Transcatheter Aortic Valve Implantation: Comparing Apples to Apples

As technological advances continue to outpace evidence-based medicine, it is imperative to encourage outcomes reporting in the literature. Prior to broad accessibility and dispersement of new technologies outside of clinical trials, it is important to standardize the manner in which future outcomes with such technology can be monitored. In this issue of the Journal, Stähli et al¹ report on 130 patients with severe aortic stenosis (AS) who were deemed inoperable by a multidisciplinary team and thus underwent transcatheter aortic valve implantation (TAVI) for whom they applied the newly established Valve Academic Research Consortium (VARC) outcome criteria.² Although two prior publications^3,4 reported outcomes after TAVI according to VARC criteria, those manuscripts were limited to a 30-day composite outcome, which does not embody the full VARC outcome recommendations. We congratulate Stähli et al for reassessing their patient outcomes following TAVI including the VARC combined efficacy endpoint (all-cause mortality from 30 days to 1 year, failure of current therapy for the aortic valve requiring hospitalization, or prosthetic valve dysfunction) out to 1 year as a pioneer for this new outcome measure. Important observations from Stähli et al’s cohort include: 1) overall 1-year survival of 80% including 68.5% of these patients living independently at home; 2) the VARC efficacy endpoint was met in 70.2% of patients; and 3) an apparent device-specific increased need for permanent pacemaker placement following Medtronic CoreValve implantation compared with the Edwards Sapien valve.

Table 1 represents commonly shared baseline characteristics and two previously identified predictors of mortality following TAVI⁵ in the present cohort and from the Placement of AoRtic TraNscathetER Valve Trial (PARTNER B).⁶ Statistical comparisons between cohorts were intentionally avoided, as this would be misleading since these were not randomized samples. As expected, the incidence of peripheral vascular disease and prior stroke is much higher for patients in the Stähli transapical group than in the PARTNER B cohort, which did not have a transapical option. The other variables listed in Table 1 appear comparable between the cohorts. Table 2 presents our attempt to categorize the PARTNER B cohort and the Stähli cohort using the VARC endpoints. Although the majority of the individual outcomes comprising the VARC composite endpoints were available in the PARTNER B manuscript, several of these were modified definitions (major bleeding and major vascular complications) and one was not reported (incorrect valve position), limiting direct comparison to the Stähli cohort.  Device success appears less in PARTNER B; however, our calculation may not be accurate due to missing information.  There were more frequent rates of major stroke, vascular complications, and bleeding in PARTNER B compared to the Stähli cohort, which accounts for the differences observed in the combined safety endpoint. Major stroke rates were numerically higher in PARTNER B than in the Stähli cohort and the need for a permanent pacemaker was higher with the Medtronic CoreValve than with the Edwards Sapien. Lower rates of all-cause mortality and prosthetic valve dysfunction in the Stähli cohort resulted in a higher rate of the combined efficacy endpoint compared to PARTNER B. The definition for acute kidney injury or need for dialysis was more inclusive as defined by Stähli than in the PARTNER B study, which might explain the six-fold higher rate in the former cohort. By our assessment, the Stähli paper had one deviation (although this may simply be a different interpretation) from the VARC definitions in their report of the failure of AS therapy requiring hospitalization as it was described between 30 days and 1 year instead of in its entirety. In order to ensure universal understanding of the VARC definitions, there is a need for further clarification and refinement of the VARC outcomes, specifically with regard to the timing of the endpoint determinants. Despite applying the VARC outcomes to both the PARTNER B and Stähli cohorts, one can appreciate that subtle modifications to some variables (e.g., the number of units of blood transfused to define major bleeding and major vascular complications as well as the differences in acute kidney injury) can create large outcome discrepancies, making direct comparisons treacherous.

Following the positive clinical data of TAVI in the PARTNER trials (A and B),^6,7 this transformative technology adds to the present armamentarium in advancing patient care and we anticipate U.S. Food and Drug Administration (FDA) approval soon. However, as with other technologies, questions remain as to how the successes observed within clinical trials will be generalized and utilized in the broader patient population once the technology gains approval. Recent evidence⁸ has demonstrated that despite guideline recommendations derived from randomized trial literature, inappropriate or excessive use of devices (coronary stents) continues. Additionally, there is widespread use of devices that have no clinical efficacy evidence (PFO closure devices) to support their use.⁹ We as a medical community must be at the forefront of ensuring appropriate use based on the indications studied in clinical trials as well as guideline adherence. Therefore, we propose to proactively establish guidelines for: 1) device availability and institutional access; 2) indications; 3) regulation and monitoring; and 4) education/training with this new technology.

