Residual Shunt After PFO Closure Increases Stroke Risk

Be careful out there. How is your doctor addressing this risk to reduce it to zero?

Residual Shunt After PFO Closure Increases Stroke Risk

Significant risk seen with moderate and large shunts

by Zeena Nackerdien PhD, CME Writer, MedPage Today 2020-06-16

Study Authors: Wenjun Deng, Shanye Yin, et al.; William G. Kussmaul
Target Audience and Goal Statement: Cardiologists, neurologists
The goal of this study was to evaluate the long-term association of residual shunt after percutaneous patent foramen ovale (PFO) closure with the incidence of recurrent neurologic events.
Question Addressed:

• What was the association of residual shunt after PFO closure with the incidence of recurrent stroke and transient ischemic attack (TIA)?

Study Synopsis and Perspective:
PFO is a remnant of fetal circulation, commonly found in adult populations, with a prevalence of 27% in autopsy studies. This channel-like communication between the atria exists in everyone before birth, but most often closes shortly after being born.

Action Points

• The presence of residual shunt after percutaneous patent foramen ovale (PFO) closure was associated with an increased risk of recurrent stroke or transient ischemic attack, according to a single-center prospective cohort study.
• Note that small residual shunts were not significantly linked to increased risk, while moderate or large residual shunts were.

As an obvious substrate for right-to-left shunting, PFO has been implicated in many pathologies, including cryptogenic stroke. The mechanism presumably involves venous thromboemboli crossing from the right to the left atria.
Several studies have shown the efficacy of PFO closure in preventing recurrent stroke, especially in patients with a large shunt. In the absence of another obvious cause of stroke, PFO closure is considered to be a reasonable treatment, especially in young patients.
However, residual shunting has been observed in up to 25% of patients after PFO closure, and nearly 10% showed moderate to large residual shunting, with unclear significance.
In a prospective cohort study, MingMing Ning, MD, MMSc, of Massachusetts General Hospital and Harvard Medical School, and colleagues found that the presence of residual shunt after PFO closure was associated with an elevated risk of stroke or TIA recurrence years after the procedure. Their findings were published in the Annals of Internal Medicine.
Ning and team analyzed single-center data collected from 2015 to 2017 from consecutive patients with PFO-attributable cryptogenic stroke who were eligible for percutaneous PFO closure. In total, 1,078 patients (mean age 49.3 years) had PFO closure with successful device placement and were followed for up to 11 years, with an average duration of 3.7 years and a total observation period of 3,988 patient-years.
At discharge, all patients received antiplatelet treatment (aspirin, clopidogrel, or both) and short- or long-term anticoagulation therapy, depending on their hypercoagulable status.
Following transcatheter closure, each patient had a transthoracic echocardiogram (TTE) with intravenous saline injection. This is the standard procedure for detecting intracardiac right-to-left shunting. TTEs were performed at 24 hours, at 1 and 6 months, and annually.
The maximum number of bubbles appearing in the left atrium within three cardiac cycles after agitated saline injection was used to determine the shunt size. No bubbles meant no shunt, one to 10 bubbles referred to a small shunt, 10 to 30 bubbles described a moderate shunt, and more than 30 bubbles referred to a large shunt.
The prespecified primary outcome was the composite of first recurrent ischemic stroke or TIA after PFO closure. Etiology or cause of recurrent stroke was determined by two independent vascular neurologists on the basis of TOAST criteria.
In keeping with findings from previous trials, the researchers observed effective closure (no or small residual shunt) in 985 patients (91.4%). No shunt was seen in 835 patients (77.5%). Residual shunt was observed in 243 patients (22.5%), with a small shunt in 150 patients (13.9%) and a moderate or large shunt in 93 patients (8.6%), according to the team.
The primary outcome occurred in 18 patients in the shunt group (2.32 per 100 patient-years) and 24 patients in the no-shunt group (0.75 per 100 patient-years). The elevated risk persisted after adjustment for factors associated with PFO closure, traditional stroke risk factors, high-risk PFO features, and medication use (adjusted HR 3.01, 95% CI 1.59-5.69).
For patients with and without residual shunt, the cumulative probability of recurrent stroke or TIA 5 years after closure was 9.3% and 2.5%, respectively.
A higher incidence of recurrent stroke or TIA was observed for patients with a moderate or large shunt compared with patients with no shunt (HR 4.50, 95% CI 2.20-9.20, P<0.001). Small residual shunts were not significantly associated with increased risk (HR 2.02, 95% CI 0.87-4.69, P=0.102).
People with moderate or large shunts were older (52.2 vs 47.1 years with small shunt, P=0.009) and had higher rates of atrial septal aneurysm, hypertension, hyperlipidemia, and diabetes. After these confounders were included for covariate adjustment, larger shunt size was still associated with a higher rate of stroke or TIA recurrence.
Source References: Annals of Internal Medicine 2020; DOI: 10.7326/M19-3583
Editorial: Annals of Internal Medicine 2020; DOI: 10.7326/M20-1879

 

Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale–Associated Stroke

So is this now the protocol for PFOs? And where is it located so stroke patients can find it and deliver it to their doctors? 

Did your hospital put this protocol in place two years ago? Do you prefer your hospital incompetence NOT KNOWING OR NOT DOING? Ask your board of directors that question and don't leave until they answer.

