Response by Banovic et al to Letter Regarding Article, "Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: The AVATAR Trial"

HomeCirculationVol. 146, No. 6Response by Banovic et al to Letter Regarding Article, “Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: The AVATAR Trial” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Banovic et al to Letter Regarding Article, “Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: The AVATAR Trial” Marko Banovic, Svetozar Putnik, Bernard Iung and Jozef Bartunek Marko BanovicMarko Banovic https://orcid.org/0000-0002-0017-6140 Belgrade Medical Faculty, Serbia (M.B., S.P.). Cardiology Department (M.B.), University Clinical Center of Serbia, Belgrade. Search for more papers by this author , Svetozar PutnikSvetozar Putnik Belgrade Medical Faculty, Serbia (M.B., S.P.). Cardiac Surgery Department (S.P.), University Clinical Center of Serbia, Belgrade. Search for more papers by this author , Bernard IungBernard Iung https://orcid.org/0000-0002-9127-348X Cardiology Department, Bichat Hospital APHP and Universite Paris Cité, France (B.I.). Search for more papers by this author and Jozef BartunekJozef Bartunek https://orcid.org/0000-0002-4927-1632 Cardiovascular Center, OLV Hospital, Aalst, Belgium (J.B.). Search for more papers by this author Originally published8 Aug 2022https://doi.org/10.1161/CIRCULATIONAHA.122.060918Circulation. 2022;146:e48–e49In Response:We thank both groups for their letters and interest in the AVATAR trial (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis).1In response to Ennezat et al, individual components of the primary composite outcome were not statistically different among randomized groups. The trial was not adequately powered to detect the difference of each component of composite primary outcome. Individual analyses of all-cause mortality and heart failure hospitalizations showed a strong trend favoring early surgery (ES), making it hypothetically plausible that, if the number of enrolled patients was higher, the difference could reach statistical significance. We believe that the relatively high rates of sudden cardiac death (SCD) further point at the unpredictability of aortic stenosis (AS) and potential hazards of a watchful waiting strategy. Two patients randomly assigned to the conservative treatment group unfortunately had SCD several months after the surgery. Accordingly, the death of these patients should not be viewed in the context of the risk of SCD associated with untreated asymptomatic AS.Serial exercise testing (ET) during follow-up was not performed in our trial. As suggested, it would be the most optimal solution for adequate implementation of a watchful waiting strategy. It is unfortunate that ET is seldom performed in a real-world clinical setting for symptom evaluation for AS.2 It is even more unlikely that serial ET could be performed for routine follow-up of asymptomatic patients. We performed ET in each patient for symptom evaluation at the beginning of the trial, and, to include truly asymptomatic patients with AS, each patient needed to reach the age-predicted heart rate followed by the implementation of regular clinical and echocardiographic follow-up per guidelines recommendations.3 Although the exclusion criterion was a fall in systolic blood pressure ≥20 mm Hg, among those included, no patient experienced a fall in systolic blood pressure.The design of the trial was event driven, with a total target of 35 events.4,5 Primary outcome curves between the groups started to diverge approximately 11 months after the randomization with a growing gap over time favoring the ES group. To assess whether that trend will continue, we are performing an extended 5-year follow-up. It is correct that the primary end point margin between the groups was relatively small. However, it was not caused by a higher than anticipated number of events in the conservative treatment group, but rather a higher than anticipated number of events in the ES group. An additional illustrative case is a patient randomly assigned to ES who died suddenly 1 day before the scheduled operation. Although in primary intention-to-treat analysis this was calculated as SCD in the ES group, clinically speaking, this unfortunate death was a typical example of the risk of SCD associated with the watchful waiting strategy. Therefore, it is reasonable