After years of debate, results of three studies confirm the benefit of closing a patent foramen ovale (PFO) in selected stroke patients in order to prevent recurrent events.
All three multicenter studies showed that the procedure significantly decreased the rate of recurrent ischemic stroke compared with medical therapy in relatively young patients who had experienced a cryptogenic stroke and had a PFO.
“This new wave of results is a breakthrough in settling that key question of whether the device closure is helpful for cryptogenic stroke,” Jeffrey L. Saver, MD, senior advisory vice chair and professor of neurology, and director, stroke unit, University of California at Los Angeles, told Medscape Medical News. Dr Saver led one of the studies, a long-term follow-up of the previously reported RESPECT trial.
In all trials, the rate of atrial fibrillation (AF) was higher in patients undergoing the PFO closure procedure but tended to be transient.
The three trials — REDUCE and CLOSE as well as long-term results of the RESPECT trial — were published September 14 in the New England Journal of Medicine (NEJM).
The REDUCE and CLOSE trials were presented in May at the European Stroke Organization Conference and reported by Medscape Medical News at that time.
PFO, an opening between the left and right atria, is relatively common in the general population but is even more prevalent among patients who have had a cryptogenic ischemic stroke, that is, a stroke of unknown cause. Some research suggests that this condition may be a more important contributor to strokes in younger patients than in older ones.
The clinical benefit of closing a PFO after a cryptogenic stoke has been debated for years. Earlier studies, including the primary analysis of the RESPECT trial, also published in NEJM in 2013, did not show a statistically significant lower risk for recurrent stroke with PFO closure than medical therapy alone at about 3 years after the procedure.
However, earlier trials used an older model device or included too few patients who were followed for a relatively short period, and so were underpowered to detect a clinically meaningful difference, said Dr Saver.
In addition, patients didn’t always get imaging confirmation of a stroke in those studies.
“Some patients probably had something other than a stroke, like migraine, that caused transient neurological symptoms,” said Scott E. Kasner, MD, Department of Neurology, University of Pennsylvania, Philadelphia, an author of another new trial, REDUCE, in an interview. “It’s going to be hard to prevent a recurring event in someone who never had one in the first place.”
Durable Devices
The primary intention-to-treat analysis of the RESPECT trial just missed statistical significance for a benefit of treatment (P = .08) but was positive in a prespecified per protocol analysis. The trial used the Amplatzer PFO Occluder (St Jude Medical), which was approved by the US Food and Drug Administration (FDA) in 2016. It’s currently the only approved device for PFO closure.
However, devices approved for other indications are being used to close PFOs, and all typically come in various sizes. Once a device is placed, a layer of cells grows over it within weeks, providing a protective tissue coating, said Dr Saver.
The devices are durable and, at least with the Amplatzer, are safe in the long term, with some patients in the follow-up RESPECT trial having had the device now for up to 10 years, he said.
The long-term analysis included 980 patients, mean age 45.9 years, who had a confirmed PFO and had experienced a cryptogenic ischemic stroke.
To rule out other causes of stroke, patients completed a battery of tests, said Dr Saver. “All patients underwent very extensive diagnostic workup of the blood vessels, the heart, and the clotting system to look for sources of stroke.”
Participants were randomly assigned to receive medical therapy alone or to undergo closure of the PFO. In the intervention group, after the device was implanted, patients received aspirin plus clopidogrel daily for a month followed by aspirin alone for 5 months, after which antithrombotic therapy was at the discretion of the site investigator. In the medical therapy group, four medical therapies were allowed: aspirin, warfarin, clopidogrel, and aspirin combined with extended-release dipyridamole.
Participants were followed for a median of 5.9 years.
Recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical therapy group (hazard ratio [HR] with PFO closure vs medical therapy, 0.55; 95% confidence interval [CI], 0.31 – 0.999; P = .046). This resulted in a rate of 0.58 events per 100 patient-years for PFO closure, vs 1.07 events per 100 patient-years with medical therapy.
With “very long-term observations,” the follow-up RESPECT trial showed “increasing evidence of a benefit,” commented Dr Saver.
The overall rate of serious adverse events was 40.3% in the PFO closure group and 36.0% in the medical therapy group (P = 0.17).
