Keywords: asymptomatic aortic stenosis, SAVR, TAVR, mild AS, moderate AS
Aortic stenosis (AS) has a quick progression which is more rapid when the aortic valve is severely stenotic and calcified. The only effective treatment is surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). Both procedures represent an interventional approach . Valve interventions are highly recommended when severe AS is associated with syncope, angina or heart failure (HF). However, in real clinical practice, some patients with severe AS may not complain of recognisable symptoms, if daily living activity is decreased. Thus, physicians may underestimate the presence of symptoms in patients with severe AS. Therefore, echocardiographic parameters may be useful for identifying subjects at a higher risk of adverse events among asymptomatic patients .
About one third of patients with severe AS are considered to be asymptomatic before exercise testing. Exercise testing should therefore be performed whenever possible to detect those patients who are not “truly asymptomatic” and who should undergo SAVR when the operative risk is acceptable. Furthermore, many subjects are unable to perform an exercise test for non-cardiac reasons. The annualised rate of sudden death for asymptomatic patients with severe AS is 1% .
Asymptomatic severe AS is divided into two categories, C1 (preserved ejection fraction [EF]) and C2 (reduced EF). Patients with C2 disease benefit from SAVR. Some patients with severe asymptomatic AS are operated on at an advanced stage of the disease, when myocardial impairment is partially irreversible, resulting in a high risk of mortality and heart failure (HF) after successful SAVR. However, the outcome of severe asymptomatic AS patients under conservative management and the operative risk of these patients are heterogeneous .
In patients with a significant risk of death under conservative management, the benefit of early surgery should outweigh the potential complications related to the surgical procedure and the prosthetic valve. These are high-risk patients with asymptomatic very severe aortic stenosis (VSAS) characterised by a dismal prognosis in the absence of SAVR .
Interventional approach to asymptomatic patients (recommendations)
Assessment of the severity of asymptomatic AS must be based on a multiparametric approach integrating the aortic valve area (AVA), the mean transaortic pressure gradient (MPG), and the peak aortic jet velocity (Vmax). Severe AS is currently defined as an AVA <1.0 cm2 and/or an MPG >40 mmHg and/or a Vmax >4 m/s [2-5]. In light of the data presented above, VSAS could be defined as Vmax >5 m/s, MPG ≥60 mmHg, AVA <0.6 cm2, indexed AVA <0.4 cm2/m2 (<0.45 cm2/m), or dimensionless index <0.20 [2,3,6]. Some data show that patients with asymptomatic VSAS and low operative risk have a significant risk of death during follow-up with medical and surgical management than patients not meeting the criteria of VSAS (EuroSCORE II ≤4%) .
Other strong echocardiographic predictors of poor outcome in asymptomatic severe AS patients indicative for SAVR are: stroke volume index (SVI) <30 mL/m2, LVEF 50%-55%, and left atrium (LA) enlargement (>95 mL) or left atrial volume index (LAVI) (>50 mL/m2) in patients in sinus rhythm [7-9].
Patients with asymptomatic VSAS and preserved LVEF, and low surgical risk should not be managed conservatively because this approach will result in an unacceptably high risk of death. According to recent data, the incidence of the composite of operative mortality or death from cardiovascular causes during the follow-up period was significantly lower among those who underwent early SAVR than among those who received conservative care [3,10]. An additional factor supporting SAVR in VSAS is the fact that the more severe the valvular lesion, the faster the progression and the continuously increasing operative risk in ageing patients managed conservatively. TAVR is not currently recommended for asymptomatic severe AS patients with low surgical risk .
The current indications for intervention and recommendations for the choice of interventional mode for asymptomatic patients with AS are listed in Table 1. The decision between TAVR and SAVR should be made by the Heart Team after careful, comprehensive evaluation of the patient, weighing the risks and benefits individually (Table 2) .
Table 1. Indications for intervention in aortic stenosis and recommendations for the choice of intervention mode.
Reproduced with permission from Baumgartner H et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-91. 
BNP: B-type natriuretic peptide; CABG: coronary artery bypass grafting; CT: computed tomography; EuroSCORE: European System for Cardiac Operative Risk Evaluation; LV: left ventricular; LVEF: left ventricular ejection fraction; SAVR: surgical aortic valve replacement; STS: Society of Thoracic Surgeons; TAVI: transcatheter aortic valve implantation; Vmax: peak transvalvular velocity
- Class of recommendation.
- Level of evidence.
