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Table of Contents
Year : 2021  |  Volume : 3  |  Issue : 2  |  Page : 54-62

Aortic stenosis: From diagnosis to treatment: A review (2021 update)

1 Department of Medicine, Faculty of Medicine, Kuwait University, Jabryia, Kuwait
2 Department of Cardiology, Sabah Al Ahmad Cardiac Centre, Al Amiri Hospital, Kuwait City, Kuwait
3 Department of Medicine, Faculty of Medicine, Royal College of Surgeons, Dublin, Ireland
4 Department of Internal Medicine with the Subspecialty of Cardiology and Functional Diagnostics Named after V.S. Moiseev, Institute of Medicine, Peoples' Friendship University of Russia (RUDN University), Moscow, Russian Federation

Date of Submission23-Nov-2021
Date of Decision16-Dec-2021
Date of Acceptance17-Dec-2021
Date of Web Publication21-Jan-2022

Correspondence Address:
Dr. Rajesh Rajan
Department of Cardiology, Sabah Al Ahmad Cardiac Centre, Al Amiri Hospital, Kuwait City 15003
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ACCJ.ACCJ_19_21

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As the aging population increases, a concurrent rise in the incidence of aortic stenosis (AS) is projected. Early recognition and diagnosis of AS are cardinal in preventing the progression of the disease into its more fatal effects. Precision in diagnosis and risk stratification is paramount, as therapy can be opted accordingly. Current therapeutic advances aim to target an elderly population with minimally invasive procedures such as transcatheter aortic valve replacement (TAVR), transforming conventional management in a more at-risk population. Despite dismal outcomes without treatment, therapy in the form of surgical aortic valve replacement or TAVR is proven to improve survival in cases of AS, with such therapeutic benefit being observable at the extreme end of the spectrum with inoperable cases. In this review, we will address the latest recommendations and guidelines on AS, with emphasis on diagnosis and treatment.

Keywords: Aortic stenosis, aortic stenosis treatment, aortic valve, surgical aortic valve replacement, transcatheter aortic valve replacement

How to cite this article:
Al Balool J, Rajan R, Al Jarallah M, Dashti R, Al Mulla K, Al Haroun R, Kobalava ZD. Aortic stenosis: From diagnosis to treatment: A review (2021 update). Ann Clin Cardiol 2021;3:54-62

How to cite this URL:
Al Balool J, Rajan R, Al Jarallah M, Dashti R, Al Mulla K, Al Haroun R, Kobalava ZD. Aortic stenosis: From diagnosis to treatment: A review (2021 update). Ann Clin Cardiol [serial online] 2021 [cited 2023 Mar 26];3:54-62. Available from:

  Introduction Top

Valvular heart disease carries a high risk of morbidity and mortality in the elderly population, particularly in the setting of an increased surgical risk associated with aging.[1] The spectrum of such lesions ranges from a trivial process of thickening and calcification of aortic leaflets, termed aortic sclerosis, to more detrimental conditions, namely aortic stenosis (AS).[2] In developed countries, AS is the third most prevailing cardiovascular disease after coronary artery disease and systemic arterial hypertension, with a reported incidence of 4.9% per year.[3],[4] As the aging population increases, a concurrent rise in AS is similarly projected.[3] Subsequently, the utilization of a minimally invasive procedure such as transcatheter aortic valve replacement (TAVR) has been growing exponentially, with the rapid expansion of its clinical indications.[5],[6] Precision in diagnosis and risk stratification of patients is the key to therapeutic success, as management approaches differ accordingly. In this review, we will address the latest recommendations and guidelines on AS, with emphasis on diagnosis and treatment.

  Diagnosis Top


A detailed history is initially essential to inquire for the triad of symptoms of AS, including syncope, angina, and dyspnea. In asymptomatic patients, the presence of the classical crescendo–decrescendo systolic murmur on auscultation may raise the suspicion of the diagnosis.[7] Since cardiac auscultation has limited value in precise diagnosis, all patients presenting with signs of AS are referred for further evaluation through echocardiography,[8],[9] which is the gold standard in the diagnosis of valvular heart disease. Echocardiography allows evidential assessment of the degree of valvular obstruction along with its possible etiology.[10] The presence of concomitant valvular lesions should accurately be investigated in the initial evaluation, as their presence has therapeutic and prognostic significance.[7] Initial parameters to be screened for using parasternal short- and long-axis views involve evaluation of the degree of calcification, leaflet number, and motion.[10] In addition, key variables to be studied include:

  1. Left ventricular outflow tract (LVOT) diameter
  2. Left ventricular ejection fraction (LVEF)
  3. Left ventricular hypertrophy
  4. Right ventricular systolic pressure
  5. Diastolic function.

