HomeCirculationVol. 145, No. 12Is Asymptomatic Severe Aortic Stenosis Still a Waiting Game? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBIs Asymptomatic Severe Aortic Stenosis Still a Waiting Game? Graham S. Hillis, MBChB, Gerry P. McCann, MD and David E. Newby, MD Graham S. HillisGraham S. Hillis Correspondence to: Graham S. Hillis, MBChB, Department of Cardiology, Level 4, South Block, Royal Perth Hospital, Perth, Western Australia, 6000, Australia. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2417-4673 Department of Cardiology, Royal Perth Hospital and Medical School, University of Western Australia, Perth (G.S.H.). Search for more papers by this author , Gerry P. McCannGerry P. McCann Department of Cardiovascular Sciences, University of Leicester and the NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (G.P.M.). Search for more papers by this author and David E. NewbyDavid E. Newby https://orcid.org/0000-0001-7971-4628 British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (D.E.N.). Search for more papers by this author Originally published21 Mar 2022https://doi.org/10.1161/CIRCULATIONAHA.121.058598Circulation. 2022;145:874–876The timing of valve replacement in patients with severe but asymptomatic aortic stenosis has long been debated. Conventional teaching and guidelines recommend a strategy of expectant management, or “watchful waiting,” with prompt aortic valve replacement (AVR) if symptoms or left ventricular systolic dysfunction develop. This is based on historic data and more recent cohort studies suggesting that the prognosis of patients with asymptomatic severe aortic stenosis is good. Conversely, once symptoms develop, patients require timely AVR.In recent years, this traditional doctrine has been questioned. This reflects a greater understanding of the impact of aortic stenosis on the myocardium, with the potential for irreversible changes that may result in long-term morbidity and premature death, even after AVR.1 Moreover, as operative and anesthetic techniques have improved, surgical AVR has become a relatively low-risk procedure. Likewise, transcatheter AVR is increasingly being applied with similarly excellent outcomes. This has lowered the threshold for intervention in aortic stenosis and makes it a less daunting prospect for patients. Registry data confirm the low risk of AVR and suggest that, in propensity-matched cohorts, patients with asymptomatic severe aortic stenosis who undergo early valve replacement have better outcomes.2 While such data have inherent limitations, they cast doubt on the prudence of established conservative practice.Two recent randomized clinical trials have further challenged the appropriateness of watchful waiting in this setting. After a median follow-up of 6 years, the RECOVERY trial (Randomized Comparison of Early Surgery versus Conventional Treatment in Very Severe Aortic Stenosis) reported a marked reduction in a composite of all-cause death within 30 days of surgery, or cardiovascular death at any time, in those randomized to early surgical AVR: from 15% to 1% (hazard ratio, 0.09 [95% CI, 0.01–0.67]; P = 0.003).3 The AVATAR trial (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis) also supports a strategy of early surgical AVR, with a substantial reduction in a composite of death, acute myocardial infarction, stroke, and heart failure hospitalization at 3 years: from approximately 35% to 15% (hazard ratio, 0.46 [95% CI, 0.23–0.90]; P = 0.02).4Considering these findings, has the time come to amend guidelines and change practice? We argue not. Although observational data are interesting, they are prone to case-selection bias and need prospectively tested in randomized trials. Moreover, although the RECOVERY and AVATAR investigators should be congratulated, we believe that it remains premature to recommend widespread, preemptive AVR. Both the RECOVERY and AVATAR trials were small, together randomizing only 302 patients with 51 primary outcome events.3,4 Both trials also recruited highly-selected populations. In the RECOVERY trial, only patients with very severe aortic stenosis (valve area ≤ 0.75 cm2 with peak velocity ≥ 4.5 m/s or mean gradient ≥ 50 mm Hg) were eligible. The trial population had an average age of approximately 64 years and 61% had a bicuspid aortic valve.3 The AVATAR trial excluded patients at high perioperative risk (≥8% likelihood of 30-day mortality), as well as those with other