Asymptomatic Severe and Moderate Aortic Stenosis: Time for Appraisal of Treatment Indications

Over the last decades, we have witnessed considerable improvements in diagnostics and risk stratification of patients with significant aortic stenosis (AS), paralleled by advances in operative and anesthetic techniques. In addition, accumulating evidence points to the potential benefit of early valve replacement in such patients prior to the onset of symptoms. In parallel, interventional randomized trials have proven the benefit of transcatheter aortic valve replacement in comparison to a surgical approach to valve replacement over a broad risk spectrum in symptomatic patients with AS. This article reviews contemporary management approaches and scrutinizes open questions regarding timing and mode of intervention in asymptomatic patients with severe AS. We also discuss the challenges surrounding the management of symptomatic patients with moderate AS as well as emerging dilemmas related to the concept of a life-long treatment strategy for patients with AS.

Valvular intervention in patients with aortic stenosis (AS) is traditionally considered only if patients present with hemodynamically severe AS associated with clinical symptoms.The prognostic significance of asymptomatic significant AS or prognostic implication of earlier stages is less understood.Consequently, clinical practice and professional guidelines advise watchful waiting for such patients with regular follow-up.
Growing clinical experience and trial evidence are supporting the breakthrough of transcatheter aortic valve replacement (TAVR) as a viable treatment option as compared to surgical aortic valve replacement (SAVR) in symptomatic patients with significant AS.In addition, the notion of an adverse impact of severe AS on clinical outcome and cardiac structure, even in the absence of overt clinical symptoms, appears to be influencing clinical practice such that the timing of SAVR is becoming more liberal in a subset of patients with critical AS who until recently would not have been considered for intervention.This dynamic clinical landscape seems to be shifting the frontier of AS treatment towards earlier stages, as attested by changes in thresholds of AS severity and left ventricular ejection fraction (LVEF) over time in guidelines for intervention in asymptomatic AS.On the other hand, appropriate life-long AS treatment strategy is emerging as a dilemma, particularly in younger patients, posing a series of challenging decisions not only in the heart team's considerations but also in patient and family shared decisionmaking in devising the optimal, patient-tailored strategy.
In this review, we address contemporary management approaches and scrutinize open questions regarding timing and mode of intervention in asymptomatic patients with severe AS, including low-flow AS.We also address challenges surrounding the management of patients with moderate AS and open questions related to the concept of life-long strategy for AS treatment in the evolving landscape of transcatheter aortic valve interventions.