Doppler echocardiography is the investigation of choice for assessing the severity of AS, rendering it superior to invasive modalities such as cardiac catheterization.[9] The basis of Doppler-echocardiographic assessment is the measurement of essential hemodynamic parameters altered by a stenotic valve.[10]

Such key variables to be studied include:

  1. Aortic jet velocity (Vmax)
  2. Mean transaortic pressure gradient (MPG)
  3. Aortic valve area (AVA).

Using continuous-wave Doppler ultrasound, Vmax can be directly measured through apical and suprasternal or right parasternal views.[10] The significance of this parameter was analyzed in conservatively managed severe AS patients, with results revealing a higher risk of AS-related events in those with higher Vmax levels.[11] As a result of a critical obstruction by a stenotic valve, a pressure gradient is expected to arise.[12] The MPG is calculated from velocity using the simplified Bernoulli equation.[10] The AVA, which is indirectly measured using the continuity equation, is considered to be the most robust parameter in severity assessment.[10],[13]

Classification of aortic stenosis

As proposed by the ESC/EACTS (2021) and the ACC/AHA guidelines (2020), the use of the aforementioned parameters aids in stratifying patients into different degrees of severity [Figure 1]. In a subset of patients, discordance in severity grading in the form of severe AVA (≤1 cm2) and nonsevere MPG (<40 mmHg) creates a diagnostic and therapeutic dilemma.[14] Under such situations, it is crucial to assess the flow status using the stroke volume index (SVI) as a surrogate for flow, with low flow defined as SVI ≤35 ml/m2.[14] Further stratification is based on the LVEF, which further sets two subgroups of low-flow low-gradient (LFLG) AS:[15]
Figure 1: Algorithm for Doppler-echocardiographic grading and management of AS. Corresponding to ACC/AHA (2020) Guidelines for the management of valvular heart disease.[18] AS: aortic stenosis; AVA: Aortic valve area, AVAi: Aortic valve area indexed, AVR: Aortic valve replacement, HG: High gradient, MG: Mean transaortic pressure gradient, Mo's: months, TTE: Transthoracic echocardiography, Vmax: Peak aortic velocity

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  1. Classical LFLG AS: AVA <1 cm2, MPG <40 mmHg, SVI ≤35 ml/m2, and LVEF <50%
  2. Paradoxical LFLG AS: AVA <1 cm2, MPG <40 mmHg, SVI ≤35 ml/m2, and LVEF ≥50% [Figure 2].
Figure 2: Paradoxical low-flow low-gradient aortic stenosis. An 86-year-old male with mild concentric left ventricular hypertrophy (RWT: 0.54, LV mass index: 126gm/m2) with normal LV systolic function (LVEF 55-60%) diagnosed as low-flow low gradient with preserved EF. (a) LVOT diameter measured from parasternal long axis. (b) AVA was calculated using the continuity equation. (c) LVEF was preserved and SVI <35 indicates low flow. (d) MPG and Vmax within the moderate range. AVA: Aortic valve area, AVAI: Aortic valve area index, Diam: Diameter, LVOT: left ventricular outflow tract, LVEF: Left ventricular ejection fraction, MPG: Mean transaortic pressure gradient, SVI: Stroke volume index, Vmax: Peak aortic velocity

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Since the variability in measuring the left ventricular outflow diameter is substantial, the use of the velocity ratio (VLVOT/Vav) is valuable in eliminating error during AVA estimation, allowing its utility in severity grading.[10] The use of the velocity ratio has also been justified in prognostication in patients with LFLG AS, with worse clinical outcomes in patients within severe cutoffs (<0.25).[16] Correspondingly, the calculation of this ratio in patients with low gradient is reasonable to further aid in severity grading (Class 2a).[8]

Given that LFLG AS is observed in 40% of AS patients in tertiary hospitals, current research aims to highlight the prognostic value of low flow in such patients.[17] In a cohort of 621 severe AS patients, the 2-year mortality of patients with low flow was twice as high as that of their counterparts.[17] Another issue of concern observed in patients with LFLG AS is a profound gender difference in therapy, with the lack of surgical referral of female cases for AVR and subsequently an increased mortality.[18] In addition, many studies aimed to investigate the determinants of low flow in patients with severe AS, with significant attribution to underlying mitral regurgitation (MR).[19] Interestingly, the reversibility of MR after TAVR was observed in 44% of LFLG-AS in the TOPAS-TAVI registry, with worse mortality outcomes in those with retained MR, necessitating a closer follow-up in such cases.[20]

Dobutamine stress echocardiography

The rationale behind the use of dobutamine stress echocardiography (DSE) comes from its role in differentiating truly severe AS from pseudosevere AS, which is typically limited to moderate AS.[8],[9] The distinction between the two is necessary, as therapy and prognosis differ considerably. The protocol for DSE involves the administration of low-dose dobutamine (5 μg/kg/min), with a gradual increase up to the maximum dose (20 μg/kg/min).[8]

In patients with pseudosevere AS [Figure 3], AVA will increase (peak stress AVA >1.0 cm2) with a subtle change in the MPG (ΔP <40 mmHg).[8],[9] In true severe AS, AVA is unaltered (AVA <1.0 cm2) with an increase in pressure gradient (ΔP ≥40 mmHg). In addition, the presence of (CR) reserve, defined as an increase of 20% in stroke volume (SV), was previously proven to have prognostic inference in terms of operative mortality;[21] however, the current literature contradicts its role in predicting survival and therapeutic advantage.[22],[23]
Figure 3: Dobutamine stress echocardiography: Pseudosevere AS. A 65-year-old female with ischemic heart disease and mild systolic dysfunction (LVEF: 40%–50%), CR >20%. During rest (a): severe AVA (<1 cm2), moderate Vmax & MPG → suspected severe LFLG AS. During stress (b): moderate AVA (>1cm), minor increase in MPG (<40)→ pseudosevere AS (moderate AS). AVA: Aortic valve area, CR: Contractile reserve, MPG: Mean transaortic pressure gradient, LVEF: Left ventricular ejection fraction, Vmax: Peak aortic velocity

