PFO Occluder Device May Be Superior to Medical Management

HONOLULU—In patients with patent foramen ovale (PFO) and cryptogenic stroke, PFO closure with the AMPLATZER PFO Occluder may help prevent large strokes and strokes with superficial vascular distribution, according to an analysis presented at the 2013 International Stroke Conference. PFO closure with the device has previously been associated with benefits for patients with atrial septal aneurysms and patients with a large shunt size.

The findings are from a new analysis of data from the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial. Jeffrey Saver, MD, Professor of Neurology at the University of California, Los Angeles, and colleagues initiated the RESPECT trial to determine whether PFO closure with the AMPLATZER device is superior to medical treatment in preventing recurrent embolic stroke.

The purpose of the new analysis was to characterize the ischemic strokes that participants in the RESPECT trial had had at baseline and the end-point ischemic strokes that they had during the trial. The investigators hoped to learn new information about the device's potential mechanisms of action.

PFO Closure Reduced Recurrent Stroke
In the RESPECT trial, which was undertaken at 69 sites in the United States and Canada, patients with PFO who had had cryptogenic ischemic stroke were randomized to closure with the AMPLATZER PFO Occluder or to medical therapy consisting of any of four guideline-approved antithrombotic regimens (ie, aspirin, warfarin, clopidogrel, or aspirin with dipyridamole). The two treatment arms had equal numbers of patients. Subjects were enrolled within 270 days of the qualifying stroke, underwent a detailed workup, and were excluded if a cause of their stroke, such as small-vessel disease, could be identified.

The primary outcome measure was the composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, and early postrandomization death. A secondary outcome measure was complete closure of the defect, as demonstrated by transesophageal echocardiography and bubble study, in the device group. An academic steering committee oversaw the trial, and clinical events were adjudicated independently.

In the intention-to-treat raw analysis and the time-to-event analysis, PFO closure with the AMPLATZER PFO Occluder was associated with a nonsignificant reduction in recurrent stroke ranging from 47 to 51%. The device was associated with a greater, significant reduction in recurrent stroke ranging from 63 to 73% in the per-protocol and as-treated analyses, said Dr. Saver.

PFO Closure May Prevent Superficial Infarcts
The follow-on analysis suggested that PFO closure with the AMPLATZER Occluder had a greater benefit in patients with an isolated superficial qualifying infarct, rather than a small and deep infarct. "Compared with the device group, the medical group had a greater number of end-point strokes that were superficial, or mixed deep and superficial, or otherwise not small and deep in distribution," said Dr. Saver.

The researchers also observed that 69% of the recurrent strokes in the medical group had a diameter greater than 1.5 cm, compared with 14% of the recurrent strokes in the device group. The difference between the groups fell just short of statistical significance, however.

Six of the 25 recurrent strokes were determined to have a definite cause other than the PFO. The other recurrent strokes were cryptogenic and were more common in the medical group than in the device group.

In the intention-to-treat analysis, nine strokes occurred in the device group. Three of these strokes occurred in patients who did not have a device in place at the time. Alternative causes were evident for two other strokes, two were small, deep infarcts, and two were superficial and cryptogenic in patients with devices.

"These data demonstrate that the RESPECT population succeeded in being stringently selected to identify patients with cryptogenic ischemic stroke," said Dr. Saver. The frequency of recurring strokes due to a defined mechanism other than PFO was 0.2% per year. "The exclusion of small, deep infarcts likely due to intrinsic small-vessel disease seemed to succeed in limiting the number of recurring small, deep infarcts," Dr. Saver added.

End-Point Event Data Were Incomplete for Some Patients
A limitation of the additional analysis is that the Forest plot subgroup analysis was limited in power because it included only 25 events. "But, clinically, the features identified as potentially having magnified device effect—having an atrial septal aneurysm, having a larger shunt size, and having a superficial distribution of the qualifying infarct—are all relevant and pathophysiologically support a potential benefit of closing a PFO with the device," said Dr. Saver.

