The Deployment of Valve Academic Research Consortium 3 (VARC-3): New Endpoints, Broader Definitions, and Plenty of Unanswered Questions

Abstract

ENTER THE term “TAVR” into the Pub Med search box and more than 4,000 titles appear. For 2020 alone, there are 1,079 citations listed. At the rate that information is being generated, it has become increasingly difficult to keep pace with this rapidly evolving technology. When Alain Cribier first published the original report of percutaneous transcatheter aortic valve replacement (TAVR) in a human in 2002, most never would have imagined that this concept would become a standard of care, and in record time to boot.1Cribier A Eltchaninoff H Bash A et al.Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: First human case description.Circulation. 2002; 106: 3006-3008Crossref PubMed Scopus (2580) Google Scholar Today, more than 800,000 such procedures have been performed worldwide.2Généreux P Piazza N Alu MC et al.Valve Academic Research Consortium 3: Updated endpoint definitions for aortic valve clinical research.Eur Heart J. 2021; 00: 1-33Google Scholar TAVR has become a multibillion dollar industry, and market research analysis estimates the number of procedures performed annually to be approximately 340,000 worldwide by 2025.3Srivasatva A, Jaiswal P. Transcatheter Aortic Valve Implantation (TAVI) Market Overview. June 2018, Allied Market Research. Available at: https://www.alliedmarketresearch.com/tavi-market. Accessed May 31, 2021.Google Scholar TAVR presently is performed in all 50 US states, along with the District of Columbia and Puerto Rico, and it is here to stay. Expanding indications, refinement, and multiple iterations of the prosthetic devices and delivery systems, along with operator familiarity and growing experience, have led to the establishment of TAVR as an accepted alternative to surgical aortic valve replacement (SAVR) in selected patients. In 2019, TAVR volume exceeded SAVR in the United States (72,991 v 57,626) compared with 13,723 TAVR cases from 2011 to 2013.4Carroll JD Edwards FH Marinac-Dabic D et al.The STS-ACC Transcatheter Valve Therapy National Registry: A new partnership and infrastructure for the introduction and surveillance of medical devices and therapies.J Am Coll Cardiol. 2013; 62: 1026-1034Crossref PubMed Scopus (165) Google Scholar The Placement of AoRTic TraNscathetER (PARTNER) trials for all risk groups were pivotal in the affirmation of this technology as an alternative to SAVR for patients with severe aortic stenosis.5Mack MJ Leon MB Smith CR et al.5-year outcomes of transcatheter aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): A randomized controlled trial.Lancet. 2015; 385: 2477-2484Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar, 6Leon MB Smith CR Mack MJ et al.Transcatheter or surgical aortic-valve replacement in intermediate-risk patients.N Engl J Med. 2016; 374: 1609-1620Crossref PubMed Scopus (3259) Google Scholar, 7Mack MJ Leon MB Thourani VH et al.Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients.N Engl J Med. 2019; 380: 1695-1705Crossref PubMed Scopus (2458) Google Scholar The results of PARTNER 3 led the United States Food and Drug Administration (FDA) to expand TAVR indications to include patients with severe aortic stenosis at low surgical risk.7Mack MJ Leon MB Thourani VH et al.Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients.N Engl J Med. 2019; 380: 1695-1705Crossref PubMed Scopus (2458) Google Scholar In parallel, the Evolut Low Risk Trial found that TAVR was statistically noninferior to SAVR.8Popma JJ Deeb GM Yakubov SJ et al.Transcatheter aortic-valve replacement with a self-expanding valve in low-risk patients.N Engl J Med. 2019; 380: 1706-1715Crossref PubMed Scopus (1885) Google Scholar The high clinical outcome standards set by the long experience with SAVR have made it challenging to adopt newly proposed alternatives. Nevertheless, the 2020 American College of Cardiology (ACC)/American Heart Association (AHA) Focused Update on Valvular Heart Disease guideline recommends SAVR as the preferred therapy for patients at low surgical risk.9Otto CM Nishimura RA Bonow RO et al.2020 ACC/AHA Guideline for the management of patients with valvular heart disease: Executive summary. A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.Circulation. 2021; 143: e35-e71PubMed Google Scholar The Valve Academic Research Consortium (VARC) is a consensus report that was first published in 2011 to standardize the definitions for important clinical endpoints associated with the procedure, and to permit relevant comparisons among various clinical trials, with the intention of incorporating the data derived into daily clinical practice.10Leon MB Piazza N Nikolsky E et al.Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials.J Am Coll Cardiol. 2011; 57: 253-269Crossref PubMed Scopus (696) Google Scholar Just recently, the VARC-3 Writing Committee published its latest update to its definitions for aortic valve clinical research in the European Heart Journal.2Généreux P Piazza N Alu MC et al.Valve Academic Research Consortium 3: Updated endpoint definitions for aortic valve clinical research.Eur Heart J. 2021; 00: 1-33Google Scholar Included in this document are new criteria for defining valve thrombosis and myocardial infarction, among others. The update is timely, as candidates for TAVR now include younger, lower-risk patients, in whom prosthetic durability is of particular importance. Device approval was initially for inoperable or extreme-surgical-risk patients in 2011, followed by high-risk patients in 2012, intermediate-risk patients in 2016, and low-risk patients in 2019. The result has been an explosive growth in numbers of procedures performed annually, with ongoing technologic improvements. The concept of the Academic Research Consortium first was established in 2006 as a collaborative effort between academic research organizations and the FDA in an advisory capacity. Its mission statement was to “promote informed and collaborative dialogue across stakeholders (researchers, clinicians, device manufacturers and the regulatory agencies), supporting the development of consensus definitions and nomenclature for targeted areas of new medical device development, and to disseminate such definitions in the public domain.”11Cutlip DE Windecker S Mehran R et al.Clinical end points in coronary stent trials: A case for standardized definitions.Circulation. 2007; 115: 2344-2351Crossref PubMed Scopus (4709) Google Scholar With the establishment of precise definitions and a transparent process, the intent was to improve the quality and speed of research, while minimizing associated research costs. The process also produced less ambiguity and more objectivity in data collection and interpretation, both for clinical trials and clinical use. Homogeneity in data over a large number of trials allows more precision in interpretation of data in a meta-analysis, making it more meaningful. Since its first publication in 2011, the VARC consensus report has been revised twice.10Leon MB Piazza N Nikolsky E et al.Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials.J Am Coll Cardiol. 2011; 57: 253-269Crossref PubMed Scopus (696) Google Scholar VARC was important in establishing consensus criteria for seven procedure-related key endpoints vis-à-vis mortality, myocardial infarction, stroke, bleeding, acute kidney injury, vascular complications, and the performance of the valve prosthesis itself. Composite endpoints defining the safety and efficacy of the procedure also were delineated, with an emphasis on procedure-related events, including conduction disturbances, arrhythmias and coronary obstruction during valve implantation; and clinical benefit endpoints, such as hospital readmission and quality of life. In addition, VARC proposed the documentation of important complications—unplanned use of cardiopulmonary bypass, conversion to SAVR, reintervention, postimplantation dilatation, second device implantation, device migration, ventricular perforations—as therapy-specific endpoints. This initial effort provided a formidable groundwork, providing future direction in clinical research, product development, and procedural modifications. The original VARC consensus document was meant to serve less as a guideline statement, and more as a means of standardizing future research endeavors, including consistency in reporting practices. The Transcatheter Valve Therapy (TVT) Registry is a benchmarking tool that was created jointly by the Society of Thoracic Surgeons and the ACC as a means of procedural and device surveillance, promoting quality assurance and improvement, and generation of evidence-based studies to expand device labeling.4Carroll JD Edwards FH Marinac-Dabic D et al.The STS-ACC Transcatheter Valve Therapy National Registry: A new partnership and infrastructure for the introduction and surveillance of medical devices and therapies.J Am Coll Cardiol. 2013; 62: 1026-1034Crossref PubMed Scopus (165) Google Scholar All patients undergoing TAVR since FDA approval in 2011 are enrolled in the registry, and standard definitions put forth by the VARC are used for data collection, although compliance with the definitions has not been universal.12Erlebach M Head SJ Mylotte D et al.VARC endpoint definition compliance rates in contemporary transcatheter aortic valve implantation studies.Eurointervention. 