CLOSURE I Published as Similar PFO Trials Forge Ahead

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Two years ago the CLOSURE I trial made headlines for showing that percutaneous closure of patent foramen ovale (PFO) fails to prevent recurrent stroke or mortality. As the debate over the treatment continues—and 2 additional randomized controlled trials near completion—the full results are now being published in the March 15, 2012, issue of the New England Journal of Medicine.

For CLOSURE I, Anthony J. Furlan, MD, of University Hospitals Case Medical Center (Cleveland, OH), enrolled 909 patients (aged 60 or younger) with a PFO and either a cryptogenic stroke or transient ischemic attack (TIA) at 87 US and Canadian sites. All subjects were randomized to 1 of 2 strategies:

  • Medical therapy (aspirin 325 mg daily, warfarin target INR 2.0-3.0, or both)
  • Percutaneous PFO closure with the StarFlex device (NMT Medical, Boston, MA) plus anticoagulation (clopidogrel 75 mg daily for 6 months and aspirin 325 mg daily for 2 years)

Procedural success, defined as implantation of 1 or more StarFlex devices at the closure site during the index procedure without periprocedural complications, was achieved in 89.4% of patients. The rate of effective closure, defined as procedural success with a grade 0 or 1 residual shunt, was 86.1% at 6 months and 86.7% at 2 years. No crossover was allowed between the 2 treatment groups, which had similar characteristics at baseline.

By the end of follow-up, the primary composite endpoint (stroke or TIA at 2 years, mortality at 30 days, or neurologic mortality from 31 days to 2 years) was numerically lower in the device closure group, driven by a slight improvement in TIAs. Stroke rates, meanwhile, were almost identical (table 1).

Table 1. Intention-to-Treat Population at 2 Years

 

Closure
(n = 447)

Medical Therapy
(n = 462)

P Value

Primary Endpoint

5.5%

6.8%

0.37

Stroke

2.9%

3.1%

0.79

TIA

3.1%

4.1%

0.44


Results for all endpoints were similar in a per protocol analysis and did not differ when broken down by shunt size or by the presence of atrial septal aneurysm. In addition, no deaths occurred within 30 days in either group; no deaths from neurologic causes were observed within 2 years.

Overall, serious adverse events were equivalent between the 2 groups (16.9% with closure vs. 16.6% with medical therapy; P = 0.90), though 3.2% of PFO closure patients experienced major vascular procedural complications. In particular, atrial fibrillation (A-fib) was more frequent with closure than with medical therapy (5.7% vs. 0.7%; P < 0.001). The complication occurred within 30 days of device implantation in 61% of cases but three-quarters of those were transient.

Alternative explanations other than paradoxical embolism were possible for many of the recurrent strokes and TIAs that occurred in both the closure (87.0%) and medical-therapy groups (75.9%). These included new-onset A-fib, a clot in the left atrium, subcortical lacunar infarction with risk factors, aortic-arch atheroma, complex migraine, vasculitis, and conversion disorder.

Trial Offers Insight Despite Flaws

In an editorial accompanying the study, S. Claiborne Johnston, MD, PhD, of the University of California, San Francisco (San Francisco, CA), cites many limitations of CLOSURE I. Among them are slow enrollment, lack of adequate statistical power, and the fact that many eligible patients may have chosen to undergo percutaneous PFO closure outside of the trial; thus the cohort may not be representative of the target population for treatment.

“In spite of these limitations, CLOSURE I provides the best evidence available regarding the role of closure in stroke prevention and should not be ignored,” he writes, agreeing with the study authors that the “results of the trial do not support closure of patent foramen ovale to prevent stroke in patients who have had a stroke or a TIA of unclear etiology. The closure procedure can have complications, is costly, and offers no proven benefits. For these patients, current [American Heart Association and American Stroke Association] guidelines recommend antiplatelet therapy, although the role of warfarin remains to be determined.”

Dr. Johnston reports that, over the course of the 9 years since CLOSURE I began, approximately 80,000 patients have received a PFO closure device at an average cost of $10,000 per procedure. “Even if only half of these patients were treated by this method for the purpose of preventing stroke,” he notes, “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.”

In a telephone interview with TCTMD, Ziyad M. Hijazi, MD, MPH, of Rush University Medical Center (Chicago, IL), noted additional drawbacks.

Each center averaged only 2 patients per year and procedural success was low for what should have been “a very simple, straightforward procedure,” he said, which raises questions about the competency of the operators and whether the closure group was inherently at a disadvantage. Moreover, the fact that nearly 14% of patients did not have effective closure at 2 years also is concerning and points to possible issues with the device itself.

The N Eng J Med paper presents nothing new, Dr. Hijazi confirmed. “Everybody knows about this already. It just basically puts [the findings] in writing now.”

Though the downsides to CLOSURE I cannot be ignored, “it’s the best one we’ve ever finished,” Robert J. Sommer, MD, of Columbia University Medical Center (New York), told TCTMD in a telephone interview. “It’s the first piece of real, prospective, randomized data that we’ve got.”

Other Studies May Wrap Things Up

Dr. Johnston argues in his editorial that with 2 trials still unfinished—RESPECT PFO (AGA Medical, Minneapolis, MN) and REDUCE (WL Gore and Associates, Flagstaff, AZ)—it remains critically important to encourage their completion “so that better decisions can be made sooner.” Enrollment can be encouraged by withholding reimbursement and limiting the use of device closure to the research setting, he suggests.

According to Dr. Sommer, the event-driven RESPECT PFO trial has now completed enrollment and may release its findings soon, while REDUCE is ongoing. “If RESPECT is positive, showing a benefit, I suspect that the Gore people are going to have a tough time enrolling [patients in] their trial,” he said, joking that it will also be hard to finish if RESPECT PFO turns out to be negative.

Rumor has it that RESPECT PFO will be presented at EuroPCR in May 2011, reported Dr. Hijazi, who is an investigator for the REDUCE trial. “If the RESPECT trial is negative like CLOSURE I, I think this will be the [final] nail in the coffin,” Dr. Hijazi related. That being said, he added, WL Gore has indicated to him that REDUCE will continue regardless of those results.

Dr. Sommer noted that the closure-related rise in A-fib, which can be a common cause of thromboembolic stroke, may be unique to CLOSURE I. “We know for certain that the StarFlex device compared with [AGA’s] Amplatzer and [Gore’s] Helex device is by far more arrhythmogenic,” he said, “just like we know that the StarFlex device is more thrombogenic than the other 2 devices.”

Future research should investigate whether certain populations, such as patients with deep vein thrombosis at the time of stroke or those in hypercoaguable states, may benefit from PFO closure, Dr. Sommer suggested, noting that longer follow-up from CLOSURE I would also be valuable.

 


Sources:
1. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366:991-999.

2. Johnston SC. Patent foramen ovale closure—closing the door except for trials. N Engl J Med. 2012;366:1048-1050.

 

 

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Disclosures
  • The trial was sponsored by NMT Medical.
  • Disclosure information for Drs. Furlan and Johnston is available with article at www.nejm.org.
  • Dr. Sommer reports being a physician trainer for AGA Medical and WL Gore and Associates as well as serving on the medical advisory board for Coherex.
  • Dr. Hijazi reports no relevant conflicts of interest.

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