This article is more than 5 years old. Information may no longer be current.
Off-label TAVR procedures common
Although in-hospital and 30-day mortality is greater among the nearly 1 in 10 patients in the United States who receive transcatheter aortic valve replacement for off-label indications, 1-year outcomes are not significantly different, according to data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry.
Among 23,847 patients (median age, 84 years) from 328 sites who underwent TAVR from November 2011 to September 2014, 9.5% received off-label TAVR, defined as use in patients with known bicuspid valve, moderate aortic stenosis, severe mitral or aortic regurgitation before the procedure or subaortic stenosis.
Implantation was successful in the majority of patients (off-label TAVR, 92.9% vs. on-label TAVR, 93%; P =. 02), but in-hospital mortality was higher among patients who received off-label TAVR compared with on-label TAVR (6.3% vs. 4.7%; P < .001).
Additionally, in the off-label group vs. the on-label group, cardiac arrest (6.6% vs. 4.8%; P < .001) and transient ischemic attack (0.5% vs. 0.2%; P = .007) were more common. Residual moderate or severe perivalvular leak was also more likely in patients who received off-label vs. on-label TAVR (12.4% vs. 7.6%; P < .001).
Mortality, CV outcomes
To evaluate 30-day and 1-year mortality and adverse CV outcomes, data were linked with the CMS for 15,397 patients. Compared with patients who received on-label TAVR, those who received off-label TAVR had higher unadjusted 30-day mortality (8.5% vs. 6.1%; P < .001) and 1-year mortality (25.6% vs. 22.1%; P = .001).
After adjustment, however, 30-day mortality remained higher among patients who received off-label vs. on-label TAVR (HR = 1.27; 95% C1, 1.04-1.55), but 1-year mortality was comparable between the two groups (HR = 1.11; 95% CI, 0.98-1.25).
Patients with severe mitral regurgitation had the highest in-hospital, 30-day and 1-year mortality rates, according to the data.
The median rate of off-label TAVR use per hospital was 6.8%, with results revealing an increased 30-day composite of adverse CV events among hospitals in the highest tertile of off-label use compared with those in the lowest tertile (HR = 1.16; 95% CI, 1.01-1.34). However, there were no differences in 30-day (HR = 1.16; 95% CI, 0.96-1.4) or 1-year composite adverse CV events (HR = 0.98; 95% CI, 0.87-1.11) after adjustment.
According to the data, off-label TAVR was more likely to be performed in patients aged 80 years or younger (OR = 1.09; 95% CI, 1.03-1.16), patients with prior carotid endarterectomy or carotid artery stenting (OR = 1.25; 95% CI, 1.03-1.51), patients with HF within 2 weeks (OR = 1.21; 95% CI, 1.02-1.44) and those who received treatment at a teaching hospital (OR = 1.31; 95% CI, 1.04-1.66).
More research necessary
Although these findings “suggest that TAVR is a therapeutic option with acceptable results at 1 year,” the researchers called for further evaluation.
“These results reinforce the continued need for additional research on the safety and efficacy of TAVR in specific patient cohorts with off-label indications for whom surgical AVR would be considered high risk or a prohibitive risk,” they wrote.
The study highlights the potential need to rethink how data are collected to answer important questions, according to Karen E. Joynt, MD, MPH, from Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health, and Daniel B. Kramer, MD, MPH, from the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center, Boston.
“Taken together, the strengths and weaknesses of the [present] study and the TVT Registry represent an opportunity to reconsider tools used by the FDA and CMS to incentivize evidence generation,” they wrote in an accompanying editorial.
“Expanding data collection to not just device recipients but to all patients referred for consideration for undergoing a TAVR, for example, could be explored as a way to capture more robust comparative effectiveness data and truly drive transformative advances in knowledge.”
In a second editorial, Robert M. Califf, MD, from Duke University School of Medicine and former FDA commissioner, discussed how the data may fit into the FDA’s decision to approve expanded indications for various devices.
“This high-profile experience offers a glimpse into the future for device development and use throughout the product lifecycle,” Califf wrote.
