Approve Sapien TAVR for High-Risk Operable Patients, FDA Advisors Say

Shelley Wood

June 14, 2012

June 13, 2012 (Gaithersburg, Maryland) — A panel of expert advisors to the US Food and Drug Administration (FDA) emphatically agrees: approved uses for the Sapien transcatheter valve (Edwards Lifesciences) should include high-risk aortic-stenosis patients who are also eligible for surgery.

In the three-part vote, the panel voted 12:0 that the device was effective and 10:2 that the device is safe and delivered 11 votes in favor of the statement that its benefits outweighed any risks (one panel member, Dr John C Somberg [Rush University Medical Center, Lake Bluff, IL], abstained on this question).

Approval of this indication would also usher in the company's transapical delivery system, allowing the device to be deployed in patients whose femoral artery is not suited to transcatheter delivery of the percutaneous valve.

Dr Valluvan Jeevanandam (University of Chicago, IL) and Somberg were the only panel members who voted "no" on the safety question. "I think this is a very good technology, and it gives us an alternative to AVR surgery, and I'm sure the device will continue to get better," Jeevanandam, a cardiovascular surgeon, told heartwire after the meeting. "However, at the current time, compared with standard AVR, this device has a higher stroke rate and a high rate of aortic insufficiency, did not meet the criteria for noninferiority in males, and has a high incidence of vascular complications."

These are all issues that need to be very clearly explained to patients as part of the informed-consent process, he stressed. Otherwise, patients who are "enamored at the idea of avoiding a sternotomy" may not fully understand these risks.

Grounds for expanding the indications for transcatheter aortic-valve replacement (TAVR) with the Sapien device come from the PARTNER A trial, as reported by heartwire . In the study, one-year mortality was similar between the surgery and TAVR groups at 26.8% and 24.2%, respectively, meeting the predefined margin for noninferiority for TAVR.

Throughout the day, the Circulatory System Devices Panel raised concerns over crossover data and how events were assigned to the different treatments, as well as the challenges of interpreting nonrandomized continued-access patients treated after the PARTNER study closed. Panel members also mulled the higher mortality rate among patients treated via the transapical route, as compared to those treated via transfemoral delivery or by conventional open surgical replacement.

Other trial conduct issues also spent some time in the spotlight, including stroke risk; delays to treatment among patients randomized to surgical aortic-valve replacement (AVR); the importance of aortic insufficiency (seen in almost 60% of TAVR patients at one year) to long-term outcomes; and the curious discrepancy between men and women in the trial--women had better survival at one year than men.

Also speaking with heartwire , Dr David Kandzari (Piedmont Heart Institute, Atlanta, GA) said he felt the panel members, who often seemed reluctant to tuck into the feast of questions put to them by the FDA, missed an opportunity.

"The panel fell short, I think, of providing answers to some of the gaps in our understanding, particularly issues of gender differences, the link between aortic regurgitation and mortality, the link between atrial fibrillation and aortic regurgitation and stroke, and the potential for reducing vascular complications," he said. "I expected today to be a bit more contentious. . . . If anything, I thought last year's panel meeting, for the cohort B data, actually had a clearer path to approval and that today's meeting would be less predictable. In this case, an alternative exists--surgery--and this trial did not demonstrate superiority. I think that left the door open for more debate than we ended up seeing today."

Even before the voting questions, panel members seemed to have made up their minds, offering only lackluster feedback to the FDA's questions on labeling, data gaps, and indications for use. That meant a long day of discussions was put to bed swiftly with paper-ballot voting (ironically, the high-tech digital voting system failed in the final hour) and a resounding thumbs-up for the FDA.

"I am delighted to see the approval process move forward," panel member Dr Magnus Ohman (Duke University Medical Center, Durham, NC) told heartwire . "This is good news for patients with [aortic stenosis], but as was observed today, we still have a lot to learn. It is my hope that the excellent path that has been started on today with the 'heart teams' will continue to build so we can foster better collaboration with [cardiothoracic] surgery in the future."

Dr Warren Laskey (University of New Mexico School of Medicine, Albuquerque), an interventional cardiologist, chaired today's 13-member panel, which also included an additional five interventional cardiologists, three cardiovascular surgeons, and one neurologist. Co–primary investigators for PARTNER, Drs Craig Smith and Martin Leon (Columbia University, New York, NY), presented on behalf of the sponsor. In a surprise appearance, a third Columbia physician, Dr Jeffrey Moses, stepped up during the open public hearing to disclose that his own father, who refused to undergo AVR surgery, had undergone a TAVR procedure.

The FDA is not required to follow the advice of its advisory panel but is widely expected to do so following today's vote. The Sapien valve is already approved in two different sizes, along with a transfemoral delivery catheter, for use in patients deemed inoperable by a multidisciplinary team. The expanded indication sought by the sponsor would extend this to patients who face a >15% risk of mortality from surgical AVR.

The valves and delivery systems have been approved in Europe for several years where they are used in both operable and inoperable patients; fear of "indication creep," wherein the device is used increasingly in less sick patients who do well with proven surgery, is a key reason why the FDA is scrutinizing this expanded indication so carefully.

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