Paper Examines Differences Between Observational, Randomized PFO Closure Studies

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When the CLOSURE I trial results were announced in 2010, many were surprised that percutaneous patent foramen ovale (PFO) closure was not superior to optimal medical therapy for prevention of cerebrovascular events in patients with a PFO. Part of the reason for the surprise was the large body of observational data that suggested there was in fact benefit. In a review of these studies, published online December 15, 2011, ahead of print in Stroke, researchers attempt to explain the contrary results and caution against overreliance on observational evidence.

CLOSURE I is the first completed randomized controlled trial comparing the safety and efficacy of percutaneous PFO closure to medical therapy alone for secondary TIA and stroke prevention in patients with PFO. It included 800 patients with cryptogenic stroke or TIA who were treated for PFO closure with either a closure device (StarFlex, NMT Medical) plus 325 mg aspirin or anticoagulation and/or aspirin 325 mg (medical arm). The estimated 2-year event rates were 6% in the medical arm and 2% in the device arm. The study provided strong evidence that percutaneous device closure is no better than medical therapy alone in preventing recurrent stroke and mortality.

For the new study, David M. Kent, MD, MS, of Tufts Medical Center (Boston, MA), and colleagues searched the medical literature and singled out 52 single-arm studies and 7 comparative nonrandomized studies of patients with presumed paradoxical embolism (including cryptogenic stroke and TIA) that investigated medical treatment or percutaneous PFO closure. A meta-analysis was performed to determine incidence rates of recurrent cerebrovascular events.

In the observational studies, the incidence of recurrent stroke was much lower with closure vs. medical therapy. In these studies, medical treatment also was associated with a higher incidence rate of TIA and the composite of all ischemic cerebrovascular events compared with closure (table 1).

Table 1. Observational Studies

Per 100 Person-Years

Closure Arm
(95% CI)

Medical Arm
(95% CI)

Recurrent Stroke






All Cerebrovascular Events



In addition, a meta-analysis limited to the 7 comparative studies showed that closure was associated with an 81% reduction in the incidence rate of stroke compared with medical treatment (0.19; 95% CI 0.07-0.54).

However, in the randomized CLOSURE I trial, there was no difference between the closure and medical therapy arms for these outcomes (table 2).

Table 2. Randomized Study (CLOSURE 1)

Per 100 Person-Years

Closure Arm
(95% CI)

Medical Arm
(95% CI)

Recurrent Stroke






All Cerebrovascular Events



Observational and randomized data comparing medical therapies were consistent, however, in suggesting that anticoagulants are superior to antiplatelets for preventing stroke recurrence (incidence rate ratio 0.42; 95% CI 0.18-0.98).

Dissecting the Discrepancy

According to Dr. Kent and colleagues, the discrepancy between the observational studies and the randomized trial “may be a reflection of inherent limitations of observational evidence.”

For example, they write, confounding by indication may have created noncomparable populations in the medical and closure treatment arms. Thus, “nonrandomized groups of patients may vary in the distribution of factors that determine both the likelihood that the index event was PFO-related and also the risk of a recurrent event.”

Another issue, they add, is that the ability of meta-analyses to examine effect modification using study-level averages of patient characteristics is limited. Other biases that may affect observational studies include:

  • Differential follow-up intensity or dropout rates of invasively vs. medically treated patients
  • Nonuniform start time
  • Differences in the quality and thoroughness of follow-up examinations

Information bias also can play a role, since unfavorable results are less likely to be published, particularly from single-center investigations. The meta-analysis by Dr. Kent and colleagues found evidence of both differential outcome ascertainment (higher probability of being followed-up by a neurologist in medically treated compared with closure-treated patients) and of publication bias among closure studies.

However, Dr, Kent and colleagues say they cannot rule out the possibility that the benefits of closure of PFOs may become apparent only with longer follow-up than was reported in CLOSURE I.

“The 2-year follow-up of CLOSURE I may be inadequate to fully capture the benefit of the intervention, and reassessment after additional person-time has accumulated may be warranted,” they write.

Lessons for the Future

Overall, though, Dr. Kent and colleagues believe the discrepancies between the observational studies and the randomized trial in the setting of PFO closure highlight “the risks of overreliance on observational evidence, particularly when [randomized controlled trials] are feasible and ethically justifiable.

“Although CLOSURE I does not provide a definitive answer (the [confidence interval] of the treatment effect was wide and cannot exclude effect sizes that may be clinically relevant), it does call into question the validity of the large body of observational evidence,” they write.

The more than 7,000 cryptogenic stroke patients who had a PFO closed in the observational trials represent only a small fraction of patients so treated, they note. But “if this sample instead had been recruited into well-designed, [randomized, controlled trials], then it is likely that the best way to prevent recurrent strokes in this population would now be known.”


Kitsios GD, Dahabreh IJ, Abu Dabrh AM, et al. Patent foramen ovale closure and medical treatments for secondary stroke prevention. A systematic review of observational and randomized evidence. Stroke. 2011:Epub ahead of print.



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  • The study was supported by grants from the National Center for Research Resources and the National Institutes for Stroke.
  • Dr. Kent reports serving as a consultant for Gore Associates.