In the JournalsPerspective

Three new studies show benefit of PFO closure on reduced risk for recurrent stroke

New data from the CLOSE, REDUCE and RESPECT trials demonstrated a lower rate of recurrent ischemic stroke after patent foramen ovale closure compared with antiplatelet therapy alone in patients with a patent foramen ovale and recent cryptogenic stroke.

The new data are in contrast to three other recent trials published in the past 5 years — CLOSURE I, PC, RESPECT (2013) — that did not show the same benefit of PFO closure over medical therapy in this patient population.

RESPECT trial

The multicenter, randomized, open-label RESPECT trial enrolled 980 patients (mean age, 46 years; 55%) with at 69 sites. Patients were randomly assigned to undergo PFO closure with the Amplatzer PFO Occluder (Abbott) medical therapy (n = 499) or medical therapy alone (n = 481). Those in the PFO closure group received aspirin with clopidogrel for 1 month, then aspirin monotherapy for 5 months. Those in the medical therapy group could receive warfarin, aspirin, clopidogrel or aspirin with extended-release dipyridamole.

The primary efficacy endpoint was a composite of fatal ischemic stroke, recurrent nonfatal ischemic stroke or early death. Follow-up was performed for a median of 5.9 years.

Initial results of the primary outcome were previously reported. Jeffrey L. Saver, MD, professor of neurology at the University of California, Los Angeles, and colleagues reported new data from the extended follow-up period. The final results out to 6 years were previously presented at the TCT Scientific Symposium in November 2016

According to the main findings:

  • recurrent ischemic stroke occurred in 3.6% in the PFO closure group (0.58 events per 100 patient-years) vs. 5.8% in the medical therapy group (1.07 events per 100 patient-years; HR = 0.55; 95% CI, 0.31-0.999);
  • recurrent ischemic stroke of an undetermined cause occurred in 2% of the PFO closure group (0.32 events per 100 patient-years) vs. 4.8% of the medical therapy group (0.86 per 100 patient-years; HR = 0.38; 95% CI, 0.18-0.79).
  • the rate of pulmonary embolism was 0.41 per 100 patient-years in the PFO closure group vs. 0.11 per 100 patient-years in the medical therapy group (HR = 3.48; 95% CI, 0.98-12.34); and
  • the rate of deep-vein thrombosis was 0.16 per 100 patient-years in the PFO closure group vs. 0.04 per 100 patient-years in the medical therapy group (HR = 4.44; 95% CI, 0.52-38.05).

“The rate of venous thromboembolism in both groups exceeded that in healthy populations, which suggests that persons who have had a cryptogenic stroke and also have a PFO have a mildly elevated long-term risk of venous thromboemboli,” Saver and colleagues wrote.

In other results, seven patients in the PFO closure group and 11 in the medical therapy group died during the study. The rate of serious adverse events was higher among patients who underwent PFO closure, but was not statistically different between the groups (40.3% vs. 36%; P = .17).

“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, in that the entry criteria and treatments were the same as those of the original trial; the main difference was that the median duration of follow-up was 2.1 years in the original trial and 5.9 years in the extended follow-up,” Allan H. Ropper, MD, executive vice chair of the department of neurology at Brigham and Women’s Hospital and professor of neurology at Harvard Medical School, wrote in a related editorial published in NEJM.

CLOSE trial

The multicenter, randomized, open-label CLOSE trial included 663 patients (mean age, 43 years; mostly male) with recurrent ischemic stroke due to a PFO, with an atrial septal aneurysm or large interatrial shunt.

In total, 524 patients were randomly assigned in a 1:1:1 ratio to undergo transcatheter PFO closure with long-term antiplatelet therapy consisting of aspirin, clopidogrel or aspirin plus extended-release dipyridamole (n = 173), anticoagulation (n = 180) or antiplatelet therapy only (n = 171). Additional randomized analyses focused on patients with contraindications to oral anticoagulants or PFO closure, who were randomly assigned to receive antiplatelet therapy or alternative noncontraindicated treatment. Neurologists performed assessments at 2 months, 6 months and every 6 months until the end of the study. Those in the PFO closure group had ECGs performed within 6 to 12 months after the procedure.

