Hard-won RESPECT for Amplatzer PFO Closure in Final Analysis

Neil Osterweil

November 01, 2016

WASHINGTON — A catheter-delivered patent foramen ovale (PFO) occluder (Amplatzer, St Jude Medical) was seen to offer superior protection against cryptogenic strokes compared with medical management in the 10-year "final" analysis of the RESPECT trial[1].

The device received FDA approval for this indication on October 28, 2016. But current neurology guidelines, issued before the final data lock for the trial in May 2016, recommend against use of the device outside of clinical trials, observers note.

A final intention-to-treat (ITT) analysis from the randomized, open-label trial showed that among patients with PFO who suffered a prior stroke of unknown origin, there were 18 recurrent strokes over a decade of follow-up among those who received the occluder, compared with 28 for patients maintained on guideline-directed medical management.

This difference translated into a hazard ratio (HR) for the device of 0.55 (P=0.046) for the end point of freedom from recurrent ischemic stroke, reported Dr David E Thaler (Tufts Medical Center, Boston), a neurologist, here at TCT 2016.

A subanalysis of strokes of unknown origin (that is, excluding patients with strokes of known, non–PFO-related origin) showed that the occluder remained superior to medical management alone (HR 0.38, P=0.007).

Dr David Thaler

"These analyses support the hypothesis that PFO closure is preventing PFO-related recurrent strokes. PFO closure cannot be expected to prevent strokes from non–PFO-related causes," Thaler said at a media briefing prior to his presentation at TCT 2016.

Results from the main RESPECT trial had been presented at TCT 2012 and subsequently published in the New England Journal of Medicine. The researchers assessed outcomes in PFO patients who were under the age of 60 years and had a cryptogenic stroke in the previous 270 days. A total of 499 were randomly assigned to PFO closure with the small Amplatzer device, which is inserted via leg vein, and 481 were assigned to medical management. Initial analysis included 3.0 and 2.7 years of follow-up, respectively.

At the time, analysis by ITT had shown showed a 46.6% risk reduction of stroke for the PFO-closure group, which was not statistically significant. However, the reduction went up to 63.4% when only patients treated per protocol were assessed, and that turned out to be significant, leading to divergent views on the trial's clinical implications, as previously reported by heartwire from Medscape.

More Definitive at 10 Years?

While praising the investigators for the analysis, briefing discussant Dr David R Holmes Jr (Mayo Clinic College of Medicine, Rochester, MN), noted that "the most recent neurology guidelines said [the occluder] should not be used."

Current American Academy of Neurology (AAN) guidelines for the management of patients with PFO at risk for recurrent stroke state that "Clinicians should not routinely offer percutaneous PFO closure to patients with cryptogenic ischemic stroke outside of a research setting."

American Heart/American Stroke Association guidelines state: "For patients with a cryptogenic ischemic stroke or [transient ischemic attack] TIA and a PFO without evidence for [deep vein thrombosis] DVT, available data do not support a benefit for PFO closure." The most recent iteration of the guidelines, however, adds the following: "In the setting of PFO and DVT, PFO closure by a transcatheter device might be considered, depending on the risk of recurrent DVT."

Thaler pointed out that the guidelines were published just after an FDA device panel meeting that requested additional follow-up data from investigators before making a final thumbs-up or -down decision. The guidelines "came out without the benefit of the data that we're presenting today, and in fact the moment those guidelines hit the press they were out of date, so I have a problem with that," he said.

He expressed the opinion that given RESPECT data, and data from the ongoing REDUCE trial of a competing septal closure device (Gore Helex, WL Gore & Associates) expected in 2017 or early 2018, "the neurology community will have to recognize that these are data. These aren't opinions; data are data."

Briefing discussant Dr Jeffrey J Popma (Beth Israel Deaconess Medical Center and Harvard Medical School, Boston) asked Thaler, "At what point in a product life cycle and evaluation are you as a neurologist comfortable recommending this for your patients, or do we have to wait 10 years until after the trial has been completed in order to have a statement that the device is really beneficial?

"If the device doesn't do harm and has a mechanistic potential benefit, should we have earlier access to these devices as we're following these patients out to get to the 10-year end point?" he added.

Asked by heartwire about device-related complications, Thaler said that there were no periprocedural strokes, device erosions, or device thromboses. The incidence of major vascular complications in the device group was 0.9%, he said.

"The only significant difference that was a little bit surprising with regard to adverse events was DVT and [pulmonary embolism] PE, which were overrepresented in the device group compared with the medical-management group," he said, noting that the events were thought to be unrelated to the procedure because of relatively late incidence.

"It's thought that there might be a subset of this whole cryptogenic-stroke population who are mildly hypercoagulable," he said. This subgroup of patients might benefit from DVT and PE prophylaxis with anticoagulation, Thaler added.

In the give-and-take following the data's formal presentation at the sessions, discussant Dr Marc D Feldman (University of Texas Health Sciences Center San Antonio) pointed out that significantly more patients in the medication-only arm took warfarin and asked Thaler whether that difference may have "made the device look better than it actually did against medical therapy."

Thaler replied that the relative merits of anticoagulants and antiplatelet agents in this population is unclear, but the answer to the question may come from ongoing trials comparing novel oral anticoagulants with warfarin in various populations, including patients similar to those in RESPECT.

The RESPECT trial was funded by St Jude Medical. Thaler disclosed major stock/shareholder equity, royalty income, intellectual property rights, and various grants, consulting fees, and honoraria from the company. Popma disclosed grant support, consulting fees, and equity in various companies, but not St Jude Medical. Holmes and Feldman reported no relevant financial relationships.

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