Early Intervention in Asymptomatic Severe Aortic Stenosis: Rationale and Current Evidence
Current professional societal guidelines recommend a watchful waiting strategy in patients with significant AS and normal left ventricular (LV) function. 1,2However, this strategy appears to be challenged by several observations (Table 1).Despite the historically carried assumption of an intrinsically low risk of asymptomatic significant AS, the risk of sudden cardiac death is higher in such patients than in the general population. 3In AS, sustained pressure overload may lead to structural myocardial changes with myocyte apoptosis followed by progressive intramyocardial fibrosis, 4 even in the absence of symptoms, and it is therefore associated with a worse outcome that may not be reversible despite a successfully performed aortic valve replacement (AVR).Furthermore, delaying intervention may expose the patient with such structural changes to increased perioperative risk if AVR is ultimately required, as well as greater long-term risks of arrhythmia and heart failure.These observations incited clinical investigations of whether early AVR might be beneficial as compared with a "watchful waiting" strategy in these patients.Several observational studies [5][6][7][8][9] have consistently demonstrated the benefit of the early SAVR approach, mainly driven by improved survival and a lower risk of heart failure hospitalizations.Yet observational studies and subsequent meta-analyses 10,11 are exposed to case-selection bias, reliance on purely anamnestic symptom evaluation, and incomplete patient data.Several studies have also included the AVR procedure as a component of the composite outcome but did not detail the number of unoperated patients who developed symptoms prior to SAVR, the number of patients who declined surgery, or the number of patients who were denied SAVR owing to unacceptable risk.
Lately, 2 randomized trials have evaluated the role of early surgery for asymptomatic very severe/severe AS and normal LV systolic function-the RECOVERY and AVATAR Trials. 12,13Although appearing similar, they differ in methodological characteristics and should be considered complementary (Table 2).The RECOVERY trial included prevalent population of patients with bicuspid etiology of AS.The conservative arm was managed per current guidelines; however, the study did not utilize systematic exercise testing or biomarker assessment to confirm asymptomatic status at inclusion, with uncertainties about truly asymptomatic status in patients presenting with severe AS with transvalvular velocity exceeding 5 m/s. 12The primary endpoint included a composite of operative mortality and death from cardiovascular causes during the entire follow-up period.At follow-up, only 1 patient had died (1%) in the treatment arm vs. 11 (15%) in the conservative management arm [hazard ratio 0.09; 95% CI 0.01-0.67;p ¼ 0.003].
The primary findings of the RECOVERY trial were corroborated by outcomes from the multinational AVATAR trial (aortic valve replacement vs. conservative treatment in asymptomatic severe aortic stenosis). 13Over a median follow-up of 3 years, patients randomized to early surgery experienced a lower composite end-point of all-cause death, acute myocardial infarction, stroke, or unplanned HF hospitalization (16.6%) compared to the conservative arm (34.7%) (hazard ratio 0.46; 95% CI 0.23-0.9;p ¼ 0.02).However, these outcomes were gathered in a different patient population 14 than the RECOVERY trial cohort.The Avatar trial included primarily patients with degenerative severe AS (83%), whose asymptomatic status was verified by thorough exercise testing.
Despite synergistically positive signals favoring a shift in the clinical approach to asymptomatic severe AS with different etiology, several limitations for both trials are to be considered.One is the relatively low number of included subjects.This was mainly the case for the AVATAR trial; the trial was event-driven and included a lower number of patients than projected due to a higher number of events and a longer follow-up.Second, the RECOVERY trial reported zero perioperative mortality.This is an exceptional surgical outcome, most likely driven by the trial's rigorous methodology and possibly by prevalence of bicuspid AS, where patients tend to be younger and have fewer comorbidities.On the other hand, the AVATAR trial reported 1.4% perioperative mortality.This appears more realistic given the patients' profile with degenerative AS.The earlier the intervention, the higher the probability of requiring future reintervention for bioprosthetic valve AVR, aortic valve replacement.ET, exercise testing; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; SAVR, surgical aortic valve replacement.
In the AVATAR trial, the difference in primary outcome was mainly driven by all-cause death and heart failure hospitalizations without a difference in cardiovascular mortality as compared to control group.There were also 2 sudden cardiac deaths during the later follow-up in the early surgery group.Though this requires further analyses, as alluded to above, it should be noted that valve replacement does not necessarily offset the risk of sudden death, as sudden cardiac death remains the second most common cause of cardiovascular death in operated patients. 15,16aken together, while promising and favoring early intervention in asymptomatic significant AS across randomized trials and observational studies, these findings require further validation in larger prospective randomized controlled trials in patients with severe AS and normal LVEF.One expected study to provide their validation is the Easy AS (NCT04204915) trial, whose sample size is set to include more than 2800 patients.In addition to conventional clinical outcome readouts, these trials should also address the impact of early intervention on patientreported outcomes.Incorporation of such end-points in the trial readouts is supported by data extracted from Partner 2 and 3 studies, which demonstrated an association between the degree of cardiac damage and quality of life after 1 year, irrespective of symptomatic status, such that patients in stages 3 and 4 had the least improvement from baseline to 1 year and those in stage 0 or 1 achieved the greatest improvement. 17In this regard, it is of note that in a subset of patients in the AVATAR trial with available cardiopulmonary exercise testing, patients randomized to early SAVR significantly improved their functional capacity after 12 months in comparison to patients who were conservatively followed and operated only after symptom onset. 18at About Low-Flow Severe Aortic Stenosis?
In patients with AS, a low-flow state, defined as a cardiac index <3.0l/min/m 2 or a stroke volume of <35ml/m 2 19 may be present, and it can be associated with either reduced LVEF (i.e., classical low-flow) or preserved LVEF (i.e., paradoxical low-flow).It is also often associated with a low transvalvular gradient, given that the gradient is highly flow-dependent. 20Whether the benefits of early surgery shown in the above-mentioned randomized trials can be extrapolated to subgroups of asymptomatic patients with low-flow, low-gradient AS is unknown.These patients are often considered to be at latter stages of the AS disease spectrum and are anticipated to be more often symptomatic.It is uncertain whether patients with "paradoxical" low-flow, low-gradient AS have worse prognosis in comparison to high-gradient AS. 21,22 A patient with low-flow, high-gradient AS is a different entity and might fall into either of 2 groups: symptomatic or asymptomatic.Nevertheless, asymptomatic or minimally symptomatic patients with low-flow, high-gradient AS and preserved LVEF have increased mortality during 5-year follow-up. 23ntil the indication for AVR in truly asymptomatic patients with severe AS and normal LVEF is established, additional parameters could facilitate patient-tailored decisions irrespective of existing flow pattern.][26][27] Although these parameters are not yet widely adopted in the practice or considered by either European or US Guidelines, their pathophysiological relevance may support their further adoption in clinical decision-making regarding optimal interventional timing in asymptomatic severe AS patients.