The primary efficacy outcome was incidence of nonfatal/fatal stroke. Secondary efficacy outcomes included disabling stroke, ischemic stroke, all-cause mortality and procedure success. Mean follow-up was 5.3 years.

According to the main findings:

  • comparing outcomes with PFO closure vs. antiplatelet therapy only, 0 strokes in PFO closure group vs. 14 strokes in the medical therapy group (HR = 0.03; 95% CI, 0-0.26);
  • a composite outcome of stroke, transient ischemic attack and systemic embolism was higher in the antiplatelet therapy group (8.9% vs. 3.4%; HR = 0.39; 95% CI, 0.16-0.82);
  • about 6% of patients had complications related to the PFO closure procedure;
  • ·new-onset atrial fibrillation or flutter occurred in 4.6% of the PFO closure group vs. 0.9% of the antiplatelet-only group (P = .02); and
  • comparing outcomes with anticoagulation vs. antiplatelet therapy only, three strokes in anticoagulation group vs. seven strokes in the antiplatelet-only group (HR = 0.44; 95% CI, 0.11-1.48).

“The rate of new-onset atrial fibrillation was significantly higher in the PFO closure group than in antiplatelet-only group in our trial, with most cases detected within 1 month after the procedure — a finding that suggests that the procedure itself induces atrial fibrillation,” Jean-Louis Mas, professor and head of the department of neurology at Hôpital Sainte-Anne in Paris, and colleagues wrote.

REDUCE trial

The multinational, prospective, randomized, controlled, open-label REDUCE trial enrolled 664 patients (mean age, 45 years) with a PFO with right-to-left shunt and cryptogenic stroke. Most patients (81%) had moderate or large interatrial shunts.

Patients were randomly assigned to undergo PFO closure with the Helex Septal Occluder or Cardioform Septal Occluder (W.L. Gore and Associates) in addition to antiplatelet therapy (n = 441; 59% men) or antiplatelet therapy alone (n = 223; 62% men). Antiplatelet therapy consisted of aspirin, clopidogrel or aspirin with extended-release dipyridamole.

Lars Søndergaard, MD
Lars Søndergaard

Patients were followed for up to 60 months, which included a visit with a neurologist, brain imaging, a questionnaire and MRI. Those who underwent PFO closure also had a follow-up ECG at 1, 12 and 24 months.

Coprimary endpoints of interest included freedom from clinical evidence of an ischemic stroke for at least 24 months and incidence of a new brain infarction. Secondary endpoints of interest were PFO closure success and adverse events. Median follow-up was 3.2 years.

According to the main findings:

  • recurrent clinical ischemic stroke occurred in 1.4% of the PFO closure group vs. 5.4% of the antiplatelet-only group (HR = 0.23; 95% CI, 0.09-0.62);
  • ·new brain infarction occurred in 5.7% of the PFO group vs. 11.3% in the antiplatelet-only group (absolute difference, 5.6 percentage points; 95% CI, 0.3-10.8; RR = 0.51; 95% CI, 0.29-0.91);
  • the rate of silent brain infarctions did not different between the two groups (P = .97); and
  • AF or flutter was observed in 6.6% of the PFO group vs. 0.4% of the antiplatelet-only group (P < .001).

“Atrial fibrillation was more commonly reported in the PFO closure group, but it was usually transient,” Lars Søndergaard, MD, professor of cardiology at the University of Copenhagen in Denmark, and colleagues wrote. “The clinical relevance of atrial fibrillation related to closure and overall risk of stroke requires further investigation.”

