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The Current State of PFO Closure
Catheter-based devices for patent foramen ovale closure are a tool to prevent recurrent stroke.
In recent years, catheter-based closure of patent foramen ovale has demonstrated some benefit over medical therapy alone in various studies. However, until recently, there were no devices approved for such use in the United States, so if a patient had a patent foramen ovale deemed to require closure, U.S. interventionalists had to improvise with off-label devices.
That changed in late October, when the FDA approved a PFO closure device (Amplatzer PFO Occluder, St. Jude Medical) for stroke prevention. This approval followed a meeting of the FDA Circulatory System Devices Panel in May, which voted 15-1 in support of the device’s safety, 9-7 in support of its efficacy and 11-5 that its benefits are greater than its risks.
Although short-term and midterm results of randomized controlled trials, including CLOSURE I, PC-Trial and RESPECT, have favored PFO closure over medical therapy, particularly in certain patient subsets, none met their primary efficacy endpoints in intention-to-treat populations until the long-term results from RESPECT, which studied the St. Jude Medical device and was a major reason for its approval, were presented.
“Having an approved PFO closure device will provide ... an opportunity to further study these patients and optimize their treatment,” John D. Carroll, MD, professor of cardiology at the University of Colorado, Denver, and principal investigator of the RESPECT trial, said in an interview.
Nonetheless, “PFO closure has proved to be one of the most polarizing topics in [CV] medicine,” Davide Capodanno, MD, PhD, associate professor and interventional cardiologist at the Ferrarotto Hospital, University of Catania, Italy, told Cardiology Today’s Intervention.
Mechanisms of Risk
The presence of a PFO may confer many risks, according to experts interviewed.
“PFO has been identified as a potential pathway for paradoxical embolism of platelet aggregations, thrombi, gas bubbles or other particulate matter from the venous circulation to the brain, or even a place for embolic thrombus formation in situ,” Capodanno said. “Several retrospective studies have suggested the implication of PFO in the pathogenesis of cryptogenic stroke, although this latter is likely a multifactorial phenomenon.”
According to Bernhard Meier, MD, professor of cardiology at University Hospital at Bern, Switzerland, the passage of thrombi, even if small, through the PFO can pose significant risk.
“Small clots that stay on the right side of the atrial septum will end up in the pulmonary arteries, where they are lysed by endogenous tissue plasminogen activator without any clinical signs or sequelae. Only large clots — larger than 1 cm — cause clinical symptoms in terms of pulmonary embolism,” Meier said. “However, even small clots can cause harm in the event that they reach the systemic circulation through the PFO, particularly in the cerebral, coronary and ophthalmic arteries.”
There are currently several existing devices used for PFO occlusion. Some are derived from the Amplatzer device, including the Occlutech Figulla Flex II (Occlutech International AB), the Cera PFO Occluder (Lifetech), the Cocoon PFO Occluder (Vascular Innovations) and the Hyperion PFO Occluder (Comed BV). The Gore Helex Septal Occluder (W.L. Gore & Associates), Intrasept Occluder (Cardia) and the Sideris buttoned device (Custom Medical Devices) are among the PFO occluders of a different design.
“Some of the earlier devices different from the Amplatzer PFO Occluder have been associated with increased thrombus formation, embolization or incidence of atrial fibrillation,” Capodanno said.
Encouraging Long-Term Results
Short-term and midterm results from CLOSURE I, PC-Trial and RESPECT vexed experts in the field because they showed the devices had benefit but not to a level of statistical significance. However, the long-term results from RESPECT were more encouraging.
“The randomized trials had missed significance in the primary endpoint, although they all pointed into the same direction — that PFO closure is better than medical therapy,” Meier told Cardiology Today’s Intervention.
CLOSURE I (n = 909), which compared the STARflex device (NMT Medical) vs. medical therapy, did not demonstrate a difference between the groups in its primary outcome, whereas PC-Trial (n = 414), which compared the Amplatzer device vs. medical therapy, did not show a significant difference in the primary outcome, ischemic events or bleeding events (see Table).
In the RESPECT trial, which is currently the largest randomized trial on PFO closure, 980 patients aged 18 to 60 years were randomly assigned medical therapy or PFO closure using the Amplatzer device. In the primary analysis at 45 days, the study did not meet the primary endpoint in the intention-to-treat analysis (see Table). However, “If you looked at patient subsets ... [PFO closure] did seem to show a treatment benefit that was statistically significant,” Clifford J. Kavinsky, MD, PhD, director of the Center for Adult Structural Heart Disease at Rush University Medical Center, Chicago, and an investigator on the in-process REDUCE trial, told Cardiology Today’s Intervention.
The most encouraging data for PFO closure are the final results of RESPECT, presented at TCT in November. After a mean follow-up of 5.9 years, in the intention-to-treat population, those assigned PFO closure had significantly reduced risk for recurrent ischemic stroke (see Table), David E. Thaler, MD, PhD, chairman of neurology at Tufts University School of Medicine, reported.
At TCT 2016, Thaler said the risk reduction associated with the device was greater when recurrent ischemic strokes of unknown mechanism were analyzed (HR = 0.38; 95% CI, 0.18-0.79; log-rank P = .007).
“These analyses support the hypothesis that PFO closure is preventing PFO-related recurrent strokes,” he said during the presentation. “PFO closure cannot prevent strokes from non-PFO-related causes.”
