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targeting calcification pathways alter disease progression.335,336 Coexistent hypertension should be treated to avoid additional afterload, preferably using renin-angiotensin system blockers, although careful titration is required to avoid symptomatic hypotension.337 In patients with symptomatic severe AS and HF, initiation of medical therapy or temporary improvement in symptoms should not delay intervention. Medication frequently requires re-adjustment following valve intervention and preventive therapies should be implemented according to current Guidelines.338 In patients with persisting HF and/or reduced LVEF, medical therapy should be introduced before and up-titrated after valve intervention according to the current HF Guidelines.339,340

8.4 Indication for intervention

8.4.1. Symptomatic severe aortic stenosis Symptomatic severe AS has an unfavourable prognosis if left untreated, and early intervention is strongly recommended in all patients with an estimated life expectancy exceeding 1 year10 (Figure 7). Intervention is recommended in all eligible symptomatic patients with high-gradient severe AS. However, management of patients with low-gradient AS is more challenging: • Low-flow, low-gradient AS with reduced LVEF: reduced LV function usually improves after intervention if it is predominantly caused by excessive afterload.341–343 However, improvement is unlikely if the primary cause is fibrosis due to myocardial infarction or cardiomyopathy. Intervention is recommended when severe AS is confirmed by CCT (calcium scoring) or stress echocardiography,341 while patients with pseudo-severe AS should receive GDMT.339,344 Although the absence of flow reserve is associated with increased surgical and long-term mortality, both modes of intervention improved LVEF and clinical outcomes in observational studies.341,342,345–347 • Low-flow, low-gradient AS with preserved LVEF: outcomes are improved with intervention (either TAVI or SAVR) compared with medical treatment alone in patients with low-flow, low-gradient AS and preserved LVEF.348,349 Intervention should therefore be considered in patients with symptoms after careful confirmation that AS is severe. • Normal-flow, low-gradient AS with preserved LVEF: prognosis of these patients is similar to that of moderate AS. Unless multimodality diagnostic evaluation clearly suggests severe AS, regular clinical and echocardiographic surveillance is recommended.293,294,350

8.4.2 Asymptomatic severe aortic stenosis

Up to 40% of patients with severe AS do not report symptoms at the time of diagnosis.351,352 In roughly one-third of these, exercise testing can uncover symptoms or reduced exercise capacity attributable to AS,102,103,318 and such patients should be treated as symptomatic. However, exercise testing is not always feasible because of frailty or impaired mobility.353 Intervention is recommended in asymptomatic patients with severe AS and an LVEF of <50% without another cause.14,102,318,319,354–360 For patients with severe high-gradient AS and no adverse prognostic features, close active clinical surveillance, so-called ‘watchful waiting’, has previously been the default management strategy. However, four RCTs comparing early AV intervention with clinical surveillance suggest that early intervention should be considered as an alternative in patients at low procedural risk.360–363 This approach is reinforced if additional adverse prognostic features (very high Vmax,14,353,364 elevated natriuretic peptides,97,317,365,366 severe valve calcification,303,364 rapid Vmax progression,353,364 or LVEF of <55%14,354,356–359) are present. Restricted local resources (that may impede close surveillance) or long waiting lists (that preclude prompt treatment when symptoms develop) are further arguments favouring an early intervention.

The Evaluation of TAVR Compared to Surveillance for Patients with Asymptomatic Severe Aortic Stenosis (EARLY TAVR) trial360 randomized 901 patients to early TAVI or clinical surveillance and demonstrated a reduction of 50% in the primary composite endpoint of all-cause mortality, stroke, or unplanned hospitalization for cardiovascular causes associated with pre-emptive intervention.360 The result was driven by 26.2% of the patients in the clinical surveillance group who converted to TAVI within 6 months of randomization due to the development of symptoms or adverse prognostic factors. There was no significant difference in strokes and all-cause mortality over 5-year follow-up. In the Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic Patients with Severe AS (EVoLVeD) RCT, which included 224 asymptomatic patients with severe AS and myocardial fibrosis (late gadolinium enhancement on CMR), early valve intervention (with SAVR or TAVI) failed to reduce the incidence of all-cause death or unplanned AS-related hospitalization compared with clinical surveillance.361 However, the study was underpowered and the median time to intervention was prolonged to 5 months in the experimental arm. Two previous smaller trials compared early SAVR with clinical surveillance. In the Randomized Comparison of Early Surgery vs Conventional Treatment in Very Severe Aortic Stenosis (RECOVERY) trial (145 patients), there was a reduction in all-cause mortality following early SAVR over a mean follow-up of 6.2 years.362 In the Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis (AVATAR) trial (157 patients), a reduction in the composite primary endpoint was noted after a mean follow-up of 2.5 years with a significant reduction in HF hospitalizations and mortality at long-term follow-up.363,367 Limitations of these surgical studies included their small sample sizes, enrolment of selected young populations at low surgical risk (mean ages 64 and 67 years, respectively), and inclusion of patients with mostly very severe AS. A meta-analysis of the four RCTs showed that early intervention is associated with a significant reduction in unplanned cardiovascular or HF hospitalization and stroke, but not all-cause or cardiovascular mortality. Limitations of this analysis include the heterogeneity of the pooled trials and lack of granularity with respect to specific events owing to the study-level analysis.368 Additional RCTs (NCT04204915 and NCT03972644) will further inform and refine the management of patients with severe asymptomatic AS.

8.4.3 Moderate aortic stenosis

Surgical intervention for moderate AS should only be performed in patients undergoing CABG,369 surgery of the ascending aorta or other valve disease (see Section 13). There is evidence of an association between moderate AS and adverse outcomes in patients with and without HF with reduced EF (HFrEF),370–372 but it is unknown whether this is causal or related to comorbidities. In an early terminated trial randomizing 178 patients with moderate AS and HFrEF to TAVI or clinical surveillance, no differences with respect to hard clinical endpoints were

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