Trial Bolsters Evidence in Favor of Closing Hole in Heart After Stroke March 2018

Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale–Associated Stroke

Akram Y. Elgendy, MD¹; Jeffrey L. Saver, MD²; Zahid Amin, MD³; et al Konstantinos Dean Boudoulas, MD⁴; John D. Carroll, MD⁵; Islam Y. Elgendy, MD⁶; Iris Q. Grunwald, MD^7,8; Zachary M. Gertz, MD⁹; Ziyad M. Hijazi, MD, MPH¹⁰; Eric M. Horlick, MD¹¹; Scott E. Kasner, MD¹²; David M. Kent, MD¹³; Preetham Kumar, MD¹⁴; Clifford J. Kavinsky, MD, PhD¹⁵; David S. Liebeskind, MD²; Helmi Lutsep, MD¹⁶; Mohammad K. Mojadidi, MD⁹; Steven R. Messé, MD¹²; Jean-Louis Mas, MD¹⁷; Heinrich P. Mattle, MD¹⁸; Bernhard Meier, MD¹⁹; Ahmad Mahmoud, MD, MSc²⁰; Ahmed N. Mahmoud, MD²¹; Fabian Nietlispach, MD, PhD²²; Nimesh K. Patel, MD⁹; John F. Rhodes, MD²³; Mark Reisman, MD²¹; Robert J. Sommer, MD²⁴; Horst Sievert, MD^7,8; Lars Søndergaard, MD²⁵; Muhammad O. Zaman, MD²⁰; David Thaler, MD¹³; Jonathan M. Tobis, MD; MSCAI14

Author Affiliations

JAMA Neurol. Published online April 13, 2020. doi:10.1001/jamaneurol.2020.0458

Abstract

Importance  Recent epidemiologic and therapeutic advances have transformed understanding of the role of and therapeutic approach to patent foramen ovale (PFO) in ischemic stroke. Patent foramen ovale is likely responsible for approximately 5% of all ischemic strokes and 10% of those occurring in young and middle-aged adults.
Observations  Randomized clinical trials have demonstrated that, to prevent recurrent ischemic stroke in patients with PFO and an otherwise-cryptogenic index ischemic stroke, PFO closure is superior to antiplatelet medical therapy alone; these trials have provided some evidence that, among medical therapy options, anticoagulants may be more effective than antiplatelet agents.
Conclusions and Relevance  These new data indicate a need to update classification schemes of causative mechanisms in stroke, developed in an era in which an association between PFO and stroke was viewed as uncertain. We propose a revised general nomenclature and classification framework for PFO-associated stroke and detailed revisions for the 3 major stroke subtyping algorithms in wide use.

Full Text

Trial Bolsters Evidence in Favor of Closing Hole in Heart After Stroke

Discuss with your doctor.

Trial Bolsters Evidence in Favor of Closing Hole in Heart After Stroke

12 March 2018 American College of Cardiology

Among people with a type of hole in the heart, known as patent foramen ovale (PFO), those who received a medical device to close this opening after a stroke fared better after two years compared with those who received stroke-preventing medications alone. These findings from a study being presented at the American College of Cardiology’s 67th Annual Scientific Session support the results of several similar trials in recent years and suggest patients with a high-risk PFO are likely to benefit most from the device.

PFO is a congenital heart defect that occurs when a small hole between the top two chambers of the heart fails to fully close after birth. An estimated 1 in 4 people have a PFO, though many are undiagnosed. The condition does not typically cause symptoms but may increase the risk of stroke. Among patients younger than 55 years of age who experience a stroke of unknown cause, a cryptogenic stroke, the prevalence of PFOs has been found to be around 46 percent, much higher than the rate of PFOs in the general population. The new findings add to a growing body of evidence that closing the PFO after this type of stroke can help prevent subsequent strokes and related problems, particularly in those with a high-risk PFO.

Researchers stopped enrollment for the trial early after determining, based on the results of several recent trials, that it would be unethical to continue assigning some patients to not receive the PFO closure device in light of mounting evidence of its clear benefits. Despite the smaller-than-expected number of participants, researchers said the new trial helps clarify which patients are likely to benefit most from the medical device based on the physical characteristics of their PFO.  

“Considering the high prevalence of PFO in the general population and cryptogenic stroke patients, the key to appropriate use of this medical device is determining how to select optimal candidates for the procedure,” said Jae Kwan Song, MD, a cardiologist at Asan Medical Center in Seoul, South Korea and the study’s lead author. “Our study showed that the potential benefit from closure can be determined on the basis of the size of the PFO and the movement of the heart wall around the PFO.”

The trial enrolled 120 patients at two centers in South Korea. All patients had recently experienced a cryptogenic stroke and were found to have a high-risk PFO, meaning either the PFO was 2 millimeters across (about the size of a peppercorn) or larger, or the PFO was accompanied by an outgrowth of tissue protruding into one of the heart’s chambers.

All patients received medications such as anticoagulants or antiplatelet drugs, which are recommended after a stroke to reduce the formation of blood clots and prevent subsequent strokes. The specific type of medication was determined by each patient’s physician, although no direct oral anticoagulants (also known as novel oral anticoagulants) were used in the study. Half of the patients were randomly assigned to receive a PFO closure device, which interventional cardiologists implanted in the heart by threading the device through a vein in the groin, while the other half received medications alone.

Researchers followed patient outcomes for two years. The study’s primary endpoint was a composite of stroke, major bleeding events and death from vascular causes (death related to the blockage or rupture of blood vessels). While no such events occurred in the 60 patients receiving PFO closure, among the 60 patients receiving medications alone, six had a stroke and one had a transient ischemic attack, or “mini-stroke.” These results suggest that treating 10 PFOs with a closure device would be expected to prevent, on average, about one stroke after two years.

“We believe that PFO closure should be done in selected patients with cryptogenic stroke and PFO,” Song said. “With our study and other recent trials, the criteria for selecting patients for the procedure are becoming clearer; in particular, the results suggest that closure is beneficial for those with high-risk PFO.”

There are several available medications to prevent blood clots in people who have experienced a stroke, including antiplatelet drugs, direct oral anticoagulants and traditional anticoagulants such as warfarin. Because trials for PFO closure devices have been inconsistent in their selection of medications, Song said additional studies are needed to clarify the potential benefits of different medications when used post-stroke in patients with PFO.

The trial was supported by a research grant from the Cardiovascular Research Foundation (CVRF) in Seoul, South Korea.

This study was simultaneously published online in the Journal of the American College of Cardiology at the time of presentation.

The ACC’s Annual Scientific Session, which is taking place March 10-12 in Orlando, brings together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention. Follow @ACCinTouch, @ACCMediaCenter and #ACC18 for the latest news from the meeting.

• Full bibliographic informationCryptogenic Stroke and High-Risk Patent Foramen Ovale: The DEFENSE-PFO Trial
  Pil Hyung Lee, et al.
  Journal of the American College of Cardiology
  Published online March 12, 2018

Meta-Analyses Support Stroke Prevention With PFO Closure

How out-of-date is your doctor if closure is not recommended? Way back to Feb. 2013? Is your doctor that bad? 

