Article

Transcatheter Aortic Valve Implantation in High-risk Patients with Severe Aortic Stenosis

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Abstract

Aortic stenosis (AS) has become an increasingly prevalent condition in ageing Western populations. Symptomatic AS is associated with significant morbidity, high hospitalisation rates and reduction in quality of life and life-expectancy. A large number of patients with severe AS are not currently receiving proper treatment, with subsequent increased mortality. While surgical aortic valve replacement continues to be an effective treatment for these patients, transcatheter aortic valve implantation is a new alternative for those at high risk from surgery. Overall, valve replacement and implantation procedures have a significant impact on prognosis and quality of life in AS patients. Referring a patient to a centre that has a multidisciplinary heart team will ensure that all treatment options are fully explored and the best clinical outcomes are reached.

Keywords

Severe aortic stenosis, transcatheter aortic valve implantation, PARTNER trial (Placement of aortic transcatheter valve trial), balloon aortic valvuloplasty, surgical aortic valve replacement, transapical approach, transfemoral approach,

Disclosure:Patricia Fonseca is an employee at Touch Briefings.

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DOI:https://doi.org/10.15420/ecr.2012.8.2.115

Support:The publication of this article was supported by Edwards Lifesciences.

Correspondence Details:Patricia Fonseca, Touch Briefings, Saffron House, 6-10 Kirby Street, London, EC1N 8TS, UK. E: patricia.fonseca@touchbriefings.com

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Degenerative aortic stenosis (AS) is a chronic progressive valvular disease that affects approximately 1.4 % of individuals over 65 years and 4.6 % of patients older than 75 years in the US.1 While the prognosis of asymptomatic patients with severe AS is generally good, that of symptomatic patients is very poor, with an overall mortality of approximately 80 % at three years once the disease becomes symptomatic (post-mortem analysis including patients with traumatic heart disease).2 A retrospective study showed that the mortality in patients with mild-to-moderate AS was 80 % higher than that in age- and gender- matched control subjects, with a high rate of aortic valve replacement related to haemodynamic progression to severe stenosis observed in the AS patients during a five-year follow-up period.3 Up to one-third of apparently asymptomatic patients actually experience limiting symptoms during an exercise test.4

Until recently, the only effective treatment available for severe AS was surgical aortic valve replacement (SAVR). In the last decade, transcatheter aortic valve implantation (TAVI) has emerged as an effective alternative therapy for inoperable AS patients or those at high risk from surgery. Although SAVR has been shown to improve outcomes in symptomatic AS patients, older patients experience higher morbidity and operative mortality. Assessing the risks and being aware of the life-expectancy of the patient are crucial when choosing the optimal intervention.5

Operative mortality increases with age and is greatly dependent on symptomatic status and surgical therapy. For SAVR on its own, the overall mortality rate is 4.3 %, while it practically doubles for SAVR combined with coronary artery bypass grafting (CABG) (see Table 1). Renal failure, emergent status and New York Heart Association (NYHA) functional class IV are among the risk factors associated with higher operative mortality rates, which increase significantly for patients over 70 years of age who undergo SAVR (5.3 % for the 70–79 age group, 8.5 % for the 80–89 age group and 14.5 % for the 90–99 age group) (see Table 2).6

Undertreatment of Severe Aortic Stenosis – Extent of the Problem and Consequences

The European Society of Cardiology (ESC) guidelines recommend TAVI in patients with severe symptomatic AS requiring aortic valve replacement who are deemed inoperable or at high risk from surgery.7 While the European System for Cardiac Operative Risk Evaluation (EuroSCORE) still successfully discriminates high-risk patients undergoing SAVR, it has become increasingly uncalibrated with absolute risk, resulting in an overestimation of the 30-day mortality rate.8 The limitations of current risk scoring systems are mentioned in a recent ESC position paper on risk assessment before intervention in patients with valvular disease.5

Nonetheless, the Euro Heart Survey showed that one-third of patients with severe symptoms of valve disease (NYHA functional class III or IV), including patients without significant co-morbidities, are not referred for aortic valve intervention.9 A similar situation was observed in the US, where Pai et al. conducted a study and found that one third of symptomatic patients with severe AS were not referred for aortic valve replacement surgery, even though some of them had a low estimated operative risk (<5 %). Many of these untreated patients died of complications related to AS within 14 months. The reasons for not performing surgery included high surgical risk unrelated to AS and patient refusal.10

Although not deemed a contraindication for intervention,7 advanced age has a significant weight in patient selection. In clinical practice, 33 % of patients aged between 75 and 80 years are not referred to surgery,11 and the clinical decisions, mainly based on age and ejection fraction values, are often inconsistent and do not take into account risk:benefit ratios. Considering the estimated prevalence of AS in patients over 65 years and the actual numbers of patients referred to surgery, it might be extrapolated that a significant proportion of patients do not receive appropriate care. The significant ageing of the Western populations will accentuate this trend over the next decades, and some projections point to a doubling of the number of patients over 65 years.