Serious adverse events were seen in 23.1% of patients assigned PFO closure and 27.8% of patients assigned antiplatelet only (P = .22). Serious device-related adverse events occurred in 1.4% of the PFO closure group.

Taken together

“One conclusion from the six trials [we have to date] … is that the potential benefit from closure is determined on the basis of the positive characteristics of the PFO rather than on the basis of exclusionary factors that make a stroke cryptogenic,” Ropper wrote in his editorial. “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.” – by Darlene Dobkowski

Editor’s note: This article was updated on Sept. 14, 2017, to correctly note that the Amplatzer PFO Occluder is manufactured by Abbott.


References:

Mas J-L, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1705915.

Ropper AH. N Engl J Med. 2017;doi:10.1056/NEJMe1709637.

Saver JL, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1610057.

Søndergaard L, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707404.

Disclosures: The RESPECT trial was funded by St. Jude Medical. The REDUCE trial was funded by W.L. Gore and Associates. Mas reports he has received personal fees from Bayer, Boehringer Ingelheim and Bristol-Myers Squibb. Ropper is a deputy editor of The New England Journal of Medicine. Saver reports he has received grants and personal fees from Boehringer Ingelheim and St. Jude Medical. Søndergaard reports he has received grant and personal fees from W.L. Gore and Associates. Please see the studies for all other authors’ relevant financial disclosures.

New data from the CLOSE, REDUCE and RESPECT trials demonstrated a lower rate of recurrent ischemic stroke after patent foramen ovale closure compared with antiplatelet therapy alone in patients with a patent foramen ovale and recent cryptogenic stroke.

The new data are in contrast to three other recent trials published in the past 5 years — CLOSURE I, PC, RESPECT (2013) — that did not show the same benefit of PFO closure over medical therapy in this patient population.

RESPECT trial

The multicenter, randomized, open-label RESPECT trial enrolled 980 patients (mean age, 46 years; 55%) with at 69 sites. Patients were randomly assigned to undergo PFO closure with the Amplatzer PFO Occluder (Abbott) medical therapy (n = 499) or medical therapy alone (n = 481). Those in the PFO closure group received aspirin with clopidogrel for 1 month, then aspirin monotherapy for 5 months. Those in the medical therapy group could receive warfarin, aspirin, clopidogrel or aspirin with extended-release dipyridamole.

The primary efficacy endpoint was a composite of fatal ischemic stroke, recurrent nonfatal ischemic stroke or early death. Follow-up was performed for a median of 5.9 years.

Initial results of the primary outcome were previously reported. Jeffrey L. Saver, MD, professor of neurology at the University of California, Los Angeles, and colleagues reported new data from the extended follow-up period. The final results out to 6 years were previously presented at the TCT Scientific Symposium in November 2016

PAGE BREAK

According to the main findings:

  • recurrent ischemic stroke occurred in 3.6% in the PFO closure group (0.58 events per 100 patient-years) vs. 5.8% in the medical therapy group (1.07 events per 100 patient-years; HR = 0.55; 95% CI, 0.31-0.999);
  • recurrent ischemic stroke of an undetermined cause occurred in 2% of the PFO closure group (0.32 events per 100 patient-years) vs. 4.8% of the medical therapy group (0.86 per 100 patient-years; HR = 0.38; 95% CI, 0.18-0.79).
  • the rate of pulmonary embolism was 0.41 per 100 patient-years in the PFO closure group vs. 0.11 per 100 patient-years in the medical therapy group (HR = 3.48; 95% CI, 0.98-12.34); and
  • the rate of deep-vein thrombosis was 0.16 per 100 patient-years in the PFO closure group vs. 0.04 per 100 patient-years in the medical therapy group (HR = 4.44; 95% CI, 0.52-38.05).

“The rate of venous thromboembolism in both groups exceeded that in healthy populations, which suggests that persons who have had a cryptogenic stroke and also have a PFO have a mildly elevated long-term risk of venous thromboemboli,” Saver and colleagues wrote.