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Another diagnostic ambiguity encountered during DSE is incomplete normalization of flow due to an inadequate increase in SV, resulting in further discordance during stress testing (peak stress gradient <40 mmHg, peak stress AVA <1 cm2).[24] Under this setting, conventional echocardiographic parameters, such as the projected AVA (AVAproj) at a fixed transvalvular flow rate (250 ml/s), serve as a homogenous method in identifying severe AS on DSE.[24],[25] The diagnostic accuracy of the latter in detecting severe AS (AVAproj ≤1 cm) was found to be 70%, compared to an accuracy of 48% and 60% observed with MPG and AVA, respectively.[25]

Computed tomography aortic valve scoring

The clinical utility of computed tomography aortic valve calcium (CT-AVC) score as a diagnostic modality has established its role in predicting disease progression and severity grading.[26] This is specifically practical in patients with discordance in echocardiographic measurements (AVA ≤1 cm2, MPG <40 mmHg).[26] In such clinical discrepancies, inconsistency in the MPG has been directly linked to a reduction in aortic valve compliance caused by heavy calcification, which can be accordingly quantified through CT-AVC.[27] The essence behind the applicability of CT-AVC in severity assessment is its lack of dependence on hemodynamic parameters on echocardiography.[28] Previous studies have defined cutoff values for severe AS as ≥1274 and ≥2065 AU in women and men, respectively, according to ROC curve analysis.[27] Different cutoffs have been proposed by the current guidelines as illustrated in [Figure 4], making CT-AVC the next confirmatory step in defining severity in LFLG AS.[8]
Figure 4: ACC/AHA vs. ESC/EACTS algorithm for the diagnosis and management of low-flow low-gradient AS. *Integrated approach: further confirmation of severe AS is through CT-AV calcium scoring and calculation of the ratio of the outflow tract to aortic velocity.[18] Considering typical symptoms, LV hypertrophy or reduced LV longitudinal function additionally aid in defining severity.[19] ACC: American College of Cardiology, AHA: American Heart Association, AS: Aortic stenosis, AVA: Aortic valve area, AVR: Aortic valve replacement, CT-AVC: Computed tomography aortic valve calcium, EACTS: European Association of Cardiothoracic Society, ESC: European Society of Cardiology, LVEF: Left ventricular ejection fraction, MPG: Mean transortic pressure gradient, SV: Stroke volume, SVI: Stroke volume index

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Stress testing

Since 50% of patients with AS are asymptomatic, exercise testing can unmask symptoms and hemodynamic compromise in the form of a drop (≤20 mmHg) or insufficient rise in blood pressure (BP), ventricular arrhythmia, and ST segment changes.[29],[30] Current guidelines recommend exercise testing exclusively in asymptomatic cases (Class 2a) with caution.[8] Since an abnormal exercise test is associated with an escalated risk of death,[30] both the European and American guidelines recommend AVR upon symptom onset during exercise testing (Class 1).[8],[9]

Alternatively, pharmacological (dobutamine) stress testing has been demonstrated to predict the onset of symptoms during follow-up. Therefore, stratifying patients as high-risk can also be obtained through stress echocardiography in the form of hemodynamic assessment of the left ventricle. In particular, a rise in MPG or lack of increase in SV during testing is associated with dismal outcomes.[29]

  Treatment Overview Top

Medical therapy

Lipid-lowering therapy

It has been proposed that lipid infiltration of the aortic valve plays a dominant role in inducing inflammation and, subsequently, calcification that is characteristic of a degenerative stenotic valve. In contrast to this theoretical perspective, AS patients enrolled in the SEAS trial did not experience risk reduction of aortic valve replacement (AVR), mortality, or hospitalization as a consequence of disease progression while on simvastatin and ezetimibe.[31] Therefore, the initiation of lipid-lowering agents is solely based on standard cardiovascular disease risk scoring systems.[8] Interestingly, in patients with familial hypercholesterolemia, the necessity for AVR was profoundly increased in a cohort enrolled in the SAFEHEART study, demanding an exceptionally tight control over their cholesterol levels.[32]

Antihypertensive therapy

The increase in systemic arterial pressure in patients with AS may induce LV remodeling, further contributing to LV dysfunction.[33] Although it is rational to initiate antihypertensive drugs in patients with AS with a BP of ≥140/90 mmHg, there is an associated risk of hypotension.[34] In terms of drug choice, conflicting evidence exists regarding the use of beta-blockers, as they have been previously believed to induce left ventricular dysfunction and hemodynamic compromise.[33] In contrast, the use of beta-blockers has been shown to improve survival in severe AS patients due to a reduction in hemodynamic overload.[35],[36]

Since the renin–angiotensin system (RAS) is upregulated in patients with AS, its blockage has been shown to reduce the risk of AVA and Vmax progression through deceleration of cardiac remodeling in the RIAS trial.[37] The advantage of haltering the progression of AS would be maximally beneficial during the initial stages of AS,[38] which is currently under investigation in the ARBAS trial (NCT04913870). According to the ESC/EACVI/EAPCI expert consensus on management of patients with hypertension and AS, RAS blockers are considered the first line of therapy, with a target BP of 130–139/80–89 mmHg.[34] However, patients with systolic dysfunction or severe AS require individualized therapy by expert opinion due to the associated risk of hypotension with RAS blockers.

