selection. What steps are typically taken to try to determine the cause of a cryptogenic stroke? This varies quite significantly. Some physicians will first perform a carotid ultrasound to rule out carotid disease, then an electrocardiogram or a day’s worth of telemetry in the hospital to rule out atrial fibrillation. If these tests are negative, an echocardiogram is often performed — and if a PFO is found, the physician may assume it was the PFO that caused the stroke. It is essential that we take a more thorough look at these patients to determine if they have intracranial arterial disease using MRA, CTA or transcranial Doppler ultrasonography. And we need to find out if these patients have atrial fibrillation in the first place. If the patient has a small, deep stroke, it is probably a lacunar stroke due to small-vessel disease, and it is very unlikely that it was caused by a small embolus that went through the heart. The CLOSURE I trial did require patients to undergo screening for a clotting disorder and some type of arterial imaging. The biggest problem with this trial was that there were probably a fair number of patients included who had lacunar strokes. There is currently no test to determine if a patient has had a small-vessel stroke, rather the strokes are evaluated according to their size and location. The one other related issue I should mention is that the CLOSURE I trial enrolled patients who had a TIA or a stroke. Many think of TIAs and strokes as sharing the same underlying mechanisms, but the TIA clot dissolves relatively quickly, whereas a stroke occurs when the clot does not resolve in time to prevent permanent injury. But patients with transient ischemic symptoms do not necessarily have a TIA, but instead may have had a migraine or a seizure. In fact, TIA patients who have normal brain scans have a very low risk of a subsequent stroke. In the CLOSURE I trial, approximately one-quarter of the patients were enrolled with a TIA and a negative brain scan. Thus, if these patients were not at risk for a future stroke, they diluted the overall results of the study. Furthermore, this would cause the CLOSURE I trial to underestimate the risk of future stroke in the patients who actually had a cryptogenic stroke with a PFO. Why do you think percutaneous device closure of PFOs to prevent recurrent stroke has become such a widespread practice as opposed to optimal medical therapy? If you presume that a stroke was due to a clot going through a PFO and on to the brain, then it is logical to think that closing it will prevent that from recurring. PFO closure is a fairly straightforward procedure for interventional cardiologists to perform, and it has become a popular option for young patients in their twenties or thirties who potentially face a lifetime of stroke risk. However, this perhaps overly popular trend has led to the FDA’s decision to rescind its humanitarian device exemption for PFO closure a few years ago. This has all been based on the presumption that PFO was the cause of stroke in certain patients and that closure of the PFO would prevent future strokes. But I have often seen TIA and stroke patients who have undergone PFO closure, then suffered another stroke later due to a clearly defined alternate cause, which strongly suggests that their TIA or stroke had nothing to do with their PFO. Tell us about Gore’s REDUCE clinical study. The Gore REDUCE clinical trial is well-designed to address some of the shortcomings of the other trials. First, all patients enrolled have had an MRI-confirmed stroke. All patients undergo vascular imaging of their head and neck and are tested for clotting disorders. Patients are who have a small-vessel or lacunar stroke are excluded from the study, as well as those with multiple vascular risk factors such as poorly controlled hypertension, smoking and diabetes — because stroke patients who have these risk factors and have a PFO can probably attribute their stroke to these risk factors, not to the PFO. These exclusion criteria will help us to better identify those patients with a truly cryptogenic stroke. The Gore® Helex Septal Occluder device (W. L. Gore & Associates, Flagstaff, Arizona) has an excellent track record with respect to the incidence of clotting and atrial fibrillation. We anticipate that the REDUCE trial will further provide proof of this. Target enrollment for the REDUCE trial is 664 patients. Enrollment in REDUCE was slow prior to the presentation of the CLOSURE I results because patients had other options: they have their cardiologist implant a PFO closure device, or they could opt for medical therapy and not participate in a clinical trial. Only a fraction of the population of cryptogenic stroke patients with a PFO is willing to be randomized to a clinical trial. After CLOSURE I failed to show that PFO closure is better than medical therapy, and many neurologists have been saying that they don’t have to worry about PFO anymore, they’re just going to put these patients on aspirin. And what I have been hearing from the cardiologists is that this was just one trial that was not done correctly, so they are going to continue with what we have been doing. So in many cases, patients are hearing increasingly divergent opinions about what to do. I think when the paper comes out, insurers ought to say that PFO closure is unproven, they will only support it in the context of clinical trials, and they encourage the trials to continue seeking the answer to this question for the appropriate patients. What do you anticipate the REDUCE study results will show? I think that with appropriately selected patients and a safe device, the REDUCE trial should be able to show that the risk of recurrent stroke can be reduced. What is being done to improve collaboration between the neurology and cardiology fields to answer the PFO closure question? Right now we’re all sort of in a state of limbo as we await the publication of the CLOSURE I results. This will generate editorials and open discussions among neurologists and cardiologists, and I hope that we will all work together to answer the question definitively in the future. I know that we have learned quite a lot from CLOSURE I, but we still have great uncertainty.
Dr. Scott E. Kasner received his M.D. from Yale University. He trained in Internal Medicine and Neurology at the University of Pennsylvania, and then in Stroke and Neurocritical Care at the University of Texas-Houston. Dr. Kasner joined the faculty of the Department of Neurology at the University of Pennsylvania in 1997 and is currently Professor of Neurology, Chief of the Division of Stroke and Neurointensive Care, and Director of the Comprehensive Stroke Center. He also earned a Master’s of Science in Clinical Epidemiology from the University of Pennsylvania. Dr. Kasner’s primary field of interest is the treatment and prevention of stroke. He is a Fellow of the American Heart Association and a member of the Stroke Council Leadership Committee. From 2007 to 2010, he chaired the American Heart Association's Stroke Oversight Committee, which commissions and reviews stroke-related guidelines and statements. He was awarded the 2000 Michael Pessin Stroke Leadership Award granted by the American Academy of Neurology. Dr. Kasner has authored over 200 publications, and he edited a textbook that focused on evidence-based stroke treatment and prevention. Dr. Kasner is the U.S. national principal investigator for a trial comparing closure vs. medical therapy for patients with stroke and PFO. He was a steering committee member for the NINDS-funded multicenter WASID trial, a pivotal study that has changed clinical practice worldwide. He chairs the Clinical Endpoint Committee for the IRIS trial and the VERITAS study, and is a member of other adjudication and data safety monitoring committees for a number of ongoing trials of acute stroke treatment and secondary stroke prevention.