In other results, seven patients in the PFO closure group and 11 in the medical therapy group died during the study. The rate of serious adverse events was higher among patients who underwent PFO closure, but was not statistically different between the groups (40.3% vs. 36%; P = .17).

“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, in that the entry criteria and treatments were the same as those of the original trial; the main difference was that the median duration of follow-up was 2.1 years in the original trial and 5.9 years in the extended follow-up,” Allan H. Ropper, MD, executive vice chair of the department of neurology at Brigham and Women’s Hospital and professor of neurology at Harvard Medical School, wrote in a related editorial published in NEJM.

CLOSE trial

The multicenter, randomized, open-label CLOSE trial included 663 patients (mean age, 43 years; mostly male) with recurrent ischemic stroke due to a PFO, with an atrial septal aneurysm or large interatrial shunt.

PAGE BREAK

In total, 524 patients were randomly assigned in a 1:1:1 ratio to undergo transcatheter PFO closure with long-term antiplatelet therapy consisting of aspirin, clopidogrel or aspirin plus extended-release dipyridamole (n = 173), anticoagulation (n = 180) or antiplatelet therapy only (n = 171). Additional randomized analyses focused on patients with contraindications to oral anticoagulants or PFO closure, who were randomly assigned to receive antiplatelet therapy or alternative noncontraindicated treatment. Neurologists performed assessments at 2 months, 6 months and every 6 months until the end of the study. Those in the PFO closure group had ECGs performed within 6 to 12 months after the procedure.

The primary efficacy outcome was incidence of nonfatal/fatal stroke. Secondary efficacy outcomes included disabling stroke, ischemic stroke, all-cause mortality and procedure success. Mean follow-up was 5.3 years.

According to the main findings:

  • comparing outcomes with PFO closure vs. antiplatelet therapy only, 0 strokes in PFO closure group vs. 14 strokes in the medical therapy group (HR = 0.03; 95% CI, 0-0.26);
  • a composite outcome of stroke, transient ischemic attack and systemic embolism was higher in the antiplatelet therapy group (8.9% vs. 3.4%; HR = 0.39; 95% CI, 0.16-0.82);
  • about 6% of patients had complications related to the PFO closure procedure;
  • ·new-onset atrial fibrillation or flutter occurred in 4.6% of the PFO closure group vs. 0.9% of the antiplatelet-only group (P = .02); and
  • comparing outcomes with anticoagulation vs. antiplatelet therapy only, three strokes in anticoagulation group vs. seven strokes in the antiplatelet-only group (HR = 0.44; 95% CI, 0.11-1.48).

“The rate of new-onset atrial fibrillation was significantly higher in the PFO closure group than in antiplatelet-only group in our trial, with most cases detected within 1 month after the procedure — a finding that suggests that the procedure itself induces atrial fibrillation,” Jean-Louis Mas, professor and head of the department of neurology at Hôpital Sainte-Anne in Paris, and colleagues wrote.

REDUCE trial

The multinational, prospective, randomized, controlled, open-label REDUCE trial enrolled 664 patients (mean age, 45 years) with a PFO with right-to-left shunt and cryptogenic stroke. Most patients (81%) had moderate or large interatrial shunts.

Patients were randomly assigned to undergo PFO closure with the Helex Septal Occluder or Cardioform Septal Occluder (W.L. Gore and Associates) in addition to antiplatelet therapy (n = 441; 59% men) or antiplatelet therapy alone (n = 223; 62% men). Antiplatelet therapy consisted of aspirin, clopidogrel or aspirin with extended-release dipyridamole.

PAGE BREAK

Lars Søndergaard, MD
Lars Søndergaard

Patients were followed for up to 60 months, which included a visit with a neurologist, brain imaging, a questionnaire and MRI. Those who underwent PFO closure also had a follow-up ECG at 1, 12 and 24 months.