Calcium targeting therapy

As the hallmark underlying the pathogenesis of AS is valvular calcification, retrospective data analyzed the influence of bisphosphonates on the course of AS, with results revealing a slower progression in mild disease.[39] However, the results of the SALTIRE trial contradict such findings, with established data showing the lack of role of denosumab or alendronate in AS progression.[40]

  Interventional Therapy Top

Mild and moderate AS

Intervention in the form of surgical AVR (SAVR) or TAVR is classically limited to severe and symptomatic AS in both guidelines (Class 1), with specific exceptions discussed later.[8],[9] Beyond that, echocardiographic follow-up is usually recommended with the range of frequencies depending on the severity [Figure 1].

Although echocardiography aims to capture early disease progression, increased mortality in nonsevere AS has been established in those with significant valve calcifications, CAD, and rapid progression of Vmax,[41] demanding closer follow-up in patients with such a clinical picture. Moreover, the natural history of moderate AS was recently examined in 729 patients, with results revealing an overall 5-year survival of 52.3%.[42] Clear survival benefits derived from early intervention in moderate AS are currently being investigated in the TAVR UNLOAD trial (NCT02661451), potentially altering future management in such cases.

Asymptomatic severe aortic stenosis

In a subset of asymptomatic severe AS patients enrolled in the AVARJIN study, symptom onset occurred in an average of 2 years in two-third of the cases.[43] Remarkably, a recent meta-analysis of 4075 asymptomatic AS patients revealed a reduction in mortality (Hazard Ratio = 0.38) with the early intervention compared to conservative management.[44] Early intervention in the form of SAVR has recently been investigated for in patients with asymptomatic severe AS patients with preserved ejection fraction (EF) in the AVATAR trial (NCT02436655). Interestingly, results revealed a reduction in all-cause death and major cardiovascular events with early surgery compared to conservative management.[45] These results may heavily impact on the development of future guidelines recommendations, potentially revolutionizing the current recommendation of watchful waiting in asymptomatic severe AS.

The ESC/EACTS and the ACC/AHA guidelines propose specific indications for AVR in asymptomatic severe AS. The European guidelines currently recommend intervention in patients with LVEF <55% (Class 2a), corresponding to an excessive mortality seen in such patients.[46] Beyond these indications, other prognostic parameters were proven to confer dismal outcomes in asymptomatic severe AS.[46],[47],[48] In the RECOVERY trial, patients with very severe AS (AVA ≤ 0.75 cm2, MPG ≥50 mmHg, Vmax ≥4.5 m/s) had improved survival outcomes with the early intervention compared to conservative management.[47] Therefore, intervention in asymptomatic AS with MPG ≥60 mmHg or Vmax >5 m/s is recommended (Class 2a).[8] Moreover, intervention is recommended in these subgroups in both guidelines (Class 2a):

  1. Increased brain natriuretic peptide levels (×3 normal range)
  2. Increased aortic velocity by ≥ 0.3 m/s per year
  3. A fall in systolic BP during exercise.

Other echocardiographic parameters have additionally been explored to predict outcomes in asymptomatic severe AS patients. For instance, impaired global longitudinal strain (GLS <15%) provides additional prognostic value in patients with preserved EF.[49] Such parameters are not taken into consideration in the current guidelines, yet they should be heavily considered during clinical evaluation.

Symptomatic severe

Braunwald and Ross have previously explored the natural history of symptomatic severe AS, with the most distinguished model in 1968 revealing 2-, 3-, and 5-year survival rate upon onset of dyspnea, syncope, and angina, respectively.[50] Current guidelines recommend intervention in symptomatic severe, high-gradient AS (Class 1).

In regard to the more challenging subtype, LFLG AS, therapy, and prognosis have been controversial. The French Multicenter Study initially established the lack of contractile reserve (CR) on dobutamine echocardiography as a marker for early postoperative mortality in patients with LFLG AS.[21] Correspondingly, in LFLG patients, intervention is indicated with Class 1 recommendation in those with CR and with only a Class 2a recommendation in patients lacking CR in the ESC 2021 guidelines.[9] More recently, the 2018 TOPAS Registry highlighted the lack of association between CR pre-TAVR and overall clinical outcomes.[51] Specifically, a demonstrable increase in LVEF was observed in patients with classical LFLG AS regardless of CR. This was further supported in the 2019 registry, where results revealed similar 1-year mortality rates despite differences in CR.[22] Successively, current guidelines by the ACC/AHA (2020) recommend AVR in all subtypes of LFLG (Class 1). Despite a similar recommendation implemented by the ESC/EACTS (2021) guidelines, AVR is indicated with a Class 2a recommendation in patients with paradoxical LFLG.[9]

Choice of intervention: TAVR versus surgical aortic valve replacement

To stratify patients into low- and high-risk groups, certain risk scores have been introduced, with the most precise being the EuroSCORE II and the STS-PROM.[52] Several trials have established the survival benefit of TAVR over SAVR in low-, intermediate-, and high-surgical risk patients along with inoperable cases. In terms of mortality outcomes, a significant survival benefit derived from TAVR was apparent in inoperable cases compared to standard care at the 1-year follow-up in the PARTNER 1 trial.[53] TAVR outcomes were additionally analyzed in high-risk patients, with results revealing similar survival rates at 1-year-follow-up.[54] In patients at intermediate surgical risk, TAVR was noninferior to SAVR in terms of mortality outcomes and stroke.[55] At the end of the spectrum, in low surgical risk, TAVR was superior to SAVR in terms of the primary endpoint, expanding its indications to low-risk subsets.[56] Recently, however, the NOTION trial assessed 8-year outcomes of low-surgical risk patients undergoing TAVR, with nonsignificant differences in mortality, stroke, or myocardial infarction.[57]

