Now that the existing inventory of FDA-approved transcatheter aortic valve replacement (TAVR) devices has received a green light for patients at low surgical risk, it’s tempting to think this device type has pretty much conquered all that lay before it. That’s not the case, however, as the question of bicuspid valve might be answered in a way that gives Edwards Lifesciences and Medtronic another sizeable patient population for their TAVR offerings.

As is widely known, the FDA recently approved two TAVR devices each by Medtronic and Edwards for aortic stenosis patients at low risk of poor outcomes under a surgical AVR approach. The two companies’ shares didn’t exactly go through the roof as this outcome was expected, but one of the interesting things about the FDA-approved physician labels is that they both include a more or less extensive discussion of bicuspid valve. The physician label for the Medtronic devices notes that the safety and effectiveness of the Evolut devices “have not been evaluated” for patients with bicuspid valve, essentially the same notation as applied to the Sapien physician label.

The meaning of ‘not evaluated’

The physician label for the Medtronic devices goes on to note that the heart team should consider the age of patients with bicuspid valve when considering treatment options. This comes with an advisory that any need for intervention in the ascending aorta must also be considered. The interesting thing is that all this language appears in a label for a device that is presumed to not be approved for stenotic bicuspid aortic valves. I posed the question to the FDA, which responded with the statement that the safety and effectiveness of these devices “has not been established” for patients with stenotic bicuspid valve. Big help.

To the casual reader, it doesn’t sound as though the agency is particularly concerned about implants in these patients, an odd notation given how much noise the FDA has made in the past about off-label device use.

For what it’s worth, the doctors are very much interested in bicuspid aortic valve, as demonstrated by a Jan. 19, 2018, statement at the website for the American College of Cardiology. The ACC said the exclusion of bicuspid valve from major clinical trials was due in part to anatomical features, such as asymmetric leaf calcification, that could lead to significant paravalvular regurgitation. Since this is a congenital condition, the age of the patient and device durability combined to raise another set of questions.

Still, the ACC said, the returns on clinical trial data were encouraging as of a year and a half ago, including that more recent generations of TAVR devices seemed to perform better in bicuspid valve patients with severe stenosis than the legacy devices. The newer versions provided outcomes that were fairly similar to outcomes in patients with tricuspid aortic valves at least in terms of two-year, all-cause mortality. The concerns over aortic dissection or rupture due to diseased bicuspid aortic valves don’t exactly improve over time, however, a fact which suggests that earlier intervention might be better intervention, even if everyone insists on staying on the fence where the device durability question is concerned.

Large market, but a long time in coming

Clinical considerations aside, the implications for Edwards and Medtronic are pretty considerable. At least one investor note said bicuspid patients comprise a relatively high percentage of patients in the low-risk group, and bicuspid aortic valve is thought to be the most common congenital defect of the human heart. Some estimates put the prevalence at as high as 2% of the general population, which in the U.S. would suggest more than 6.5 million. Assuming only 1% of this population are good candidates for a TAVR each year, that’s 65,000 a year. That estimate of annual need may be quite conservative, indeed.

Some of the concerns about clinical capacity with regard to the FDA approval for low-risk tricuspid valve patients have been waved off as being somewhere between minimal and trivial, but one has to wonder if those concerns might become more salient over time if the FDA moves on bicuspid valves. There may indeed be a fair number of these patients getting TAVR devices in clinical trials, but that might not work in routine clinical practice unless a hospital is willing to get a letter from a Medicare administrative contractor advising the hospital that it just did this procedure on its own dime. It seems plausible to assume that doctors are talking to both the FDA and industry about this population, so we might not have long to wait. After all, these patients aren’t going to get better by attending yoga classes.

The net effect of all this might be to declare the TAVR device a smash hit with no end in sight, but let’s not forget how long it took for all this to come to the fore. After all, one of the earliest mentions of the Carpentier-Edwards porcine bioprosthesis in the literature was in the September 1984 issue of the Journal of Thoracic and Cardiovascular Surgery, which makes note of implants that took place in 1976. Some may think the TAVR device stands effortlessly astride the world of interventional cardiology, but the achievements to date were more than four decades in the making.