One in 10 TAVR Procedures Off-Label in US: TVT Registry

Megan Brooks

July 06, 2017

SEATTLE, WA — About one in 10 patients in the US have transcatheter aortic-valve replacement (TAVR) for an off-label indication, especially aortic or mitral regurgitation and bicuspid aortic valves, a new analysis shows[1].

In multivariate analysis, 1-year mortality was no different in patients who had TAVR for an off-label condition relative to those who had TAVR for an on-label indication.

"Patients with off-label indications who were excluded from the trials but are inoperable or high-risk surgical candidates may stand to benefit from TAVR," lead author Dr Ravi S Hira (University of Washington, Seattle) told theheart.org|Medscape Cardiology.

"It is important to note," he added, "that we evaluated only patients with off-label conditions who underwent TAVR and have not compared the safety, efficacy, or cost-effectiveness of TAVR with surgical AVR or medical therapy in these patients. Many patients with off-label indications are not surgical candidates or are considered high risk for surgery. There is a need for studies to further evaluate treatment options in these patients."

TAVR is currently approved by the US Food and Drug Administration to address severe aortic stenosis in patients who are unable to have surgery or are at high operative risk. But it's also used off-label in lower-risk patients, although data on such use are scarce, the authors point out in the study, published online June 21, 2017 in JAMA Cardiology.

Using the Society of Thoracic Surgeons/American College of Cardiology (STS/ACC) Transcatheter Valve Therapy (TVT) registry, with linkage to Centers for Medicare and Medicaid services data, the researchers evaluated trends and outcomes of off-label TAVR use in 328 US sites performing TAVR between November 9, 2011 and September 30, 2014.  

The cohort included 23,847 patients (11,876 women and 11,971 men), with a median age of 84 years. A total of 2272 patients (9.5%) underwent TAVR for an off-label indication, defined as bicuspid aortic valve (435 patients), moderate aortic stenosis (189 patients), severe mitral regurgitation (935 patients), severe aortic regurgitation (853 patients), or subaortic stenosis (three patients).

Implantations were successful in nearly all procedures (92% off-label and 93% on-label).

Patients who had off-label compared with on-label TAVR had higher unadjusted mortality at 30 days (8.5% vs 6.1%; P<0.001) and 1 year (25.6% vs 22.1%; P=0.001). After adjustment for relevant covariates, 30-day mortality remained higher in the off-label TAVR group (hazard ratio [HR], 1.27; 95% CI 1.04–1.55; P=0.02), while 1-year mortality was similar in the two groups (HR 1.11; 95% CI 0.98–1.25; P=0.11)

Cumulative survival following off-label TAVR was 74.4% at 1 year, a rate comparable to that reported for high-risk patients in the CoreValve trials, the investigators note.

Off-label TAVR use varied widely among the 328 hospitals performing the procedure, with a median rate of 6.8% (range 0%–34.7%). The data also suggest that "experienced sites and operators are expanding their use of TAVR to patients who would not have been routinely considered candidates at the beginning stages of site development," Hira and colleagues write.

"Our results suggest that TAVR may prove to be a reasonable alternative with acceptable outcomes. In addition, several insurance plans may not cover TAVR for patients falling outside the FDA label, and this may change as further indications are evaluated," Hira said.

In one of two accompanying editorials[2], Drs Karen E Joynt and Daniel B Kramer (Harvard Medical School, Boston, MA) caution that the TVT registry, by design, includes only patients who received a TAVR. "Understanding whether off-label use carries acceptable risks and is associated with meaningful benefits requires data on patients with similar comorbidities who did not undergo a TAVR, including those who underwent surgery and those who received no intervention," they point out.

A related problem is that the TVT registry cannot answer "important long-term effectiveness questions that are essential to evaluating emerging technologies, particularly in the case of off-label use," note Joynt and Kramer. While the registry is helpful for tracking the adoption, dissemination, and outcomes of TAVR nationally, it falls short of delivering "maximal clinical insights into the potential expanded uses for and limitations of this important technology."

"The next steps in evidence generation will require more ambitious data collection focused not just on device recipients, but on all patients potentially eligible for this transformative technology," conclude Joynt and Kramer.

This is a "good paper" and represents "what we need to see more of, which is looking at real-world data to try to supplement the findings of traditional clinical trials," former FDA commissioner Dr Robert M Califf (Duke University School of Medicine, Durham, NC) said in a JAMA Cardiology podcast.

"What I liked about this paper is that it was an example of where the broader observational information is useful," he said.

In his editorial[3], Califf writes that the authors are "appropriately cautious" in interpreting their data. Finding no differences in statistically adjusted outcomes between on-label and off-label use is "far less convincing as a basis for labeling, payment, or a clinical recommendation than a randomized controlled trial directly comparing TAVR with surgery among specific subsets of off-label populations," he explains.

Califf notes the FDA has "signaled its interest in using registry analyses for expanded indications for devices proven safe and effective by more conventional standards, and payers are increasingly performing their own observational studies. It will be interesting to see whether additional data are needed to expand the indications for TAVR and ensure payment."

Hira reported no relevant financial relationships. Disclosures for the coauthors are listed in the paper. Joynt has received fees for contract work for the Office of the Assistant Secretary for Planning and Evaluation of the US Department of Health and Human Services. Kramer disclosed consulting fees from the Circulatory Systems Advisory Panel of the FDA and the Baim Clinical Research Institute for clinical trials of medical devices. Califf is currently employed with Verily Life Sciences.

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