“As experience grows with observational analyses and randomized controlled trials embedded within an increasingly sophisticated information fabric composed of prospective registries, electronic health records, and claims data, expanded indications will be evaluated. Inventors and device manufacturers will see reductions in development and evaluation costs, while clinicians, the FDA, and CMS will have higher-quality evidence to inform decision making at the individual and population levels,” he wrote. – by Melissa Foster
For more information:
Califf RM. JAMA Cardiol. 2017;doi:10.1001/jamacardio.2017.1733.
Hira RS, et al. JAMA Cardiol. 2017;doi:10.1001/jamacardio.2017.1685.
Joynt KE, Kramer DB. JAMA Cardiol. 2017;doi:10.1001/jamacardio.2017.1732.
Disclosure: Please see the full study for a list of the researchers’ relevant financial disclosures. Before being appointed commissioner of food and drugs at the FDA, Califf reports receiving research grant funding from Amylin and Eli Lilly; research grants and consultant fees from Bristol-Myers Squibb, Janssen Research and Development, Merck and Novartis; consultant fees from Amgen, Bayer Healthcare, BMEB Services, Genentech, GlaxoSmithKline, Heart.org—Daiichi Sankyo, Kowa, Les Laboratories Servier, Medscape/Heart.org, Regado and Roche; and holding equity in N30 Pharma and Portola. He reports currently receiving consultant fees from Merck and being employed by Verily Life Sciences. Joynt reports receiving fees for contract work for the Office of the Assistant Secretary for Planning and evaluation of the HHS. Joynt reports no relevant financial disclosures. Kramer reports receiving consultant fees from the Circulatory Systems Advisory Panel of the FDA and the Baim Clinical Research Institute for clinical trials of medical devices.
Perspective
Back to Top
These large national registry findings suggest that almost 1 in 10 patients received TAVR for an off-label indication in the United States for the period of 2011 to 2014. Although off-label TAVR use was associated with higher in-hospital, 30-day and 1-year mortality rates compared with on-label TAVR use, after adjustment, 1-year mortality was similar in the two groups. Patients with severe mitral regurgitation as the only off-label indication had the highest unadjusted in-hospital, 30-day and 1-year mortality rates compared with patients receiving TAVR for other off-label indications.
As pointed out by the investigators, the findings of this study should be treated with caution. The lack of differences in statistically adjusted outcomes between on-label and off-label use should not be a basis for new clinical recommendation. The high rate of off-label use (9.5%) captured in this registry implies high demand in patients with multiple comorbidities. Certain off-label indications may have better outcomes than others, and further randomized controlled trials directly comparing TAVR with surgery or optimal medical therapy among specific subsets of off-label populations, such as those with moderate aortic stenosis, severe aortic insufficiency and severe mitral regurgitation, are necessary to expand the indications for TAVR.
Perspective
Back to Top
This study is important because the researchers used registry data to identify the risks of off-label TAVR and they have pretty definitively identified the high-risk group in this off-label category. This is very constructive.
Nevertheless, the editorialists may have overstated the value of this study. We do not really understand the severity of mitral regurgitation experienced by these patients. Additionally, because these are registry data, we do not know when the severe mitral regurgitation developed, or whether it was functional vs. anatomical. This is a significant limitation in the context of the bigger picture of identifying what the high-risk group comprises. However, this limitation merely stimulates further studies in this subgroup, and I would hope that the FDA would require further study in these patients. On the other hand, although the other subgroups identified do not seem to be at an increased risk, the numbers are so small that we cannot consider that to be a definitive conclusion either. At this point, I do not believe this kind of study or analysis is going to fast-track anything. It is a very good study, but only hypothesis-generating.
Moving forward, we need prospective trials to evaluate these particular subgroups. Investigation of the mitral regurgitation issue may be more difficult because of the potential increased risk associated with off-label TAVR in this subgroup, but looking more closely at the bicuspid valve and aortic regurgitation issues would likely be less complicated. Also, patients with those characteristics also tend to be elderly, have HF and be at high surgical risk, so we need to go through the whole spectrum of patients in whom the procedures have been performed to resolve the questions raised.
I would also have liked to see more data on whether the centers that perform the majority of these off-label procedures are among the highest-volume TAVR centers. I am not surprised that 1 in 10 procedures were performed off label, but I would be concerned if they were being done in low-volume centers.