MIAMI—Percutaneous patent formulae ovale (PFO) closure for secondary prevention of thromboembolism showed no significant reduction in ischemic and bleeding events compared with medical treatment, according to the late-breaking PC trial. However, the stroke reduction led physicians on a panel to be encouraged.

The trial was presented Oct. 25 at the annual Transcatheter Cardiovascular Therapeutics (TCT) conference.

A PFO is a flap-like opening between the left and right upper atria of the heart, which typically fuses shut after birth. In approximately 25 percent of people, the opening does not fuse shut and in some cases, a blood clot may pass through the PFO and potentially travel to the brain, causing an ischemic stroke.

“Whether percutaneous PFO closure is superior to medical treatment among patients with stroke of unknown origin, or cryptogenic stroke, remains controversial,” reported lead investigator Stephan Windecker, MD, head of interventional cardiology at the Swiss Cardiovascular Center in Bern, Switzerland. Among these issues are:

• Lower risk of recurrence with PFO closure compared with medical treatment;
• Influence of device type on success and thrombus formation; and
• CLOSURE I failed to show superiority of PFO closure over medical treatment.

When designing the trial, the researchers hypothesized that among patients with cryptogenic shock and peripheral embolism, percutaneous PFO using the Amplatzer PFO Occluder (St. Jude Medical) is superior to medical treatment with antiplatelet agents or vitamin K antagonists for secondary prevention of thromboembolism. The device is not approved in the U.S.

In the study, patients were randomized in a one-to-one fashion in 29 centers in Europe, Brazil, Canada and Australia. Enrollment of 414 patients was completed in February 2009—204 in the PFO arm and 210 in the medical therapy arm. The primary endpoint of the trial was a composite of death from any cause, nonfatal stroke, transient ischemic attack (TIA) and peripheral embolism at mean follow-up of 4.5 years.

In the PFO arm, patients received the Amplatzer PFO Occluder, acetylsalicylic acid (100-325mg qd) and ticlopidine (250-500mg qd) or clopidogrel (75mg qd) for six months. In the medical therapy arm, patients received oral anticoagulation or antiplatelet therapy at the discretion of the neurologist.

The patients in the trial were younger than 60 years, and had a presence of PFO with or without aspirin. They also had a clinically and neuro-radiologically verified ischemic stroke or TIA with documented corresponding intracranial ischemic lesion or clinically and radiologically verified extracranial peripheral thromboembolism.

“This trial’s patient population, as well as the population in RESPECT, is not what we would typically treat in clinical practice, because of the strict inclusionary criteria,” said Windecker, adding that the RESPECT researchers used a much more contemporary definition of stroke than in PC trial.   

For the primary composite endpoint, the trial found a relative risk reduction of 37 percent when using the investigational device; this reduction was not statistically significant. Results also indicated no significant reduction in ischemic and bleeding events in patients who underwent PFO closure compared to those who received medical therapy (2.9 vs. 5.7 percent).

Importantly, the relative risk reduction of stroke through use of the device was 80 percent with a number needed to treat of 40, but this reduction was also not statistically significant.

Also, speaking to the young profile of the patient population, study panelist Ted E. Feldman, MD, of North Shore University Health System of Chicago, said that “doctors don’t treat numbers, we treat patients. If you’re facing a 25-year-old patient who’s had a stroke, and you discover a treatment that may result in an infrequent recurrence of another stroke, the conversation takes a different tone. Sometimes a disabling stroke can be more impactful than a mortality endpoint.”

Windecker acknowledged that the study power and sample size were limitations of the trial. “The observed event rate in the medical therapy group [5.2 percent] was lower than anticipated [12 percent] at a mean follow-up of four years, he said. “It was powered to detect a hypothesized 66 percent relative risk reduction less than 40 percent.”

In this trial, “the risk of recurrence is fortunately relatively low, and therefore, our hypothesis was overly optimistic and therefore, unrealistic. But, it is a good thing that the risk of recurrent stroke is low.”

In terms of reimbursement considerations, study panelist Ajay J. Kirtane, MD, of of New York-Presbyterian and Columbia University Medical Center in New York City, said that reimbursement will be influenced by the low event rates and the number of patients needed to treat in order to prevent an event from occurring. “Taking a look at costs, PFO closure may a one-stop fix, as opposed to medications over a long period of time, which may be more expensive to the patient. If approved, it will be a difficult decision for many patients and physicians.”

Windecker suggested that the next step should be to conduct a pooled analysis from RESPECT and PC in order to better understand the benefits or risks of this therapy.