March 20th, 2013

Controversial PFO Closure Trials Published in NEJM

Two controversial trials testing PFO closure in patients with cryptogenic stroke, first presented last fall at the TCT meeting, have now been published in the New England Journal of Medicine. Both trials missed their primary endpoints but contained suggestions of possible benefit. The results appear unlikely to resolve the ongoing controversy over the value, or lack of value, of this procedure; but, as an accompanying editorial states, both advocates and critics of PFO closure will find source material for their arguments in these papers.

The PC Trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism) randomized 414 patients with PFO who had had an ischemic stroke, a TIA, or a peripheral thromboembolic event to either medical therapy or PFO closure with the Amplatzer PFO Occluder.

After 4.1 years of follow-up in the closure group and 4.0 years in the medical-therapy group, there were no significant differences in the primary endpoint (the composite of death, nonfatal stroke, TIA, or peripheral embolism) or the individual components of the endpoint:

  • Primary endpoint: 3.4% in the closure group versus 5.2% in the medical-therapy group (HR 0.63, CI 0.24 – 1.62, p=0.34)
  • Nonfatal stroke: 0.5% versus 2.4% (HR 0.20, CI 0.02 – 1.72, p=0.14)
  • TIA: 2.5% versus 3.3% (HR 0.71, CI 0.23 – 2.24, p=0.56)

The RESPECT trial similarly randomized 980 patients to medical therapy or PFO closure. More patients in the medical-therapy group dropped out during the course of the trial. There was no significant difference in the main, intention-to-treat analysis, which was performed after 25 primary endpoint events occurred (a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization), but prespecified per-protocol and as-treated analyses turned up significant benefits for PFO closure:

  • Primary endpoint (intention-to-treat): 9 events in the closure group versus 16 in the medical-therapy group (HR 0.49, CI 0.22 – 1.11, p=0.08).
  • Recurrent stroke (per-protocol): 6 versus 14 events (HR 0.37, CI 0.14 to 0.96, p=0.03)
  • Recurrent stroke (as-treated): 5 versus 16 events (HR 0.27, CI 0.10 – 0.75, p=0.007)

In the accompanying editorial, Steven Messé and David Kent write that both trials suffered from slow enrollment, “which was probably due to widespread off-label use of atrial septal closure devices.” They note that RESPECT and PC, like the only other randomized trial in the field, CLOSURE 1, did not show significant benefits in the main intention-to-treat analysis, but did present some evidence of possible benefit.

They conclude:

…we are left for the moment to make decisions under conditions of uncertainty. In such circumstances, evidentiary standards vary among decision makers — patients, clinicians, authors of practice guidelines, and regulatory authorities — depending not only on the interpretation of the results, but also on the potential consequences of their decisions. Some of them may interpret the data as supporting closure of a patent foramen ovale as a viable therapeutic option, even while conceding the failure of trials to show the superiority of closure over medical therapy. Yet given the prevalence of patent foramen ovale in the general population, the enormous potential for overuse of percutaneous closure of a patent foramen ovale, and the relatively low risk of stroke in patients who are treated medically, the routine use of this therapy seems unwise without a clearer view of who, if anyone, is likely to benefit…. Randomized studies of closure may come to an end, however, if the Amplatzer device is approved. Thus, all eyes will be on the regulatory agencies to see how they will interpret these results in light of their own evidentiary standards.

One Response to “Controversial PFO Closure Trials Published in NEJM”

  1. Rafael Diaz, MD says:

    A simple message

    Trend toward a benefit for the PFO closure approach
    Consistent direction of the effect in both trials
    Wide confidence intervals due to small sample sizes
    Conclusions limited to patients with prior cryptogenic stroke

    I agree with the editorialists:

    Still uncertainty!