The Clinical Significance of Moderate Aortic Stenosis
Moderate AS is defined as a maximal aortic jet velocity (V max ) of 3.0-3.9m/s and/or a mean pressure gradient of 20-39 mm Hg and/or an aortic valve area (AVA) of >1 1.5 cm 2 . 3Moderate AS is a progressive disease; 1/3 of patients with moderate AS progress to severe AS in a time frame of approximately 2 years, and this progression is associated with a higher risk of cardiac events. 28,29As acknowledged by current European Society of Cardiology and American Heart Association/American College of Cardiology guidelines, patients with rapidly progressive AS (>0.3 m/s annually) also have a higher risk for adverse events, and therefore intervention should be considered in such patients when AS becomes severe. 1,21][32] With these data being unveiled, the question arises whether this increased risk of an adverse outcome is a sufficient reason to refer patients with moderate AS to AVR.
It is recognized that patients with moderate AS might also have low-flow state, leading to a discrepancy between measured AVA and mean gradient.Patients with low LV stroke volume (stroke volume index 35 mL/m 2 ) may have lower mean gradient for a given AVA (AVA <1.0 or 1.5 cm 2 ).Likewise in case of patients with severe AS, the combination may exist in the setting of both preserved and reduced systolic function, 28,29 termed either concordant or discordant moderate AS.Discordant grading is relatively frequent in patients with moderate AS, encompassing up to 1/3 of patients. 33The classified LV flow patterns have been recently shown to have prognostic significance in patients with moderate AS. 34Patients with normal flow, low-gradient moderate AS have better survival compared with those with "paradoxical low-flow low-gradient AS" and patients with "classical low-flow low-gradient" moderate AS.Yet, their survival is worse compared to patients with concordant moderate AS (mean gradient 20 to 40 mmHg, and AVA >1 1.5 cm 2 ).Nevertheless, patients with moderate AS have reduced survival irrespective of whether they present with a concordant or discordant moderate AS, and this has been shown consistently across studies and meta-analyses (Table 3).A large observational study including US and Australian patient population demonstrated the hazard ratio for all-cause mortality was similar for moderate as compared to severe AS (1.38 [95% CI, 1.24-1.53]vs. 1.36 [95% CI, 1.17-1.59],respectively). 39The relationship was sustained after adjusting for cofounders that may influence the patient's individual clinical trajectory and prognosis, such as hypertension, diabetes, coronary artery disease and/or subsequent coronary revascularization, chronic kidney disease, and medications. 37Factors that are particularly associated with worse survival in moderate AS are alike to those in patients with severe AS and include reduced LVEF, LV hypertrophy, smaller AVA, and impaired right ventricular function. 43In fact, 5-year all-cause mortality exceeds 40% in patients with mean gradient between 20 mmHg and 40 mmHg after adjusting for age, gender, left ventricular systolic and diastolic function, and aortic regurgitation. 43In agreement, data from the Heart Valve Clinic International Database revealed 78% mortality in moderate AS patients during an 8-year follow-up. 6Particularly poor outcome has been observed in patients with moderate AS and impaired LVEF, with more than 60% reaching the combined end-point of heart failure hospitalization or death by 4-year follow-up. 44A meta-analysis of 25 observational studies reported an all-cause mortality rate of 9/100 patients/year, with the majority being cardiac deaths. 28In the same meta-analysis, moderate AS patients presenting with diabetes, coronary artery disease, LV dysfunction, and AS-related symptoms had a greater risk for all-cause mortality.LV systolic dysfunction was particularly ominous with 4-fold higher all-cause mortality.
As decision-making is becoming more complex, clinical practice is embracing the growing evidence that dedicated heart valve clinics bring additional value to diagnostics, treatment and risk stratification of both asymptomatic patients with severe AS and patients with moderate AS. 45,46Given the growing notion of poor outcomes in moderate AS and impaired myocardial function, the decision to intervene in moderate AS is increasingly debated.Initial retrospective studies have demonstrated that patients with moderate AS, especially those who were symptomatic and/or with impaired LVEF, have benefited from AVR. 40,47 Table 4 summarizes ongoing randomized trials investigating whether early AVR yields benefit on top of optimal medical management in patients with moderate AS (Table 4).All ongoing randomized trials use an exclusively transcatheter approach.
The rationale for intervention in patients with moderate AS and with heart failure symptoms seems clinically reasonable, as heart failure is the essential driver of symptoms and increases susceptibility to poor outcomes. 40Patients with reduced systolic LV function are vulnerable to the increased LV afterload due to even moderate AS 48 and experience a 3-fold increase in mortality as compared to those without AS. 44Moderate AS, even if asymptomatic, might also be accompanied by changes in the structure of the myocardium, as was documented with the presence of focal irreversible fibrosis and scar formation by cardiac magnetic resonance. 49These structural myocardial changes in patients with moderate AS appear to be predictive of all-cause mortality to the same extent as in patients with severe AS. 49 The potential to halt or even reverse some of the maladaptive structural and functional cardiac changes that can accompany moderate AS through earlier valve replacement and load reduction may deserve the consideration to test clinically such hypothesis.

