Brief History of Patent Foramen Ovale and Stroke
Lechat is usually credited with first calling attention to patent foramen ovale (PFO) and stroke in 1988.1 Previous studies of the role of echocardiography in stroke rarely, if ever, mentioned PFO and focused on now-almost-forgotten disorders, such as mitral valve prolapse.2
Interest in PFO has emerged for 3 main reasons: (1) renewed interest in cryptogenic stroke especially in younger patients; (2) technical advances, including bubble contrast transthoracic echocardiography, transesophageal echocardiography, and saline contrast transcranial doppler; and (3) perhaps most importantly, the emergence of endovascular device closure as a treatment option.
Cryptogenic stroke is highly prevalent in stroke populations under the age of 55 years. Many of these patients have circumstantial evidence for embolism on MR, such as cortical infarct location or multiple silent infarcts in different vascular territories. Large PFO with a substantial shunt and atrial septal aneurysm has been identified in many (although not all) studies as anatomic comorbidities associated with stroke. However, as with PFO detection, new technology, including implantable cardiac monitors and MR plaque morphological analysis, has identified occult atrial fibrillation and acute rupture of benign atherosclerotic plaques as underdiagnosed causes of crytpogenic stroke.3 This suggests that in many patients with cryptogenic stroke, a PFO may be coincidental.
The explosion of device technology has played a central role in the PFO renaissance. Reimbursement policies and an inherent bias in young patients with stroke to close the hole bolstered by numerous observational case series provided a strong incentive for endovascular device closure.4
With this background, 3 randomized clinical trials of the management of patients with cryptogenic stroke and PFO have recently been completed. Given the lingering controversy, it is important to review why the 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 (CLOSURE),5 the Percutaneous Closure of Patent Foramen Ovale in Cryptogenic Stroke (PC),6 and the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT)7 trials were done in the first place.
All 3 trials began >10 years ago. Before October 2006, PFO device closure for stroke prevention was approved under a Humanitarian Device Exemption (HDE) by the Food and Drug Administration (FDA). The HDE was predicated on <4000 procedures performed annually and required a recurrent stroke (not first stroke and not transient ischemic attack [TIA]) while on warfarin (not aspirin) for which no other explanation was apparent (phanerogenic stroke in arcane FDA language). However, it was likely that many >4000 patients were being closed annually in the United States alone using devices which were approved for ventricular septal defect or atrial septal defect off label. The exact numbers were never divulged publically by industry; ≥7 different devices were being used off label when CLOSURE was designed. As well, the neurological indications for off-label closure were not disclosed in any systematic fashion, and it is naive to think that the HDE requirements (eg, only recurrent stroke only on failed warfarin) were strictly adhered to in all instances. In fact, it was common knowledge that patients with nonspecific neurological complaints were being closed and sometimes without neurological input. As the FDA itself acknowledged,8 there were powerful financial incentives for device closure, as well as inherent patient, and physician bias favoring device closure. It is important to recall this state of affairs before the completion of these trials because some interventionalists now disingenuously claim that only carefully selected patients were being closed during the HDE era.
CLOSURE was designed as a 2-year superiority trial with the intent of securing Premarket Approval for the NMT StarFlex device for stroke prevention in patients with cryptogenic stroke or TIA and a PFO. RESPECT was designed as an event-driven trial also with the intent of securing a Premarket Approval for the St. Jude Amplatzer device. The PC trial was an investigator-driven trial planned for 4.5 years also using the Amplatzer device. All 3 trials took much longer time to complete than anticipated and had great difficulty in recruiting patients because of off-label closure. Indeed, in October 2006, the FDA took the unprecedented action of removing the HDE in an attempt to help recruitment into these trials while refusing to restrict off-label PFO closure. Not surprisingly, removing the HDE had no discernible effect on the recruitment rates in CLOSURE, RESPECT, or PC.
The 3 trials used slightly different inclusion criteria and end points. CLOSURE used the most liberal inclusion criteria in that well-defined and independently adjudicated TIA was randomized. TIA was also included as an end point. Contrary to some opinions, these patients were not atypical or wrong. 2 In fact, the CLOSURE inclusion criteria were developed by the Executive Committee, half of whom were nationally known interventional cardiologists, precisely to be representative of patients being referred for PFO device closure at that time. As discussed in the article, we also calculated that the sample size for a 2-year study would have been prohibitively large and not feasible if only patients with stroke were randomized (subsequently borne out by PC and RESPECT). PC included clinical TIA with a positive diffusion-weighted MRI (as did CLOSURE) but also included patients with peripheral embolism; despite 9 years of effort, only 414 patients were randomized, and PC is seriously underpowered. In an attempt to identify patients more likely to have paradoxical embolism, RESPECT used the most restricted inclusion criteria and included only patients with stroke. An effort was made in RESPECT to exclude subcortical lacunar infarcts. Only RESPECT used an event-driven outcome that was restricted to stroke. Hence, the main differences between these trials are the inclusion of clinical TIA with negative baseline MR in CLOSURE, the inclusion of peripheral events in PC, the attempted exclusion of lacunar infarcts in RESPECT, and, of course, the different devices.
