The AVATAR Trial for Severe Asymptomatic Aortic Stenosis: Wait or Operate?

Abstract

Like most decisions in medicine, the choice of how to manage severe aortic stenosis (AS) is decided based on a cost-benefit analysis. Because no medical therapy has been shown to improve mortality or slow disease progression, the decision instead centers around the timing of aortic valve replacement (AVR), which is not without morbidity and mortality.1Rossebø AB Pedersen TR Boman K et al.Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.N Engl J Med. 2008; 359: 1343-1356Crossref PubMed Scopus (1257) Google Scholar,2Schwarz F Baumann P Manthey J et al.The effect of aortic valve replacement on survival.Circulation. 1982; 66: 1105-1110Crossref PubMed Scopus (457) Google Scholar Simply put, whenever the value assigned to either side of this “wait-versus-operate” equation changes, we must reassess our management. When intervention becomes safer than observation, we choose to perform AVR. Traditionally, surgical aortic valve replacement (SAVR) resulted in a known, stable risk of morbidity and mortality, and therefore the timing of intervention was indicated based on the dynamic progression of AS, with the accepted threshold to operate crossed only with the onset of symptoms.3Webb JG Wood DA. Current status of transcatheter aortic valve replacement.J Am Coll Cardiol. 2012; 60: 483-492Crossref PubMed Scopus (160) Google Scholar However, if treatment with SAVR or transcatheter aortic valve implantation (TAVI) can be made safer, or if medical management of certain subtypes of asymptomatic AS is found to be more dangerous, early intervention may be warranted. Our understanding of AS pathophysiology and treatment has advanced appreciably during the transcatheter era, and as a result there is renewed discussion regarding the treatment of severe asymptomatic disease.4Carabello BA. Should severe aortic stenosis be operated on before symptom onset? Aortic valve replacement should be operated on before symptom onset.Circulation. 2012; 126: 112-117Crossref PubMed Scopus (51) Google Scholar, 5Shah PK. Should severe aortic stenosis be operated on before symptom onset? Severe aortic stenosis should not be operated on before symptom onset.Circulationa. 2012; 126: 118-125Crossref PubMed Scopus (41) Google Scholar, 6Lindman BR Dweck MR Lancellotti P et al.Management of asymptomatic severe aortic stenosis: Evolving concepts in timing of valve replacement.JACC Cardiovasc Imaging. 2020; 13: 481-493Crossref PubMed Scopus (44) Google Scholar Data from the recently completed Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis (AVATAR) Trial provide additional material for this important clinical question.7Banovic M Putnik S Penicka M et al.Aortic valve replacement versus conservative treatment in asymptomatic severe aortic stenosis: The AVATAR trial.Circulation. 2022; 145: 648-658Crossref PubMed Scopus (58) Google Scholar In this editorial, we review the controversy surrounding management of severe asymptomatic AS before discussing the results of the AVATAR Trial and other ongoing studies. Up to 50% of patients are asymptomatic when diagnosed with severe AS.8Généreux P Stone GW O'Gara PT et al.Natural history, diagnostic approaches, and therapeutic strategies for patients with asymptomatic severe aortic stenosis.J Am Coll Cardiol. 2016; 67: 2263-2288Crossref PubMed Scopus (158) Google Scholar Although the annual mortality rate may approach 30% once symptoms develop, before onset the prognosis is considered good and a strategy of watchful waiting is common.9Kelly TA Rothbart RM Cooper CM et al.Comparison of outcome of asymptomatic to symptomatic patients older than 20 years of age with valvular aortic stenosis.Am J Cardiol. 1988; 61: 123-130Abstract Full Text PDF PubMed Scopus (237) Google Scholar In a study of 1,375 asymptomatic patients with moderate or severe AS (AV area of ≤1.5 cm2) and a preserved left ventricular ejection fraction (LVEF) from 10 international heart valve clinics, sudden death was reported as 2.5 cases per 1,000 patient-years during medical management.10Lancellotti P Magne J Dulgheru R et al.Outcomes of patients with asymptomatic aortic stenosis followed up in heart valve clinics.JAMA Cardiol. 