PARTNER: Promising initial results countered by need for patience

Results provide hope for patients with severe aortic stenosis, but how well TAVI will perform in those at lower risk, what its long-term effects will be and when it will be available for patients in need remains to be seen.

In the fall of 2010, hundreds of attendees at the Transcatheter Cardiovascular Therapeutics meeting were presented with the findings from one of the most anticipated trials of that year: the Placement of Aortic Transcatheter Valves trial, or PARTNER. It produced results that many cardiologists — interventionalists and surgeons alike — said will change the face of treatment for patients with severe aortic stenosis.

These data, published 1 month later in the Oct. 21 issue of The New England Journal of Medicine, documented a 20% reduction in all-cause mortality for transcatheter aortic valve implantation (TAVI; Sapien, Edwards Lifesciences) compared with standard therapy, including balloon aortic valvuloplasty and medical care (30.7% vs. 50.7%; P<.001) in patients with inoperable aortic stenosis and a mean age of 83 years.

“As interventionalists, we rarely have the opportunity to brag about saving lives,” Martin Leon, MD, associate director of the Center for Interventional Vascular Therapy, New York-Presbyterian Hospital/Columbia University Medical Center, and PARTNER investigator, said in a presentation at this year’s Cardiovascular Research Technologies meeting. “We’ve always been criticized that all we have the ability to do is prevent restenosis, make people feel better, [while] death and MI don’t change. However, the number needed to treat to save a life in this study was five. This is the new standard of care for inoperable [aortic stenosis] patients.”

Also substantially improved in TAVI patients, Leon said, was patients’ quality of life assessed by the Kansas City Cardiomyopathy Questionnaire (KCCM), based on work done by David Cohen, MD.

“With five points regarded as a significant difference [in KCCM score], here the difference in a year is almost 25 points. The largest delta they have ever seen in any study,” Leon said. “So, not only does TAVI add years to life but also adds life to years.”

And this enthusiasm is echoed by others who were not involved with the trial, as well. “This is going to become a major approach to [aortic stenosis] sometime in the future,” Alfred Bove, MD, professor emeritus of medicine at Temple University in Philadelphia, and immediate past-president of the American College of Cardiology, said in an interview with Cardiology Today.

“This technology, which has been proven to work, is going to improve over the next 4 or 5 years just because of the way the bioengineering world works. There are companies that invested money into this, and there will be more companies developing new and improved technologies. So it’s going to be a major step forward in [aortic stenosis] care.”

Obstacles for TAVI

Peter Block

On the downside to this breakthrough in treatment, however, are the yet unresolved concerns with TAVI, not the least of which being cost.

“We don’t yet have cost-analysis in the United States,” Peter Block, MD, professor of medicine and cardiology at Emory University in Atlanta, and investigator in PARTNER, said in an interview. “We have always been concerned about the cost of the device; it is expensive. On the other hand, what we’ve not appreciated is how expensive cardiac surgical care actually is. We don’t have a good handle on that here in the US. But the initial indications are that we probably underestimated the cost for cardiac surgical aortic valve replacement. So TAVI may actually be competitive.”

This lingering question of cost, however, will be addressed in data presented at this year’s ACC meeting in New Orleans, Block said.

Another prominent concern that arises with the procedure, according to Bove, is vascular complications. “After all, you’re opening up an artery in an older individual with a lot of atherosclerosis, so we’re going to have major vascular complications, which were significantly higher in TAVI,” he said. This higher rate of major vascular complications at 1 year (TAVI, 16.8% vs. standard therapy, 2.2%), as well as the higher rate of major strokes (TAVI, 7.8% vs. standard therapy, 3.9%), although being clinically significant, is not unexpected, Bove said.

“You cross a highly calcified valve with a lot of debris. When you blow up the balloon, bits and pieces break off from the original valve and embolize through the arterial system up into the brain. So the expected complications, an increase in stroke rate and significant increase in vascular complications, are demonstrated in the trial,” he said. “But the key thing is the significant reduction in mortality.”

PARTNER 1A cohort to be presented at ACC

As of the printing of this article, information regarding the PARTNER 1A cohort of patients, involving TAVI in high-risk surgical candidates, had not been made available to the public. However, this month’s ACC meeting is set to reveal data from this cohort of patients, and physicians offered their thoughts on what they expect to see. “I think everyone is anticipating to see what the [PARTNER 1A] randomization will show,” Peter Block, MD, said. “It’s a noninferiority trial, so the proof will be that TAVI is not inferior to cardiac surgery. I don’t know how that will come out, but my guess is that it will come out to be noninferior, simply because there are data out of Europe that indicate this from nonrandomized trials, and there’s no reason to suspect that the randomized trials will be significantly different from those data.” This is the expectation of Alfred Bove, MD, as well. “The best I can say is that chances are they will turn out to be even, 30% [mortality] in both groups,” he said. “If the technology for TAVI improves, we might find a much lower vascular complication rate and much lower stroke rate. I think you’ll find in the surgical cohort that stroke will be similar to TAVI, but probably with fewer vascular complications since they are not invading the vascular system. But you’d have more surgical complications, such as wound infections.” If TAVI proves to be noninferior, then “that expands our ability to use this in patients who are high risk,” Block said. “The next question would then be how far down the risk ladder can we go using this technology, and we don’t know the answer to that. Those are the next trials that will be coming up, [involving] lower-risk patients.”

TAVI’s availability still limited

Currently, TAVI has yet to change clinical practice because it is only available on a continued access basis within the trial.

“There is no accessibility to all the folks out there unless they’re part of the continued access portion of PARTNER 1B,” said Block, who is also the Intervention section editor at Cardiology Today.

As a result of the FDA limiting implantation to only allow a certain number per month, there has been what Block called a “terrible tension” between the physicians and the administration.

“We know that [TAVI] is a home run hitter and that it does very well for patients, but we simply can’t put it in because the FDA will shut us down,” he said. “So it’s a difficult problem, but hopefully once the device is approved, there will be a greater ability to get this out to patients that need it.”

Once TAVI finally passes the hurdles of approval, Block said he expects that the procedure will be limited to a fairly select number of centers in the United States.

“It takes a lot of work and personnel, and it’s time-consuming and labor-intensive,” he said. “It’s not something you can do quickly in an hour and go on to the next patient. And that may separate it from coronary stenting, for example, or balloon angioplasty or balloon aortic valvuloplasty, for that matter. My initial guess is that there will be a center in each state that will be primarily doing these kinds of cases. But we’ll see.” – by Brian Ellis

For more information:

• Leon M. N Engl J Med. 2010;363:1597-1607.