2016; 12: 375-380Crossref PubMed Scopus (11) Google Scholar In 2012, the first revision of the initial document, VARC-2, was published, with the goal of a better understanding of patient risk stratification and case selection.13Kappetein AP Head SJ Généreux P et al.Updated standardized endpoint definitions for transcatheter aortic valve implantation: The Valve Academic Research Consortium-2 consensus document.Eur J Cardiothorac Surg. 2012; 42: S45-S60Crossref PubMed Scopus (655) Google Scholar A multidisciplinary heart team model was proposed, consisting of interventional cardiologists, cardiovascular surgeons, imaging specialists, anesthesiologists, geriatricians, and neurologists to individualize the optimal customized treatment option for each patient. Emphasis was placed on risk factors not included in traditional models, such as the presence of a porcelain or severely atherosclerotic aorta, frailty indices, severe liver disease, a hostile chest (defined as conditions rendering sternal entry a prohibitive risk), severe pulmonary hypertension, and right ventricular dysfunction. Beyond modification of the clinical endpoints defined in the earlier consensus report, echocardiographic parameters for evaluation of prosthetic valve dysfunction were defined in this revision. Specific timing intervals for the various approaches also were stated in the document. So what are the main differences between VARC-2 and VARC-3? One of the main goals was to better define procedural outcomes, as well as long-term outcomes now that TAVR is being performed on relatively younger, healthier patients. The VARC-3 updated guidelines now include 15 proposed clinical endpoints as follows: mortality; neurologic events; hospitalization/rehospitalization; bleeding/transfusions; vascular/access-related complications; cardiac structural complications; other procedural/valve-related complications; new conduction disturbances/arrhythmias; acute kidney injury; myocardial infarction; bioprosthetic dysfunction; leaflet thickening/reduced motion; clinically significant valve thrombosis; patient-reported outcomes/health status; and composite endpoints. Also included are new or modified definitions with regard to hospital readmissions, access site-related complications, and prosthetic dysfunction and failure among others. A more “granular” grading of paravalvular regurgitation also is included in the update. Standardized definitions should facilitate the identification of specific endpoints. Clinical criteria have been created to better define prosthetic dysfunction, including structural and nonstructural deterioration, thrombosis, and endocarditis. Prosthetic deterioration has been subdivided further into three stages with separate criteria as follows: stage 1, morphologic valve deterioration; stage 2, moderate hemodynamic valve deterioration; and stage 3, severe hemodynamic valve deterioration. Leaflet pathophysiology also is addressed in the new consensus guidelines, including criteria for identifying hypoattenuated leaflet thickening and reduced leaflet motion. The definition of valve thrombosis has been modified so that it must be “clinically significant.” Stated otherwise, there must be clinical sequelae, such as stroke or evidence of thromboembolic events to name a few, worsening stenosis or regurgitation in the presence of stage 2 or stage 3 hemodynamic deterioration, or diagnosis during imaging (transesophageal echocardiography, computed tomography). Also included in the new definition is the diagnosis of valve thrombosis without clinical sequelae in the presence of stage 3 deterioration and confirmation by imaging. These new definitions of valve thrombosis have drawn some criticism from at least one surgeon on social media (the PARTNER 3 trial in low-risk patients used the older VARC definitions, which favored SAVR at two years).14Wendling P. VARC-3 sets goalpost for future aortic valve trials. Available at: https://www.medscape.com/viewarticle/950012. Accessed May 30, 2021.Google Scholar Arguments in favor of the new definition raise the issue of leaflet thickening or restricted mobility unrelated to thrombosis, adding the element of valve morphology. A randomized trial comparing rivoroxaban plus aspirin to clopidogrel plus aspirin for the first three months after TAVR was terminated early because of a greater rate of death or first thromboembolic event, and a higher incidence of bleeding in the former group.15Dangas GD Tijssen JGP Wöhrle J et al.A controlled trial of rivoroxaban after transcatheter aortic-valve replacement.N Engl J Med. 2020; 382: 120-129Crossref PubMed Scopus (287) Google Scholar These findings occurred despite a reduction in hypoattenuated leaflet thickening and reduced leaflet motion at 90 days in a substudy analysis.16De Backer O Dangas GD Jilaihawi H et al.Reduced leaflet motion after transcatheter aortic-valve replacement.N Engl J Med. 2020; 382: 130-139Crossref PubMed Scopus (161) Google Scholar These findings have raised the question of whether routine imaging for the detection of reduced leaflet motion or routine anticoagulation after TAVR to prevent leaflet motion abnormalities is even clinically useful.17Kaul S. Raising the evidentiary bar for guideline recommendations for TAVR.J Am Coll Cardiol. 