Meta-Analyses Support Stroke Prevention With PFO Closure

Fewer recurrent strokes than with medical therapy alone in pooled data

• by Nicole Lou, Reporter, MedPage Today/CRTonline.org January 08, 2018

Percutaneous closure of the patent foramen ovale (PFO) reduced risk of recurrent stroke compared to medical therapy alone, according to two separate meta-analyses pooling the PC, RESPECT, CLOSE, and REDUCE trials.
The first, by Ciro Indolfi, MD, of Italy's Magna Graecia University, and colleagues, found that PFO closure among those have suffered a cryptogenic stroke reduced the risk of stroke or transient ischemic attack (TIA) to 3.36% over more than 3 year's follow-up compared with 8.94% with medical management (risk difference -0.029, 95% CI -0.050 to -0.007).
In fact, the larger the interatrial shunt, the more effective PFO closure appeared to be, according to the study published in the Annals of Internal Medicine. PFO closure did increase the risk of new-onset atrial fibrillation (Afib) or atrial flutter, however (4.62% versus 0.85%, risk difference 0.033, 95% CI 0.012-0.054).
"The results of this meta-analysis demonstrate that PFO closure prevents cardioembolic cerebrovascular events in patients with cryptogenic stroke and PFO. This finding represents a positive change in evidence, because three recent randomized trials [PC, RESPECT, CLOSURE I] failed to demonstrate superiority of PFO closure over medical therapy alone," the authors wrote. "Undersizing or inadequate sample sizes initially were blamed for the failure of these trials to demonstrate benefit, but the reasons are probably multifactorial."
Altogether, almost 3,000 participants were included in the meta-analysis.
"We believe that the new evidence warrants a revision of current practice guidelines. In addition, we think this finding of efficacy of PFO closure for patients with cryptogenic stroke might ignite further discussion regarding extending this treatment to primary prevention," Indolfi's group added.
"However, diverging results among single studies suggest that candidates for PFO closure should be selected carefully by using cardiac imaging to maximize clinical benefit and to avoid unnecessary risks for complications," they noted.
A separate meta-analysis of the same trials, published in the same journal, also suggested that the risk of recurrent stroke fell with PFO closure (1.81% versus 4.57% for medical therapy alone, risk difference -0.032, 95% CI -0.050 to -0.014).
In this analysis, there was no uptick in TIA or major bleeding with either strategy, according to researchers led by Rahman Shah, MD, of University of Tennessee in Memphis. PFO closure was, however, again associated with more new-onset Afib.
"Because recurrent stroke rates are low even with medical therapy alone and PFO closure might affect Afib risk, shared decision making is crucial for this treatment," the authors said.
Shah and colleagues emphasized that the PC, RESPECT, CLOSE, and REDUCE trials differed widely in devices tested and antithrombotic strategy allowed.
FDA-approved in 2016, St. Jude Medical's Amplatzer PFO Occluder was the sole device tested in the PC and RESPECT trials and accounted for more than half of cases in the 11-device CLOSE trial. REDUCE had tested the Gore Helex Septal Occluder and Gore Cardioform Septal Occluder.

Indolfi reported receiving grants from St. Jude Medical.
Shah listed no relevant conflicts of interest.

2018-01-08T17:45:00-0500

• Primary Source

  Annals of Internal Medicine

  Source Reference: De Rosa S, et al "Percutaneous closure versus medical treatment in stroke patients with patent foramen ovale: a systematic review and meta-analysis" Ann Intern Med 2018; DOI: 10.7326/M17-3033.

• Secondary Source

  Annals of Internal Medicine

  Source Reference: Shah R, et al "Device closure versus medical therapy alone for patent foramen ovale in patients with cryptogenic stroke: a systematic review and meta-analysis" Ann Intern Med 2018; DOI: 10.7326/M17-2679.

New Positive Data Push PFO Closure Pendulum Back to Positive

So only if you are the right candidate, otherwise you are fucking screwed. Stroke survivors once again being left behind.
https://www.medpagetoday.com/Cardiology/Strokes/67892?

Victory for devices seen in three trials

• by Nicole Lou, Contributing Writer, MedPage Today September 13, 2017
• This article is a collaboration between MedPage Today® and:
  

Action Points

• Note that three different randomized trials evaluating PFO closure for cryptogenic stroke show a benefit of the procedure, in contrast to prior studies.
• These studies differed from prior studies in several respects, but prominently in a focus on selecting patients with PFO characteristics that seemed highly amenable to beneficial closure.

