Data from the first-ever randomized trial of a transcatheter aortic heart valve show a substantial one-year survival benefit for Edwards Lifesciences' Sapien versus standard medical therapy, giving the firm major momentum as it prepares to submit one of two upcoming PMAs for the device.

Edwards' percutaneous valve has attracted significant attention in both the clinical and financial communities, representing a potential new approach to treating aortic valve stenosis and one of the most promising market opportunities in the implantable device arena.

The PARTNER results presented last week did not disappoint. Researchers reported a 46% all-cause mortality advantage for Sapien after one year of follow-up in patients with severe disease who are deemed too sick or frail for open heart surgery.

Given the data on hand, "balloon-expandable [transcatheter aortic valve implantation] should be the new standard of care for patients with aortic stenosis who are not suitable candidates for surgery," concluded Martin Leon, PARTNER principal investigator.

Leon, an interventional cardiologist at New York-Presbyterian Hospital, is chairman of the TCT-organizing Cardiovascular Research Foundation and co-founder of the company that invented Sapien.

He presented the data Sept. 23 at the Transcatheter Cardiovascular Therapeutics conference in Washington, D.C. The results also appeared online in the New England Journal of Medicine Sept. 22.

Trial Meets Both Primary Endpoints

PARTNER is a 1,058-patient, two-cohort, four-arm trial, but data was only presented from the 358 "Cohort B" patients with comorbidities or other characteristics making them unsuitable for standard open heart surgery.

Cohort B subjects were randomized 1:1 to receive either the Sapien valve via the femoral artery or medical therapy, which included medication and, in most cases, balloon aortic valvuloplasty.

PARTNER met both its primary endpoints in these high-risk patients. The one-year rate of death from any cause was 30.7% with Sapien versus 50.7% in the control group, and the composite rate of death from any cause or repeat hospitalization was 42.5% with Sapien versus 71.6%.

The mortality rates appear higher than outcomes from available registry data on transcatheter valves, including Sapien and its only competitor, Medtronic's CoreValve ; both are available in Europe and other countries outside the U.S.

For instance, data from the SOURCE registry presented this summer showed one-year mortality of 18.9% in patients who received Sapien via the femoral artery (¹ Also see "Transcatheter Valve Data Gets Top-Line Attention At EuroPCR" - Medtech Insight, 31 May, 2010.). But the PARTNER trial enrolled sicker patients, enrollment data suggests.

"This constitutes the sickest of the sick cohort of patients," Leon said. "Frankly, I'm not that surprised that more than half [in the standard therapy group] died in the first year."

Sapien patients also showed reduced cardiac symptoms following implantation and lower rates of death from cardiovascular causes, according to the PARTNER study.

"Frequent" Short-Term Complications In Sapien

Sapien was associated with significantly higher rates of major strokes (5.0% vs. 1.1%), vascular complications (16.2% vs. 1.1%) and bleeding (16.8% v. 3.9%) compared to control patients within 30 days of treatment, study investigators reported.

Investigators, who acknowledged that the Sapien events were "frequent", suggested that complication rates may be due to the perhaps-cumbersome size of the first-generation valve, and that newer iterations of the device may address the problem.

"This was a very large profile device in elderly patients," Leon said at TCT. "We're hoping that the next-generation devices, the Sapien XT which is 40% smaller in profile, and current devices which are being used in Europe like the CoreValve will obviate the vascular complications and reduce the bleeding complications."

Edwards received FDA approval Sept. 23 to begin the first of two planned cohorts in the PARTNER II U.S. pivotal trial of its thinner, next-generation Sapien XT valve, which launched in Europe earlier this year (see sidebar: " ² PARTNER II: Ready To Launch ").

Added to the composite primary endpoint in the valve vs. medical therapy cohort of PARTNER II, along with mortality and repeat hospitalization, is stroke, a complication that remains a concern, investigators say, but also may be improved with less traumatic devices.

In the meantime, "you tell the patient there's a 1 in 20 chance that they are going to have a stroke, as opposed to a 1 in 2 chance that they're going to be dead in a year," Leon said. "They have to understand what the relative risks are."

FDA Emphasizes Longer-Term Data, Bench Testing

Leon noted that longer-term data on the chronic performance of transcatheter valves is needed. "The ultimate value of TAVI will still depend on a careful assessment of bioprosthetic valve durability, which will mandate obligatory, long-term clinical and echocardiographic follow-up of all TAVI patients," he said.

Bram Zuckerman, director of FDA's cardiovascular device review division, hammered in the point during a discussion session at TCT.

"We're looking at very short term results," Zuckerman said. "It's really important for all investigators to recognize that longer-term follow-up, done responsibly, is going to be really important in this space."

Zuckerman signaled the need for more randomized trials in the transcatheter valve space, as well as more robust preclinical and engineering data.

"These devices are incredibly complex engineering, and they're really being asked to perform at design parameters that stretch the limits of these devices."

Computer modeling should be a key component of preclinical evaluation, he said. FDA is pursuing better computer models to simulate cardiovascular device performance in the body (³ Also see "FDA, Industry Seek Better Computer Models For Cardio Device Development" - Medtech Insight, 14 June, 2010.).

"We need to be able to build chronic implants with more confidence that they aren't going to fail chronically," he said. "There are ways to do it."

Edwards CEO Mike Mussallem responded on a same-day investor call that, "you could tell from the tone of the conversation that simply great clinical results ... are insufficient." FDA is "really focused on long-term durability of the valve and it is part of their thinking when it comes to approved trials and approving use," Mussallem said.

Edwards is expected to submit a PMA for Sapien in non-surgical candidates at the end of the year, though approval is not anticipated until late 2011.

Data comparing Sapien to surgery is also expected as early as March of next year. In "Cohort A," which includes about 700 randomized patients who are at high risk but are still considered surgical candidates, researchers will need to show that Sapien, delivered via either the transfemoral or transapical route, is non-inferior to surgery.

The PARTNER trial protocol was changed, with FDA's go-ahead, several times after enrollment began, including the addition of the co-primary mortality/repeat hospitalization endpoint for the non-surgical cohort and an increase in enrollment size for the entire trial.

The Sapien system consists of a trileaflet bovine pericardial valve and a balloon-expandable, steel support frame.

An Untapped Market

Sapien and CoreValve essentially now split the international transcatheter valve market 50-50, but Edwards is far ahead in the race to reach the U.S. market, with Medtronic still awaiting FDA approval to begin enrollment for its U.S. pivotal trial.

About 30% of patients with severe symptomatic aortic stenosis do not undergo aortic valve replacement surgery because of age, left ventricular dysfunction or coexisting conditions, according to Leon and colleagues. He predicted there are "tens of thousands" of patients who could benefit from a transcatheter valve procedure.

In a separate session at TCT, Martyn Thomas of St. Thomas' Hospital, London, said use of transcatheter valve implantation could increase 30%-40% in the next five years. "I think in the very low risk, it will be very, very difficult for us to really compete with surgery, and similarly I truly believe that there are some patients who are too high risk and should not be done," he said. "But somewhere in the middle, I hope we'll be able to find the sweet spot, where at some measure of risk there is mortality benefit to TAVI over surgery."

Analysts predict the worldwide market size for transcatheter valves, including non-surgical candidates and as an alternative to surgery in an expanding number of cases, could reach $2 billion in the next seven years.

- Jessica Bylander ( ⁴ j.bylander@elsevier.com )

Edwards' Sapien Valve: Big Survival Boost In Those Too Sick For Surgery

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