By Bob Marshall, , Chief Editor, Med Device Online
In the U.S., stroke is the leading preventable cause of long-term severe disability and the fifth-leading cause of death.
I recently spoke with Jacob Goble, Structural Heart Business Unit Leader at W.L. Gore, following the FDA’s recent approval for an expanded indication for the company’s Cardioform Septal Occluder. The device, already approved for closure of atrial septal defects (ASDs) up to 17 mm, now is also approved for the closure of a patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in certain patients. The catheter-delivered occluder comprises two independent conformable discs that span and cover the heart’s anatomy to close defects. Gore’s proprietary ePTFE film covers the minimal wire frame, which enables rapid tissue ingrowth for immediate closure and long-term performance. See how it works.
Most people with a PFO — a hole occurring in the upper wall between the left and right atria of the heart — do not experience any issues when blood flows from one atrium to the other; however, serious problems can occur. “If you examined a random sample of the population, about 1 in 4 individuals would have a PFO. Most of the time, this is completely normal and doesn’t cause any issues. But, about 1 out of 1000 of these individuals are estimated to potentially have a stroke if a blood clot passes from the right to left atria, through a patent foramen ovale, and then to the brain,” Goble explained.
I asked Goble about the challenges Gore faced getting this expanded indication and he quickly went to the REDUCE clinical study. “The literature prior to us taking on the trial talked about the association of PFO and cryptogenic ischemic stroke, where the cause of the stroke is not known. Studies have shown that PFO can be found in up to 40-50 percent of patients who have had a cryptogenic stroke, which is significantly higher than the 25 percent anticipated in the general population,” Goble commented.
“But, that correlation does not indicate causation. What we had to do was take these individuals that had a stroke of unknown origin and a PFO, and apply through randomization either the standard of care – which is medical management with antiplatelet therapy – versus applying a device therapy, like closure with the Cardioform device, in conjunction with medical management,” Goble said. “It took a large number of patients – 664 patients were in our trial – and a couple years of follow-up, at a minimum, for each of these patients before we crossed the line demonstrating that intervening with Cardioform to close the PFO and antiplatelet therapy was superior to the option of just antiplatelet therapy.”
The length of the clinical study was a significant challenge for Gore, with the first enrollment occurring nearly a decade ago, in 2008. While the study was being conducted, the medical management of potentially recurring stroke changed. The antiplatelet drug Plavix came off patent and its generic form – clopidogrel bisulfate – was shown to be cost effective, compared to aspirin, in some of the regions where clinical investigation was occurring. These advances in medical management impacted the control of the study, which also faced enrollment challenges.
“We projected the study to finish a number of years before it actually did, but a number of patients did not want to be subjected to the randomization of the study, and a number of closures were happening off-label, which shunted potential subjects from the study,” Goble explained. “To alleviate this issue, we increased the number of sites participating in the study over time. We began with 40-50 approved sites and, in the end, we had 63 sites that participated in the study. We also went multi-national, with the study including Finland, Sweden, Norway, Denmark, the UK, Canada, and the U.S. Both Canada and the UK were not in the original clinical plan, but contributed a significant number of subjects to the trial.”
What about inclusion and exclusion criteria for such a large study? Previous studies – a French study called CLOSE and a Korean study called DEFENSE-PFO — both limited the enrollment to a particular type of PFO; either the diameter of the PFO, the shunt size going through it, or whether there was a lot of movement of the septum. What did Gore decide regarding the patient population they would study?
“We did not restrict the enrollment in that way. We accepted all anatomy types of PFO; patients just needed to demonstrate the presence of a PFO,” Goble explained. “Where we did have consistent restrictions with prior studies was these patients had to demonstrate through exclusion there was no other known cause of the stroke. This required extensive vascular imaging, looking for history of arrhythmia, conducting bloodwork to look for hypercoagulability disorders or other things that could be the potential culprit for the stroke. This is one of the things that helped us get a very clean population for assessment in this study.”
“In the end, it came down to simple inclusion criteria – a patient had a cryptogenic stroke and has a demonstrated presence of PFO,” Goble continued. “When we did sub-group analysis of the patient population on the back end of the study, none of the anatomical parameters came out as significant differentiators. You don’t [get] better results going after big shunts, rather than smaller ones. If we had limited ourselves in that way earlier on, we would have only harmed our enrollment rate even further.”
The decision not to sub-divide or limit the study population on the front end also gave Gore a rather broad indication for use. What are benefits of the lengthy study and FDA approval with broad indication? Scott Kasner, MD, Neurologist in the Perelman School of Medicine at the University of Pennsylvania, and U.S. Neurology National Principal Investigator for the REDUCE Study, summed it up well:
“Results of the REDUCE Study changed the neurology community’s perspective on PFO closure when they were announced. The REDUCE Study was the first U.S. Investigational Device Exemption (IDE) study to show a statistically significant reduction in stroke recurrence in the primary intent-to-treat analysis. It was also the first study to show PFO closure reduces new brain infarct,” Kasner said. “[I] believe these data prove the value of closing PFOs to prevent recurrent ischemic stroke when utilized in an appropriate patient population.”