A total of 25 serious adverse events in the PFO group were considered to be device- or procedure-related. Seven periprocedural events of AF occurred in the PFO closure group, including serious and nonserious events.
PFO closure devices, which are placed on atrial muscle tissue, seem to slightly irritate the tissue electrically and can cause AF, especially within the first few weeks, said Dr Saver.
In this trial, all such events resolved before hospital discharge. “In the RESPECT trial, once you got beyond that first month, there was no difference between the medical group and the device group in terms of long-term observed atrial fibrillation,” said Dr Saver. He noted that the current generation of PFO closure devices has “much less tendency to produce atrial fibrillation.”
The rate of venous thromboembolism, including events of pulmonary embolism and deepvein thrombosis, was higher in the PFO closure than in the medical therapy group, and in both groups, it exceeded that in healthy populations. This suggests patients who have had a cryptogenic stroke and have a PFO have a mildly elevated longterm risk for venous thromboemboli, the authors write.
There were 7 deaths in the PFO closure group and 11 in the medical therapy group. All deaths were adjudicated as being unrelated to the trial.
There is some suggestion from RESPECT and other trials that patients with a larger PFO might get the most benefit from closure. “With more shunting, more blood crosses them, and this could carry a clot from the right side of the heart to the left and skip being filtered out in the lungs,” explained Dr Saver.
Most Provocative
In an editorial published in the same issue of the NEJM, Allan H Ropper, MD, professor, neurology, Harvard Medical School, and Brigham and Women’s Hospital, Boston, Massachusetts, commented that the extended follow-up of the RESPECT trial is “the most provocative of the trials with positive results because it serves as its own control.” The entry criteria and treatments were the same as those of the original trial, with the main difference being the length of follow-up, he said.
The FDA approved the Amplatzer device on the basis of the primary 3-year RESPECT analysis when results were not quite significant, “although the FDA was further assured by the fact that the benefits were growing over time with the additional observation from additional years,” said Dr Saver.
In a Perspective article also published in the NEJM, Andrew Farb, MD, and colleagues from the Center for Devices and Radiological Health at the FDA, said that the data on the Amplatzer PFO Occluder met the FDA’s threshold for approval — a reasonable assurance of safety and effectiveness.
“The FDA concluded that although there were few recurrent strokes in both groups and some uncertainty regarding the reduction in stroke risk attributable to the device, preventing recurrent stroke is of high value,” they write. “The benefit associated with closure of a patent foramen ovale was weighed against a low rate of serious adverse events, and the balance was found to be acceptable for appropriate patients.”
In a separate article published in this issue of NEJM, the CLOSE investigators report on their trial, which included patients in Germany and France, mean age about 44 years. These patients had had a recent cryptogenic stroke attributed to PFO and an associated atrial septal aneurysm or large inter-atrial shunt. The study was led by Jean-Louis Mas, MD, Department of Neurology, Hôpital Sainte-Anne, Paris, France.
A total of 524 patients were randomly assigned to one of three groups: PFO closure with 1 of 11 closure devices, antiplatelet therapy alone, or oral anticoagulation. Another 129 patients who had a contraindication to oral anticoagulants were randomly assigned to PFO closure or antiplatelet therapy alone. Ten patients with a contraindication to PFO closure got antiplatelet or anticoagulation therapy alone.
All patients who underwent PFO closure received dual antiplatelet therapy with aspirin plus clopidogrel for 3 months, followed by single antiplatelet therapy for the rest of the trial.
The primary efficacy outcome was the occurrence of fatal or nonfatal stroke. The mean follow-up was 5.3 years.
In this study, none of the patients in the PFO closure group had a stroke vs 14 patients in the antiplatelet-only group (HR, 0.03; 95% CI, 0 – 0.26; P < .001).
Of these 14 recurrent strokes, 9 occurred among the 12.2% of patients who had both PFO and an atrial septal aneurysm, and 5 occurred among the 3.1% of patients who had large PFO without atrial septal aneurysm.
Major procedural complications occurred in 5.9% of patients in the PFO closure group. Again, the rate of new-onset atrial fibrillation and flutter was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs 0.9%; P = .02).
But as in RESPECT, most cases of new-onset atrial fibrillation were detected within a month after the procedure.
Serious adverse events occurred in 35.7% of patients in the PFO closure group and in 33.2% of those in the antiplatelet-only group (P = .56).