Limiting the availability of TAVI to “regional” centers of excellence has been previously suggested;¹⁰ however, this could potentially lead to an unintended restriction of this critical technology based on an institution’s geographical juxtaposition, rather than merit. We would suggest that instead of imposing restrictions on availability, our goals should outline the pathway and key components needed to achieve a successful valve program and perform TAVI with optimized outcomes. Institutional support to allocate needed time, resources, and personnel is critical to establishing a comprehensive program.  This should undoubtedly include a multidisciplinary team of specialists and health care providers for selection and management of both inpatients and outpatients.

Indications for TAVI should come directly from the evidence-based literature, especially in the early phases of this new technology. Unfortunately, the difficulty of monitoring device implantation across multiple centers allows for inappropriate applications. Requiring a multidisciplinary team approach should help to minimize misuse and avoid the oversimplification of eligibility based on a EuroScore or Society of Thoracic Surgeons score, which lends itself to the same abuses as treating a coronary lesion solely based on the angiographer’s interpretation rather than taking into account all of the patient-related factors.

Regulation and monitoring of all TAVI implantations should occur and be maintained as an FDA-sponsored and industry-funded national registry of valvular heart disease to ensure appropriate selection criteria, quality short- and long-term outcomes, comparative effectiveness, quality of life assessments, and cost effectiveness.^11,12 Furthermore, this registry will provide long-term data to better understand device durability, paravalvular leaks, and quality of life metrics. Issues with funding, access to, and maintenance of such a registry represent complicated issues that will need to be addressed simultaneously with the U.S. FDA TAVI approval process.

Training for the TAVI devices must be developed for those within fellowship programs as well as those physicians already in established practice. This training will likely involve a combination of simulator-based modules and hands-on proctoring.  Industry support of such a training process is critical, but will require strict guidelines and policies. Ultimately, credentialing for TAVI and criteria for maintenance of privileges must be established. An important component of the education process should include an understanding of appropriate device use.

The establishment of standardized VARC outcomes is a critical step forward to allow direct comparisons between hospitals and across trials. However, as differences between TAVI devices emerge (e.g., pacemaker requirement), it will be imperative to allow the VARC outcome measures to grow and adapt. As noted in the current example, the definitions must be clearly understood and not modified in order to allow comparisons between registries and institutions. Applying VARC standardized outcomes to TAVI procedures moving forward will hopefully eschew comparisons akin to apples versus oranges.

References

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2. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: A consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol 2011;57:253–269.
3. Nuis RJ, Piazza N, Van Mieghem NM, et al. In-hospital complications after transcatheter aortic valve implantation revisited according to the Valve Academic Research Consortium definitions. Catheter Cardiovasc Interv 2011 May 11 [Epub ahead of print].
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6. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–1607.
7. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic valve replacement in high-risk patients. N Engl J Med 2011;364:2187–2198.
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9. Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention With STARFlex Technology (MIST) trial: A prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 2008;117:1397–1404.
10. Holmes DR Jr, Mack MJ. Transcatheter valve therapy A professional society overview from the American College of Cardiology Foundation and the Society of Thoracic Surgeons. J Am Coll Cardiol 2011;92:380–389.
11. Rosengart TK, Feldman T, Borger MA, et al. Percutaneous and minimally invasive valve procedures: A scientific statement from the American Heart Association Council on Cardiovascular Surgery and Anesthesia, Council on Clinical Cardiology, Functional Genomics and Translational Biology Interdisciplinary Working Group, and Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2008;117:1750–1767.
12. Vahanian A, Alfieri O, Al-Attar N, et al. Transcatheter valve implantation for patients with aortic stenosis: A position statement from the European Association of Cardio-Thoracic Surgery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2008;29:1463–1470.

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From the Baystate Medical Center, Western Campus, Tufts University School of Medicine, Springfield, Massachusetts.
The authors report no conflicts of interest regarding the content herein.
Address for corresondence: Gregory R. Giugliano, MD, SM, FACC, FSCAI, Baystate Medical Center, Western Campus, Tufts University School of Medicine, 759 Chestnut Street, Springfield, MA 01199. Email: Gregory.Giugliano@baystatehealth.org