Clinicians at the Medical University of Vienna, Austria, presented data at the Euroecho meeting, showing that two subsets of patients need to be differentiated. On the one hand, there are patients who are symptomatic at the time of first presentation; strikingly, these patients have had symptoms for approximately one year before seeking medical help. On the other hand, there are patients enrolled in a follow-up programme who were asymptomatic when they first presented; among those who regularly attend their six-monthly visits, only 79 % report symptoms soon after they become symptomatic and 70 % report symptoms only at their next scheduled visit. Patients usually report their symptoms about three months after onset when they attend their next scheduled visit. Although they are instructed to report symptoms as soon as possible, only 21 % will call the clinic to do so soon after onset (typically 20 days later).

Considering late symptom reporting and subsequent late referral to surgery, the risk stratification of asymptomatic patients is an important step towards the identification of those who are likely to develop symptoms in the near future, which can occur very rapidly and warrant surgical intervention. In patients with severe AS (defined by a peak aortic jet velocity >4m/s) who have calcified aortic valves and a rapid haemodynamic progression (increase of the peak aortic jet velocity by ≥0.3 m/s within 12 months), the event-free survival rate at two years is only 20 %.12

In patients with severe asymptomatic AS and peak aortic jet velocities of 4.0–5.0 m/s, 5.0–5.5 m/s or >5.5 m/s, the event-free survival rates at three years are 49 %, 33 % and 11 %, respectively. In addition to their importance with regard to risk stratification, these data suggest that the definition of ‘very severe’ AS should be based on a peak aortic jet velocity ≥5.0 m/s.13 The event-free survival curve of ‘very severe’ AS matches that of ‘severe’ AS with valve calcification and rapid haemodynamic progression;12 hence these parameters define high-risk subsets of patients in whom early elective surgery may be considered.

The failure to recognise and report symptoms also has implications for the symptomatic status of patients. More than 60 % of the mildest symptomatic cases (NYHA functional class II) undergo surgery. More than 50 % of patients presenting for the first time at a symptomatic stage with mainly severe symptoms are in NYHA functional class II-III or greater. The surgery waiting list death rate is approximately 13.5 % per year.14 For these patients at high risk, the timing and choice of procedure are critical. According to the already mentioned ESC position paper, the patient’s life-expectancy and personal preferences, an individualised risk assessment, the natural history of the disease, the risk posed by intervention and the expected long-term post-procedural outcomes must all be taken into account in the treatment decision-making process.5

In Europe as well as in the US, the life expectancy of 65-year-old AS patients is approximately 19 years. For 80-year-olds, it is around nine years. And in the absence of significant co-morbidities, 85-year-old AS patients still have a life expectancy of six years or more.15 Therefore, the undertreatment of AS is also a concern in elderly patients, who can present with extensive co-morbidities and have different expectations towards therapy.

The causes behind the undertreatment of AS are multifactorial and include difficulty in determining disease severity based on peak aortic jet velocities, non-recognition of symptoms (by both patients and physicians) and of the need for surgery, denial of symptoms and refusal of intervention. Addressing undertreatment – by monitoring patients closely, by educating them about the importance of follow-up and prompt symptom reporting and by implementing risk stratification assessments – will contribute to timely procedures and improved clinical outcomes.

Transcatheter Aortic Valve Implantation – Evolution, Applications and Patient Selection

The first bioprosthetic valve stent was invented by Heinning Andersen, who placed a valve in a wire stent and implanted it in pigs, but it was received with lukewarm interest. Percutaneous balloon aortic valvuloplasty (BAV) was first described in humans by Alain Cribier in 1986.16

However, the procedure was extremely complex and the mortality rate was high at one year (45 %), reaching 77 % after three years; early re-stenosis and recurrent hospitalisations were common.17 Since then, the technology has greatly improved, with new devices and imaging techniques, and has evolved into the reliable, safe and effective TAVI procedure.

