On the heels of positive results from the first phase of the PARTNER trial comes another milepost for the fledgling field of transcatheter aortic valve implantation (TAVI): a consensus set of standardized clinical endpoint definitions developed by the Valve Academic Research Consortium (VARC). By providing a uniform framework for reporting and interpreting TAVI results, the VARC definitions aim to improve the quality of future research and enable meaningful comparisons among clinical trials.

The consensus report, written by a committee led by Martin B. Leon, MD, of Columbia University Medical Center (New York, NY), was published online January 7, 2011, ahead of print in the Journal of the American College of Cardiology and copublished in the European Heart Journal.

VARC is a collaboration of academic research organizations, US and European specialty societies, independent experts, and stakeholders including device manufacturers and the US Food and Drug Administration (FDA). The definitions of the major clinical endpoints were guided by a number of criteria, the authors report, aiming to address safety and/or efficacy issues while representing key clinical outcomes in a consistent manner that reflect the unique aspects of TAVI and lend themselves to statistical analysis.

The authors specify that although the report represents a consensus and has been broadly reviewed, it is not intended to be a guidelines statement.

Key TAVI Clinical Endpoints

The clinical endpoints defined are:

• Mortality
• MI
• Stroke
• Bleeding complications
• Acute kidney injury
• Vascular complications

The VARC statement also addresses several endpoint categories that facilitate evaluation of TAVI. These include prosthetic valve dysfunction, which is typically characterized by symptoms of regurgitation or stenosis and is assessed by echocardiography.

For prosthetic valve ‘associated’ complications, VARC recommends documenting any new conduction system abnormalities including indications for new permanent pacemaker implantation within 30 days after the procedure. It also advises paying careful attention to signs of mechanical coronary artery obstruction or new mitral valve dysfunction or disruption.

Specific endpoints to establish clinical benefit after TAVI include heart failure parameters such as exercise performance, assessment of NYHA functional status, or quality-of-life questionnaires. Other endpoint components include a measure of frailty as well as hospitalization for symptoms of valve or cardiac deterioration requiring a valve procedure or more intensive medical management.

Given the complex nature of TAVI and the rapid evolution of devices and procedural techniques, the report also proposes that an open category of therapy-specific endpoints be included in case reports.

To provide an overall impression of safety and effectiveness, VARC proposes 3 composite endpoints:

• Device success, characterized by the device and procedural factors underlying vascular access, delivery, and performance
• Combined safety endpoint at 30 days
• Combined efficacy endpoint at 1 year or later, incorporating major clinical and valve performance factors

However, the authors note, “by intent, this consensus manuscript was not device-specific and the definitions can be applied to next-generation and iterative TAVI devices already under early stages of clinical investigation.”

Early FDA Involvement Key

In an accompanying commentary, Matthew G. Hillebrenner, MSE, Julie A. Swain, MD, and Bram D. Zuckerman, MD, of the FDA write, “The FDA anticipates incorporating many of the recommendations put forth in the consensus document into the TAVI clinical trials reviewed and regulated by the Agency. As such, we believe that the VARC document can help improve the efficiency with which TAVI clinical trials are designed and executed.

“It is our hope that publication of the VARC document will encourage sponsors and investigators to make use of early interaction with the Agency. For this field to mature in the USA, it is essential that FDA, sponsors, and investigators continue to collaborate closely to develop high-quality clinical data that ultimately results in benefits for patients,” the FDA authors conclude.

Responding to a Clear Need

In an interview with TCTMD, Dr. Leon described the impetus behind the VARC project. “Unlike in coronary disease, TAVI does not have a history of randomized controlled trials,” he said. “As this new hybrid field emerged, there was no thoughtful process with careful selection of appropriate endpoints and delineation of definitions. People did studies and reported data, and it was impossible to interpret the outcomes because the endpoints from the standpoint of standardized definitions were very confused. You would look at multiple publications and see [wide] variations. For instance, in vascular complications, it could be as low as 5% or as high as 45%, and you never knew if it was just the definitions or it was a meaningful difference.”

Dr. Leon said that VARC was an offshoot of the process initiated by ARC, which established criteria for stent thrombosis. “But it was meant to be more inclusive,” he observed. “It was by intent multidisciplinary and international, and it included multiple societies in cardiology and cardiac surgery as well as experts in other areas such as vascular medicine, echocardiography, and neurology to get input into these endpoints.”

Importantly, Dr. Leon noted, “the FDA was involved from the beginning. We wanted them to communicate with us and give us feedback. When they disagreed about certain endpoints, we scheduled meetings and met with experts to see if we could achieve consensus. So whenever we went forward with this, the FDA could feel reasonably comfortable that the endpoints were pretty close to the definitions that they would have liked to see.”

Certain Endpoints Problematic

Dr. Leon acknowledged that achieving consensus was especially challenging for certain endpoints. “Stroke and vascular complications we agonized over,” he said. “We view stroke as a very important complication, [but] it is in evolution regarding how it is defined, the use of neuroimaging, and differentiation between major and minor stroke. We used a modified Rankin score as a way of determining whether or not a stroke is clinically meaningful.” On the other hand, vascular complications have never been well defined, and there is little good literature to draw upon, Dr. Leon observed, adding, “We had to come up pretty much de novo with a meaningful definition.”

In a telephone interview with TCTMD, Josep Rodés-Cabau, MD, of Laval University (Quebec City, Canada), singled out the definition of periprocedural MI. “For me, it is a bit conservative—with a tenfold increase in cardiac enzymes and signs of ischemia, the rate of MI following the procedure will be very low. But we are very early in our experience with TAVI, and some of the definitions will change depending on what future studies show about the prognostic significance of these complications,” he noted. That is especially true if TAVI is extended to younger, less sick patients, Dr. Rodés-Cabau added. For example, the restricted definition of MI may be appropriate in a very old patient but not in a younger patient with longer life expectancy.

Dr. Leon agreed that the current definitions are only a starting point. “As data continue to pour in, we’ll be revising these definitions on a fairly regular basis,” he said.

Overall, adoption of standardized definitions is very helpful, Dr. Rodés-Cabau underlined, not only for interpreting data on a particular kind of prosthetic valve but across different types of devices. “Now with something as simple as ‘procedural success,’ on the basis of the VARC definitions everyone will understand what you are talking about,” he commented.

Dr. Leon added that the VARC definitions can also serve as a template for clinical research in other catheter-based valve therapies. “Many of the basic endpoints are ubiquitous. Others that are more directed toward mitral valve therapy, for example, would need to be clarified,” he said. Moreover, he added, “the whole area of clinical trial methodology in the valve field needs to be looked at.”

Note: Dr. Leon is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

2. Hillebrenner MG, Swain JA, Zuckerman B. VARC consensus report: The FDA perspective. J Am Coll Cardiol. 2011;57:270-271.

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