The tide may be turning on patent foramen ovale (PFO) closure to prevent recurrent cryptogenic strokes, with three new trials reporting that the procedure can be effective with careful patient selection.
In October 2016, the Amplatzer PFO Occluder won FDA approval despite the large RESPECT trial showing it was not significantly better than medical management at preventing recurrent ischemic strokes.
How do the latest trial data -- all published in the Sept. 14 issue of the New England Journal of Medicine -- push PFO closure into positive territory? Following are highlights from the three new analyses.
CLOSE
There were no strokes observed more than 5 years after PFO closure whereas they occurred in 6.0% of those receiving antiplatelet therapy alone (HR 0.03, 95% CI 0-0.26) among patients eligible for either therapy (including those contraindicated to anticoagulants).
Atrial fibrillation (Afib) rates were elevated after PFO closure, however (4.6% versus 0.9% for antiplatelets-alone, P=0.02), in the randomized, multicenter CLOSE study conducted in France and Germany by Jean-Louie Mas, MD, PhD, of the Hôpital Sainte-Anne in Paris, and colleagues.
CLOSE enrolled 663 patients ages 16-60 with cryptogenic stroke attributed to PFO within the previous 6 months, and with an associated atrial septal aneurysm or large interatrial shunt. All were randomized to transcatheter PFO closure plus long-term antiplatelet therapy, antiplatelets alone, or oral anticoagulation.
Eleven different occluder devices were available for PFO occlusion.
Patients contraindicated to PFO closure exhibited stroke rates of 1.6% and 4.0% on anticoagulants and antiplatelet therapy, respectively.
While 5.9% of patients in the PFO closure arm had procedural complications, this group was at no greater risk for serious adverse events.
RESPECT Extension
With follow-up extended to a median 5.9 years, participants in RESPECT randomized to Amplatzer PFO closure had fewer combined recurrent nonfatal ischemic strokes, fatal ischemic strokes, and early deaths than the medical therapy group: 0.58 versus 1.07 events per 100 patient-years, HR 0.55, 95% CI 0.31-0.999).
ASCOD-adjudicated recurrent strokes of undetermined cause were reduced in this group (0.32 versus 0.86 per 100 patient-years, HR 0.38, 95% CI 0.18-0.79), as were TOAST-adjudicated cryptogenic strokes (0.03 versus 0.41 per 100 patient-years, HR 0.08, 95% CI 0.01-0.58), according to the team led by Jeffrey L. Saver, MD, of UCLA.
These investigators did not find significantly more periprocedural Afib after PFO occlusion (0.48 versus 0.34 per 100 patient-years with medical therapy, HR 1.47, 95% CI 0.64-3.37).
RESPECT randomized 980 patients to PFO closure or medical therapy alone. Notably, the extended follow-up period saw a particularly high dropout rate in the medical-therapy group (33.3% versus 20.8% with the occluder).
Gore REDUCE
PFO closure scored another win with the Gore Helex and Cardioform Septal Occluders, which brought recurrent strokes over a median 3.2 years' follow-up down to 1.4% (versus 5.4% for antiplatelets only, HR 0.23, 95% CI 0.09-0.62), according to the Gore REDUCE data.
The 24-month incidence of new brain infarcts -- combined clinical ischemic strokes and silent brain infarctions -- was halved (5.7% versus 11.3%, RR 0.51, 95% CI 0.29-0.91), reported Scott E. Kasner, MD, of Philadelphia's University of Pennsylvania, and colleagues. This finding was driven by the advantage in reduced clinical strokes (1.3% versus 6.8%, RR 0.19, 95% CI 0.07-0.54) -- with no difference detected for silent infarcts.
Device-related events occurred 1.4% of the time. After PFO closure, 6.6% still experienced Afib (versus 0.4% of controls, P<0 .001="" p=""> Gore REDUCE was a multicenter trial conducted across North America and Europe. Its 664 participants received baseline and 24-month brain imaging and were randomized 2:1 to PFO closure or antiplatelet therapy alone.
Rates of serious adverse events were no different between groups (23.1% versus 27.8%, P=0.22).
Making Sense of the Data
"How can we now have three trials showing that closure prevents recurrent stroke, given that in the past 5 years, the Journal published articles from three other trials that showed the opposite?" asked Allan Ropper, MD, of Brigham and Women's Hospital in Boston, in an editorial.
Ropper declared it "futile" to try to find the answer in antithrombotic therapy or follow-up duration differences among the trials (although he called the extended RESPECT trial "the most provocative" of the three because of the longer follow-up, he maintained that it doesn't answer the question).
Instead, he zeroed in on the "stringent" entry criteria in the CLOSE trial, which showed no strokes at all after PFO closure and had required that patients present at enrollment with a large interatrial shunt at rest (more than 30 microbubbles in the left atrium within three cardiac cycles after opacification of the right atrium) or an atrial septal aneurysm (a septum primum excursion greater than 10 mm).
"The Gore REDUCE trial, a trial with positive results that are also reported in this issue of the Journal, represented a middle ground by including patients with a moderate-to-large interatrial shunt but not requiring that patients have an atrial septal aneurysm (approximately 20% of the patients in the PFO closure group were found to have one at the time of the procedure)," he noted. Accordingly, Gore REDUCE still exhibited a low stroke rate over 3-year follow-up.
It appears that the effectiveness of PFO closure depends on choosing the right patients, the editorialist concluded. "[I]n 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."
The FDA's Take
In an accompanying NEJM perspective, three FDA officials practically gloated at the new results.
"The published results of these trials appear to support the general conclusions reached by the FDA in the evaluation of the Amplatzer PFO Occluder," wrote Andrew Farb, MD, and two colleagues from the agency's Center for Devices and Radiological Health.
Last year, the FDA decided that despite the uncertainty regarding the reduction in stroke risk attributable to the device, the potential benefit of PFO closure was viewed favorably in light of a low rate of serious adverse events. "[T]he balance was found to be acceptable for appropriate patients," Farb's group recalled.
"When determining whether to use this device, it's important that clinicians perform the recommended testing to target appropriate patients, understand the strengths and limitations of available clinical trial data, and discuss potential risks and benefits with their patients."

CLOSE was funded by the French Ministry of Health.
RESPECT was funded by Amplatzer’s manufacturer, St. Jude Medical (now Abbott).
Gore REDUCE was sponsored by W.L. Gore.

• Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

last updated 09.14.2017

• Primary Source

  New England Journal of Medicine

  Source Reference: Mas JL, et al "Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke" New Engl J Med 2017; DOI: 10.1056/NEJMoa1705915.

• Secondary Source

  New England Journal of Medicine

  Source Reference: Søndergaard L, et al "Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke" New Engl J Med 2017; DOI: 10.1056/NEJMoa1707404.

• Additional Source

  New England Journal of Medicine

  Source Reference: Saver JL, et al "Long-term outcomes of patent foramen ovale closure or medical therapy after stroke" New Engl J Med 2017; DOI: 10.1056/NEJMoa1610057.

Tipping Point for Patent Foramen Ovale Closure

I guess you are totally on your own figuring out what to do about your PFO.
https://t.co/redirect?url=http%3A%2F%2Fwww.nejm.org%2Fdoi%2Ffull%2F10.1056%2FNEJMe1709637%3Ft%3D1%26cn%3DZmxleGlibGVfcmVjcw%253D%253D%26refsrc%3Demail%26iid%3Dcb00a62393a84227adf05b182070a13e%26uid%3D625967110%26nid%3D244%2B281088008&t=1&cn=ZmxleGlibGVfcmVjcw%3D%3D&sig=7432cdbdb9033dd29ba4f63fdee9bf216c0831c0&iid=cb00a62393a84227adf05b182070a13e&uid=625967110&nid=244+281088008

Allan H. Ropper, M.D.

