Efficacy of PFO Closure Still Undetermined

San Francisco, CA—Randomized data have been largely inconclusive, although devices show promise for the prevention of cryptogenic stroke.

Significant questions still remain surrounding percutaneous closure of patent foramen ovale (PFO) vs. medical therapy in patients with cryptogenic stroke, despite several high-profile randomized trials and a host of meta-analyses that have followed them. Several experts discussed the available data on PFO closure and where it leaves the field moving forward during a session at TCT 2013.

“After 20 years research, and spending probably millions and millions of dollars, all randomized trials have been negative, but all of them are pointing in the direction of closure,” said Horst Sievert, MD, of the CardioVascular Center in Frankfurt, Germany.

Three major clinical trials have examined PFO closure: PC, RESPECT and CLOSURE. But Mark Reisman, MD, of the Seattle Science Foundation, said all had significant problems recruiting patients, and low event rates make firm conclusions difficult. The trials all tested the Amplatzer PFO Occluder or the StarFlex Occluder vs. medical therapy in patients with strokes of unknown origin. In the PC trial, which enrolled 414 patients randomized to either PFO closure or medical therapy, there was a non-significant reduction with regard to the composite endpoint of death from any cause, non-fatal stroke, transient ischemic attack and peripheral embolism.

RESPECT and CLOSURE

Similar results were seen in the RESPECT trial. There were only nine total primary endpoint events — defined as death within 45 days of ischemic stroke in the device group, and 16 in the medical therapy group, for a risk reduction of 46.6%. The relative risk was 0.534 (95% CI 0.234-1.220; P=.157). In an intention-to-treat analysis, there was a 50.8% risk reduction associated with device closure, but this still did not reach significance. In an as-treated analysis, however, there was a significant improvement with the device, with an HR of 0.273 (P=.0067).

In the CLOSURE trial, the StarFlex device (n=447) was compared with medical therapy (n=462). Among patients who entered the trial with stroke rather than TIA, no difference was seen in event rates at 2 years (P=.82). Among patients with TIA, there was a trend toward fewer events with the device, but this again did not reach significance (7.4% vs. 13.3%; P=.17).

Reisman also said that going forward, the RoPE calculator (Risk of Paradoxical Embolism) may provide a good method for determining which patients will benefit from PFO closure. “I think this is going to be the game changer,” he said. RoPE uses age, smoking status, presence of cortical infarct on imaging and other charactaristics to determine a risk score that can guide treatment.

Meta-analyses 

Despite the clinical trial data, the question as to whether PFO closure is truly better than medical therapy remains unanswered, however. Sievert added that among the meta-analyses that have been conducted on the topic, the use of a variety of statistical methods has yielded essentially conflicting results — some suggest closure is better, while others suggest it offers no benefit. The conclusion, Sievert said, is that a “meta-analysis is no substitute for more randomized data.”

Patients with stroke related to PFO also ideally would be followed for decades rather than just a few years, given that the medical therapy will be a lifelong treatment. Reisman concluded that with further follow-up from existing trials as well as some refinement based on the RoPE study, this field may soon get some more definitive answers. “The final story has not been told,” he said. “Hopefully, the FDA will be responsive to this very needy group of patients.”

Disclosures:

Sievert reports conflicts of interest with several device and pharmaceutical manufacturers. 

Reisman reports receiving consultant fees/honoraria from Boston Scientific and major stock holdings/equity in Biostar Ventures.