This relatively simple, minimally invasive technique avoids cardiopulmonary bypass, cross-clamping and sternotomy, and has shown promising results in a subgroup of patients with calcified aortic stenotic valve ineligible for open surgical replacement. It is not approved in patients who are eligible for traditional aortic valve surgery and is contraindicated in patients with bicuspid aortic valves, endocarditis or other active infections, or who do not tolerate anticoagulation/antiplatelet therapy. The number of procedures has increased rapidly in the past few years. According to data from the German Society for Thoracic and Cardiovascular Surgery, the percentage of CABG surgeries performed in AS patients is decreasing. At the same time, the number of graft implantations and valve procedures performed (half of which involve the aortic valve) is increasing. In 2010, a quarter of the isolated aortic valve replacement procedures performed in AS patients were TAVIs.\

The Edwards SAPIEN XT™ Transcatheter Heart Valve is a balloon-expandable stent valve that consists of a cobalt chromium frame covered with a polyethylene terephthalate skirt to prevent paravalvular leaks. The frame holds three leaflets made of bovine pericardial tissue and is held in place by the calcium on the patient’s affected leaflets. It is currently available in three sizes, 23, 26 and 29 mm, for an annulus diameter of 18–22, 21–25 and 24–27 mm, respectively. Delivery can be performed both via the femoral artery (transfemoral approach – see Figure 1) or the left ventricular (LV) apex (transapical approach), but pacing is required and the valve cannot be repositioned. One of its main advantages is the low incidence of permanent pacemaker implantation, in the 2–5 % range, but the cost is still high and the procedure requires intensive resources.

The less invasive transfemoral approach consists of a BAV procedure followed by valve implantation under fast-pacing. In patients with narrow vessels, severe tortuosity and calcification of the iliac/femoral arteries, the transapical approach constitutes an alternative procedure, with reported success rates equivalent to those of the transfemoral procedure. The transapical procedure is performed in four steps: incision and exposure of the LV apex; BAV; valve implantation; and final check for valve position, coronary obstruction (which may occur due to small annulus and leaflets when valve is inflated), paravalvular leak, mitral valve function and haemodynamic recovery. Because it avoids the femoral arteries and the aortic arch, transapical TAVI carries a very low risk of stroke (0.3 %), and the need for urgent cardiopulmonary bypass is extremely small despite an overall high mortality rate (22 %), which can be explained by the higher EuroSCORE values in this series (11 points; 27% risk of mortality).18

The novel transaortic approach, involving a mini-sternotomy and aortic cannulation followed by purse-string sutures, has the advantage of being familiar to surgeons and has shown to be relatively safe, with no deleterious effects on the left ventricle.19,20

Appropriate patient selection involves the assessment of valve morphology and severity of calcification and the sizing of the aortic annulus in order to prevent aortic regurgitation and valve migration. Essential pre-operative tests include transoesophageal echocardiogram (TOE), with three-dimensional (3D) reconstruction if available, and left heart catheterisation (coronary angiography) for precise annulus measurement, localisation of the calcium deposit and identification of coronary disease. Femoral angiography, non-contrast computed tomography (CT) and lung function tests provide important additional information about the condition of the patient’s peripheral vessels and the possibility of using a transfemoral approach.

The recent NovaFlex+™ Transfemoral Delivery System (Edwards Lifesciences) allows for additional deployment stability and, together with the new expandable 16 or 18 French eSheaths™ (Edwards Lifesciences), smaller calibre vessels can be accepted. On the other hand, the Ascendra2™ Transapical Delivery System (Edwards Lifesciences) provides greater haemostatic control, with small sheaths sizes and a simple single-handed push-button operation. Further improvements in valve positioning and delivery systems are expected in the near future.

In spite of the importance of bioengineering and methodological advances, imaging techniques are the next frontier in cardiac surgery and interventions. Imaging is critical in TAVI to recognise the appropriate imaging plane, identify the optimal deployment site and avoid complications due to poor placement. Most of the procedures are currently performed under fluoroscopy and a trend towards the use of 3D echography guidance can be seen. With multimodal coregistration imaging, it is possible to use a pre-operative CT scan within a single imaging system, or an integrated system such as the HeartNavigator® (Philips), still at experimental stage, which uses 3D CT images overlaid with live X-ray fluoroscopy. Likewise, the joint Volcano–Paieon image fusion system combines X-ray angiography with intravascular ultrasound to rapidly assess the coronary vascular system. New and improved imaging systems will certainly enable greater accuracy in valve selection and positioning and reduce the potential for complications.

Clinical Evidence for Transcatheter Aortic Valve Implantation to Treat Severe Aortic Stenosis

The PARTNER trial (Placement of aortic transcatheter valve trial; ClinicalTrials.gov identifier NCT00530894), the first and, to date, only randomised, controlled study assessing the safety and effectiveness of the TAVI technique versus conventional therapy, involved two groups of patients.