common chronic health conditions. In addition, patients had to be able to complete exercise stress testing. This resulted in a low-risk population (30-day risk of mortality, 1.7%) averaging 67 years of age.4In addition to the characteristics of the study population, the operative mortality in RECOVERY was unexpectedly low (zero in both groups) and the closeness of follow-up in the expectant management group has been questioned. Likewise, in AVATAR, there was no difference in cardiovascular death (9 in each arm).4 These results raise concerns regarding chance findings, how well matched the groups were, and comorbidities for which adjustments were not made. Hospitalized heart failure, another component of the primary outcome, was lower among those randomized to early AVR (1 vs 7 patients), but it is unclear whether this was adjudicated according to standard criteria.5Randomized long-term follow-up data are crucial. Prosthetic valves are associated with complications, such as thrombosis, endocarditis, and valve failure, that become more evident over time. Thus, although upfront mortality from early AVR may be low, it may also result in more repeat procedures and their attendant risks.The prevalence of severe aortic stenosis rises markedly in elderly adults, reaching an estimated 3.4% of those ≥75 years of age in the United States. This is reflected in considerable increases in the number of elderly patients undergoing AVR. For example, the number of Medicare beneficiaries undergoing AVR more than doubled between 2009 and 2015 to almost 50 000 per year. This was primarily driven by rapid uptake of transcatheter AVR, but surgical AVR also increased by ≈3% per year. Outcomes are generally excellent but the risk of serious complications, including death and debilitating morbidity, increases with age. Likewise, the effect of competing risks is much greater in elderly patients. The decision to replace a stenosed aortic valve in the context of equivocal symptoms is easier in an active younger patient without comorbidities than in an elderly, multimorbid patient who is limited by, and may succumb to, other conditions.In summary, the results of recent trials are encouraging and suggest that a strategy of early AVR may improve the outcome of patients with asymptomatic severe aortic stenosis. However, these studies are far from definitive. Clinicians have been led astray many times by promising results of initial small trials and we concur with the authors of the AVATAR trial that their findings “require further confirmation” in larger studies. This is imperative before adopting a radical change in the management of this increasingly common condition, thereby ending any opportunity to obtain more definitive and generalizable data. Trials should recruit a broad range of patients with asymptomatic severe aortic stenosis, including older patients and those with common comorbidities. We also need to assess long-term results, cost-effectiveness, and patient-orientated outcomes—the latter of which are of particular relevance to many older patients. Despite the challenges of recruiting the required patient numbers and the need for enrollment over many years, during which clinical practice and guidelines may change, several such trials are underway (see the Table). Until these bigger, more definitive studies become available, we should continue to play the waiting game.Table 1. Trials of Early Aortic Valve Replacement Versus Expectant Management in Patients With Severe Asymptomatic Aortic StenosisTrialClinicalTrials.gov registrationDefinition of severe aortic stenosisOther key inclusion criteriaOther key exclusion criteria*Method of AVRPrimary outcomeSample sizeDuration of follow-upStatusRECOVERY (Randomized Comparison of Early Surgery versus Conventional Treatment in Very Severe Aortic Stenosis)NCT01161732(1) AVA ≤0.75 cm2; and (2) Vmax ≥4.5 m/s and/or mean pressure gradient ≥50 mmHg20–80 yLVEF <50%;previous cardiac surgery;positive exercise test (selective)Surgical AVRAll-cause death (≤30 days from AVR) and cardiovascular death (any time)145 patientsMinimum, 4 y; median, 6.2 y (early AVR) vs 6.1 y (conservative)Completed and reported;see Kang et al3AVATAR (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis)NCT02436655(1) Vmax ≥4 m/s and/or mean pressure gradient ≥40 mmHg; and(2) AVA ≤1 cm2 or ≤0.6 cm2/m2≥18 y;STS score <8% (30-day mortality)LVEF <50%;Vmax >5.5 m/s;previous cardiac surgery; atrial