GAITHERSBURG, Md.—The discussion at the July 20 meeting of the FDA’s Circulatory System Devices Panel, which is evaluating the Sapien transcatheter heart valve (Edwards Lifesciences) for an expected recommendation to the FDA, has been largely focused on the complication of stroke associated with transcatheter aortic valve implantations (TAVI) found in the PARTNER Cohort B trial. PARTNER investigator Michael J. Mack, MD, explained to Cardiovascular Business why the researchers did not standardize the stroke protocol differently at the trial onset.
In reviewing the results of the Cohort B PARTNER trial, which enrolled 358 inoperable patients who were randomized to either TAVI (179 patients) or standard therapy (179 patients), the study’s Co-Principal Investigator Martin B. Leon explained that the investigators assessed the cause of suspected strokes or transient ischemic attacks (TIA) to determine whether they should be classified as ischemic, hemorrhagic or unknown.
“We tried to conform to the new VARC and FDA consensus definition, but during the trial, we realized the need for greater sensitivity and greater refinement of the stroke analysis, ” said Leon, who is the director of the Center for Interventional Vascular Therapy at New York-Presbyterian Hospital/Columbia University Medical Center in New York City. Therefore, the trial utilized neurology consultants, participating within Clinical Events Classification (CEC), to perform post-hoc severity of stroke between minor and major, based upon a modified Rankin score of two or greater.
“When you examine the totality of data in this patient population, the biggest concern is going to involve stroke, which is why it is such a big focus of this panel,” Society of Thoracic Surgeons (STS) President Mack explained to Cardiovascular Business. “Our ranking was CEC adjudicated; however, event reporting was left up to each site, meaning there wasn’t a baseline neurologist assessment.
“We did the best job we could five years ago when we designed the trial,” added Mack, who is medical director of cardiovascular surgery for the Baylor Healthcare System in Plano, Texas. “Although we always knew that stroke would be an issue, we didn't realize the degree of scrutiny that would be required, as we thought it would be easier to define major stroke.”
Responding to a question from ACC Past-President Ralph G. Brindis, MD, on the FDA panel, Leon said that taking dual-antiplatelet therapy out to six months was recommended for each patient. However, the individual study sites had discretion to recommend based on the patient's individual condition, and he suggested that the majority of patients did not take dual-antiplatelet out to six months. Considering other pharmacological considerations, half of the atrial fibrillation patients were taking anti-thrombin medications, and the decision was left to the individual caretakers. “There were attempts to unify the protocols initially,” Leon explained. “There is a much more rigorous antiplatelet and anticoagulant regimen for PARTNER II, which we hope will be applied more uniformly.”
During the FDA’s clinical review presentation, Julie A. Swain, MD, cardiovascular surgeon at the FDA’s division of cardiovascular devices, said that the PARTNER data presented today by Edwards used “post-hoc adjudicated data and not the pre-specified data, but the FDA will use the pre-specified data.” She said that the understanding that the pre-specified definition of stroke should not be too stringent because it is commonly used in stroke studies.
Swain added that retrospective stroke ranking “really can’t be done, and the sponsor [Edwards] agrees.” She noted that post-stroke disability is more important than the stroke classification of major and minor, and those data are not available.
Swain also said that stroke was very difficult to assess in this trial, adding that the causes for stroke appear to be multi-factorial. “There are peri-procedural events, where strokes were recognized within four or five days, but may well have occurred before then, but there also are definite incidents of these neurological events after the peri-procedural time period,” she said.
Despite her criticisms about the protocol usage, Swain ultimately concluded that the reduction in mortality in inoperable patients outweighed the significant safety issues with the device, most notably stroke and vascular injury.
During the summary of the FDA clinical review,