N Engl J Med 2017; 377:1093-1095September 14, 2017DOI: 10.1056/NEJMe1709637

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This article has no abstract; the first 100 words appear below.

On the basis of what I had read previously in the Journal, I recently explained to my 44-year-old patient that closing his patent foramen ovale (PFO) after his stroke was not advisable. How can we now have three trials showing that closure prevents recurrent stroke, given that in the past 5 years, the Journal published articles from three other trials that showed the opposite? It would be simple if the conversion from a negative to a positive outlook with respect to PFO closure could be explained by studying the various antiplatelet and anticoagulant treatments, or the various durations of follow-up . . .

Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.

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PFO Closure for Cryptogenic Stroke Prevents Recurrences

This was a long time coming.
https://www.medpagetoday.com/Cardiology/Strokes/65348?

First overall stroke reduction with closure reported in two trials

• by Crystal Phend
  Senior Associate Editor, MedPage Today May 16, 2017

Endovascular device closure of patent foramen ovale (PFO) reduced overall stroke risk for patients with a prior cryptogenic stroke, the CLOSE and REDUCE trials found.
The two trials reported at the European Stroke Organisation Conference (ESOC) in Prague are the first to find overall stroke reduction with the procedure.
Earlier results from the RESPECT trial gained FDA approval for the Amplatzer PFO Occluder based on a reduction in PFO-related second strokes without any effect on overall stroke risk, as was the case in the PC Trial with the device.
In the three-arm open-label CLOSE trial, which randomized 663 of a planned 900 patients to PFO closure with various investigational devices or to antiplatelet treatment or antithrombotic therapy, the hazard ratio for fatal or nonfatal stroke was 0.03 with closure versus antiplatelet therapy alone (95% CI 0-0.25, P<0.001; 0 versus 14 strokes over mean 5.3 years). The two medical arms didn't differ.
In the open-label REDUCE trial, randomizing 664 patients 2:1 to PFO closure with the Helex Septal Occluder or Cardioform Septal Occluder plus antiplatelet therapy versus antiplatelet therapy alone, the device intervention reduced recurrent clinically-apparent stroke (HR 0.23, 95% CI 0.09-0.62, P=0.001) and new brain infarction on MRI (RR 0.51, 95% CI 0.29-0.91, P=0.024).
Both trials showed an increase in largely periprocedural atrial fibrillation, as in prior trials.
"These data will change clinical practice in patients with cryptogenic stroke with atrial septal aneurysm or a large shunt," Jean-Louis Mas, MD, PhD, of Hôpital Sainte-Anne in Paris, said in a release from ESOC. "I also believe the question of whether or not to close a PFO in this subset of patients has been answered by these data – the answer is yes."
Heinrich Mattle, MD, of Bern University Hospital in Switzerland, agreed, saying "this will change secondary prevention in cryptogenic stroke," in his interview with Mas released by the conference organizers.
The REDUCE trial "looks impressive on the surface," commented Sanjay Kaul, MD, MPH, of Cedars-Sinai Medical Center in Los Angeles. The "5.6% absolute difference in silent brain infarct is pretty good; 76% relative difference in recurrent stroke also looks good, the latter has a more robust P value!"
"To what extent is the large treatment effect driven by the choice of the control (antiplatelet therapy) remains an open question. The 2016 AAN practice advisory leaned towards favoring antiplatelet over anticoagulant therapy for this scenario (level C recommendation). There is no randomized, controlled trial evidence conclusively supporting anticoagulant over antiplatelet therapy. So, if the data pass muster, they could be potentially practice changing!" Kaul said.
An effect that large is unlikely to be by chance, he suggested, but why these new trial results differ from RESPECT's wasn't clear given broadly similar inclusion criteria.
RESPECT included patients ages 18 to 60 who had a cryptogenic stroke but also had a PFO that could have been responsible for their index stroke.
CLOSE included patients ages 16 to 60 with cryptogenic stroke and PFO with atrial septal aneurysm or PFO with large shunt.
REDUCE included "highly selected" patients ages 18 to 60 with cryptogenic ischemic stroke or transient ischemic attack of presumed embolic infarction verified by a neurologist and PFO seen on positive bubble study with transesophageal echocardiography. No difference appeared in effect between patients with small versus large shunts.
While the prior trials were negative for overall stroke reduction "there were clues" in two of them -- trends that "just missed statistical significance," Mas noted in the ESOC interview.
Gore announced that it plans to submit the REDUCE data to the FDA later this year to seek a PFO indication for its Cardioform Septal Occluder.

Patent Foramen Ovale Closure Device Shows Long-Term Benefit vs Medical Management in Stroke Prevention

So this seems to argue that closing a PFO is better than medical drug treatment. Challenging all these previous studies. When will your doctor tell you about this?

Stroke Rounds: PFO Closure Works Long-Term Only for Some

 

Landmark Study Finds Expensive Catheter Procedure to Close Hole in Heart No More Effective Than Medical Therapy to Prevent Strokes

 

AAN Nixes Routine PFO Closure

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http://dgnews.docguide.com/patent-foramen-ovale-closure-device-shows-long-term-benefit-vs-medical-management-stroke-prevention?overlay=2&nl_ref=newsletter&

By Alex Morrisson
HOUSTON, Tex -- February 28, 2017 -- After a decade of follow-up, the use of patent foramen ovale (PFO) closure device appears to reduce the risk of stroke recurrence significantly better than medical treatment alone, according to a study presented here at the 2017 International Stroke Conference (ISC).
In the final analysis of the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) study, of the 499 patients assigned to be implanted with the Amplatzer PFO Occluder, 18 stroke-related events occurred compared with 28 events among the 481 patients treated medically -- a relative risk reduction of 45% (P = .046).
“These analyses support the hypothesis that PFO closure is preventing PFO-related recurrent strokes,” reported David Thaler, MD, Tufts University School of Medicine, Boston, Massachusetts. “PFO closure cannot prevent strokes from non-PFO related causes.”
The final results of the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) awaited US Food and Drug Administration (FDA) regulatory decision. The data, which was first collected in 2003 was completed in 2015, was analysed by an FDA Advisory Panel in 2016. Dr. Thaler trial said the low rate of events required longer follow-up. The device was approved in Europe in 1998. The FDA approved the device in October 2016.
The researchers enrolled patients from 69 sites in the United States and Canada from 2003 to 2011. Patients who were believed to have PFO-related strokes were randomised between having the device implants and guideline-driven medical management. Patients were eligible if they experienced cryptogenic strokes within the last 9 months, were found to have a PFO, and were aged 18 to 60 years.
The composite endpoint was the occurrence of non-fatal ischaemic stroke, fatal ischaemic stroke or death within 45 days of randomisation. The definition of stroke for the study was neurological deficit due to cerebral ischaemia observed on imaging scans or stroke symptoms that lasted longer than 24 hours.
“In the RESPECT trial, PFO-closure with the Amplatzer PFO Occluder was more beneficial than medical management alone in the intention-to-treat population for the primary outcome,” Dr. Thaler concluded.
[Presentation title: PFO Closure Reduces Long Term Recurrence of Ischemic Stroke: Final Primary and Secondary Population Results From the RESPECT Multicenter Trial. Abstract 71]