Despite these design differences, the primary results of CLOSURE, PC, and RESPECT were the same: the intent to treat analysis for the primary end point in all 3 trials failed to demonstrate the superiority of device closure compared with medical therapy. The annual risk of stroke was low in all 3 studies. Per-protocol analyses for stroke were negative in CLOSURE and PC, but in RESPECT, device was superior to medical therapy; the RESPECT per-protocol analysis is at the root of the ongoing controversy. It will be of interest to see how the FDA weighs these results. Of note, CLOSURE presented many subgroup analyses to the FDA, 1 of which suggested benefit for device in patients under the age of 40 years (paradoxically, patients under the age of 45 years did better with device in RESPECT). However, the FDA did not feel these analyses were persuasive enough to approve any follow-up studies. As a result, the sponsor NMT Medical, Boston, filed for bankruptcy.
Of note, despite similar baseline demographics (age, % vascular risk factors, and % substantial shunting), it took RESPECT 8 years to accumulate 25 strokes, the same number that occurred in CLOSURE in 2 years. It is claimed that patients in RESPECT more likely had paradoxical embolism as the index event. RESPECT attempted to exclude subcortical lacunar infarcts, yet ≥13% (n=127) of the patients randomized in RESPECT had a single small deep infarct compared with 18% (n=97) in CLOSURE. On the basis of inclusion criteria, it is therefore not clear why the same number of strokes occurred in 2 years in CLOSURE as during 8 years in RESPECT. Stroke causes other than paradoxical embolism were evidently more apparent in CLOSURE than in RESPECT. Clearly, these PFO patient populations behaved differently. Because the stroke rates were low in all the trials, it is possible that slight differences in patient demographics and devices account for the variable results.
The different results may also be partly explained by the different devices used. Overall, the Amplatzer device performed better than the StarFlex device in terms of effective closure rate, and the rate of atrial fibrillation although major procedural complication rates (atrial thrombus, perforation, bleeding, and periprocedural stroke) were similar. It will therefore not be possible to extrapolate the results of these trials to other devices.
An overlooked aspect of the trials is medical therapy. The best medical therapy remains unknown. Historically, warfarin was the drug of choice. Indeed, the apparent need for long-term warfarin was 1 of the rationales for endovascular device closure of PFO. However, when the (underpowered) PFO in Cryptogenic Stroke Study (PICSS) failed to show the statistical superiority of warfarin compared with aspirin, the American Academy of Neurology recommended aspirin as an acceptable therapy.9,10 In all 3 trials, ≈80% of patients randomized to medical therapy used aspirin. Possibly, if a subgroup can be identified with a higher likelihood of venous paradoxical embolism, then warfarin or a new antithrombotic would be the drug of choice and not aspirin. For example, in the Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVVEROES) study,11 a novel Xa inhibitor (apixaban) showed bleeding complications similar to aspirin with fewer cardioembolic strokes and peripheral emboli, suggesting that 1 of the new antithrombotic agents might be as safe as and superior to antiplatelet agents or device closure for preventing paradoxical embolism. On the other hand, in patients with PFO but not cardioembolic infarcts, such as atherosclerosis-related lacunar infarcts, perhaps antiplatelet therapy would be the medical therapy of choice.
As CLOSURE acknowledged, perhaps subgroups can be identified in whom device closure was safe and superior to medical therapy. PC provides no insight into this issue, but RESPECT suggests (but does not prove) that patients without vascular risk factors, with a cryptogenic cortical infarction and a large shunt with or without atrial septal aneurysm may benefit slightly from device for several years. However, because recurrent event rates in the medical group in all 3 trials were particularly high in the first half of the observation period, a long follow-up will be required to determine whether the apparent benefit in the device group in RESPECT will be sustained for many years.
CLOSURE put the brakes on the indiscriminate closure of PFOs with devices. RESPECT refined the patient selection criteria and suggested, but did not prove, that highly selected patients may benefit from the Amplatzer device for many years. PC demonstrated the difficulty of recruiting patients into PFO trials. A Risk of Paradoxical Embolism (ROPE) score has been proposed for determining the relative likelihood of a stroke being related to a PFO.12
In the absence of definitive clinical trial results, the precise definition of which patient subgroup should be considered for PFO device closure should be agreed to by the stakeholder societies. Any FDA approval should be similarly restricted. Furthermore, guidelines for the evaluation of patients with cryptogenic stroke are needed. Other trials are ongoing (GORE Septal Occluder for Patent Foramen Ovale [PFO] Closure in Stroke Patients––REDUCE) but will likely have the same statistical challenges experienced by CLOSURE, PC, and RESPECT. A definitive large randomized clinical trial will not likely be done and would be feasible only if device reimbursement is linked with trial participation.
It would be unfortunate to relegate patient treatment decisions to a discussion of statistics without any clinical context whatsoever. In the absence of definitive randomized clinical trial evidence or FDA approval, the best approach is to discuss the results of these trials with the patient. Inform the patient about treatment alternatives, such as aspirin or warfarin, with the perspective of a new decision when data from meta-analysis are available or new prophylactic drug treatment for cryptogenic stroke has been approved. Emphasize the low risk of recurrent stroke regardless of therapy choice. Realize that patients under the age of 50 years without risk factors with large shunts and cortical infarcts are most likely to have a paradoxical embolism and that PFO closure with the Amplatzer device seems slightly better than aspirin for a follow-up of many years. Oh! make sure insurance will cover the procedure.
Dr Furlan is a Principal Investigator of CLOSURE I, NMT Medical, Boston.
- Received December 2, 2014.
- Revision received December 16, 2014.
- Accepted December 17, 2014.
- © 2015 American Heart Association, Inc.
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- Miller VT
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- Mohr JP