A comparison of the anticoagulation group with the antiplatelet-only group showed that stroke occurred in 3 patients (1.6%) in the former group and in 7 patients (4.0%) in the latter group. The 5-year cumulative estimate of the probability of stroke was 1.5% in the anticoagulant group and 3.8% in the antiplatelet-only group.
The authors noted that this comparison was underpowered and stressed that the effects of oral anticoagulant therapy compared with antiplatelet therapy on the risk for stroke recurrence could not be determined.
However, they noted that a previous systematic review suggested anticoagulant therapy may be superior to antiplatelet therapy for the prevention of stroke recurrence in patients with PFO.
Novel anticoagulants have come on the market since some studies were carried out, commented Dr Saver. Whether these new agents offer advantages above those tested in the trials needs further investigation, he said.
A third trial reported in this issue of NEJM, REDUCE, assessed two versions of a PFO closure device (Helex Septal Occluder or Cardioform Septal Occluder; both W.L Gore and Associates devices) plus antiplatelet therapy compared with antiplatelet therapy alone. This study was led by Lars Søndergaard, MD, Department of Cardiology, University of Copenhagen. Dr Kasner was among the authors.
The two Gore devices contain a flexible polytetrafluoroethylene material that has very little metal, so poses little risk for erosion or other complications, said Dr Kasner. The newer device (Cardioform) is easier to implant, and since the start of the REDUCE study it has replaced the older version.
The Gore devices are approved for atrial septal defects but not for PFOs.
Imaging Confirmation
Here again, study patients had a PFO and had had a cryptogenic ischemic stroke. The trial design required that all patients have imaging confirmation of their stroke “so we knew for sure it was a stroke,” Dr Kasner told Medscape Medical News.
The trial allowed all PFO sizes, but about 81% were moderate to large, he said.
Researchers also “scrupulously tried to avoid lacunes as a source of confounding or noise within the trial,” Dr Kasner noted. While other trials may also have tried to do so, “perhaps we did it better or differently,” he said.
The patients were randomly assigned to undergo PFO closure plus antiplatelet therapy or to receive antiplatelet therapy alone. At each center, antiplatelet therapy was the same in the two study groups, although each participating site could choose this therapy.
Antiplatelet therapy could consist of aspirin alone, a combination of aspirin and dipyridamole, or clopidogrel. Patients in the PFO closure group were treated with one dose of clopidogrel before or immediately after the procedure, followed by daily doses for 3 days, after which they resumed or started the chosen antiplatelet therapy option.
In contrast to some trials, REDUCE did not allow anticoagulation therapy.
The two co-primary endpoints were freedom from clinical evidence of an ischemic stroke to at least 24 months (rate of recurrence) and incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected by the presence of at least one new hyperintense lesion of 3 mm or greater in diameter between the screening MRI and the 24-month MRI.
The study included 664 patients, mean age 45.2 years and 81% with moderate or large inter-atrial shunts. Patients were followed for a median of 3.2 years.
During follow-up, recurrent clinical ischemic stroke occurred in 1.4% in the PFO closure group and in 5.4% in the antiplatelet-only group (HR for recurrent stroke, 0.23; 95% CI, 0.09 – 0.62; P = .002).
New brain infarction occurred in 5.7% of the PFO closure group and in 11.3% of the antiplatelet-only group (relative risk, 0.51, 95% CI, 0.29 – 0.91, P = .04).
However, the incidence of silent brain infarction did not differ significantly between the study groups.
“We had anticipated that silent strokes — clinically unapparent strokes that you can detect on a scan — would be substantially more prevalent than the clinical strokes,” as almost every study of patients with prior stroke and more traditional risk factors has shown this, said Dr Kasner. “But we found the biggest impact was on clinical events.”
Serious adverse events occurred in 23.1% of the PFO closure group and 27.8% in the antiplatelet-only group (P = .22). Two deaths occurred in the PFO closure group and none in the antiplatelet-only group.
In the PFO closure group, procedure-related serious adverse events occurred in 2.5% of the patients, and device-related serious adverse events occurred in 1.4%.
The risks for major bleeding, deep-vein thrombosis, and pulmonary embolism did not differ significantly between study groups. Here again, atrial fibrillation or flutter occurred in significantly more patients in the PFO closure group than in the antiplatelet-only group (6.6% vs. 0.4%; P < .001).