FDA Approves PFO Closure Device Amplatzer device

So this seems to implicitly argue that closing a PFO is better than medical drug treatment. Challenging all these previous studies.

Stroke Rounds: PFO Closure Works Long-Term Only for Some

 

Landmark Study Finds Expensive Catheter Procedure to Close Hole in Heart No More Effective Than Medical Therapy to Prevent Strokes

 

AAN Nixes Routine PFO Closure

The latest here:

http://www.medpagetoday.com/Cardiology/Strokes/61096?xid=nl_mpt_DHE_2016-10-29&eun=g424561d0r&pos=1 

The FDA approved the Amplatzer PFO Occluder device to reduce stroke risk for patients with prior cryptogenic stroke believed to be caused by a patent foramen ovale (PFO)-related blood clot.
The move marks a return to market after being withdrawn in 2006, when the FDA determined it no longer qualified for a humanitarian device exemption as the target population for this device was greater than 4,000 patients. "For the past 10 years, no FDA-approved heart occluder devices have been on the market specifically indicated to close PFOs to reduce the risk of a recurrent stroke in patients with a prior cryptogenic stroke," the FDA announcement of the approval noted.
The panel advising the FDA on the Amplatzer device in May had voted overwhelmingly in favor of its safety, although adverse effects can include injury to the heart; atrial fibrillation; blood clots in the heart, leg, or lung; bleeding; and stroke.
But the panel was fairly split on efficacy (9-7 vote), citing problems with the RESPECT trial, which was the basis for approval but had failed to find superiority of the device over medical management alone for prevention of recurrent cryptogenic strokes. Subsequent analyses, however, showed fewer PFO-related second strokes.
Earlier this year, the American Academy of Neurology recommended against routine PFO closure for cryptogenic ischemic strokes.
"The Amplatzer PFO Occluder provides a nonsurgical method for doctors to close a PFO," Bram Zuckerman, MD, director of the Division of Cardiovascular Devices in the FDA's Center for Devices and Radiological Health, said in a press release. "But as the device labeling clearly states, patients need to be evaluated carefully by a neurologist and cardiologist to rule out other known causes of stroke and help ensure that PFO closure with the device is likely to assist in reducing the risk of a recurrent stroke."
The Amplatzer device is contraindicated for patients with a heart valve infection or other untreated infections, a heart tumor or blood clot at the implant site, other abnormal connections between the heart chambers, or if cardiovascular anatomy or blood clots would interfere with catheter mobility.

 

Catheter-Based Closure Not Recommended for Patients With Heart Defect, Stroke

Low risk for the doctor because it doesn't affect the doctor, you as the patient bears all the damage.
Will that doctor guarantee full recovery if a stroke does occur? Buying an insurance policy from Lloyds of London?
http://www.docguide.com/catheter-based-closure-not-recommended-patients-heart-defect-stroke?
MINNEAPOLIS, Minn -- July 27, 2016 -- An updated recommendation from the American Academy of Neurology (AAN) states that catheter-based closure should not be routinely recommended for people who have had a stroke and also have a patent foramen ovale (PFO).
The practice advisory, which updates a previous AAN guideline, is published in the July 27, 2016, online issue of the journal Neurology.
To develop the advisory, researchers reviewed all available scientific studies on people with PFO who also had an ischemic stroke or a transient ischemic attack (TIA).
“Compared with other ways to prevent a second stroke, such as medications to reduce blood clots, the devices used to close a patent foramen ovale have limited evidence to support their use,” said practice advisory author Steven R. Messé, MD, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. “It’s still uncertain how effective these devices are in reducing stroke risk, and the procedure is associated with uncommon but potentially serious complications.”
In addition, Dr. Messé noted that the devices used for PFO closure are not available for routine use in the United States, so the procedure must be done off-label with a device approved for treating a similar heart defect or with another device that does not have strong evidence regarding its use. At the time of publication, the US Food and Drug Administration (FDA) is currently reviewing the one device that has the best evidence regarding closure.
“People should know that having a PFO is common -- 1 in 4 people have one -- and the risk of having a second stroke is low,” said Dr. Messé.
When the AAN developed the earlier guideline on this topic in 2004, not enough evidence was available to make a recommendation on whether closing a PFO was effective in reducing stroke risk.
The advisory also recommends that aspirin or other antiplatelet drugs be used to prevent blood clots instead of blood thinners unless there is another reason to use blood thinners, such as a person with a history of blood clots in the legs or lungs.
SOURCE: American Academy of Neurology

Catheter-Based Closure Not Recommended for Patients With Heart Defect, Stroke

Popular news here, dumping all the risk on the patient.If you want the closure it means you will have to out argue your medical staff and insurance company. Be prepared.
http://dgnews.docguide.com/catheter-based-closure-not-recommended-patients-heart-defect-stroke?