fibrillation; need for aortic surgery; coronary heart disease requiring revascularization†; chronic obstructive pulmonary disorder with FEV1 <70%;diabetes with HbA1c >9%; pulmonary artery systolic pressure >50 mmHg; positive exercise test (mandated)Surgical AVRAll-cause death, myocardial infarction, stroke, and/or unplanned heart failure hospitalization157 patientsMedian, 32 mo (28 mo [early AVR]; 35 mo [conservative])Completed and reported;see Banovic et al4ESTIMATE (Early Surgery for Patients With Asymptomatic Aortic Stenosis)NCT02627391Vmax >4 m/s and/or mean pressure gradient >40 mmHg18–80 y; EuroSCORE II ≤5% (30-day mortality)LVEF ≤50%; creatinine >160 µmol/L; positive exercise test (mandated)Surgical AVRAll-cause death360 patients‡1 yHaltedEARLY-TAVR (Evaluation of Transcatheter Aortic Valve Replacement Compared to Surveillance for Patients with Asymptomatic Severe Aortic Stenosis)NCT03042104(1) AVA ≤1 cm2 or ≤0.6 cm2/m2; and(2) Vmax ≥4 m/s and/or mean pressure gradient ≥40 mmHg≥65 y;STS score ≤10% (30-day mortality)LVEF <50%; technically unsuitable for transcatheter AVR; positive exercise test (selective)§Transcatheter AVRAll-cause death, stroke, and unplanned cardiovascular hospitalization901 patientsMinimum, 2 yRecruitment completeEVOLVED (Early Valve Replacement Guided by Biomarkers of Left Ventricular Decompensation in Asymptomatic Patients with Severe Aortic Stenosis)NCT03094143(1) Vmax ≥4 m/s; or(2) Vmax ≥3.5 m/s with AVA <0.6 cm2/m2≥18 y; midwall LV fibrosis on cardiac MRI scanLVEF <50%;eGFR <30 mL/(min·1.73 m2); contraindication to cardiac MRI scanningSurgical or transcatheter AVRAll-cause death and unplanned aortic stenosis–related hospitalization400 patients‡Average, 2.75 yRecruitingDANAVR (Danish National Randomized Study on Early Aortic Valve Replacement in Patients With Asymptomatic Severe Aortic Stenosis)NCT03972644(1) AVA ≤1 cm2; and (2) Vmax ≥3.5 m/s; and (3) deemed severe by Heart Team18–85 y; signs of increased LV filling pressure or reduced longitudinal strainLVEF <50%;Vmax >5 m/s;eGFR <30 mL/(min·1.73 m2)Surgical or transcatheter AVRAll-cause death1700 patients‡≈5 yRecruitingEASY AS (Early Valve Replacement in Severe Asymptomatic Aortic Stenosis)NCT04204915(1) Vmax ≥4 m/s and/or mean pressure gradient ≥40 mmHg; and(2) AVA ≤1 cm2 or ≤0.6 cm2/m2≥18 yLVEF <50%; positive exercise test (selective)Surgical or transcatheter AVRCardiovascular death and hospitalization for heart failure2844 patients‡Median, 5 yRecruitingFor all clinical trials, URL: https://www.clinicaltrials.gov; Unique identifiers are indicated in the table. AVA indicates aortic valve area; AVR, aortic valve replacement; eGFR, estimated glomerular filtration rate; EuroSCORE, European System for Cardiac Operative Risk Evaluation; FEV1, forced expiratory volume in the first second; LV, left ventricular; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; STS, Society of Thoracic Surgeons; and Vmax, peak transaortic valvular gradient (by Doppler echocardiography).* Selected criteria, see ClinicalTrials.gov for full details. In general, all trials exclude patients with any symptoms attributable to aortic stenosis, other significant valvular disease, other indications for cardiac surgery, or significantly reduced life expectancy.† Requirement removed partway through study.‡ Anticipated recruitment.§ Mandated if patient can perform stress test; otherwise, absence of symptoms based on clinical assessment.Article InformationSources of FundingNone.Nonstandard Abbreviations and AcronymsAVATARAortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic StenosisAVRaortic valve replacementRECOVERYRandomized Comparison of Early Surgery versus Conventional Treatment in Very Severe Aortic Stenosis trialDisclosures All authors are senior investigators on the EASY AS (Early Valve Replacement in Severe Asymptomatic Aortic Stenosis) trial (URL: https://www.clinicaltrials.gov; Unique identifier: NCT04204915). Drs McCann and Newby are also senior investigators on the EVOLVED (Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic Patients With Severe Aortic Stenosis) trial (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03094143).FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 876.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Graham S. Hillis, MBChB, Department of Cardiology, Level 4, South Block, Royal Perth Hospital, Perth, Western Australia, 6000, Australia. Email graham.[email protected]wa.gov.au