You can choose from a myriad of metaphors– closing the book, sealing the deal, fixing a hole– but the story is simple: the publication of CLOSURE 1 in the New England Journal of Medicine is the final act of the long and sad melodrama of the CLOSURE 1 trial. As initially reported at the American Heart Association in 2010, Anthony Furlan and the CLOSURE I investigators randomized 909 patients with crytpogenic stroke to either medical therapy or PFO closure with the STARFlex Septal Closure System. There were no significant difference in the composite endpoint or its components(stroke or TIA in the first two years, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years):
Composite end point: 5.5% in the closure group versus 6.8% in the medical-therapy group (HR 0.78, CI 0.45 to 1.35, p=0.37)
- Stroke: 2.9% vs 3.1% (p=0.79)
- TIA: 3.1% vs 4.1% (p=0.44).
- Deaths at 30 days and deaths from neurological events at 2 years: zero in both groups
- Major vascular procedural complicaton : 3.2% vs 0% (p<0.001)
- Atrial fibrillation: 5.7% vs 0.7% (p<0.001)
In an accompanying editorial, S. Claiborne Johnston discusses the troubling issues raised by the trial. Because of off-label use of closure devices, enrollment in the trial took 5 years and forced a reduction in the sample size of the trial. He continues:
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 $10,000 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 million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved. 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.