MINNEAPOLIS, Minn -- July 27, 2016 -- An updated recommendation from the American Academy of Neurology (AAN) states that catheter-based closure should not be routinely recommended for people who have had a stroke and also have a patent foramen ovale (PFO).
The practice advisory, which updates a previous AAN guideline, is published in the July 27, 2016, online issue of the journal Neurology.
To develop the advisory, researchers reviewed all available scientific studies on people with PFO who also had an ischemic stroke or a transient ischemic attack (TIA).
“Compared with other ways to prevent a second stroke, such as medications to reduce blood clots, the devices used to close a patent foramen ovale have limited evidence to support their use,” said practice advisory author Steven R. Messé, MD, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. “It’s still uncertain how effective these devices are in reducing stroke risk, and the procedure is associated with uncommon but potentially serious complications.”
In addition, Dr. Messé noted that the devices used for PFO closure are not available for routine use in the United States, so the procedure must be done off-label with a device approved for treating a similar heart defect or with another device that does not have strong evidence regarding its use. At the time of publication, the US Food and Drug Administration (FDA) is currently reviewing the one device that has the best evidence regarding closure.
“People should know that having a PFO is common -- 1 in 4 people have one -- and the risk of having a second stroke is low,” said Dr. Messé. (Well shit, Dr. Messé you are not the person at risk for a stroke.You can blithely talk about it without consequence.)
When the AAN developed the earlier guideline on this topic in 2004, not enough evidence was available to make a recommendation on whether closing a PFO was effective in reducing stroke risk.
The advisory also recommends that aspirin or other antiplatelet drugs be used to prevent blood clots instead of blood thinners unless there is another reason to use blood thinners, such as a person with a history of blood clots in the legs or lungs.
SOURCE: American Academy of Neurology

AAN Nixes Routine PFO Closure

So what is the consensus? Let the patient worry and hope the warfarin or aspirin works well enough not to have another stroke? What do our fucking failures of stroke associations have to say about this? Or will they once again hide and say this is a medical decision that your doctors should handle?
http://www.medpagetoday.com/Neurology/Strokes/59347?xid=nl_mpt_DHE_2016-07-28&eun=g424561d0r&pos=1

Questions definition of 'routine'

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• by Nicole Lou
  Reporter, MedPage Today/CRTonline.org

Patent foramen ovale (PFO) closure is not recommended as a routine therapy for patients with cryptogenic ischemic stroke, according to the American Academy of Neurology (AAN).
A systemic review of the literature for the Academy's stroke care guideline update published in Neurology turned up no stroke prevention benefit with the STARFlex PFO occluder compared with medical therapy alone (risk difference [RD] 0.13%, 95% CI -2.2% to 2.0%).
With the Amplatzer, however, there was a decreased risk of recurrent stroke (RD -1.68%, 95% CI -3.18% to -0.19%) at the cost of more new-onset atrial fibrillation (RD 1.64%, 95% CI 0.07% to 3.2%) and a procedural complication risk of 3.4% (95% CI 2.3% to 5%).
Thus, "in rare circumstances, such as recurrent strokes despite adequate medical therapy with no other mechanism identified, clinicians may offer the Amplatzer PFO Occluder if it is available (Level C)," the guideline development subcommittee of the AAN wrote.
Yet "this practice advisory is out of date," warned John Carroll, MD, of University of Colorado Hospital in Aurora, because the AAN did not have access to the latest 5-year data from the RESPECT trial. "The composition of the AAN group did not include one interventional cardiologist," he added. "In 2016 it is odd to have a proclamation about the value of a procedure without anyone on the group ever having performed the procedure."
The new numbers from RESPECT were taken into account during an FDA advisory meeting in May 2016 wherein the majority of panelists voted that the evidence tilted towards safety and efficacy with the Amplatzer compared to medical therapy alone. "Clinicians and patients should have the option of PFO closure with an approved device," said Carroll, who was not involved with the guidelines.
Even David E. Thaler, MD, PhD, of Boston's Tufts Medical Center -- and member of the dissemination committee for the AAN guideline -- seemed to agree. "I think the recommendations are cautious and already a little dated," Thaler told MedPage Today.
When asked if the guideline updates regarding routine PFO closure were appropriate, Thaler said it "depends on the definition of 'routine.'"
"If 'routine' is what currently happens in some practices – i.e., an episode of dizziness, interpreted by primary care provider as transient ischemic attack, not seen by neurology, echo shows PFO, referred to cardiology for closure – then yes, indeed, I agree with the recommendation."
"However, if 'routine' is as it should be – i.e., a stroke patient, evaluated by a vascular neurologist with 'complete investigations' (which is a changing landscape), a high RoPE score, a well-educated patient with regard to the current state of PFO science, realistic expectations of treatments, adherence to long-term secondary stroke prevention measures even after possible closure – then no, I think the recommendation is too cautious and dismissive of the totality of the evidence that shows that closure is probably better and no evidence to indicate that it's worse than medical management," he said.
Thaler's allusion to the uncertainty around PFO was echoed by Patrick D. Lyden, MD, of Cedars-Sinai Medical Center in Los Angeles.
"I have found a tendency for clinicians to stop looking for stroke causes once they find a PFO. It's important to complete a full evaluation on every patient, and not jump too quickly to conclude the PFO is the cause of the stroke," he told MedPage Today.
"Here is how I explain it to patients: we have two studies in favor and two studies against PFO closure. Let's wait for the 'tie breaker' study to finish before we decide to close your PFO," Lyden said. So let the patient bear all the risk? It is not the doctors brain that is in danger, so what the hell.

Closing PFO “hole in the heart” may prevent strokes linked to this heart defect

This comes to a different conclusion that previous research.

Stroke Rounds: PFO Closure Works Long-Term Only for Some

Landmark Study Finds Expensive Catheter Procedure to Close Hole in Heart No More Effective Than Medical Therapy to Prevent Strokes

 

Closing PFO “hole in the heart” may prevent strokes linked to this heart defect

Stroke survivors who also have patent foramen ovale (PFO), a hole in the heart, could benefit from a device that closes the PFO to help prevent future strokes, according to research presented at the American Stroke Association’s International Stroke Conference 2016.
Researchers studied 980 stroke survivors, ages 18 to 60, who had strokes that were determined to be of unknown cause (cryptogenic) but had a PFO. A PFO results when a hole between the heart’s chambers does not close at birth. It is thought that blood clots from a vein may travel through the PFO, block an artery in the brain and cause a stroke. Researchers implanted a PFO closure device in half the patients and prescribed blood thinning medications to the other half to determine which treatment might be better for preventing subsequent strokes.
In a long-term follow-up, researchers found:

• Forty-two patients had recurrent strokes, including 18 in the group that received the device and 24 in the medicine group.
• 56 percent of the device group’s recurrent strokes were cryptogenic and the remainder were unrelated to their PFO.
• 79 percent of the medication group’s recurrent strokes were cryptogenic.
• The size and location of the recurrent strokes also tended to be different. Those without the device tended to have large strokes more often than those with the device, and they were more often on the edges of the brain than deep inside.