The workup of the end-point events was incomplete for patients whose strokes occurred outside the study centers. Although all patients underwent a detailed workup at the time of their qualifying stroke, not all were subjected to the full repeat workup. Complete data were available for most of the patients, however.

RESPECT Versus CLOSURE Trials
Dr. Saver suggested several possible reasons that PFO closure with a device was associated with a likely benefit in the RESPECT trial, although the procedure did not demonstrate a benefit in the previous CLOSURE trial. "We followed patients up to eight years, and CLOSURE only followed patients for two years. If you look at the Kaplan–Meier curves that we have up to two years, they look very similar to the Kaplan–Meier curves for CLOSURE, which were going in the right direction, but they did not reach statistical significance," said Dr. Saver.

The RESPECT trial included more stringent criteria for patient selection than CLOSURE, and may also have tested a better device, noted Dr. Saver. The AMPLATZER PFO Occluder was not associated with a significant increase in atrial fibrillation in patients who received it. It thus did not create risk factors for stroke as other devices have, he added.

"Consideration of the neurovascular aspects of the RESPECT trial reinforces the primary analysis," said Dr. Saver. "Stringent patient selection to identify patients with a history of cryptogenic stroke and PFO closure with the AMPLATZER PFO Occluder showed evidence of benefit over medical management alone," he concluded.

HONOLULU—In patients with patent foramen ovale (PFO) and cryptogenic stroke, PFO closure with the AMPLATZER PFO Occluder may help prevent large strokes and strokes with superficial vascular distribution, according to an analysis presented at the 2013 International Stroke Conference. PFO closure with the device has previously been associated with benefits for patients with atrial septal aneurysms and patients with a large shunt size.

The findings are from a new analysis of data from the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial. Jeffrey Saver, MD, Professor of Neurology at the University of California, Los Angeles, and colleagues initiated the RESPECT trial to determine whether PFO closure with the AMPLATZER device is superior to medical treatment in preventing recurrent embolic stroke.

The purpose of the new analysis was to characterize the ischemic strokes that participants in the RESPECT trial had had at baseline and the end-point ischemic strokes that they had during the trial. The investigators hoped to learn new information about the device's potential mechanisms of action.

PFO Closure Reduced Recurrent Stroke
In the RESPECT trial, which was undertaken at 69 sites in the United States and Canada, patients with PFO who had had cryptogenic ischemic stroke were randomized to closure with the AMPLATZER PFO Occluder or to medical therapy consisting of any of four guideline-approved antithrombotic regimens (ie, aspirin, warfarin, clopidogrel, or aspirin with dipyridamole). The two treatment arms had equal numbers of patients. Subjects were enrolled within 270 days of the qualifying stroke, underwent a detailed workup, and were excluded if a cause of their stroke, such as small-vessel disease, could be identified.

The primary outcome measure was the composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, and early postrandomization death. A secondary outcome measure was complete closure of the defect, as demonstrated by transesophageal echocardiography and bubble study, in the device group. An academic steering committee oversaw the trial, and clinical events were adjudicated independently.

In the intention-to-treat raw analysis and the time-to-event analysis, PFO closure with the AMPLATZER PFO Occluder was associated with a nonsignificant reduction in recurrent stroke ranging from 47 to 51%. The device was associated with a greater, significant reduction in recurrent stroke ranging from 63 to 73% in the per-protocol and as-treated analyses, said Dr. Saver.

PFO Closure May Prevent Superficial Infarcts
The follow-on analysis suggested that PFO closure with the AMPLATZER Occluder had a greater benefit in patients with an isolated superficial qualifying infarct, rather than a small and deep infarct. "Compared with the device group, the medical group had a greater number of end-point strokes that were superficial, or mixed deep and superficial, or otherwise not small and deep in distribution," said Dr. Saver.