But yet again, AF was usually short lived. “It happened within the first two weeks after the procedure and typically resolved spontaneously,” said Dr Kasner.
“It looks like the atrial fibrillation rate has perhaps gone up from one trial to the next, and some of that might be observer bias” because doctors are “maybe looking harder” for it, he said. “We will follow people for 5 years so we will know more about atrial fibrillation over time.”
In this trial, patients in the antiplatelet-only group could have PFO closure and 14 underwent this procedure outside the trial. This, said the authors, may have affected the generalizability of the results.
Not allowing use of anticoagulants in the medical therapy group might have lessened bias in this group, the authors note. Also, in previous trials, discontinuation of antithrombotic therapy was permitted after PFO closure, which may have increased the risk for stroke due to causes other than PFO, they said.
The REDUCE trial, said Dr Ropper in his editorial, represents “a middle ground” by including patients with a moderate to large interatrial shunt but not requiring that patients have an atrial septal aneurysm.
“Therefore, in patients who have had a stroke, are younger than 60 years of age, and have a PFO with characteristics that are highly likely to allow paradoxical embolism to occur, the effect of closure becomes persuasive.”
One conclusion from all the studies, added Dr Ropper, is that the potential benefit from closure is determined on the basis of the positive characteristics of the PFO rather than of exclusionary factors that make a stroke cryptogenic.
“Restricting PFO closure entirely to patients with high-risk characteristics of the PFO may perhaps be too conservative, but the boundaries of the features that support the procedure are becoming clearer,” he concludes.
The three new trials, said Dr Saver, “amply confirm” the “signals of benefit” seen in earlier trials, and “finally convincingly demonstrate” the benefit for PFO closure in relatively young patients with cryptogenic stroke.
Selection Critical
In an email, Dr Farb stressed that it’s “critically important that prospective patients review with their physicians the benefits and risks of PFO closure versus medical therapy, taking into account the absolute and relative risk reduction of recurrent stroke and the safety of the device.”
Ideal candidates for the PFO closure procedure, said Dr Farb, would be young patients with a cryptogenic ischemic stroke “confirmed by a neurologist and cardiologist who both conclude that the stroke was probably caused by a paradoxical embolism.”
A comprehensive evaluation should be carried out, he added, “to exclude other potential mechanisms for ischemic stroke.” These include atrial fibrillation, left atrial appendage thrombus, left ventricular thrombus, significant cardiac valve pathology, aortic arch atheroma, intracranial and extracranial cerebrovascular disease, small vessel disease, and a hypercoagulable state, he said.
As patients get older, the likelihood of a stroke not being linked to PFO grows, so it’s increasingly difficult to show a benefit of PFO closure, said Dr Kasner.
That said, he would not be strict about an age cutoff. “I might consider the procedure in a 64- or 65-year old who has no other vascular risk factors and who has an embolic-appearing stroke,” and perhaps also a moderate or large PFO.
On the other hand, he wouldn’t recommend the procedure for a 45-year old who has hypertension and diabetes, smokes, and has multiple small lacunes.
For his part, Dr Saver agreed that older patients “tend to have more competing causes of stroke so it’s less certain that PFO was the cause.”
The new results, though, raise the question about the benefit of the procedure in patients over age 60 years (60 or 59 was the upper age limit for the new trials).
“In the wake of these positive findings, I expect trials will be organized in older patients with cryptogenic stroke,” said Dr Saver.
The RESPECT trial was supported by St Jude Medical. Dr Saver reports grants and personal fees from St. Jude Medical during the conduct of the study, as well as grants and personal fees from Boehringer Ingelheim outside the submitted work. The CLOSE trial was supported by a grant from the French Ministry of Health. Dr Mas reports receiving advisory board fees and lecture fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Daiichi Sankyo. The REDUCE trial was supported by W L Gore and Associates. Dr Kasner reports grants from WL Gore and Associates during the conduct of the study. Disclosures for all other coauthors of the studies are available at www.nejm.org . Dr Farb reports no relevant financial disclosures. Dr Ropper reports he is a deputy editor at NEJM and reports no other disclosures.
N Engl J Med. Published online September 14, 2017. CLOSE, RESPECT, REDUCE, Editorial, Perspective
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