CLOSURE I shows no benefits of PFO closure in cryptogenic stroke
MedWire News: Closing a patent foramen ovale (PFO) in patients with cryptogenic stroke does not reduce the rate of recurrent stroke or transient ischemic attack (TIA), the CLOSURE I team reports in The New England Journal of Medicine.
However, the trial was hampered by slow recruitment caused by a high rate of off-label PFO closure, leading to a reduced sample size - from a planned 1600 to an eventual 909 - and, consequently, wide confidence intervals around the primary endpoint.
Editorialist S Claiborne Johnston (University of California, San Francisco, USA) notes that patients at the highest risk for recurrence were probably also treated off-label, further reducing the event rate and power of the trial. But he says that, in spite of this, "CLOSURE I provides the best evidence available regarding the role of closure in stroke prevention and should not be ignored."
The patients were aged between 18 and 60 years and had stroke or TIA within the previous 6 months presumed to be caused by paradoxical embolism through a PFO. Those randomly assigned to undergo PFO closure were treated with the STARFlex Septal Closure System (made by NMT Medical, Boston, Massachusetts, USA, which also funded the study). The procedure was successful in 89.4% of patients, meaning that the device was successfully implanted with no procedural complications.
The primary composite endpoint comprised stroke or TIA, death from any cause during the first 30 days after treatment, and death from neurologic causes beyond 31 days. The researchers say that they included TIA in the primary endpoint because the sample size would otherwise have been prohibitively large.
The investigators, led by Anthony Furlan (University Hospitals Case Medical Center, Cleveland, Ohio, USA), followed up the patients for 2 years, during which 5.5% of patients in the closure group and 6.8% of those who received medical therapy alone met the primary endpoint. The adjusted hazard ratio for the primary endpoint was 0.78, with the 95% confidence interval (0.45 to 1.35) encompassing a 55% reduced risk with PFO closure, but also a 35% increased risk.
The 2-year stroke rates were 2.9% in the PFO closure group and 3.1% in the medical-therapy group and the corresponding TIA rates were 3.1% and 4.1%. No patient in either group died.
Although patients' qualifying events were cryptogenic, the researchers were able to determine a possible cause for 20 of 23 strokes or TIAs that occurred in the PFO closure group and for 22 of 29 that occurred in the medical-therapy group. These included a clot in the left atrium, aortic-arch atheroma, complex migraine, and new-onset atrial fibrillation.
Notably, atrial fibrillation occurred significantly more often in the PFO closure group than the medical-therapy group, at 5.7% versus 0.7%. The overall adverse event rate was not significantly different between the two groups, however.
In his editorial, Johnston writes: "During the 9 years it took for the results of this trial to be reported, approximately 80,000 patients have had a patent foramen ovale closed with the use of a device at an average cost of [US]$ 10,000 [€ 7610] per procedure.
"Even if only half these patients were treated by this method for the purpose of preventing stroke, it would suggest that during that period of time $ 400 [€ 304] million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved."
He says: "By limiting the use of device closure to within the remaining clinical trials, such an expense could be curtailed and completion of these trials might be accelerated. In this setting, a strategy of withholding reimbursement for unproven device therapy unless such treatment is part of a randomized trial seems justified."
By Eleanor McDermid