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Meta-analysis: PFO Closure Better Than Medical Therapy at Reducing Future Stroke

By Yael L. Maxwell

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In patients with cryptogenic stroke, transcatheter patent foramen ovale (PFO) closure appears to reduce the risk of recurrent vascular events compared with medical treatment, according to a meta-analysis published online July 11, 2013, in the European Heart Journal. In addition, the benefit of closure may be greatest in patients with substantial shunt.

Abel Romero-Corral, MD, MSc, of Einstein Medical Center (Philadelphia, PA), and colleagues combined data from 3 trials (CLOSURE I, PC, and RESPECT) of 2,303 patients randomized to either transcatheter PFO closure (n = 1,150) or best medical therapy (n = 1,153) from 2000 to 2009. Devices used were the Amplatzer PFO Occluder (St. Jude Medical, St. Paul, MN) and STARFlex (NMT Medical, Boston, MA).

Clear Benefit over Medical Therapy

After a mean follow-up of 3.45 years, a total of 98 TIAs or strokes (primary endpoint) occurred in both the closure (3.47%) and medical therapy (5.03%) groups, reflecting an advantage with closure (HR 0.59; 95% CI 0.36-0.97; P = 0.04). However, the benefit disappeared when looking at stroke alone (HR 0.62; 95% CI 0.36-1.07; P = 0.09).

The composite outcome of death, recurrent neurological events, and peripheral embolism showed a trend toward a lower risk with closure in an intention-to-treat analysis (HR 0.67; 95% CI 0.44-1.00; P = 0.05), which was maintained in a per-protocol analysis of 2 of the studies (HR 0.62; 95% CI 0.38-1.00; P = 0.05).

Subgroup analyses showed that while the efficacy of closure was not affected by the presence of “high-risk” characteristics such as atrial septal aneurysm or older age, patients with substantial shunt at baseline (studied in 2 trials) saw a trend toward fewer vascular events after PFO closure (HR 0.35; 95% CI 0.12-1.03; P = 0.06). The trend was no longer evident when testing for interaction between type of intervention and shunt magnitude (P = 0.15).

Device implantation success was 93.8% on average; lowest with the STARFlex device in CLOSURE I (89.4%). The vascular complication rate was 1.13% on average. There were 2 cases of cardiac perforation and no deaths. Of note, new onset A-fib was higher in the closure group compared with the medical therapy group (2.7% vs. 0.5%; P < 0.001).

Larger Shunt, Higher Risk

In an e-mail communication with TCTMD, Dr. Romero-Corral and co-author Pablo A. Rengifo-Moreno, MD, also of Einstein Medical Center, acknowledged the negative individual outcomes of each of the 3 trials. “However, a big concern was that all 3 studies were underpowered for the primary outcome, an ideal scenario [in which] to perform a meta-analysis,” they said. “In our study, by having a larger population and greater number of adverse vascular events, we were able to overcome the underpowered concern and show a statistical benefit of transcatheter PFO closure.”

With regard to the subanalyses, Drs. Romero-Corral and Rengifo-Moreno said “a larger PFO facilitates a larger amount of debris to travel into the left-sided circulation, thus making it more likely to produce a significant clinical event. Furthermore, it has been hypothesized that fluid dynamics across a small and narrow PFO may be a protective factor when considering thrombus formation.”

Ziyad M. Hijazi, MD, MPH, of Rush University Medical Center (Chicago, IL), told TCTMD in a telephone interview that this finding is “intuitive.” Previous studies have focused more on the association between events and atrial septal aneurysm, but the meta-analysis likely did not find a relationship because not all of the included trials looked at this complication, he said.

Device Superiority vs. Operator Experience

New-onset A-fib is a real concern with PFO closure, Dr. Hijazi continued. “Nonetheless, it has a low event rate and some of the patients who had A-fib did not have a stroke. So the fact that you develop A-fib does not mean necessarily that you will have a stroke,” he said, adding that A-fib was more common with STARFlex vs. Amplatzer.

The authors agreed, suggesting that device type “might play a role” in this complication.

Because STARFlex was studied before Amplatzer, the question arises of how much operator experience factored into results, according to Dr. Hijazi. “The learning curve was so high [during CLOSURE I], so when the Amplatzer came [along], [the procedure] was a piece of cake,” he said. “But down deep in my heart I know it’s the device. The STARFlex is not as good a device as Amplatzer.

“I would love to see if the FDA will buy into the meta-analysis of randomized trials because [although] each trial individually is not very strong, if you look at the 3 trials combined, then we are talking about something significant,” he concluded.

 

Source:
Rengifo-Moreno P, Palacios IF, Junpaparp P, et al. Patent foramen ovale transcatheter closure vs. medical therapy on recurrent vascular events: A systematic review and meta-analysis of randomized controlled trials. Eur Heart J. 2013;Epub ahead of print.

 

 

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Disclosures
  • Drs. Romero-Corral, Rengifo-Moreno, and Hijazi report no relevant conflicts of interest.

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