The current ESC/EACTs guidelines consider age and surgical risk scores when considering the choice of intervention[9] [Figure 5]. The importance of a patient-centered approach where decision-making is made by the heart team has additionally been emphasized, implementing the choice and timing of therapy based on several factors, including clinical characteristics and availability of resources and expertise, along with expected procedural outcomes and the overall patient's preferences. The ACC/AHA guidelines additionally incorporate the patient's life expectancy into the clinical decision-making.[8] Taking surgical risk scores into account, high risk or inoperable cases with at least 1-year life expectancy after TAVR are candidates for TAVR; however, if life expectancy is expected to be less, palliative care should be considered (Class 1).
Figure 5: ACC/AHA vs. ESC/EACTS Guidelines on the Choice of Intervention (TAVR vs SAVR). *Shared decision-making: SAVR or TAVI is both appropriate between 65 and 80 years of age. Factors to consider include vascular access, comorbid conditions, life expectancy, and functional capacity after AVR along with the patient's preferences.[19] ACC: American College of Cardiology, AHA: American Heart Association, EACTS: European Association of Cardio-Thoracic Society, ESC: European Society of Cardiology, EuroSCORE: European System for Cardiac Operative Risk Evaluation, TAVR: Transcatheter aortic valve replacement, LE: Life expectancy, SAVR: Surgical aortic valve replacement, STS: Society of Thoracic Surgeons – predicted risk of mortality, TAVR: Transcatheter aortic valve replacement

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As patients with LFLG are considered a high surgical risk, a recent meta-analysis by Ueyama et al.[58] analyzed AVR outcomes in such patients, with results revealing a clear reduction in all-cause mortality with AVR, with no significant difference between SAVR and TAVR. However, in the recent TOPAS registry,[59] transfemoral TAVR was concluded to be the optimal management in such cases, contradicting their results. Established guidelines by the ACC/AHA and ESC do not address a certain predilection of TAVR over SAVR in these patients, however.[8],[9]

  Anticoagulation Top

Mechanical valves

According to the ACC/AHA guidelines, all patients with mechanical aortic valves require long-term anticoagulation with VKA to prevent valve thrombosis and thromboembolic events (Class 1a). Target INR levels have been established, requiring ongoing monitoring of PT/INR levels to fit the following recommendations (Class 1).[8]

  1. In the absence of risk factors for hypercoagulability, an INR of 2.5 is desirable
  2. In the presence of risk factors (AF, left ventricular dysfunction, previous TE, or with an older-generation valve implanted), an INR of 3.0 is desirable.

Similar recommendations have been implemented by the ESC, additionally considering the addition of low-dose aspirin in patients with concomitant atherosclerotic disease (Class 2b)

Bioprosthetic valves

In patients with bioprosthetic valves, current ACC/AHA recommendations propose 3-6 months of anticoagulation with VKA along with life-long aspirin therapy (Class 2a). In contrast, in patients with no baseline indication for oral anticoagulation, the ESC currently recommends either VKA or low-dose aspirin in the first 3 months (Class 2a), with controversy regarding the choice of therapy.

Posttranscatheter aortic valve replacement anticoagulation

Several trials have aimed to determine the optimal anticoagulation after TAVR. In the POPular TAVI trial, the benefit of aspirin alone compared to dual antiplatelet therapy was established in reducing the risk of bleeding, with a similar reduction in ischemic events.[60] Correspondingly, the ESC/EACTS currently recommend lifelong single antiplatelet therapy in patients with no baseline indication for anticoagulation (Class 1).[8] The role of direct factor Xa inhibitor (rivaroxaban) was additionally investigated, with results revealing a higher risk of death, thromboembolic events, and bleeding compared to antiplatelet-based strategy.[61] These results were further supported in the ATLANTIS trial, where results revealed nonsuperiority of apixaban to antiplatelet therapy in terms of the primary endpoint in patients with no baseline indication for anticoagulation.[62] The role of edoxaban has recently been established in the ENVISAGE AF trial, with results revealing noninferiority of edoxaban to warfarin in patients with baseline atrial fibrillation undergoing TAVR, on the expense of a higher associated risk of bleeding.[63] Additional ongoing trials are yet to determine the ideal therapy in patients after TAVR, upon which standard guidelines can be set.