In the first group (cohort B), patients with severe AS (aortic valve area <0.8 cm2; mean pressure gradient ≥40 mmHg; peak aortic jet velocity ≥4 m/s; Society of Thoracic Surgeons [STS] Score ≥10 and EuroSCORE ≥15; NYHA functional class II–IV) were deemed by two cardiothoracic surgeons to be unsuitable for surgery because of a predicted probability of 50 % or more of death by 30 days after surgery or the presence of a serious irreversible condition. These patients were randomised to receive either TAVI with the SAPIEN valve or standard medical therapy. After 12 months, the absolute reduction in all-cause mortality was 20 % (p<0.001) with TAVI and was sustained for up to two years (see Figure 2). Death attributable to cardiovascular events was 19.6 % with TAVI versus 41.9 % with standard therapy (p<0.001). The rate of cardiac symptoms (NYHA functional class III–IV) was lower with TAVI than with standard therapy (25.2 % versus 58.0 %, p<0.001). Moreover, exercise ability was significantly improved following TAVI. These significant improvements in the composite endpoint of death from any cause or repeat hospitalisation, morbidity and quality of life position TAVI as the new standard of care for AS patients who are not suitable candidates for surgery.21

In the second group (cohort A), symptomatic patients at high surgical risk were randomised to receive either TAVI with the SAPIEN valve (transfemoral or transapical delivery) or SAVR. In these high-risk AS patients, TAVI appeared to be non-inferior to SAVR. All-cause mortality at 12 months was 24.2 % and 26.8 % (p=0.001) and mortality due to cardiovascular causes was 14.3 % and 13.0 %, respectively, with TAVI and with SAVR. Mortality at 30 days was lower than expected in both arms: 3.4 % with TAVI (the lowest reported in any series, despite the use of an early-generation device and limited operator experience) and 6.5 % with SAVR (p=0.07).22 At 30 days, peri-procedural complications, which occurred infrequently, included vascular injuries (11.0 % with TAVI versus 3.2 % with SAVR, p<0.001), major bleeding (9.3 % versus 19.5 %, p<0.001), new-onset atrial fibrillation (8.6 % versus 16.0 %, p=0.006), stroke (3.8 % versus 2.1 %, p=0.20), ischaemia (0.9 % versus 0.3 %, p=0.33) and cardiac failure (0 % versus 0.6 %, p=0.16).22 The risk of such complications can be minimised through a multidisciplinary approach involving the care of a cardiothoracic surgeon, an interventional cardiologist, an anaesthesiologist, an imaging specialist and a perfusion team. Both TAVI and SAVR are acceptable in high-risk patients, but the differing peri-procedural risk profiles observed should influence treatment decision-making on a case-by-case basis.

The main results of the PARTNER trial at one year are summarised in Table 3.

Recent data from the SOURCE XT Registry (SAPIEN XT™ aortic bioprosthesis multi-region outcome registry; ClinicalTrials.gov identifier NCT01238497) revealed, as well, major complications such as death (6.3 % and 10.3 % with transfemoral and transapical TAVI, respectively), stroke (2.6 % and 2.4 %), renal failure (1.3 % and 7.0 %) and cardiac failure requiring a pacemaker (6.0 % and 7.7 %).23 The mean procedural success rate was 93.8 % and the overall one-year survival rate was 76.1 % (72.1 % and 81.1 % for the transapical and transfemoral approaches, respectively).24

In spite of these exciting results, the TAVI technique should not be used indiscriminately; its use should be justified and supported by long-term safety and durability data. The TAVI technique is currently restricted to high-risk patients or those with contraindications for surgery, and further studies will determine the feasibility of extending it to lower-risk patient populations.25

Conclusions

Valve replacement procedures have a significant impact on the prognosis and quality of life of AS patients. Recent improvements in cardiothoracic surgery and percutaneous therapy offer good therapeutic options, even for patients who were traditionally considered as being at very high risk from intervention.

Non-recognition of the progression of mild or moderate AS to severe disease, underestimation of the disease severity, non-referral to surgery and refusal of intervention need to be recognised as reasons behind the undertreatment of AS and subsequent suboptimal outcomes.

While SAVR is still the treatment of choice for eligible patients with severe AS, TAVI is considered the new standard of care for patients who are deemed unsuitable for surgery and shows excellent outcomes in patients at high surgical risk. The future should see an expansion of the indications for this technology, which may extend to valve-in-valve procedures to ‘replace’ degenerated bioprosthesis and even to valve-in-ring (valves in mitral or tricuspid rings) applications.

Long-term safety and durability data are expected to become available in the near future. In addition, risk scores specifically adapted for TAVI are under development. Meanwhile, technological advances in valve design and performance, together with smaller delivery systems, will make the procedure safer and decrease the workload of the multidisciplinary TAVI team.

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