PFO Closure for Cryptogenic Stroke?
PFO Closure for Cryptogenic Stroke?
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study.
Source: Furlan AJ, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012;366:991-999.
Some patients who experience stroke or transient ischemic attack (TIA) of unknown cause (i.e., cryptogenic) are subsequently found to have a patent foramen ovale (PFO). The presence of PFO has been associated with a higher rate of cryptogenic stroke in observational studies. However, whether closing PFO (percutaneously or surgically) reduces the rate of subsequent stroke compared to optimal medical therapy (OMT) remains unknown. Thus, Furlan and colleagues performed a prospective, multicenter, open-label, randomized trial of optimal medical therapy vs percutaneous device closure of PFO in patients with a prior stroke or TIA.
The primary endpoint was a composite of stroke or TIA during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years. Inclusion criteria were age 18-60 years, stroke (proven by MRI) or TIA (typical symptoms or positive diffusion-weighted MRI) within the prior 6 months, and a transesophageal echo (TEE) demonstrating a positive bubble study for right-to-left shunting during Valsalva maneuver. Exclusion criteria included any identified potential cause of ischemic stroke or TIA other than the PFO, such as carotid artery stenosis > 50%, complex aortic arch atheroma, clinically significant left ventricular dysfunction or left ventricular aneurysm, or atrial fibrillation. Patients randomized to optimal medical therapy were scheduled to receive high-dose aspirin (or low dose only if gastrointestinal intolerance) and/or warfarin titrated to therapeutic INR at the discretion of the treating physician. Those randomized to closure underwent percutaneous device closure using the Starflex device (made by NMT medical, the sponsor of the trial), with aspirin 325 mg daily for life (or low dose only if gastrointestinal intolerance), and clopidogrel 75 mg daily for 6 months. The initial sample size was calculated at 1600 patients to detect a difference between groups, based on an event rate of 6% in the OMT group vs 3% in the device group. This was reduced to a total sample size of 800 patients because of a change in the expected rates of ischemic events in the device group, which was revised down to 2%. Subsequently, the DSMB increased the sample size to 900 patients after a change in the rate of evaluable patients at follow-up.
It took more than 5 years to recruit 909 patients (n = 447 randomized to device closure and n = 463 randomized to OMT). The mean age of patients was 46 years and 52% were male. There was a trend toward more hypertension and dyslipidemia in the device arm. In the device group, 405 patients underwent attempted closure, which was successful in 89%. As analyzed by the intention-to-treat principle, the primary endpoint occurred in 5.5% of the device closure group vs 6.8% in the OMT group (hazard ratio [HR] 0.78; P = 0.37). The rates of stroke and TIA were 2.9% vs 3.1% (HR 0.90; P = 0.79) and 3.1% vs 4.1% (HR 0.75; P = 0.44) in the device vs OMT groups, respectively. There were no deaths at 30 days in either group and there were no neurological deaths in either group at 2 years. The study was also analyzed by a modified intention-to-treat analysis and by per-protocol analysis (i.e., which treatment was actually received), and there was no difference in the outcome.
At 6-month TEE, only 86% of those who underwent device closure had achieved closure, and at 2 years that rate was 87%. Thrombus was present in the LA of four patients (1.1%) in the device closure group and two of the four patients had a stroke. Vascular complications occurred in 3.2% of the device arm and in none of the OMT group. Atrial fibrillation occurred in 5.7% of the device group vs 0.7% of the OMT group (P < 0.0001). Importantly, in those patients who experienced stroke or TIA, there were potential explanations in the vast majority (such as new-onset atrial fibrillation, a clot in the left atrium, subcortical lacunar infarction with risk factors, aortic arch atheroma, complex migraine, vasculitis, and conversion disorder). The authors conclude that in patients with cryptogenic stroke or TIA who had a PFO, closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA.
Commentary
The authors are to be commended on performing this randomized controlled trial of percutaneous device closure vs medical therapy in patients with cryptogenic stroke and PFO. This is the first such trial for this patient group. The data presented reassure us that OMT with either high-dose aspirin or warfarin (at the physician's discretion) is a safe alternative to percutaneous device closure, at least out to 2 years. Importantly, there were no deaths in the first 30 days and no neurological deaths at 2 years in either group. Furthermore, there was no higher rate of stroke in those with atrial septal aneurysm, which was traditionally thought to confer higher risk of recurrence.
However, there are several limitations to this study and the results must be interpreted in the light of these. First, the study was significantly underpowered. The expected event rates in both the device closure and the OMT groups were underestimated. Thus, both the initial power calculation and the subsequent revised sample sizes effectively under-powered the study to determine a statistically significant difference between groups. Second, there were issues specific to the Starflex device that was used. Both the rates of left atrial thrombus (1.1%) and the rates of incomplete closure of the defect (13.3% had moderate or substantial shunt 2 years after "closure") were higher than could be expected using some other devices, based on prior literature. Third, dual antiplatelet therapy was mandated in the device group but not in the medical therapy group. The medical therapy group could use aspirin or warfarin at the physician's discretion. This difference in anti-platelet/anticoagulant therapy may have introduced bias and we are not told how many patients were taking warfarin. Fourth, this may not have been a truly "cryptogenic" stroke group. After stroke was experienced, possible alternate causes were found in 20 of 23 (87%) patients in the closure group and 22 of 29 (76%) in the OMT group. Perhaps more rigorous screening for these causes would not have labeled these patients as "cryptogenic" in the first place.
In light of these new data, how are we to treat patients who suffer a stroke or TIA and have a PFO? Certainly a rigorous evaluation for other causes of stroke and treatment of these is warranted. Conditions such as paroxysmal AF, untreated hypertension, and aortic arch atheroma are common and represent a treatable "cause" of stroke. If not treated, they are more likely to result in future stroke than a small PFO is. These patients should have their traditional stroke risk factors aggressively managed, and we should consider adding aspirin therapy if there is not already a clear indication for it. Beyond this, clinicians should use their clinical judgment in each situation. Clearly, a "close all PFOs" approach appears to have little if any benefit in this study. Future trials with more rigorous inclusion criteria and better devices may yield different results. Until such data are available, clinicians should exercise caution before recommending device closure of PFOs, particularly in the presence of other causes of stroke.
Some patients who experience stroke or transient ischemic attack (TIA) of unknown cause (i.e., cryptogenic) are subsequently found to have a patent foramen ovale (PFO).Subscribe Now for Access
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