  Conclusion Top

The incidence of AS is expected to increase concordantly with the aging population, potentially resulting in an epidemic of AS. Precise diagnosis is built upon echocardiography, allowing risk stratification into different degrees of severity. To date, no medical therapy has proven to halt the progression of AS, necessitating future trials to explore alternative therapies. AVR remains the gold standard treatment for severe and symptomatic cases, with certain indications for asymptomatic cases. The surgical risk and uncertainty with SAVR has been drastically transformed with the introduction of TAVR, improving survival outcomes in high-risk and inoperable patients. Future research should focus on broadening the indications of TAVR, potentially reversing the need for surgery in all patients. In addition, long-term outcomes of TAVR should also be addressed, as the current literature is limited.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Rostagno C. Heart valve disease in elderly. World J Cardiol 2019;11:71-83.  Back to cited text no. 1
Milin AC, Vorobiof G, Aksoy O, Ardehali R. Insights into aortic sclerosis and its relationship with coronary artery disease. J Am Heart Assoc 2014;3:e001111.  Back to cited text no. 2
Nathaniel S, Saligram S, Innasimuthu AL. Aortic stenosis: An update. World J Cardiol 2010;2:135-9.  Back to cited text no. 3
Eveborn GW, Schirmer H, Heggelund G, Lunde P, Rasmussen K. The evolving epidemiology of valvular aortic stenosis. The Tromsø study. Heart 2013;99:396-400.  Back to cited text no. 4
Osnabrugge RL, Mylotte D, Head SJ, Van Mieghem NM, Nkomo VT, LeReun CM, et al. Aortic stenosis in the elderly: Disease prevalence and number of candidates for transcatheter aortic valve replacement: A meta-analysis and modeling study. J Am Coll Cardiol 2013;62:1002-12.  Back to cited text no. 5
Trends in European TAVI Practice – Cardiac Interventions Today; 2018. Available from: [Last accessed on 2021 Aug 01].  Back to cited text no. 6
Czarny MJ, Resar JR. Diagnosis and management of valvular aortic stenosis. Clin Med Insights Cardiol 2014;8:15-24.  Back to cited text no. 7
Writing Committee Members; Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP 3rd, 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. J Am Coll Cardiol 2021;77:e25-197.  Back to cited text no. 8
Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2021, ehab395. Advance online publication.  Back to cited text no. 9
Chair BH, Co-Chair HJ, Bermejo J, Chambers JB, Edvardsen T, Goldstein S, et al. Recommendations on the echocardiographic assessment of aortic valve stenosis: A focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc Imaging 2017;18:254-75.  Back to cited text no. 10
Nakatsuma K, Taniguchi T, Morimoto T, Shiomi H, Ando K, Kanamori N, et al. Prognostic impact of peak aortic jet velocity in conservatively managed patients with severe aortic stenosis: An observation from the CURRENT AS registry. J Am Heart Assoc 2017;6:e005524.  Back to cited text no. 11
Paul A, Banerjee R, Narayanan A, Effat M, Paquin J. Reducing the inconsistency between Doppler and invasive measurements of the severity of aortic stenosis using aortic valve coefficient: A retrospective study on humans. J Comput Med 2014;2014:1-6.  Back to cited text no. 12
González-Mansilla A, Martinez-Legazpi P, Prieto A, Gomá E, Haurigot P, Pérez Del Villar C, et al. Valve area and the risk of overestimating aortic stenosis. Heart 2019;105:911-9.  Back to cited text no. 13
Zeitoun D, Guy L. Aortic valve stenosis: Evaluation and management of patients with discordant grading. E J Cardiol Pract 2018; 15: N 26. Available from: -evaluation -and-management-of-patients-with-discordant- grading. [Last accessed on 2021 Aug 04].  Back to cited text no. 14
Delgado V, Bax JJ. Left ventricular stroke volume in severe aortic stenosis and preserved left ventricular ejection fraction: Prognostic relevance. Eur Heart J 2018;39:2000-2.  Back to cited text no. 15
Jander N, Gohlke-Baerwolf C, Gerdts E, Bahlmann E, Pedersen TR, Wachtell K. Velocity ratio predicts outcome in patients with low gradient severe aortic stenosis with preserved ejection fraction. Eur Heart J 2013;34:P4736.  Back to cited text no. 16
Sen J, Huynh Q, Stub D, Neil C, Marwick TH. Prognosis of severe low-flow, low-gradient aortic stenosis by stroke volume index and transvalvular flow rate. JACC Cardiovasc Imaging 2021;14:915-27.  Back to cited text no. 17
Saeed S, Vamvakidou A, Zidros S, Papasozomenos G, Lysne V, Khattar RS, et al. Sex differences in transaortic flow rate and association with all-cause mortality in patients with severe aortic stenosis. Eur Heart J Cardiovasc Imaging 2021;22:977-82.  Back to cited text no. 18
Benfari G, Clavel MA, Nistri S, Maffeis C, Vassanelli C, Enriquez-Sarano M, et al. Concomitant mitral regurgitation and aortic stenosis: One step further to low-flow preserved ejection fraction aortic stenosis. Eur Heart J Cardiovasc Imaging 2018;19:569-73.  Back to cited text no. 19
