Doubt Cast on Major Role for PFO Closure in Cryptogenic Stroke

I find 11 reasons why the CLOSURE I results are misleading and should not deter physicians from performing a closure procedure in patients who have had a cryptogenic stroke and have a patent foramen ovale.

1. The study tested whether PFO closure is superior to medical therapy. This was an inappropriate design because the efficacy of medical therapy had never previously been studied in a trial.

2. Patients in the PFO closure arm also received aspirin therapy for 24 months. This was a design mistake because if medical therapy is effective then PFO closure would not be expected to add any additional benefit.

3. The trial should not have excluded patients with deep vein thrombosis or hypercoagulopathy because these patients should benefit most from PFO closure.

4. The trial enrolled patients very slowly, at a rate of about two patients per year at each of the participating centers, a pace that must have introduced a selection bias.

5. The total number of about 900 enrolled patients and the study design’s presumption that the event rates would be 6% in the medical arm and 2% in the closure arm were too optimistic to produce a statistically significant difference between the two treatments tested. The study’s original design called for 1,600 patients.

6. The 2-year follow-up was too short. The average age of the patients in the study was 46. Patients like this choose to have PFO closure to avoid 30 years of anticoagulation therapy. The advantages of PFO closure would have become clearer during longer follow-up, as patients on warfarin therapy typically abandon it after several years.

7. The control, medical-therapy arm showed some strange outcomes. The event rates were higher in patients with smaller PFOs, and in those without a septal aneurysm.

8. Some of the operators performed PFO closures while still relatively inexperienced, early in their learning curve.

9. The STARFlex closure device used in the study is now outdated. It results in higher rates of atrial fibrillation and clot formation than do other closure devices now available.

10. Long-term anticoagulation is not a viable option for most patients. About 70% of patients on a warfarin regimen stop taking the drug after 5 years.

11. The 17% complication rate in patients undergoing PFO closure was unusually high. In the reported, worldwide experience with PFO closure the serious complication rate is about 3%.

Even if patients and physicians believe the CLOSURE I results despite all these problems, the question remains of which treatment option seems best for patients who have had a cryptogenic stroke and have a PFO. Doing nothing is not a good option, and closing the PFO by open surgery is not attractive because the periprocedural mortality rate is 0.5%-1.0%. The CLOSURE I results showed that medical therapy is no better and no safer than is endovascular PFO closure, and the annual risk for a major bleed on warfarin is 0.5%. For the long term, endovascular closure of a PFO is the most reliable way to prevent recurrent paradoxical embolism, and it has no downside; it was as safe as medical therapy. Patients with a PFO will usually prefer endovascular closure because they then won’t have to face the prospect of having to take anticoagulation therapy for the rest of their lives.

Dr. Horst Sievert is director of the CardioVascular Center in Frankfurt, Germany. He said that he has received consulting fees, travel expenses, or honoraria from Access Closure, AGA, Ardian, Arstasis, Atritech, Atrium, Avinger, Bard, Boston Scientific, Bridgepoint, CardioKinetix, CardioMEMS, Coherex, Contego, CSI, EndoCross, Epitek, Evalve, ev3, FlowCardia, Gore, Guidant, Lumen Biomedical, HLT, Kyoto Medical, Lifetech, Lutonix, Medinol, Medtronic, NDC, NMT, Occlutech, Osprey, Ovalis, pfm, Medical Mepro GmbH, ReCor, Rox Medical, Sorin, Spectranetics, Square One, TriReme Medical, Trivascular, Veryan Medical, and Viacor. He said that he owns stock or has stock options in CardioKinetix, Access Closure, CoAptus, Lumen Biomedical, and Coherex. He made these comments during a talk in January at the annual International Symposium on Endovascular Therapy in Miami Beach.