Growing TAVR Adoption: Open Questions and Life-Long Treatment Strategy in AS
TAVR has proven efficient and competitive as an alternative to SAVR across groups of patients with different surgical risk, including low-risk symptomatic AS patients. 50,51Yet, until now, the benefit of early AVR in asymptomatic patients with similarly severe AS and normal LVEF has been demonstrated only for a surgical approach.Among currently ongoing randomized trials, only the Early TAVR trial is testing an exclusively transcatheter femoral approach.However, before TAVR could be implemented as an intervention of choice for all patients with AS, irrespective of age, symptoms, or risk, it will need to demonstrate long-term durability comparable to surgically implanted prosthetic valves.Until then, the whole range of SAVR approaches should be considered, particularly in younger patients, including bioprosthetic/mechanical valves, SAVR with aortic root enlargement, and in prespecified younger patients, the Ross procedure.In the hands of an experienced surgeon, the Ross procedure may be a viable option for carefully selected younger patients who are anatomically suitable, owing to its better survival rates compared to conventional SAVR with both TAVR, transcatheter aortic valve replacement.
mechanical and bioprosthetic valves. 52In younger asymptomatic patients with an anticipated longer life-span and active lifestyle as compared to elderly patients, several TAVR complications, such as the need for reintervention, permanent pacemaker implantation, mild paravalvular regurgitation, or the TAVR stent frame height leading to a possible barrier to future coronary access, are not acceptable (Table 5).Hence, we face the question of how to manage younger AS patients over a long-term period with life-span of >15 years and provide them with the highest possible assurance of durable treatment outcome.Surgery is still considered the standard of care for patients <75 years of age.According to current guidelines, 1,2 in patients younger than 50 years, a mechanical valve is indicated, while in patients between 50-65 years, an individualized approach is recommended, with consideration of individual patient factors and informed shared decision-making.Thus, patients <50 years should preferably receive a mechanical valve, and consequently, there should be no room for debate about a long-term treatment strategy.Nevertheless, these patients should be served with rigorous follow-up and control of anticoagulation.
In patients above 50 years and less than 80, several strategies are possible to consider.In the context of encouraging TAVR outcomes, the majority of patients and some physicians may be inclined to opt initially for less invasive TAVR as a treatment of choice, including low-risk patients.Regardless of whether a biological surgical or TAVR valve is implanted, ultimately these valves will start to degenerate and will need replacement.In the case of surgical valves, the durability will typically reach 10-15 years, while TAVR valve durability has been demonstrated up to 8 years so far in a limited number of patients. 53Of note, the risk of structural valve deterioration was shown to be lower after TAVR in comparison to surgical valves in patients with low-to-moderate surgical risk for 5 years of follow-up. 53,54However, these data should be interpreted carefully, as structural valve degeneration after SAVR is increased in situations of patient-prosthesis mismatch.The patient-prosthesis mismatch occurs typically in %10% of patients. 55owever, it has been reported that 40% of surgical patients experience early surgical valve degeneration. 53In addition, the clinical impact of patient-prosthesis mismatch in patients undergoing TAVR is not entirely clear. 56Life expectancy is another variable influencing the choice of treatment strategy, as suggested by current European guidelines.It is, however, region-and country-specific and difficult to predict for an individual patient.
Patients undergoing AVR in their early 60s may conceivably require additional valve replacement during their lifetime. 57This potentially might lead to the "Matryoshka doll" effect if only TAVR were considered.In such a scenario, several TAVR valve-in-valves implanted into each other would lead to too small an effective orifice area, insufficient for adequate blood pumping in the long-term.This may also lead to increased risk of coronary obstruction and jeopardized coronary access, especially in the setting of acute coronary syndrome when percutaneous coronary intervention (PCI) is time-sensitive.It is then common sense that SAVR should remain a first choice as being safer and likely more efficient at younger age.This is also supported by recent findings reporting excessive surgical mortality in SAVR after a previous TAVR procedure, ranging from 20% to 40%. 58,59Though new TAVR valves undergo further refinements with each new generation, their durability or adverse impact regarding, for instance, future coronary access, is being evaluated in the new Alliance trial (NCT05172960) using the newest, fourth generation of a balloon-expandable valve.With evolving designs of TAVR prosthetic valves, a randomized trial comparing TAVR with SAVR in low-risk, middle-aged, asymptomatic patients with normal LV systolic function might be an adequate approach to address this clinically critical question.From the caregiver perspective, health economic analysis of such an approach addressing the procedure-related cost-effectiveness in the long term is also relevant.Finally, aortic valve interventions in patients with concomitant coronary artery disease require further attention.One aggravating fact is that coronary artery disease might be masked in patients with hemodynamically significant AS. 60 The prevalence of coronary artery disease in AS patients is high, ranging between 40 and 80%, depending on age and surgical risk. 50,51In younger, low-risk patients, especially those with more complex coronary artery disease, the benefit of concomitant SAVR and coronary artery bypass grafting is established and recommended by guidelines. 1,2On the other hand, the benefits and optimal timing of PCI in TAVR candidates are still a matter of ongoing debate and research.A recent study found no benefit of a "PCI first" strategy in patients undergoing TAVR.However, it demonstrated higher 5-year all-cause mortality for TAVR patients with coronary artery disease, with increased risk correlated with coronary artery disease complexity. 61Nevertheless, in the ACTIVATION trial, mortality and rehospitalization rates at 1 year were similar between PCI and no PCI prior to TAVR, and PCI resulted in higher bleeding complications. 62Hence, more robust data are needed regarding the role of PCI in TAVR candidates.Until then, SAVR and coronary artery bypass grafting remain the most optimal strategies for these patients, especially for more complex coronary artery disease.

