One in 10 TAVR Patients Treated Off-Label: TVT Registry

Rather than being “inappropriate,” off-label treatment may be a reasonable choice in patients with few other options, experts say.

One in 10 TAVR Patients Treated Off-Label: TVT Registry

Approximately one in 10 patients undergoing transcatheter aortic valve replacement receive treatment for an off-label indication, according to a new analysis of registry data.

Among 23,847 patients treated in the Society of Thoracic Surgeons/American College of Cardiology (STS/ACC) Transcatheter Valve Therapy (TVT) Registry, the overall rate of off-label use was 9.5% and included patients with severe mitral regurgitation or severe aortic regurgitation, among other indications. Implantation success rates were nearly identical in the on- and off-label treatment groups, but off-label treatment was associated with significantly higher unadjusted rates of in-hospital, 30-day, and 1-year mortality, as well as higher rates of heart failure at 30 days.

However, after adjusting for multiple variables, including higher baseline risk, only the 30-day mortality remained significantly higher among patients treated off-label. At 1 year, there was no difference in the adjusted mortality rates in patients treated for approved and unapproved indications (HR 1.11; P = 0.11).

“The patients receiving off-label use in our analysis tended to be sicker with procedures more likely to be done in urgent or emergent situations,” lead investigator Ravi Hira, MD (University of Washington, Seattle), told TCTMD. “Prior to these results, we didn’t know how these patients do long-term after TAVR. Survival in these patients at 1 year is about 75%, which is helpful to know and can help guide therapy in these patients who may not have another option, or in whom the surgical option is extremely high risk.”

As part of the study, which was published June 21, 2017, in JAMA Cardiology, investigators did not evaluate the safety or efficacy of TAVR compared with other treatments, such as medical therapy or surgical aortic valve replacement, which are the approved options for such patients. As a result, researchers said they can’t make any comments on whether these off-label TAVR patients would have fared better with surgery or medical therapy.   

“Still, it’s reassuring that these patients are having similar adjusted outcomes at 1 year compared with patients treated on-label,” said Hira. “There is still a need to exercise caution and choose patients appropriately—not every patient with a biscuspid valve, severe mitral regurgitation, or severe aortic regurgitation does equally well.”

In an editorial accompanying the study, Karen Joynt, MD (Brigham and Women’s Hospital, Boston, MA), and David Kramer, MD (Beth Israel Deaconess Medical Center, Boston), state that the cohort of off-label patients included in the TVT Registry “clearly needs effective treatments.” Registry data, they say, can provide useful estimates for procedural success and acute safety.

Like Hira, though, the editorialists note such data are limited in that there are no numbers on patients with similar comorbidities who underwent surgery or received no intervention. As a result, “the TVT Registry cannot answer important long-term effectiveness questions that are essential to evaluating emerging technologies,” particularly those used off-label, they conclude.

Wide Range of Off-Label Use

Of the 2,272 patients treated off-label, 435 had a bicuspid aortic valve, 935 had severe mitral regurgitation, 189 had moderate aortic stenosis, 853 had severe aortic regurgitation, and 3 patients had subaortic stenosis.

Investigators say the standard of care in these off-label patients is surgical aortic valve replacement. However, many of these patients are high risk for surgery—the median STS score in the off-label group was 7.2—or ineligible for surgery. Patients undergoing TAVR for an off-label indication tended to be younger and were more likely to receive care in a teaching hospital. Overall, off-label use among the 328 hospitals included in the analysis ranged from zero to almost 35%.  

“Depending on the hospital you’re at, the off-label use of TAVR is different. A lot of it depends on where you practice,” said Hira. “For example, if you are a high-volume or university center, you often end up receiving patients from smaller centers that are high risk or inoperative candidates and after weighing the risks and benefits, off-label use of therapy may be the best option for a particular patient.”

Christopher Meduri, MD (Piedmont Heart and Vascular Institute, Atlanta, GA), who was not involved in the study, said he was surprised that nearly 10% of TAVR procedures are performed off-label.

“In terms of the outcomes, though the mortality was higher when you looked at the pure on-label use versus off-label, I think the numbers overall are within reason,” said Meduri. “I think it can be challenging to interpret the true mortality for a couple of reasons, though. They’ve adjusted for a lot of variables to try to equalize the groups, but if there is a reason that makes somebody off-label—meaning we don’t have as much evidence of support—it’s likely there are some things that made them higher risk than we can gather from the data.”

That said, Meduri noted the TVT Registry reflects early TAVR experiences in these off-label indications and that he expects outcomes to improve further as operators gain experience treating these types of patients.

In the current analysis, patients with severe mitral regurgitation who received a TAVR device had the highest in-hospital, 30-day, and 1-year mortality rates. Regarding such patients, which represent approximately 40% of the off-label cohort, Meduri said they tend to have worse left ventricular function and more comorbidities, in general, which increases their baseline risk.

Off-Label, Not Inappropriate

Hira said the overall data suggest that patients treated off-label do relatively well, for the most part, and that he suspects TAVR may gain an expanded indication for the treatment of bicuspid aortic valves as well as for use in patients with moderate aortic stenosis with symptoms. Regarding use in patients with severe mitral regurgitation, aortic insufficiency, or subaortic stenosis, “it’s more of a grey area,” he said.  

Hira stressed off-label use should not be misconstrued to mean patients are receiving inappropriate care. He noted that when drug-eluting stents were first approved, registry data suggested approximately 10% of patients received the devices for off-label indications.

“When most people think of off-label, they think you’re doing something wrong, or doing something to harm the patient,” he said. “As with valve-in-valve, you will have an expansion of most therapies over time. It really shows us that there are a lot of patients in whom TAVR warrants further testing as they weren’t included in the randomized controlled trials but could stand to benefit from the therapy.”

To TCTMD, Meduri said that when he speaks with referring physicians, many are unaware TAVR can be performed in patients with aortic insufficiency or mitral regurgitation. He noted that while some might question why operators are performing TAVR off-label in these patients, the reason is that these challenging patients were not captured by the randomized trials but still don’t have any other good options.

“You say to yourself, can you try to make use of the technology available, which may be off-label but could potentially make the patient better?” said Meduri. While there are always “potential issues” when physicians veer outside regulatory pathways, these are patient populations that need something to be done, he said.

In an accompanying viewpoint, Robert Califf, MD (Duke University School of Medicine, Durham, NC), the former commissioner of the US Food and Drug Administration (FDA), states that Hira and colleagues were “appropriately cautious” interpreting their data. He notes the FDA has signaled an interest in using registry data for expanded indications for devices shown safe and effective in randomized trials.

Earlier this month, in fact, the FDA expanded the Sapien 3 (Edwards Lifesciences) indication to included treatment of a previously placed bioprosthetic aortic or mitral valve in high-risk surgical patients. The valve-in-valve approval was based on data from 314 patients who underwent aortic valve-in-valve replacement and 311 patients who underwent mitral valve-in-valve procedures in the TVT Registry. 

“Significant ‘off-label’ use captured in registries may be an important mechanism for motivating further clinical study and converting ‘off-label’ uses to important “on-label” ones,” writes Califf.

Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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  • Hira reports no conflicts of interest.
  • Joynt reports grant support and contract work from the US Department of Health and Human Services. Kramer receives consulting fees from the US Food and Drug Administration and the Baim Clinical Research Institute for clinical trials of medical devices.
  • Califf is the former commissioner of the FDA. He currently receives consulting fees from Merck and is employed with Verily Life Sciences, a subsidiary of Google.