2018; 3: 1060-1068Crossref PubMed Scopus (130) Google Scholar In a subset of 861 patients with AV area ≤1.0 cm2, overall survival was 92% at 2 years, 80% at 4 years, and 65% at 8 years, and AVR-free survival rates were 54%, 32%, and 12%, respectively. Median time to AVR was 8.7 months. Mortality at 30 days after AVR was 0.9%, indicating no or minimal increase in risk due to delayed surgery. These results suggest a strategy of delaying intervention is rational, although the period before eventual AVR was short. It should be noted that this study population was followed at high volume, research-oriented centers with outstanding surgical outcomes. This best-case scenario may not be a reality for all patients. Real world watchful waiting requires consideration of the following: Accuracy of Symptom Reporting. As many as 50% of patients who self-report as asymptomatic may have symptoms unmasked by stress testing. Elderly, sedentary, and patients with diabetes may be particularly vulnerable. Contributing to the lack of sensitivity, there is no consensus for the threshold that qualifies as a positive test, and even the type of testing (exercise v pharmacologic) varies.11Redfors B Pibarot P Gillam LD et al.Stress testing in asymptomatic aortic stenosis.Circulation. 2017; 135: 1956-1976Crossref PubMed Scopus (35) Google Scholar Predictability of AS Progression. The hemodynamic progression of AS has been described as somewhat predictable, with an annual increase in AV jet velocity of ≈0.3 m/s.12Otto CM Burwash IG Legget ME et al.Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome.Circulation. 1997; 95: 2262-2270Crossref PubMed Scopus (899) Google Scholar However, clinical outcomes vary widely and may be related to a faster rate of increase in jet velocity, or more severe valvular calcification.13Rosenhek R Binder T Porenta G et al.Predictors of outcome in severe, asymptomatic aortic stenosis.N Engl J Med. 2000; 343: 611-617Crossref PubMed Scopus (1062) Google Scholar Overall the rate of progression to symptoms is high in severe AS, and the risk of sudden death has been estimated to be 1% to 1.5% per year.8Généreux P Stone GW O'Gara PT et al.Natural history, diagnostic approaches, and therapeutic strategies for patients with asymptomatic severe aortic stenosis.J Am Coll Cardiol. 2016; 67: 2263-2288Crossref PubMed Scopus (158) Google Scholar,14Pellikka PA Sarano ME Nishimura RA et al.Outcome of 622 adults with asymptomatic, hemodynamically significant aortic stenosis during prolonged follow-up.Circulation. 2005; 111: 3290-3295Crossref PubMed Scopus (626) Google Scholar Myocardial Injury. Although sudden death is the greatest concern of delayed intervention, irreversible myocyte damage can occur even in the absence of symptoms and carries a poor clinical prognosis.8Généreux P Stone GW O'Gara PT et al.Natural history, diagnostic approaches, and therapeutic strategies for patients with asymptomatic severe aortic stenosis.J Am Coll Cardiol. 2016; 67: 2263-2288Crossref PubMed Scopus (158) Google Scholar A decrease in LVEF and advanced age also increases morbidity and mortality with AVR. Standardization of Surveillance. Although no formal recommendation exists, European guidelines suggest follow-up should be at least every 6 months to allow for early detection of symptoms. There is no consensus as to what this evaluation should entail, or whether it should involve routine use of echocardiography, stress testing, or serum analysis.15Vahanian A Beyersdorf F Praz F et al.2021 ESC/EACTS Guidelines for the management of valvular heart disease.Eur Heart J. 2022; 43: 561-632Crossref PubMed Scopus (810) Google Scholar The decision of when to intervene for severe AS is therefore more nuanced than simply assessing for the presence of symptoms. As such, the guidelines recommend AVR for severe symptomatic AS (Class 1 recommendation) and also for severe asymptomatic disease in patients with an LVEF <50% (Class 1), those undergoing cardiac surgery for other reasons (Class 1), patients who fail a stress test (Class 2a), and those at low surgical risk with either very severe AS (Class 2a) or rapid disease progression (Class 2a).16Nishimura RA Otto CM Bonow RO et al.2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Circulation. 2017; 135: e1159-e1195Crossref PubMed Scopus (1435) Google Scholar The most recent guidelines further expanded the indication for intervention to include patients with severe asymptomatic AS who have an elevated B-type natriuretic peptide level of >3 times normal (Class 2a) and those with a progressive decrease in LVEF to <60% (Class 2b).17Otto CM Nishimura RA Bonow RO et al.2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.Circulation. 2021; 143: e72-227PubMed Google Scholar It should be noted that the recommendations for treatment of asymptomatic AS were based largely on moderate quality evidence from nonrandomized, observational, or registry studies. An exception was the Randomized Comparison of Early Surgery versus Conventional Treatment in Very Severe Aortic Stenosis (RECOVERY) Trial, a multicenter study from Korea comparing early SAVR to conservative treatment for severe asymptomatic AS.18Kang DH Park SJ Lee SA et al.Early surgery or conservative care for asymptomatic aortic stenosis.N Engl J Med. 2020; 382: 111-119Crossref PubMed Scopus (209) Google Scholar, 19Mack 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, 20Popma 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 Although the investigators acknowledged the overall low risk of asymptomatic AS, they postulated that advances in surgical technique and device technology had shifted the verdict in favor of early intervention.21Brennan JM Edwards FH Zhao Y et al.Long-term survival after aortic valve replacement among high-risk elderly patients in the United States: Insights from the Society of Thoracic Surgeons adult cardiac surgery database, 1991 to 2007.Circulation. 2012; 126: 1621-1629Crossref PubMed Scopus (123) Google Scholar Published in 2020, the study reported a lower incidence of operative death or death from a cardiovascular cause with early SAVR (1% v 15%, hazard ratio: 0.09; [95% CI: 0.01-0.67]; p = 0.003) compared with watchful waiting after a median follow-up of 6.2 years. Because patients enrolled in the RECOVERY Trial had a median AV jet velocity of 5.1 m/s, results supported the recommendation for AVR in asymptomatic patients with very severe AS, defined as an AV jet velocity ≥5 m/s. One major limitation of the RECOVERY Trial was that exercise stress testing was “performed selectively” but not required during patient screening. As a result, an unknown but likely significant number of patients enrolled may have had a more significant progression of AS than appreciated and may have met criteria for AVR had additional testing been performed. Although this would have affected both treatment arms similarly, those randomized to SAVR would have received appropriate intervention, whereas those randomized to conservative treatment could remain at increased risk of adverse events, potentially contributing to the difference in outcomes. The AVATAR investigators were troubled by the variability in management of severe asymptomatic AS in patients with a normal LVEF, citing a low level of evidence supporting guidelines. They noted the annual risk of sudden death may be higher than the operative risk of AVR, and stated that in some countries long waiting lists exist with the time between onset of symptoms and SAVR approaching 12 months.22Banovic M Iung B Bartunek J 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: 147-153Crossref PubMed Scopus (52) Google Scholar The AVATAR Trial was therefore created as a prospective randomized controlled trial to evaluate the safety of early SAVR compared with conservative treatment with watchful waiting in patients with severe asymptomatic AS (NCT02436655).7Banovic M Putnik S Penicka M et al.Aortic valve replacement versus conservative treatment in asymptomatic severe aortic stenosis: The AVATAR trial.Circulation. 2022; 145: 648-658Crossref PubMed Scopus (58) Google Scholar The study was investigator initiated with no sources of funding and carried out at 9 centers from 7 European countries, although 73% of patients ultimately were enrolled at a single institution. Although not emphasized in their prestudy rationale, the investigators were fortunate to have designed their study with rigorous eligibility screening, which included mandatory stress testing.22Banovic M Iung B Bartunek J 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: 147-153Crossref PubMed Scopus (52) Google Scholar After the RECOVERY Trial was published as the first randomized control trial evaluating asymptomatic AS, the AVATAR Trial authors clearly underscored the definitively symptom-free population in their study as a distinguishing feature in their manuscript.7Banovic M Putnik S Penicka M et al.Aortic valve replacement versus conservative treatment in asymptomatic severe aortic stenosis: The AVATAR trial.Circulation. 2022; 145: 648-658Crossref PubMed Scopus (58) Google Scholar They excluded patients with an LVEF <50% or those with an AV peak velocity of >5.5 m/s at rest, consistent with the European guidelines published before the RECOVERY Trial.15Vahanian A Beyersdorf F Praz F et al.2021 ESC/EACTS Guidelines for the management of valvular heart disease.Eur Heart J. 2022; 43: 561-632Crossref PubMed Scopus (810) Google Scholar With a mean AV peak velocity of 4.5 m/s in each treatment arm at enrollment, the study was fairly precise in selecting a patient population that fell just short of current criteria for intervention, although some patients were enrolled above the updated 5.0 m/s cutoff for intervention. Patients randomized to conservative management were followed with in-person visits and echocardiography every 6 months. These patients were referred for surgery upon onset of symptoms, or when surveillance echocardiography detected a decrease in LVEF <50% or an increase in AV peak velocity of >0.3 m/s. Rather than designing a study to be powered appropriately to a specific number of patients, the investigators