Conclusion
Symptomatic AS is an ominous disease requiring timely valve intervention.Growing evidence indicates a detrimental clinical impact of asymptomatic significant AS and even of moderate AS in symptomatic patients.While 2 randomized trials in the setting of asymptomatic AS provide preliminary support for early intervention in such patients, ongoing studies are addressing the impact of such interventions in moderate AS.After the TAVR procedure has emerged as a viable alternative to SAVR across the whole spectrum of symptomatic AS patients with different surgical risks, new directions in clinical research have been set to address how to optimally manage other patient groups.This requires carefully designed trials to rigorously address questions related to the durability of interventional strategy balancing the consequence of the primary choice with the patient's future life-span.

Table 1
Pro and contras for AVR in asymptomatic severe aortic stenosis

Table 2
Principal comparative characteristics of Avatar and Recovery trials No difference in major bleeding, thromboembolic complications, repeated MACE No difference in cardiovascular mortality Death from any cause occurred in 5 patients in the early-surgery group (7%) and in 15 patients in the conservative-care group (21%) (hazard ratio, 0.33; 95% CI, 0.12 to 0.90).No perioperative death Incidence of hospitalization for heart failure lower in the early-surgery group vs.the conservative-care group (0% vs. 11%) Take homes Support for early SAVR in severe, truly asymptomatic aortic stenosis, in low-risk patients with normal LVEFEarly SAVR resulted in a significantly lower risk of operative mortality or cardiovascular death

Table 3
Studies with >100 patients and meta-analysis investigating the impact of valve replacement in symptomatic patients with moderate AS AS, aortic stenosis; AVA, aortic valve area; AVR, aortic valve replacement; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; MG, mean gradient.

Table 5
Open questions in asymptomatic severe aortic stenosis and symptomatic moderate aortic stenosis Ongoing trials evaluating TAVR valve durability throughout the long-term follow-up (up to 10 y follow-up) in low-risk patients (Partner 3,Evolut-low risk trial extended follow-up) 3. The ongoing Alliance Trial (NCT05172960) 4. Warranted randomized trial of SAVR vs. TAVR in asymptomatic middle-aged severe AS patients with normal LVEF 1. Several ongoing trial evaluating TAVR in symptomatic patients with moderate AS (see Table4)AS, aortic stenosis; asAS, asymptomatic aortic stenosis; AVR, aortic valve replacement; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; PVL, paravalvular leak; SAVR, surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement.