The past, present and future of aortic stenosis treatment

Epidemiology of AS

Prevalence

AS is the most common valvular heart disease, accounting for 43% of valvular pathologies.¹ Most cases are caused by calcification of the aortic valve leading to valve degeneration (termed calcified aortic valve disease [CAVD]), but rheumatic disease and congenital defects may also be responsible.^8,9

The number of CAVD cases worldwide has been estimated at 9.4–12.6 million,^9,10 although this may be an underestimate since many cases are asymptomatic and remain undiagnosed.¹¹ Prevalence is particularly high in regions with a high sociodemographic index, including Europe, North America and Australasia, possibly reflecting regional variations in access to diagnostic echocardiography or associated risk factors.^9,12

The prevalence of AS increases with age,^2,10 rising from <50 cases per 100,000 in those aged 25–49 years to >1,300 cases per 100,000 in those aged 80 years or over.¹⁰ In Europe, the estimated number of patients with AS is <1 million in the population aged 20–64 years and almost 2.5 million in those >85 years of age.² Ageing populations worldwide have led to a dramatic increase in the global prevalence of AS, from 46 cases per 100,000 people in 1990 to 116 cases per 100,000 in 2019.¹² These numbers are expected to rise even further over the next 20–30 years, with estimates in some regions predicting a doubling before 2050.¹¹

Mortality

The increasing worldwide prevalence of AS is reflected in an increasing number of associated deaths, which rose by 138% between 1990 and 2019.¹⁰ In line with prevalence data, age-standardised mortality associated with AS is highest in Western Europe, North America, southern Latin America and Australasia.^9,10 Mortality is proportionate to disease severity – data from an Australian registry indicate five-year mortality rates in moderate and severe AS of 56% and 67%, respectively.⁵ Furthermore, the large iENHANCED-AS study found that even patients with mild AS have increased risk of 10-year mortality, regardless of age, gender or comorbidities, with adjusted mortality risks similar to those in moderate and severe AS.¹³ Importantly, patients with severe symptomatic AS who remain untreated have a particularly poor prognosis; in the Placement of Aortic Transcatheter Valve (PARTNER™) I trial, those considered unsuitable for surgery who did not undergo transcatheter intervention had a five-year mortality rate of 94%, highlighting the importance of effective and timely treatment.¹⁴

Evolution of AS treatment

Open-heart surgery for AS was introduced in 1913 and the first surgical aortic valve replacement (SAVR) was performed in the early 1960s using a caged-ball prosthesis.¹⁵ Since then, surgery has evolved towards less invasive approaches (mini-sternotomy or mini-thoracotomy) to reduce tissue trauma, and the use of minimal extracorporeal circulation to reduce the inflammatory effects of cardiopulmonary bypass.¹⁶ Until the 1980s, SAVR was the only effective treatment option for patients with AS, although many of those aged >70 years were considered too high risk for surgery and remained untreated.¹⁷ In 1985, Alain Cribier developed the first catheter-based approach for the treatment of AS – balloon aortic valvuloplasty – which provided early improvement in quality of life for inoperable patients but was steadily discarded due to high rates of restenosis.^17,18 Following successful development in pre-clinical models, the first-in-human transcatheter aortic valve implantation (TAVI) was conducted by Cribier and colleagues in Rouen in 2002.¹⁹ Despite early pushback from the medical community, this ground-breaking achievement triggered a revolution in the treatment of AS and opened the field for transcatheter treatment of mitral, tricuspid and pulmonary valve disease.

The 20-year period since the first TAVI procedure has witnessed growing adoption of the technique, driven by technological and procedural advances (figures 1–2).²⁰ Successive bioengineering improvements have resulted in progressively smaller delivery systems and increasingly sophisticated devices, including balloon-expanding, self-expanding and mechanically expanded bioprostheses.²⁰ National and international TAVI registries established to monitor outcomes in different regions (including TVT,²⁰ OCEAN-TAVI,²¹ the UK TAVI registry,²² the Asia Pacific TAVI registry,²³ GARY,²⁴ FRANCE 2 and FRANCE TAVI,²⁵) have highlighted significant changes in patient baseline characteristics, treatment approaches, and procedural and clinical outcomes.^20,25

Procedures were initially focused on inoperable or high-risk patients, but have expanded to intermediate- and low-risk patients over time.^20,25 Transfemoral access now predominates and use of conscious sedation with local anaesthesia has become increasingly common.^20,25 Growing operator experience and procedural simplification combined with emphasis on pre-procedural imaging and planning have reduced vascular access site complications, paravalvular aortic regurgitation and the need for blood transfusion.^20,25 This has been accompanied by a shorter duration of hospitalisation (with resulting cost benefits) and significant improvements in 30-day all-cause mortality.^20,25

The evolution of AS treatment guidelines

Treatment guidelines for AS are constantly evolving, driven by accumulating clinical experience, the availability of new treatment options, and a growing body of clinical evidence.

