March 14th, 2012

Achieving CLOSURE: Final Act of PFO Closure Device Trial

You can choose from myriad 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 in 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 or TIA to either medical therapy or PFO closure with the STARFlex Septal Closure System. There were no significant differences in the composite endpoint or its components (stroke or TIA in the first 2 years, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years):

Composite endpoint: 5.5% in the closure group and 6.8% in the medical-therapy group (HR 0.78, CI 0.45 to 1.35, p=0.37):

  • Stroke: 2.9% and 3.1% (p=0.79)
  • TIA: 3.1% and 4.1% (p=0.44).
  • Deaths at 30 days and deaths from neurologic events at 2 years: zero in both groups

As expected, there were more major vascular complications related to the procedure in the treatment group, as well as a higher incidence of atrial fibrillation:

  • Major vascular procedural complications: 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 competition with 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.

To comment on this topic, please go to Rick Lange’s and David Hillis’s blog post: The $800 Million Gamble: Jumping Aboard or Jumping the Gun?

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