Freitas-Ferraz AB, Lerakis S, Barbosa Ribeiro H, Gilard M, Cavalcante JL, Makkar R, et al. Mitral regurgitation in low-flow, low-gradient aortic stenosis patients undergoing TAVR: Insights from the TOPAS-TAVI registry. JACC Cardiovasc Interv 2020;13:567-79.  Back to cited text no. 20
Monin J, Quéré J, Monchi M. Low-gradient aortic stenosis: operative risk stratification and predictors for long-term outcome: A multicenter study using dobutamine stress hemodynamics. ACC Curr J Rev 2003;12:37.  Back to cited text no. 21
Maes F, Lerakis S, Barbosa Ribeiro H, Gilard M, Cavalcante JL, Makkar R, et al. Outcomes from transcatheter aortic valve replacement in patients with low-flow, low-gradient aortic stenosis and left ventricular ejection fraction less than 30%: A substudy from the TOPAS-TAVI registry. JAMA Cardiol 2019;4:64-70.  Back to cited text no. 22
Buchanan KD, Rogers T, Steinvil A, Koifman E, Xu L, Torguson R, et al. Role of contractile reserve as a predictor of mortality in low-flow, low-gradient severe aortic stenosis following transcatheter aortic valve replacement. Catheter Cardiovasc Interv 2019;93:707-12.  Back to cited text no. 23
Annabi MS, Clavel MA, Pibarot P. Dobutamine stress echocardiography in low-flow, low-gradient aortic stenosis: Flow reserve does not matter anymore. J Am Heart Assoc 2019;8:e012212.  Back to cited text no. 24
Annabi MS, Touboul E, Dahou A, Burwash IG, Bergler-Klein J, Enriquez-Sarano M, et al. Dobutamine stress echocardiography for management of low-flow, low-gradient aortic stenosis. J Am Coll Cardiol 2018;71:475-85.  Back to cited text no. 25
Pawade T, Clavel MA, Tribouilloy C, Dreyfus J, Mathieu T, Tastet L, et al. Computed tomography aortic valve calcium scoring in patients with aortic stenosis. Circ Cardiovasc Imaging 2018;11:e007146.  Back to cited text no. 26
Clavel MA, Messika-Zeitoun D, Pibarot P, Aggarwal SR, Malouf J, Araoz PA, et al. The complex nature of discordant severe calcified aortic valve disease grading: New insights from combined Doppler echocardiographic and computed tomographic study. J Am Coll Cardiol 2013;62:2329-38.  Back to cited text no. 27
Pawade T, Sheth T, Guzzetti E, Dweck MR, Clavel MA. Why and how to measure aortic valve calcification in patients with aortic stenosis. JACC Cardiovasc Imaging 2019;12:1835-48.  Back to cited text no. 28
Redfors B, Pibarot P, Gillam LD, Burkhoff D, Bax JJ, Lindman BR, et al. Stress testing in asymptomatic aortic stenosis. Circulation 2017;135:1956-76.  Back to cited text no. 29
Saeed S, Rajani R, Seifert R, Parkin D, Chambers JB. Exercise testing in patients with asymptomatic moderate or severe aortic stenosis. Heart 2018;104:1836-42.  Back to cited text no. 30
Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56.  Back to cited text no. 31
Pérez de Isla L, Watts GF, Alonso R, Díaz-Díaz JL, Muñiz-Grijalvo O, Zambón D, et al. Lipoprotein(a), LDL-cholesterol, and hypertension: Predictors of the need for aortic valve replacement in familial hypercholesterolaemia. Eur Heart J 2021;42:2201-11.  Back to cited text no. 32
Rieck ÅE, Cramariuc D, Boman K, Gohlke-Bärwolf C, Staal EM, Lønnebakken MT, et al. Hypertension in aortic stenosis: Implications for left ventricular structure and cardiovascular events. Hypertension 2012;60:90-7.  Back to cited text no. 33
Mancusi C, de Simone G, Brguljan Hitij J, Sudano I, Mahfoud F, Parati G, et al. Management of patients with combined arterial hypertension and aortic valve stenosis: A consensus document from the Council on Hypertension and Council on Valvular Heart Disease of the European Society of Cardiology, the European Association of Cardiovascular Imaging (EACVI), and the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J Cardiovasc Pharmacother 2021;7:242-50.  Back to cited text no. 34
Bang CN, Greve AM, Rossebø AB, Ray S, Egstrup K, Boman K, et al. Antihypertensive treatment with β-blockade in patients with asymptomatic aortic stenosis and association with cardiovascular events. J Am Heart Assoc 2017;6:e006709.  Back to cited text no. 35
Hansson NH, Sörensen J, Harms HJ, Kim WY, Nielsen R, Tolbod LP, et al. Metoprolol reduces hemodynamic and metabolic overload in asymptomatic aortic valve stenosis patients: A randomized trial. Circ Cardiovasc Imaging 2017;10:e006557.  Back to cited text no. 36
Bull S, Loudon M, Francis JM, Joseph J, Gerry S, Karamitsos TD, et al. A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril in Aortic Stenosis (RIAS trial). Eur Heart J Cardiovasc Imaging 2015;16:834-41.  Back to cited text no. 37
Kang TS, Park S. Antihypertensive treatment in severe aortic stenosis. J Cardiovasc Imaging 2018;26:45-53.  Back to cited text no. 38
Sterbakova G, Vyskocil V, Linhartova K. Bisphosphonates in calcific aortic stenosis: Association with slower progression in mild disease – A pilot retrospective study. Cardiology 2010;117:184-9.  Back to cited text no. 39
Pawade TA, Doris MK, Bing R, White AC, Forsyth L, Evans E, et al. Effect of denosumab or alendronic acid on the progression of aortic stenosis: A double-blind randomized controlled trial. Circulation 2021;143:2418-27.  Back to cited text no. 40