Experts Weigh Pros, Cons
The FDA advisory panel outcome — particularly in the 9-7 vote on the question of efficacy — did not suggest unequivocal agreement on PFO closure with the Amplatzer device, but the panel, ultimately, recommended its approval.
The agency’s decision was aided by the final results of RESPECT, the data for which were locked in May and shared with the FDA shortly after the panel meeting, Thaler said during his presentation at TCT.
Capodanno said the breakdown of votes from the FDA panel meeting suggested reservations among the two neurologists on the panel.
“Interventional cardiologists on the panel were almost unanimously in favor of recommending approval, while neurologists voted no on efficacy, although one voted yes on the benefit–risk question,” he said.
However, Steven R. Messé, MD, associate professor of neurology at the Hospital of the University of Pennsylvania and the lead author of an American Academy of Neurology statement opposing the routine use of closure devices for PFO, said not all neurologists take issue with this technology.
“It is worth noting that I know neurologists who are true believers in PFO closure for select patients, and cardiologists who do not believe that closure has been proven effective yet,” Messé said in an interview. “So, opinions do not break down exactly along party lines.”
Kavinsky, who spoke during the public portion of the meeting on behalf of the Society for Cardiovascular Angiography and Interventions, said, “There is a strong clinical unmet need for certain patients — those who have had clear strokes, young people, perhaps young people with large shunts or atrial septal aneurysms — to have access to this kind of procedure.”
Demonstrating the efficacy of PFO closure in a clinical trial has historically been “problematic,” Kavinsky said, citing difficulties with inclusion criteria.
“These trials, because the inclusion criteria can be difficult, can span many years, and in an effort to finish these trials in a timely way, the sponsors start to loosen up the inclusion criteria. This leads to patients who do not have paradoxically mediated stroke being let into the trial,” he said. “Many high-risk patients with paradoxical stroke and a PFO don’t want to be randomized to a trial and, in these early trials, many of these patients had closures done outside the trial. What then happens is the patients in the trial end up being very low risk, and it is hard to show any treatment benefit.”
Carroll said he hopes that more evidence will be gleaned from the REDUCE trial, which is evaluating PFO closure using the Gore Helex Septal Occluder and is currently in follow-up.
“The results will be reported in 2017,” Carroll said. “It suffers from many of the same study flaws as RESPECT, but will likely produce important new information.”
Future of PFO Closure
Although FDA approval has improved the outlook of catheter-based devices for PFO closure, some physicians may remain unconvinced by the current body of evidence, Capodanno said.
“This [controversy] is likely to happen regardless of FDA approval, although market clearance, and eventually, upgrade of current guidelines, where recommendation for PFO closure is quite low, may make difference in renewing the interest of skeptics,” he said.
Carroll cited the need for a multidisciplinary approach as a key element of ensuring patients with a PFO in need of recurrent stroke prevention are treated properly.
“One of the take-home lessons from [RESPECT] is that the optimal way these patients are evaluated and advised is through a multidisciplinary approach,” he said. “First, they really need to see, if possible, a neurologist at the time of their first stroke to do a complete, comprehensive evaluation of why they had that stroke. Second, the multidisciplinary team needs to include cardiologists, and perhaps specifically interventional cardiologists, to assess the cardiac mechanisms that could cause stroke, to determine whether they had a PFO and to characterize that PFO completely.”
Carroll said the approval could usher in a new era of treatment for select high-risk patients.
“I am optimistic that we are moving out of a very prolonged period of not really knowing how to optimize the secondary prevention of stroke in these young to middle-aged patients with no obvious reason for having a stroke,” he said. — by Jennifer Byrne
- References:
- Carroll JD, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1301440.
- Carroll JD, et al. RESPECT Trial: Extended Follow-Up. Presented at: TCT Scientific Symposium; Oct. 11-15, 2015; San Francisco.
- Furlan AJ, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1009639.
- Meier B, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1211716.
- Thaler DE, et al. First Report Investigations 3. Presented at: TCT Scientific Symposium; Oct. 29-Nov. 2, 2016; Washington, D.C.
- For more information:
- Davide Capodanno, MD, PhD, can be reached at the Cardio-Thoracic-Vascular Department,Ferrarotto Hospital, University of Catania, Via Citelli, 6, Catania, Italy, 95124; email: dcapodanno@gmail.com.
- John D. Carroll, MD, can be reached at University of Colorado Hospital, 12605 E. 16th Ave., Aurora, CO 80045; email: john.carroll@ucdenver.edu.
- Clifford J. Kavinsky, MD, PhD, can be reached at University Cardiologists, 1725 W. Harrison St., Professional Building Suite 1159, Chicago, IL 60612; email: clifford_j_kavinsky@rush.edu.
- Bernhard Meier, MD, can be reached at Cardiovascular Department, University Hospital of Bern, Bern CH-3010, Switzerland; email: bernhard.meier@insel.ch.
- Steven R. Messé, MD, can be reached at Department of Neurology, Hospital of the University of Pennsylvania, 3400 Spruce St., 3 W. Gates Building, Philadelphia, PA 19104; email: messes@uphs.upenn.edu.
Disclosure: Capodanno, Kavinsky and Messé report no relevant financial disclosures. Carroll reports serving on the steering committee of the RESPECT trial, for which his institution receives payment from St. Jude Medical. Meier reports receiving institutional research grants and speaker fees from St. Jude Medical.