MIAMI—Although the much-anticipated late-breaking RESPECT trial assessing patent foramen ovale (PFO) closure for cryptogenic stroke failed to meet its primary endpoint, physicians on a lively panel discussion Oct. 25 at the Transcatheter Cardiovascular Therapeutics (TCT) conference stressed that the decision-making about the use of this device in patients with previous cryptogenic stroke remains a discussion that physicians and patients need to explore, if the device receives approval.
A PFO is a flap-like opening between the left and right upper atria of the heart, which typically fuses shut after birth. In approximately 25 percent of people, the opening does not fuse shut and in some cases, a blood clot may pass through the PFO and potentially travel to the brain causing an ischemic stroke.
“This trial addresses a serious clinical problem of secondary prevention of stroke in relatively young people. Up to 40 percent of ischemic strokes are reported to be cryptogenic—one that has no identified cause—and the prevalence of PFO is up to three times greater in this population,” explained lead investigator John Carroll, MD, medical director of the Cardiac and Vascular Center at the University of Colorado in Denver. “Patients age 20 to 54 are now a larger percentage of all stroke patients and among first ever strokes in the younger population there is growth in ischemic strokes.”
In this prospective, randomized trial, the researchers enrolled 980 patients over the course of eight years in 69 sites in the U.S. and Canada. All patients were diagnosed with cryptogenic stroke and a PFO—49 percent of the patients had large strokes as a qualifying stroke event—but otherwise, these patients were healthy. The average age in the study was 46 years old, and the youngest patient was 18 years old.
“The issue of age is very, very important in clinical decision-making because many think of stroke as an elderly problem, not one for the young,” noted panelist Ajay J. Kirtane, MD, of New York-Presbyterian and Columbia University Medical Center in New York City. “This also plays into having to treat a patient with a device for a much longer period of time, as opposed of the option to be taken off of medical therapy.”
Also, it isn’t always clear if the stroke relates to the PFO, which impacts patient selection criteria, said panelist Ted E. Feldman, MD, of North Shore University Health System in Chicago. “When you counsel patients on undergoing the procedure, you cannot guarantee to them that their next stroke could be prevented. You can only tell them the likelihood that you can reduce their risk in years.”
Kirtane told Cardiovascular Business that it comes down to discussing the risks and benefits with patients, if the device becomes available on the U.S. market. Also, he said the cost question will play into these decisions. “The real question will be how many patients you have to treat in order to reduce one event,” he said.
In a 1:1 fashion, the patients were randomized to two arms: closure with the Amplatzer PFO Occluder (St. Jude Medical) plus medical therapy (anticoagulant for one month and aspirin for six months post-implant, medical management beyond six months at the discretion of the physician) or medical therapy (aspirin, warfarin, clopidogrel or aspirin with dipyridamole, aspirin with clopidogrel). Of note, the Amplatzer is not approved in the U.S.
Stroke risk reduction was observed across the totality of analyses. The two-year event rates were low in both the device and medically treated groups: 1.6 vs. 3 percent respectively, and all primary events were nonfatal, recurrent ischemic strokes. The clinical risk reduction of stroke using the device ranged from 46.6 to 72.7 percent compared with medical management alone, depending on the analysis population being assessed.
Among the intent-to-treat analysis population, this reduction achieved “borderline” statistical significance, according to the researchers. The primary analysis of the intention-to-treat cohort was not statistically significant even though it trended toward superiority while secondary analyses suggested superiority, Carroll reported. In per-protocol and as-treated analyses, the reductions were statistically significant.
Serious adverse event rates did not differ between the device and medical groups: 23 vs. 21.6 percent respectively. The total incidence of atrial fibrillation was not significantly different between the device and medical group: 3 vs. 1.5 percent, respectively. These findings are important in the context of the CLOSURE I trial, which showed that PFO closure was associated with major vascular complications, atrial fibrillation and major bleeding.
Carroll pointed out that RESPECT had more positive outcomes, compared with CLOSURE I, because “we had a well-defined cryptogenic stroke population, with no transient ischemic attack patients. The closure device is also different in this trial.
“For carefully selected patients with history of cryptogenic stroke and PFO,” Carroll said that RESPECT “provides evidence of benefit in stroke risk reduction from closure with the Amplatzer PFO Occluder over medical management alone.”
However, panelist Alice Jacobs, MD, of Boston Medical Center, said that “it is left to physicians to put the totality of evidence together. The intention-to-treat was not a positive study, but the other analyses are heartening, with results we’ve been looking for.”
These results are “spot on” with a meta-analysis of approximately 5,000 patients, as well as nonrandomized trials that have been published over the past several years, and “highly confirmatory and positive findings,” Feldman concluded.
Carroll noted that follow-up of patients is ongoing and will continue to provide additional longer-term data on benefits, risks and differential treatment effects in subpopulations.
St. Jude Medical of St. Paul, Minn., sponsored the trial.