to state that, in the AVATAR trial, the absence of serial ET in the conservative treatment group was not the cause for the lower margin of the primary end point.In response to Dweck et al, we recognize that the main limitation of the AVATAR trial is the relatively small number of included patients. Acknowledging this limitation, we concluded that the results should be viewed as preliminary. Likewise, they should not be extrapolated to the patients with significant comorbidities and higher operative risk. We want to emphasize that an independent 3-member data and safety monitoring board, including a cardiologist and cardiac surgeon with experience in conducting clinical trials, adjudicated all trial events. Investigators were not blinded to the trial allocation, but we believe this was unlikely to result in biased decisions.We believe that relatively low screening failure rates reflect the trial’s generalizability to real-world practice. It was probably helpful for the enrollment that a number of patients were referred for evaluation of asymptomatic AS from other centers that were not actively participating in the trial. If the patients were initially seen exclusively in the participating centers, the percentage of patients who would decline to participate might have been higher.The primary composite outcome and overall clinical experience from the AVATAR trial offer preliminary evidence for ES benefit in low-risk asymptomatic patients with severe AS, normal left ventricular ejection fraction, and without significant comorbidities. Until 10 years ago, no randomized trial had been conducted in asymptomatic patients with severe AS6; now, there are several. Indeed, the results of ongoing randomized trials are eagerly awaited and should provide further evidence about the best treatment approach to various subsets of these asymptomatic patients.Article InformationDisclosures None.FootnotesCirculation is available at www.ahajournals.org/journal/circReferences1. Banovic M, Putnik S, Penicka M, Doros G, Deja MA, Kockova R, Kotrc M, Glaveckaite S, Gasparovic H, Pavlovic N, et al. Aortic valve replacement versus conservative treatment in asymptomatic severe aortic stenosis: the AVATAR trial.Circulation. 2022; 145:648–658. doi: 10.1161/CIRCULATIONAHA.121.057639LinkGoogle Scholar2. Iung B, Delgado V, Rosenhek R, Price S, Prendergast B, Wendler O, De Bonis M, Tribouilloy C, Evangelista A, Bogachev-Prokophiev A, et al; EORP VHD II Investigators. Contemporary presentation and management of valvular heart disease: the EURObservational Research Programme Valvular Heart Disease II Survey.Circulation. 2019; 140:1156–1169. doi: 10.1161/CIRCULATIONAHA.119.041080LinkGoogle Scholar3. Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, Capodanno D, Conradi L, De Bonis M, De Paulis R, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease.Eur Heart J. 2022; 43:561–632. doi: 10.1093/eurheartj/ehab395CrossrefMedlineGoogle Scholar4. Banovic M, Iung B, Bartunek J, Asanin M, Beleslin B, Biocina B, Casselman F, da Costa M, Deja M, Gasparovic H, et al. Rationale and design of the Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): a randomized multicenter controlled event-driven trial.Am Heart J. 2016; 174:147–153. doi: 10.1016/j.ahj.2016.02.001CrossrefMedlineGoogle Scholar5. Banovic M, Iung B, Bartunek J, Penicka M, Vanderheyden M, Casselman F, van Camp G, Nikolic S, Putnik S. The Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): a protocol update.Am Heart J. 2018; 195:153–154. doi: 10.1016/j.ahj.2017.10.005CrossrefMedlineGoogle Scholar6. Banovic M, Putnik S, Nikolic S. A randomized trial in patients with asymptomatic severe aortic stenosis: a future has begun!J Am Coll Cardiol. 2016; 67:1970–1971. doi: 10.1016/j.jacc.2016.01.068CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Santangelo G, Bernardi N, Faggiano A, Bonelli A, Toriello F, Faggiano P and Carugo S (2022) Perspective Chapter: Lipoprotein (a), Cardiac Amyloidosis, and Aortic Stenosis - Underestimated Associations Aortic Stenosis - Recent Advances, New Perspectives and Applications, 10.5772/intechopen.102902 August 9, 2022Vol 146, Issue 6 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.060918PMID: 35939543 Originally publishedAugust 8, 2022 PDF download Advertisement SubjectsAortic Valve Replacement/Transcatheter Aortic Valve ImplantationStatements and Guidelines