Coprimary endpoints of interest included freedom from clinical evidence of an ischemic stroke for at least 24 months and incidence of a new brain infarction. Secondary endpoints of interest were PFO closure success and adverse events. Median follow-up was 3.2 years.

According to the main findings:

  • recurrent clinical ischemic stroke occurred in 1.4% of the PFO closure group vs. 5.4% of the antiplatelet-only group (HR = 0.23; 95% CI, 0.09-0.62);
  • ·new brain infarction occurred in 5.7% of the PFO group vs. 11.3% in the antiplatelet-only group (absolute difference, 5.6 percentage points; 95% CI, 0.3-10.8; RR = 0.51; 95% CI, 0.29-0.91);
  • the rate of silent brain infarctions did not different between the two groups (P = .97); and
  • AF or flutter was observed in 6.6% of the PFO group vs. 0.4% of the antiplatelet-only group (P < .001).

“Atrial fibrillation was more commonly reported in the PFO closure group, but it was usually transient,” Lars Søndergaard, MD, professor of cardiology at the University of Copenhagen in Denmark, and colleagues wrote. “The clinical relevance of atrial fibrillation related to closure and overall risk of stroke requires further investigation.”

Serious adverse events were seen in 23.1% of patients assigned PFO closure and 27.8% of patients assigned antiplatelet only (P = .22). Serious device-related adverse events occurred in 1.4% of the PFO closure group.

Taken together

“One conclusion from the six trials [we have to date] … is that the potential benefit from closure is determined on the basis of the positive characteristics of the PFO rather than on the basis of exclusionary factors that make a stroke cryptogenic,” Ropper wrote in his editorial. “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.” – by Darlene Dobkowski

Editor’s note: This article was updated on Sept. 14, 2017, to correctly note that the Amplatzer PFO Occluder is manufactured by Abbott.


References:

Mas J-L, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1705915.

Ropper AH. N Engl J Med. 2017;doi:10.1056/NEJMe1709637.

Saver JL, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1610057.

Søndergaard L, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707404.

Disclosures: The RESPECT trial was funded by St. Jude Medical. The REDUCE trial was funded by W.L. Gore and Associates. Mas reports he has received personal fees from Bayer, Boehringer Ingelheim and Bristol-Myers Squibb. Ropper is a deputy editor of The New England Journal of Medicine. Saver reports he has received grants and personal fees from Boehringer Ingelheim and St. Jude Medical. Søndergaard reports he has received grant and personal fees from W.L. Gore and Associates. Please see the studies for all other authors’ relevant financial disclosures.

    Perspective

    Steven R. Messe

    These manuscripts, one reporting additional follow-up from a previously published randomized trial and two new randomized trials of PFO closure, all demonstrate a reduction in recurrent stroke risk in patients who underwent closure compared to those treated only with medication.

    These findings absolutely have implication for clinical practice. Although it has taken a long time to complete the studies, there is finally strong evidence that, in carefully selected patients, PFO closure does reduce recurrent stroke risk. The challenge will be to select patients in clinical practice to recommend for PFO closure. Stroke is a heterogeneous disorder and PFO is common in adults (found in about 1 in 4 on transesophageal echo), so not every PFO that is identified is the cause of the stroke. Sticking to the inclusion/exclusion criteria for these studies will be a good place to start.
    There are reasonable data to question whether a direct oral anticoagulant would be as effective as PFO closure for stroke prevention, and more effective for venous thromboembolism. The ESUS (embolic stroke of uncertain source) trials comparing direct oral anticoagulants to antiplatelets, of which there are at least two underway and a third starting soon, may shed some light on this topic. 

    We need to continue to follow patients who have received a closure device, as the very long term sequelae have not been well characterized.

    • Steven R. Messe, MD
    • Associate Professor of Neurology
      Director, Vascular Neurology Fellowship
      Hospital of the University of Pennsylvania

    Disclosures: Messe reports he was the local principal investigator for the Gore REDUCE PFO closure study.