instead chose an event-driven protocol whereby the study was designed to be powered appropriately and completed once the target number of 35 primary end point events were observed. The primary end point was defined as a composite of all-cause mortality or major adverse cardiac events, which included acute myocardial infarction, stroke, or any unplanned hospitalization for heart failure requiring intravenous diuretic or inotropic medications. Secondary end points of operative mortality and repeat SAVR in both groups, repeated major adverse cardiac events, major bleeding, thromboembolic complications, time to death, and time to first unplanned hospitalization also were analyzed. The study enrolled patients 157 patients between June 2015 and September 2020, with follow-up completed in May 2021. As anticipated, this population was low risk (median Society for Thoracic Surgeons predicted risk of mortality score 1.7%) and young (mean, age 67), with few differences among study groups. Using intention to treat analysis, the early SAVR group had a significantly lower incidence of the composite primary end point compared with the conservative treatment group (16.6% v 32.9%, hazard ratio: 0.46 [95% CI: 0.23-0.90]; p = 0.02) with no significant difference in any of the individual components or secondary end points. Beyond the stated objectives of the study, one must consider what may be gained by watchful waiting. During 28 months of follow-up, 25 of 79 patients (31.6%) in the conservative treatment group ultimately underwent SAVR a median of 400 days after randomization, with new onset symptoms being the indication for surgery in 15 patients (60%). By comparison, patients in the early SAVR had surgery a median of 55 days after randomization. Therefore, adverse outcomes aside, roughly one in 3 patients who delayed surgery only managed to do so for about 1 year. In the RECOVERY Trial an even larger number of patients randomized to conservative treatment ultimately underwent TAVI or SAVR (74%), likely due to longer follow-up and greater disease burden.18Kang DH Park SJ Lee SA et al.Early surgery or conservative care for asymptomatic aortic stenosis.N Engl J Med. 2020; 382: 111-119Crossref PubMed Scopus (209) Google Scholar Additional research has found the probability of remaining free of cardiac surgery at 1, 2, and 5 years was 82%, 67%, and 33%, respectively.14Pellikka PA Sarano ME Nishimura RA et al.Outcome of 622 adults with asymptomatic, hemodynamically significant aortic stenosis during prolonged follow-up.Circulation. 2005; 111: 3290-3295Crossref PubMed Scopus (626) Google Scholar How to interpret these data to make a clinical decision is ultimately different for each patient, however a stronger argument to forgo surgery could be made if, for example, one could delay SAVR for closer to 10 years and therefore potentially reduce the overall number of lifetime cardiac surgeries. The AVATAR investigators conclude their study provides support for early surgery for severe AS, regardless of symptoms once severe AS develops. Making one clear recommendation for all patients with severe AS would certainly improve adherence to guidelines on the whole. As outlined, accurately determining if a patient is symptomatic remains challenging, and the 7 current carve-outs that call for asymptomatic intervention are cumbersome. Creating a single unified recommendation certainly would be convenient for physicians. It also would be wrong to do given the current evidence. This second randomized controlled trial, well designed but small, still leaves this area of study with far less support than the level of evidence for severe symptomatic disease. More likely, the authors of future guidelines would consider eliminating each clause for asymptomatic intervention, and instead create a blanket Class 2a, “it is reasonable” level of recommendation (and not Class 1), but only for the low-risk population. Even this change likely is dependent upon the results of several key trials expected to be completed in 2024. The EARLY TAVR Trial (NCT03042104) is an open label, parallel assignment study randomizing patients with severe symptomatic AS to either balloon-expandable TAVI or surveillance. The Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic Patients With Severe AS Trial will randomize a similar population to intervention (SAVR or TAVI) or routine care. The AVATAR Trial provides new information to the wait-versus-operate question for patients with severe asymptomatic aortic stenosis, but significant change to recommendations at present would be premature and would impede future opportunity to study this population or an older, high-risk population. We advocate for delaying definitive conclusions, pending further high-quality data. It will be worth the wait. None.