2020; 76: 985-991Crossref PubMed Scopus (10) Google Scholar The inclusion of all rehospitalization as a primary (rather than secondary) clinical efficacy endpoint (the same category as death and stroke) also has been put into question, since it only was included in PARTNER 3 among all major trials, and, not surprisingly, put the more invasive SAVR at a disadvantage. VARC-3 defines rehospitalization as “any admission after the index hospitalization or study enrollment to an inpatient unit or hospital ward for at least 24 hours,” compared with VARC-2, in which rehospitalizations were for valve-related symptoms or worsening heart failure as part of the clinical efficacy (after 30 days) endpoint. Another area of criticism has been the manner in which periprocedural myocardial infarction <48 hours after SAVR or TAVR is defined (using the same changes in peak CK-MB or cardiac troponin for both to define clinical events). VARC-2 diagnosed periprocedural myocardial infarction using biomarkers, as well as ischemic signs or symptoms. Only using biomarkers is more likely to favor nonsurgical interventions. The ACC and the AHA recently updated their guidelines for the management of patients with valvular heart disease.9Otto CM Nishimura RA Bonow RO et al.2020 ACC/AHA Guideline for the management of patients with valvular heart disease: Executive summary. A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.Circulation. 2021; 143: e35-e71PubMed Google Scholar In this document, guidelines are clear for ages >80 years and <65 years. For symptomatic patients >80 years or patients with a life expectancy <ten years and no anatomic contraindication, TAVR is recommended (Class 1, Level A), and for symptomatic and asymptomatic patients <65 years or with a life expectancy >20 years and any indication for AVR, SAVR is recommended (Class 1, Level A). Between 65 and 80 years with no contraindications to either approach, a shared decision between patient and physician, taking into account life expectancy and valve durability, is recommended (Class 1, Level A). Despite these recommendations, off-label use of TAVR is not so uncommon in clinical practice.18Hira RS Vemulapalli S Li Z et al.Trends and outcomes of off-label use of transcatheter aortic valve replacement. Insights from the NCDR STS/ACC TVT registry.JAMA Cardiol. 2017; 2: 846-854Crossref PubMed Scopus (47) Google Scholar Shared decision-making between patient and physician furthermore should take into consideration that many patients seek out medical advice and information through social media, including support groups, which may make them biased toward the lesser intervention, and inadequately informed about potential consequences. There is also a sense among some in the interventional cardiology community that “TAVR now should be considered the preferred first therapy in ALL (emphasis added) patients with severe symptomatic aortic stenosis, independent of risk profiles, who are good candidates for TAVR (transfemoral access and favorable aorta and valve anatomy), and surgery now should be reserved for patients who are POOR (emphasis added) candidates for TAVR. This undeniable and justified trend favoring TAVR will be amplified by recent medical social changes that recognize the importance of patient preference and shared decision-making in complex therapy choices.”19George I Kodali SK Leon MB. Changing the conversation to TAVR first! Aftermath of the low-surgical risk TAVR studies.J Am Coll Cardiol Cardiovasc Interv. 2019; 12: 908-910Crossref Scopus (4) Google Scholar Does this imply that all low-risk patients should undergo TAVR over SAVR despite ACC/AHA guidelines? What about long-term prosthetic durability? How will TAVR impact the ability to engage the coronary ostia should future percutaneous intervention become necessary? Does shared decision-making also include surgical consultation? Important and not insignificant considerations also should include the greater need for permanent pacemakers, higher rates of vascular complications, increased incidence of paravalvular regurgitation, and valve intervention with TAVR. In PARTNER 3, the incidence of mild paravalvular regurgitation was substantially higher with TAVR (29.4% v 2.1%),7Mack MJ Leon MB Thourani VH et al.Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients.N Engl J Med. 2019; 380: 1695-1705Crossref PubMed Scopus (2458) Google Scholar and though this degree of valvular insufficiency may seem insignificant, there is still no information on the effect of mild aortic regurgitation on left ventricular remodeling in a cohort with longer life expectancy. The incidence of conduction abnormalities also is higher in the TAVR population, including new-onset left bundle-branch block, which in itself is a risk factor for adverse outcomes.7Mack MJ Leon MB Thourani VH et al.Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients.N Engl J Med. 2019; 380: 1695-1705Crossref PubMed Scopus (2458) Google Scholar,8Popma JJ Deeb GM Yakubov SJ et al.Transcatheter aortic-valve replacement with a self-expanding valve in low-risk patients.N Engl J Med. 2019; 380: 1706-1715Crossref PubMed Scopus (1885) Google Scholar Regardless of whether SAVR or TAVR is the optimum choice of therapy, patients must have a clear understanding of the pros and cons of each approach. Importantly, outcomes from studies using the new VARC-3 definitions could shape future recommendations for the management of aortic stenosis. Hopefully, adoption of these new definitions will shed more light on the role of TAVR in intermediate- and low-risk patients, in whom the stakes are much higher than short-term palliation and symptom relief. The great unknown is valve durability, most importantly in patients with longer life expectancy. Standardized definitions for structural valve degeneration (SVD) were published in 2017 by the European Association of Percutaneous Cardiovascular Intervention, the European Society of Cardiology, and the European Association for Cardio-Thoracic Surgery.20Capodanno D Petronio AS Prendergast B et al.Standardized definitions of structural deterioration and valve failure in assessing long-term durability of transcatheter and surgical aortic bioprosthetic valves: A consensus statement from the European Asociation of Percutaneous Cardiovascular Interventions.Eur Heart J. 2017; 38: 3382-3390PubMed Google Scholar Standardized definitions also have been published by the Valve-in-Valve International Data Group, with an emphasis on the staged progression of valve degeneration.21Dvir D Bourguignon T Otto CM et al.Standardized definition of structural valve degeneration for surgical and transcatheter bioprosthetic aortic valves.Circulation. 2018; 137: 388-399Crossref PubMed Scopus (269) Google Scholar With regard to SAVR, SVD has been poorly defined, and the need for reoperation has, in general terms, been used as a surrogate that does not necessarily take into account non-SVD indications for reoperation.22Capodanno D Søndergaard L. How to define durability of transcatheter and surgical bioprosthetic aortic valves. Facts and misconceptions.J Am Coll Cardiol Intv. 2020; 13: 257-260Crossref Scopus (1) Google Scholar Stated otherwise, freedom from reoperation does not equate with freedom from SVD. This has made durability comparisons between SAVR and TAVR unreliable. Hopefully, these new definitions, in conjunction with the “common language” of VARC-3 for reporting, will allow for more precise head-to-head comparisons between TAVR and SAVR, and provide more meaningful and nonspeculative answers to the durability question. Although the new VARC guidelines lean toward more detail, precision and “granularity,” one must consider: will the devil be lost in the detail? The guidelines do lend a great deal of objectivity; however, certain endpoints may not be valid sans some level of subjectivity. Nevertheless, the advent of VARC-3 is yet another stepping stone in establishing a more meaningful roadmap for industry, clinicians, researchers, and, possibly, the consumer. Various other Academic Research Consortiums, such as Mitral ARC, Bleeding ARC, and Neurologic ARC, provide focused and precise endpoints in their particular fields to harmonize and amalgamate data derived from various clinical trials. The United States Aortic Research Consortium is yet another example aimed at advancing the development of endovascular therapies for aortic diseases. As cardiothoracic anesthesiologists work alongside cardiothoracic surgeons and interventional cardiologists, one now must ask: is it time that the anesthesia community also adopt similar processes? The Society of Thoracic Surgeons and ACC have coordinated their efforts to create thorough guidelines, definitions and benchmarks to aid in clinical research and optimal evidence-based patient care. Various focused novel or adopted definitions for endpoints developed by multidisciplinary stakeholders may be a need of the hour for our own community. This could be pertinent to outcomes research programs in the fields of cardiac, vascular, and thoracic anesthesia. The perils of indecision on such a matter are invoked by the English writer Edward Young, who so eloquently stated, “Procrastination may truly be the thief of time.” None.