The researchers also observed that 69% of the recurrent strokes in the medical group had a diameter greater than 1.5 cm, compared with 14% of the recurrent strokes in the device group. The difference between the groups fell just short of statistical significance, however.

Six of the 25 recurrent strokes were determined to have a definite cause other than the PFO. The other recurrent strokes were cryptogenic and were more common in the medical group than in the device group.

In the intention-to-treat analysis, nine strokes occurred in the device group. Three of these strokes occurred in patients who did not have a device in place at the time. Alternative causes were evident for two other strokes, two were small, deep infarcts, and two were superficial and cryptogenic in patients with devices.

"These data demonstrate that the RESPECT population succeeded in being stringently selected to identify patients with cryptogenic ischemic stroke," said Dr. Saver. The frequency of recurring strokes due to a defined mechanism other than PFO was 0.2% per year. "The exclusion of small, deep infarcts likely due to intrinsic small-vessel disease seemed to succeed in limiting the number of recurring small, deep infarcts," Dr. Saver added.

End-Point Event Data Were Incomplete for Some Patients
A limitation of the additional analysis is that the Forest plot subgroup analysis was limited in power because it included only 25 events. "But, clinically, the features identified as potentially having magnified device effect—having an atrial septal aneurysm, having a larger shunt size, and having a superficial distribution of the qualifying infarct—are all relevant and pathophysiologically support a potential benefit of closing a PFO with the device," said Dr. Saver.

The workup of the end-point events was incomplete for patients whose strokes occurred outside the study centers. Although all patients underwent a detailed workup at the time of their qualifying stroke, not all were subjected to the full repeat workup. Complete data were available for most of the patients, however.

RESPECT Versus CLOSURE Trials
Dr. Saver suggested several possible reasons that PFO closure with a device was associated with a likely benefit in the RESPECT trial, although the procedure did not demonstrate a benefit in the previous CLOSURE trial. "We followed patients up to eight years, and CLOSURE only followed patients for two years. If you look at the Kaplan–Meier curves that we have up to two years, they look very similar to the Kaplan–Meier curves for CLOSURE, which were going in the right direction, but they did not reach statistical significance," said Dr. Saver.

The RESPECT trial included more stringent criteria for patient selection than CLOSURE, and may also have tested a better device, noted Dr. Saver. The AMPLATZER PFO Occluder was not associated with a significant increase in atrial fibrillation in patients who received it. It thus did not create risk factors for stroke as other devices have, he added.

"Consideration of the neurovascular aspects of the RESPECT trial reinforces the primary analysis," said Dr. Saver. "Stringent patient selection to identify patients with a history of cryptogenic stroke and PFO closure with the AMPLATZER PFO Occluder showed evidence of benefit over medical management alone," he concluded.

HONOLULU—In patients with patent foramen ovale (PFO) and cryptogenic stroke, PFO closure with the AMPLATZER PFO Occluder may help prevent large strokes and strokes with superficial vascular distribution, according to an analysis presented at the 2013 International Stroke Conference. PFO closure with the device has previously been associated with benefits for patients with atrial septal aneurysms and patients with a large shunt size.

The findings are from a new analysis of data from the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial. Jeffrey Saver, MD, Professor of Neurology at the University of California, Los Angeles, and colleagues initiated the RESPECT trial to determine whether PFO closure with the AMPLATZER device is superior to medical treatment in preventing recurrent embolic stroke.

The purpose of the new analysis was to characterize the ischemic strokes that participants in the RESPECT trial had had at baseline and the end-point ischemic strokes that they had during the trial. The investigators hoped to learn new information about the device's potential mechanisms of action.

PFO Closure Reduced Recurrent Stroke
In the RESPECT trial, which was undertaken at 69 sites in the United States and Canada, patients with PFO who had had cryptogenic ischemic stroke were randomized to closure with the AMPLATZER PFO Occluder or to medical therapy consisting of any of four guideline-approved antithrombotic regimens (ie, aspirin, warfarin, clopidogrel, or aspirin with dipyridamole). The two treatment arms had equal numbers of patients. Subjects were enrolled within 270 days of the qualifying stroke, underwent a detailed workup, and were excluded if a cause of their stroke, such as small-vessel disease, could be identified.