The latest iteration of the European Society of Cardiology and European Association for Cardio-Thoracic Surgery (ESC/EACTS) guidelines for the management of valvular heart disease includes expanded indications for earlier intervention in patients with asymptomatic AS and a number of revised Class I recommendations regarding the mode of intervention in AS (primarily based on age thresholds rather than surgical risk scores) (figure 3).²⁶ Importantly, the guidelines emphasise the critical role of the Heart Team in coordinating AS treatment and the importance of including the values and preferences of the patient (and their family) in the decision-making process.²⁶

In the ESC/EACTS guidelines, SAVR is recommended for younger patients with severe AS who are low risk for surgery (<75 years and STS-PROM/EuroSCORE II <4%) and those who are operable and unsuitable for transfemoral TAVI, whereas TAVI is recommended for older patients (≥75 years) or those who are high risk (STS-PROM/EuroSCORE II >8%) or unsuitable for surgery. For remaining patients, SAVR or TAVI should be considered according to individual clinical, anatomical and procedural characteristics.²⁶ These recommendations are based on a series of pivotal randomised studies involving patients in different surgical risk categories. See the following link (https://academic.oup.com/view-large/figure/364291378/ehab395f4.jpeg).

The PARTNER I™ and CoreValve US Pivotal High Risk trials laid foundations for the use of TAVI in high-risk and inoperable patients with severe AS. PARTNER I™ demonstrated similar rates of mortality at one, two, three and five-year follow-up after TAVI or SAVR in high-risk patients,²⁷ and a substantial reduction in five-year mortality after TAVI compared with medical treatment (with or without balloon aortic valvuloplasty) in inoperable patients.¹⁴ Similarly, the CoreValve US Pivotal High Risk Trial demonstrated no difference in mid-term survival in high-risk patients randomised to TAVI or SAVR.²⁸

Data from the PARTNER IIA™ and SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) trials then drove expansion of TAVI to intermediate-risk patients with equivalent rates of the primary composite end point of death from any cause or disabling stroke at two-year follow-up.^29,30 More recently, the PARTNER 3™ and Evolut Low Risk (Evolut Surgical Replacement and Transcatheter Aortic Valve Implantation in Low Risk Patients) trials have supported further expansion of the use of TAVI to low-risk patients. In the PARTNER 3™ trial, TAVI demonstrated superiority over SAVR with regards to the primary end point of death, stroke or re-hospitalisation at one- and two-year follow-up, accompanied by shorter hospital stay and improved quality of life at 30 days.^31,32 Meanwhile, the Evolut Low Risk Trial demonstrated non-inferiority of TAVI compared with SAVR in relation to death or disabling stroke at two years.³³

Most randomised trials comparing TAVI or SAVR in specific surgical risk groups have been conducted in Europe or the US. However, there are marked geographic variations in life expectancy around the world and treatment decisions should take account of differing age thresholds for SAVR and TAVI, according to regional patient characteristics.

The American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend use of a mechanical prosthesis in patients aged <50 years at the time of SAVR and either a mechanical or bioprosthetic valve for patients aged 50–65 years (or with a life expectancy >20 years).³⁴ TAVI is recommended in those aged >80 years (or with a life expectancy <10 years). Patients aged 65–80 years remain eligible for either TAVI or SAVR, the choice being determined by anticipated longevity, valve durability and shared decision-making with the patient.³⁴ (https://www.ahajournals.org/doi/10.1161/CIR.0000000000000923#d1e4306)

In Japan (where life expectancy is three to five years longer than in Europe and the USA), guidelines recommend composite clinical assessment rather than a specific age threshold to determine the choice between TAVI or SAVR, but suggest use of TAVI in patients aged ≥80 years and SAVR in those aged <75 years.⁸

Although surgery remains the gold-standard treatment in younger, low-risk patients, the use of TAVI is also expanding in this cohort.^19,26,34 Primary barriers to wider adoption in younger patients include concerns over long-term durability of transcatheter valves, paravalvular leak, permanent pacing and need for re-operation. Latest data from the PARTNER™ study indicate stable valve haemodynamics five years after TAVI,²⁷ whilst eight-year data from the NOTION (Nordic Aortic Valve Intervention) study (using different definitions of durability) demonstrate lower risk of structural valve deterioration and equivalent risk of bioprosthetic valve failure in low-risk patients treated with TAVI or SAVR.³⁵

These findings may allay some concerns over valve durability following TAVI, but the extended lifespan of younger patients means that longer term follow-up data are still required. Paravalvular leak is consistently higher after TAVI than after SAVR in clinical trials,^27,36 although rates of paravalvular leak comparable with surgery have been achieved with balloon-expandable TAVI valves.³² Similarly, pacemaker implantation rates are often worse following TAVI compared with SAVR,³³ but appear similar with balloon-expandable TAVI valves.^27,32 Pacemaker implantation rates are typically low in younger patients,³² but long-term implications for patients with extended life expectancy are unknown. Finally, the question of a second (or even third) procedure is a significant consideration for younger patients. While TAVI in TAVI procedures are feasible, this is still an emerging field with limited outcome data, and surgical explantation of TAVI bioprostheses is not always straightforward due to neo endothelialisation between the device and native tissue.^37–40

COVID-19 as a potential catalyst of TAVI adoption

During the COVID-19 pandemic, cardiac surgery was limited to emergency cases in many institutions to reduce COVID-19 infection among patients and healthcare workers, and to protect hospital resources.⁴¹ Since continued access to treatment is crucial in severe AS, diversion of management from SAVR to TAVI was recommended for many patients.⁴² For those eligible, TAVI demonstrated several advantages over SAVR in this setting, including reduced need for mechanical ventilation and intensive care, shorter length of hospital stay, and reduced risk of COVID-19 infection for patients and healthcare workers.⁴² Furthermore, since extended waiting times can impact on clinical outcomes,⁴³ significant streamlining of the TAVI pathway was achieved in many centres, allowing treatment of additional patients throughout the pandemic (see article by Durand E et al. later in this supplement on pages S17–S23). Despite the intense pressure on healthcare resources during this period, use of TAVI was associated with no excess complications or mortality and no significant time delays for treatment.^44,45

Conclusion

Since its introduction for the treatment of patients with inoperable AS, use of TAVI has steadily expanded to high-, intermediate- and low-risk patient populations, driven by a wealth of clinical evidence.^{27,28,30,32,33} Developments in TAVI over the last 10 years have resulted in improved patient survival and lower complication rates that match or improve on those seen with SAVR, and reduced impact on hospital resources.^20,27,32 Based on Class IA evidence, the ESC/EACTS guidelines recommend transfemoral TAVI as the standard of care for patients aged 75 years and over.²⁶ These guidelines emphasise the need for a Heart Team assessment to balance clinical evidence and patient perspectives to ensure an individualised treatment choice.²⁶

Ongoing studies provide the opportunity for generation of complementary long-term evidence. In the PARTNER 3™ trial, for example, data are beginning to accumulate for low-risk patients who were aged <75 years at the time of intervention, and these studies will provide long-term follow-up to determine whether initially positive outcomes after TAVI are sustained in patients with longer life expectancy.³² Other studies to evaluate whether early intervention using TAVI is beneficial in asymptomatic patients with moderate or severe AS are approaching completion,^6,7,46 whilst the utility of alternative access routes is being explored in high-risk patients who are unsuitable for transfemoral TAVI and currently require surgery.⁴⁷

While the full potential of TAVI in different patient populations is still emerging, its introduction 20 years ago has already revolutionised the treatment of AS and paved the way for transcatheter treatment of mitral, tricuspid and pulmonary valve disease. Remaining barriers to the wider treatment of AS include physician and patient awareness, variations in access to diagnostic imaging, and the reluctance of general practitioners, general physicians and cardiologists to refer patients based on perceived futility of treatment. Educational efforts and greater collaboration between Heart Teams, physicians and elderly care specialists are now required to ensure timely referral and prompt Heart Team assessment of all patients with severe AS to enable appropriate intervention that will enhance their quality of life and overall survival.

Key messages

• Aortic stenosis (AS) is the most common valvular heart disease and mortality is high if left untreated
• Transcatheter aortic valve implantation (TAVI) has revolutionised the treatment of AS and benefits a broad patient population encompassing high-, intermediate- and low-risk patients
• Current treatment guidelines endorse the role of TAVI in the treatment of AS and place increasing emphasis on individualised treatment by balancing clinical evidence with patient preference
• More data are required to better understand the full potential of TAVI in different patient populations, particularly younger, lower risk patients and those with asymptomatic severe AS

Conflicts of interest

HE has received speaker/consultancy fees from Edwards Lifesciences. CL has received unrestricted institutional educational and research grants from Edwards Lifesciences, and speaker/consultancy fees from Abbott and Edwards Lifesciences. BP has received unrestricted institutional educational and research grants from Edwards Lifesciences, and speaker/consultancy fees from Abbott, Anteris, Edwards Lifesciences and Medtronic.

Funding

HE has received two grants from the French Government, managed by the National Research Agency (ANR) under the program ‘Investissements d’avenir’ with the reference ANR-16-RHUS-0003, and from the GCS G4 (FHU CARNAVAL).

Hélène Eltchaninoff
Interventional Cardiologist and Head of Department
Normandie Univ, UNIROUEN, U1096, CHU Rouen, Department of Cardiology, F-76000 Rouen, France

Clinton Lloyd
Consultant Cardiac Surgeon
Department of Cardiothoracic Surgery, University Hospitals Plymouth NHS Trust, Plymouth, Devon, PL6 8DH

Bernard Prendergast
Chair of Cardiology, Cleveland Clinic London; Consultant Cardiologist, St Thomas’ Hospital, London
St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK

Correspondence to:
[email protected]

Articles in this supplement

Introduction: overcoming barriers to treating severe aortic stenosis
A standardised network to improve the detection and referral of patients with aortic stenosis
Ensuring continuous and sustainable access to aortic stenosis treatment

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