Researchers said the device can only prevent strokes related to PFO. PFO-related strokes tend not to have another cause, are larger and on the edge of the brain. There were fewer such strokes in the device group than in the medical group, lending support to the probability that the PFO device prevents PFO recurrences.
Additional Resources:

• Any available multimedia related to these tips are on the right column of this linkhttp://newsroom.heart.org/news/isc-16-wednesday-news-tips?preview=0a5ba41ae6d06babec5f52bf7f717541
• Stroke Caregiver Resources
• Emotional and Behavioral Conditions After Stroke
• Join the AHA/ASA Support Network to talk with others going through similar journeys including depression after stroke. 
• Follow news from the American Stroke Association’s International Stroke Conference 2016 via Twitter: @HeartNews #ISC16.

http://newsroom.heart.org/news/isc-16-wednesday-news-tips?preview=0a5ba41ae6d06babec5f52bf7f717541

Stroke Rounds: PFO Closure Works Long-Term Only for Some

You can find out how good your doctor is by how long or whether s/he ever tells you about this study.  Good luck.
http://www.medpagetoday.com/Cardiology/Strokes/54184?
Long-term follow-up of the RESPECT trial continued to show no overall outcome advantage of patent foramen ovale (PFO) closure, although the procedure did pan out for reducing recurrent cryptogenic strokes, particularly for younger adults.
With an addition of about 2.5 years of follow-up on average, risk of all-cause strokes was no different for patients who had PFO closure with the investigative Amplatzer device than for those on medical management alone (P=0.16), John D. Carroll, MD, of the University of Colorado Denver, and colleagues found.
Because other components of the primary composite endpoint -- recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization -- were likewise no different between treatment arms, the conclusion was the same as in the main intent-to-treat result at an average of 3 years of follow-up.
"This is a study that started in 2003 and there have been a lot of lessons learned," Carroll said, adding, "Things we learned over the 10 years were not all recurrent events are going to be due to paradoxical embolism, and when one out of five patients are now over the age of 60, we cannot look at PFO closure as curative."
But he pointed to side analyses that suggested the device did what it should have been expected to do.
For example, there was a 54% relative reduction in recurrent cryptogenic stroke in the PFO closure group in the intent-to-treat analysis compared with medical management group in long-term follow-up (P=0.042).
Looking just at patients with a device in place versus those who never got a device in the trial, the relative reduction was 70% (P=0.004), Carroll noted. Eleven percent of the control group sought off-study PFO closure at some point.
In sensitivity analysis, people under age 60 had a 52% relative risk reduction of any recurrent stroke in the intent-to-treat analysis, which was significant (P=0.035).
One-third of the recurrent strokes had a known mechanism that PFO closure would not have been able to prevent, from things like small vessel disease, cardioembolism from endocarditis, and atrial fibrillation.
During extended follow-up, one in five patients who reached the over-60 age group were excluded from the trial in the initial enrollment criteria, because of the higher likelihood of other confounding etiologies for stroke with older age.
"In those patients who have recurrent strokes that were not PFO mediated and had a separate mechanism, it really stresses another important take-home message...that there has to be attention to modification of other stroke risk factors," Carroll told reporters at a press conference.
Carroll reported the findings at a late-breaking clinical trial presentation at the Transcatheter Cardiovascular Therapeutics (TCT) meeting in San Francisco.
And for the 620 patients with substantial shunts or atrial-septal abnormalities, the benefit of PFO closure in preventing recurrent cryptogenic stroke was also significant in the intent-to-treat analysis (hazard ratio 0.245, P=0.007).
However, extended follow-up out to an average of 5.5 years in the PFO occluder arm and 4.9 years in the medical management arm included a declining proportion of patients as follow-up went on, noted press conference discussion panelist Roxana Mehran, MD, of Mount Sinai School of Medicine in New York City. "By the second or third year...your number at risk is half of the original population. And then when you get out to 10 years, you're down to 15 patients or so."
And considering that the initial intent-to-treat results were negative, the subgroup results have to be taken "with a grain of salt," she argued. "There's no question the curves are separating, and it's good to see that. And I do believe that those patients in the original subgroup with a significant shunt and the atrial-septal aneurysm are probably the best patients to think about for sure for recurrent cryptogenic stroke."
Carroll responded that there were still almost 600 patients being followed at 4 or 5 years and that this is probably the best evidence that will become available. "We're never going to have a trial like this again in terms of such extensive follow-up of so many patients."
There is another trial coming -- the REDUCE trial with a different PFO closure device -- though with a somewhat more modest 664 patients and 24-month primary endpoint.
While all the panel said, via a hand-raising vote, that they were convinced by the data for specific subgroups and would want the device themselves in such a circumstance, FDA approval will be a challenge with such data, predicted press conference moderator and conference co-director Ajay J. Kirtane, MD.
With such a low event rate in RESPECT, 600 out of almost 900 "doesn't really pass muster for most clinical trials in terms of follow-up," said Kirtane, of New York-Presbyterian Hospital/Columbia University Medical Center in New York City.
On the other hand, "this device looks incredibly safe," said panelist Howard C. Herrmann, MD, of the University of Pennsylvania in Philadelphia.
In adjudicated safety findings, there were no intra-procedure strokes and no cases of device embolism, thrombosis, or erosion. The rates of major vascular complications and device explant were "very low" at 0.9% and 0.4%, respectively.
The deep vein thrombosis or pulmonary embolism rate was higher with the PFO occluder than with medical management (0.61 versus 0.12 per 100 patient-years).
The difference was of "unclear significance" because of no association with procedure or access site, lack of thrombophilia evaluation in the trial, and allowance of warfarin use in the medical management group. Also, Carroll noted, the difference could have been due to differential follow-up as more participants dropped out in the medical management group.