- In patients with a small valve area but low gradient despite preserved LVEF, explanations for this finding other than the presence of severe aortic stenosis are frequent and must be carefully excluded. See Figure 2 and Table 6 of the 2017 ESC/EACTS Guidelines for the management of valvular heart disease .
- STS score (calculator: http://riskcalc.sts.org/stswebriskcalc/#/calculate); EuroSCORE II (calculator: http://www.euroscore.org/calc.html); logistic EuroSCORE I (calculator: http://www.euroscore.org/calcge.html); scores have major limitations for practical use in this setting by insufficiently considering disease severity and not including major risk factors such as frailty, porcelain aorta, chest radiation, etc.103 EuroSCORE I markedly overestimates 30-day mortality and should therefore be replaced by the better-performing EuroSCORE II with this regard; it is nevertheless provided here for comparison, as it has been used in many TAVI studies/registries and may still be useful to identify the subgroups of patients for decision between intervention modalities and to predict 1-year mortality.
- Moderate aortic stenosis is defined as a valve area of 1.0–1.5 cm2 or a mean aortic gradient of 25–40 mmHg in the presence of normal flow conditions. However, clinical judgement is required.
Table 2. Aspects to be considered by the Heart Team when deciding for the decision between SAVR and TAVI in patients at increased surgical risk. Reproduced with permission from Baumgartner H et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-91. 
CABG: = coronary artery bypass grafting; CAD = coronary artery disease; EuroSCORE = European System for Cardiac Operative Risk Evaluation; LV = left ventricle; SAVR = surgical aortic valve replacement; STS = Society of Thoracic Surgeons; TAVI = transcatheter aortic valve implantation.
- STS score (calculator: http://riskcalc.sts.org/stswebriskcalc/#/calculate); EuroSCORE II (calculator: ); logistic EuroSCORE I (calculator: ); scores have major limitations for practical use in this setting by insufficiently considering disease severity and not including major risk factors such as frailty, porcelain aorta, chest radiation etc.103EuroSCORE I markedly overestimates 30-day mortality and should therefore be replaced by the better performing EuroSCORE II with this regard; it is nevertheless provided here for comparison as it has been used in many TAVI studies/registries and may still be useful to identify the subgroups of patients for decision between intervention modalities and to predict 1-year mortality.
- See section 3.3 of the 2017 ESC/EACTS Guidelines for the management of valvular heart disease , general comments, for frailty assessment.
Interventional approach in patients with mild and moderate AS
Earlier stages of AS have been disregarded as targets for aortic interventions given an unfavourable risk-benefit balance, specifically due to the relatively high rates of periprocedural adverse events . Echocardiographic diagnosis poses a challenge as current guidelines are directed towards determining severe AS, and different presentations of moderate and mild AS have generally been neglected.
An increasing number of patients are referred for coronary artery bypass grafting (CABG) with the presence of mild to moderate AS. It is well accepted that patients with severe AS and coronary artery disease (CAD) should undergo a combined intervention, which carries an operative mortality of approximately 5-7%. For patients with CAD and mild AS, controversy persists regarding concomitant SAVR during CABG . Thus, an attempt should be made to identify patients who are likely to progress rapidly from mild to severe AS and who would therefore benefit from SAVR/CABG. The most important variables include the aetiology of AS, the rate of progression, the patient's life expectancy and general condition. Despite these observations, it is difficult to predict reliably the progression of disease for an individual. For patients with mild AS who are undergoing CABG, a tailored approach involving intraoperative transoesophageal echocardiography and valve inspection is the most appropriate surgical option .
It has been shown that AS progresses at a rate of 5-10 mmHg/year, and the AVA decreases by about 0.1 cm2/year. The progression of AS is more rapid in elderly patients, in the presence of CAD, and in patients with a calcific degenerative aetiology. In contrast, patients with congenital bicuspid valves or rheumatic pathology demonstrate slower progression. The approach regarding the decision to perform SAVR/CABG is based on the MPG and AVA [2,3]. If the MPG is >25 mmHg, SAVR should be considered. If the MPG is <10 mmHg, then only CABG is performed. The severity of leaflet calcification and leaflet mobility should be taken into account when deciding to perform concomitant SAVR/CABG for intermediate MPG (10-25 mmHg).