The primary outcome measure was the composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, and early postrandomization death. A secondary outcome measure was complete closure of the defect, as demonstrated by transesophageal echocardiography and bubble study, in the device group. An academic steering committee oversaw the trial, and clinical events were adjudicated independently.

In the intention-to-treat raw analysis and the time-to-event analysis, PFO closure with the AMPLATZER PFO Occluder was associated with a nonsignificant reduction in recurrent stroke ranging from 47 to 51%. The device was associated with a greater, significant reduction in recurrent stroke ranging from 63 to 73% in the per-protocol and as-treated analyses, said Dr. Saver.

PFO Closure May Prevent Superficial Infarcts
The follow-on analysis suggested that PFO closure with the AMPLATZER Occluder had a greater benefit in patients with an isolated superficial qualifying infarct, rather than a small and deep infarct. "Compared with the device group, the medical group had a greater number of end-point strokes that were superficial, or mixed deep and superficial, or otherwise not small and deep in distribution," said Dr. Saver.

The researchers also observed that 69% of the recurrent strokes in the medical group had a diameter greater than 1.5 cm, compared with 14% of the recurrent strokes in the device group. The difference between the groups fell just short of statistical significance, however.

Six of the 25 recurrent strokes were determined to have a definite cause other than the PFO. The other recurrent strokes were cryptogenic and were more common in the medical group than in the device group.

In the intention-to-treat analysis, nine strokes occurred in the device group. Three of these strokes occurred in patients who did not have a device in place at the time. Alternative causes were evident for two other strokes, two were small, deep infarcts, and two were superficial and cryptogenic in patients with devices.

"These data demonstrate that the RESPECT population succeeded in being stringently selected to identify patients with cryptogenic ischemic stroke," said Dr. Saver. The frequency of recurring strokes due to a defined mechanism other than PFO was 0.2% per year. "The exclusion of small, deep infarcts likely due to intrinsic small-vessel disease seemed to succeed in limiting the number of recurring small, deep infarcts," Dr. Saver added.

End-Point Event Data Were Incomplete for Some Patients
A limitation of the additional analysis is that the Forest plot subgroup analysis was limited in power because it included only 25 events. "But, clinically, the features identified as potentially having magnified device effect—having an atrial septal aneurysm, having a larger shunt size, and having a superficial distribution of the qualifying infarct—are all relevant and pathophysiologically support a potential benefit of closing a PFO with the device," said Dr. Saver.

The workup of the end-point events was incomplete for patients whose strokes occurred outside the study centers. Although all patients underwent a detailed workup at the time of their qualifying stroke, not all were subjected to the full repeat workup. Complete data were available for most of the patients, however.

RESPECT Versus CLOSURE Trials
Dr. Saver suggested several possible reasons that PFO closure with a device was associated with a likely benefit in the RESPECT trial, although the procedure did not demonstrate a benefit in the previous CLOSURE trial. "We followed patients up to eight years, and CLOSURE only followed patients for two years. If you look at the Kaplan–Meier curves that we have up to two years, they look very similar to the Kaplan–Meier curves for CLOSURE, which were going in the right direction, but they did not reach statistical significance," said Dr. Saver.

The RESPECT trial included more stringent criteria for patient selection than CLOSURE, and may also have tested a better device, noted Dr. Saver. The AMPLATZER PFO Occluder was not associated with a significant increase in atrial fibrillation in patients who received it. It thus did not create risk factors for stroke as other devices have, he added.

"Consideration of the neurovascular aspects of the RESPECT trial reinforces the primary analysis," said Dr. Saver. "Stringent patient selection to identify patients with a history of cryptogenic stroke and PFO closure with the AMPLATZER PFO Occluder showed evidence of benefit over medical management alone," he concluded.