Rosenhek R, Klaar U, Schemper M, Scholten C, Heger M, Gabriel H, et al. Mild and moderate aortic stenosis. Natural history and risk stratification by echocardiography. Eur Heart J 2004;25:199-205.  Back to cited text no. 41
Du Y, Gössl M, Garcia S, Enriquez-Sarano M, Cavalcante JL, Bae R, et al. Natural history observations in moderate aortic stenosis. BMC Cardiovasc Disord 2021;21:108.  Back to cited text no. 42
Heuvelman HJ, van Geldorp MW, Kappetein AP, Geleijnse ML, Galema TW, Bogers AJ, et al. Clinical course of patients diagnosed with severe aortic stenosis in the Rotterdam area: Insights from the AVARIJN study. Neth Heart J 2012;20:487-93.  Back to cited text no. 43
Gahl B, Çelik M, Head SJ, Vanoverschelde JL, Pibarot P, Reardon MJ, et al. Natural history of asymptomatic severe aortic stenosis and the association of early intervention with outcomes: A systematic review and meta-analysis. JAMA Cardiol 2020;5:1102-12.  Back to cited text no. 44
Banovic M, Putnik S, Penicka M, Doros G, Deja MA, Kockova R, et al. Aortic valve replacement versus conservative treatment in asymptomatic severe aortic stenosis: The AVATAR trial. Circulation 2021; Advance online publication. [doi: 10.1161/CIRCULATIONAHA.121.057639].  Back to cited text no. 45
Bohbot Y, de Meester de Ravenstein C, Chadha G, Rusinaru D, Belkhir K, Trouillet C, et al. Relationship between left ventricular ejection fraction and mortality in asymptomatic and minimally symptomatic patients with severe aortic stenosis. JACC Cardiovasc Imaging 2019;12:38-48.  Back to cited text no. 46
Kang DH, Park SJ, Lee SA, Lee S, Kim DH, Kim HK, et al. Early surgery or conservative care for asymptomatic aortic stenosis. N Engl J Med 2020;382:111-9.  Back to cited text no. 47
Gu H, Saeed S, Boguslavskyi A, Carr-White G, Chambers JB, Chowienczyk P. First-phase ejection fraction is a powerful predictor of adverse events in asymptomatic patients with aortic stenosis and preserved total ejection fraction. JACC Cardiovasc Imaging 2019;12:52-63.  Back to cited text no. 48
Thellier N, Altes A, Appert L, Binda C, Leman B, Marsou W, et al. Prognostic importance of left ventricular global longitudinal strain in patients with severe aortic stenosis and preserved ejection fraction. J Am Soc Echocardiogr 2020;33:1454-64.  Back to cited text no. 49
Braunwald E. Aortic stenosis: Then and now. Circulation 2018;137:2099-100.  Back to cited text no. 50
Ribeiro HB, Lerakis S, Gilard M, Cavalcante JL, Makkar R, Herrmann HC, et al. Transcatheter aortic valve replacement in patients with low-flow, low-gradient aortic stenosis: The TOPAS-TAVI registry. J Am Coll Cardiol 2018;71:1297-308.  Back to cited text no. 51
Ad N, Holmes SD, Patel J, Pritchard G, Shuman DJ, Halpin L. Comparison of EuroSCORE II, original EuroSCORE, and the society of thoracic surgeons risk score in cardiac surgery patients. Ann Thorac Surg 2016;102:573-9.  Back to cited text no. 52
Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597-607.  Back to cited text no. 53
Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187-98.  Back to cited text no. 54
Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609-20.  Back to cited text no. 55
Mack MJ, Leon MB, Thourani VH, Makkar R, Kodali SK, Russo M, et al. Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients. N Engl J Med 2019;380:1695-705.  Back to cited text no. 56
Jørgensen TH, Thyregod HG, Ihlemann N, Nissen H, Petursson P, Kjeldsen BJ, et al. Eight-year outcomes for patients with aortic valve stenosis at low surgical risk randomized to transcatheter vs. surgical aortic valve replacement. Eur Heart J 2021;42:2912-9.  Back to cited text no. 57
Ueyama H, Kuno T, Harrington M, Takagi H, Krishnamoorthy P, Sharma SK, et al. Impact of surgical and transcatheter aortic valve replacement in low-gradient aortic stenosis: A meta-analysis. JACC Cardiovasc Interv 2021;14:1481-92.  Back to cited text no. 58
Annabi MS, Côté N, Dahou A, Bartko PE, Bergler-Klein J, Burwash IG, et al. Comparison of early surgical or transcatheter aortic valve replacement versus conservative management in low-flow, low-gradient aortic stenosis using inverse probability of treatment weighting: Results from the TOPAS prospective observational cohort study. J Am Heart Assoc 2020;9:e017870.  Back to cited text no. 59
Nijenhuis VJ, Brouwer J, Delewi R, Hermanides RS, Holvoet W, Dubois CL, et al. Anticoagulation with or without clopidogrel after transcatheter aortic-valve implantation. N Engl J Med 2020;382:1696-707.  Back to cited text no. 60
Dangas GD, Tijssen JG, Wöhrle J, Søndergaard L, Gilard M, Möllmann H, et al. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement. N Engl J Med 2020;382:120-9.  Back to cited text no. 61
Dharam JK. American College of Cardiology; 2021. Available from: [Last accessed on 2021 Sep 01].  Back to cited text no. 62
Van Mieghem NM, Unverdorben M, Hengstenberg C, Möllmann H, Mehran R, López-Otero D, et al. Edoxaban versus vitamin K antagonist for atrial fibrillation after TAVR. N Engl J Med 2021;385:2150-60.  Back to cited text no. 63


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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