Clinical management of patients with only moderate AS and symptoms of HF due to reduced EF (HFrEF) is challenging. Current guidelines recommend that clinical evaluation with multimodality imaging and SAVR should be delayed until the AS becomes severe [2,3,11]. SAVR is recommended in patients with moderate AS undergoing CABG or surgery of the ascending aorta or of another valve (class IIa C) . Moreover, patients undergoing CABG before 70 years of age with a peak gradient above 30 mmHg and a documented yearly progression of 5 mmHg may benefit from SAVR . These represent the only two mentions of moderate AS in the ESC/EACTS guidelines for the management of valvular heart disease and are largely supported by retrospective data .
Such interventions are referred to as “prophylactic SAVR”, aiming to avoid a second open heart procedure due to the risk of damaging patent grafts, calcified aortic arches and scarring of the mediastinum and the increase of post-procedural mortality up to 16% [5,8,14]. In patients with prior CABG who require SAVR, TAVR is progressively replacing SAVR [5,14]. In a study including 3,880 records in each group, TAVR and SAVR showed similar in-hospital mortality (2.3 vs 2.4%, p=0.71); however, TAVR was associated with a lower incidence of procedural complications including myocardial infarction (1.5% vs 3.4%, p<0.001), stroke (1.4 vs 2.7%, p<0.001), bleeding (10.6 vs 24.6%, p<0.001), and acute kidney injury (16.2 vs 19.3%, p<0.001). Consequently, the rationale of exposing the patient to a prophylactic SAVR in order to avoid a second open heart surgery is currently challenged .
The concept of “therapeutic” TAVR in patients with moderate AS is evolving [1,15]. In a retrospective analysis of 1,090 patients with moderate AS and reduced EF, SAVR within 90 days versus no intervention was associated with a 41% reduction of all-cause mortality after a median follow-up of 1.2 years [9,16]. Moreover, this benefit remained in a subgroup of patients with reduced EF without CAD [16,17].
Better characterisation of high-risk populations among patients with moderate AS together with advances in TAVR could identify a niche population which would benefit from an earlier intervention [3,17].
Moderate AS and reduced EF constitute a therapeutic target for TAVR. This is defined by an MPG between 20 and 40 mmHg and an AVA between 1.0 and 1.5 cm2 in patients with EF <50% . These patients (0.8%) are younger and show a higher frequency of previous myocardial infarction than those with severe AS randomised to TAVR in recent trials. In two retrospective studies including patients with moderate AS and reduced EF, the one-year mortality rate differed (9 and 32%) and it was significantly increased in patients treated with medical therapy only.
The TAVR to unload the LV in patients with advanced HF trial (TAVR UNLOAD) is exploring whether TAVR would improve outcomes in patients receiving optimal HF therapy (OHFT). This was an international, multicentre, randomised open-label trial in patients with advanced HF comparing TAVR in addition to OHFT versus OHFT alone in patients with moderate AS and reduced EF . The findings may have a significant impact on how to diagnose, refer and manage these patients, especially when HFrEF is present.
Offering TAVR to patients with moderate AS and reduced EF would be a change of a clinical paradigm. Due to the currently non-existing treatment alternatives apart from established HF therapies, these patients do not come under any specific clinical recommendations.
Moreover, once the diagnosis is confirmed, the technical plausibility of TAVR needs to be assessed by means of pre-TAVR multislice computed tomography . Current evidence supports the use of transfemoral over non-transfemoral access for TAVR, given a lower rate of procedural complications and lower one-year mortality . Thus, a transfemoral approach should be considered as first option for this high-risk population, commonly avoiding the need for general anaesthesia.
Current recommendations advise watchful waiting and periodic echocardiographic follow-up in patients with moderate AS and reduced EF . This approach may change if the results of ongoing trials prove to be clinically meaningful . The single most important requirement to promote TAVR as a therapeutic option in patients with moderate AS and reduced EF is to create confirmatory prospective evidence that this intervention is clinically significant [2-4,9,16].
The symptoms of AS (spontaneous or exercise testing) remain the most significant indication for intervention. The presence of predictors of rapid symptom development can justify early surgery in asymptomatic patients, particularly when the surgical risk is low. Although current data favour TAVR in elderly patients who are at increased risk for surgery, particularly when a transfemoral access is possible, the decision between TAVR and SAVR should be made by the Heart Team after careful, comprehensive evaluation of the patient, weighing the risks and benefits individually. The criteria for identification of patients who would benefit from early elective surgery in asymptomatic severe AS require further research. Criteria for the decision between TAVR and SAVR in patients at increased operative risk who are eligible for both must be refined.