TAVI: from an experimental procedure to standard of care

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts Calcific aortic valve stenosis is more and more common in ageing Western populations and has become an increasing economic and health issue. With the development of transarterial valve implantation, or TAVI, a less invasive treatment option has become available for frail patients and those at high surgical risk. Of note, since the first pioneering intervention by Michel Cribier in Rouen in 2002, the technique and the valves have been optimized, making TAVI a standard procedure1 not only in high-,2 but also in intermediate-risk patients.3 Aortic stenosis, once present, inevitably progresses and has a poor prognosis in symptomatic patients. As there are no medical therapies able to prevent or regress aortic valve degeneration, surgical valve replacement or TAVI are the only treatment options.4 The more improved knowledge of the mechanisms underlying disease progression is an unmet medical need as outlined in the review entitled ‘Calcific aortic valve stenosis: hard disease in the heart. A biomolecular approach towards diagnosis and treatment’ by Frederique Peeters and colleagues from the Maastricht University Medical Centre in The Netherlands.5 Indeed, calcific aortic valve stenosis is regulated by numerous mechanisms with a key role for the calcification process which involves cellular and humoral factors that may offer targets for future diagnosis and intervention. For instance, vitamin K-dependent proteins inhibit aortic valve calcification. This review discusses processes involved in calcific aortic valve stenosis progression and potential therapeutic options. In addition, TAVI is at centre stage and expands its indication, as projected in a second review ‘Trascatheter aortic valve implantation: current status and future perspectives’, by Thomas Cahill and colleagues from the Oxford University Hospitals NHS Foundation Trust in Oxford, UK.6 Of note, simplification of the procedure, clinical experience, and improvements in valve design and delivery systems have dramatically reduced complication rates. These advances have allowed for an ongoing expansion of TAVI to lower risk populations. Indeed, the PARTNER 2A7,8 and SURTAVI trials7 provided evidence for its use in intermediate-risk patients, and indications for TAVI expand further towards lower risk, younger, and asymptomatic populations. The number of TAVI procedures is rapidly increasing. This has a major impact on healthcare resource planning. However, the annual numbers of TAVI candidates per country are unknown. In a meta-analysis article ‘Annual number of candidates for transcatheter aortic valve implantation per country: current estimates and future projections’, Andras Peter Durko and colleagues from the Erasmus MC in Rotterdam, The Netherlands estimated current and future numbers of annual TAVI in 27 European countries, the USA, and Canada using data from 37 studies with 26 402 patients.9 The calculated incidence of severe aortic stenosis was 4.4‰/year in patients 65 years or older. Symptoms were present in two-thirds with severe aortic stenosis (Figure 1A). Despite having severe symptomatic aortic stenosis, 42% did not undergo aortic valve replacement (Figure 1B). Of the non-operated patients, two-thirds received TAVI. The model predicted 114 757 European and 58 556 Northern-American TAVI candidates annually. Thus, ∼180 000 patients would be TAVI candidates in the European Union and in Northern America annually, which may increase up to 270 000, if indications are expanded to low-risk patients. These findings have major implications for healthcare resource planning which is put into context in a thought-provoking Editorial by Stephan Windecker from the University Hospital Bern in Switzerland.10 Forest plots of the different steps in the model. (A) Prevalence of symptoms in patients with severe aortic stenosis. (B) Percentage of patients not receiving surgical aortic valve replacement despite having severe symptomatic aortic stenosis. AS, aortic stenosis; CI, confidence interval; SAVR, surgical aortic valve replacement (from Durko AP, Osnabrugge RL, Van Mieghem NM, Milojevic M, Mylotte D, Nkomo VT, Kappetein AP. Annual number of candidates for transcatheter aortic valve implantation per country: current estimates and future projections. See pages 2635–2642). Echocardiography11 and tomographic imaging12,13 have documented dynamic and pathological changes in aortic stenosis geometry and severity during both the cardiac cycle and increases in cardiac output. In their article entitled ‘Pressure gradient vs. flow relationships to characterize the physiology of a severely stenotic aortic valve before and after transcatheter valve implantation’, Nils P. Johnson and colleagues from the University of Texas Medical School at Houston in Texas, USA note that pressure gradient vs. flow relationships have not been described.14 Therefore, in 16 TAVI procedures, graded dobutamine infusions were performed before and after implantation with pressure wires in the aorta and left ventricle, and a pulmonary artery catheter providing data on cardiac output (Figure 2). Before TAVI, pressure gradients did not display a consistent relationship with transvalvular flow. Neither linear resistor nor quadratic orifice models at rest predicted the values observed during stress; the severely stenotic valve behaved like a combination. The unitless ratio of aortic to left ventricle pressures during systolic ejection under stress conditions correlated best with post-TAVI flow improvement. After TAVI, a highly linear relationship indicated a valid valve resistance. Thus, pressure loss vs. flow curves offer a fundamental fluid dynamic synthesis describing aortic valve pathophysiology. Severe aortic stenosis does not consistently behave like an orifice or a resistor, whereas TAVI devices behave like a pure resistor. During peak dobutamine, the ratio of aortic to left ventricle pressures during systolic ejection provides a ‘fractional flow reserve’ of the aortic valve that closely approximates the complex, changing fluid dynamics. Because resting assessment cannot reliably predict stress haemodynamics, ‘valvular fractional flow’ warrants study to explain exertional symptoms in patients with only moderate aortic stenosis at rest. The manuscript is accompanied by an Editorial by Rick A. Nishimura from the Mayo Clinic in Rochester, Minnesota (USA).15 Conceptual framework for aortic stenosis physiology. The shape of the curve linking systolic ejection transvalvular pressure gradient (ΔP) to transvalvular flow (Q) provides a physiological ‘fingerprint’ of haemodynamics unique to that stenotic valve. A single rest measurement (coloured blue) cannot predict which path will be observed during dobutamine stress (coloured red). Five patterns of increasing severity can be anticipated, from most severe (worse than the quadratic shape assumed by the Gorlin orifice model) to least severe (better than the linear shape of a resistor). Three examples from the cohort, plus the example in the right panel of Figure 2, provide visual evidence of the heterogeneity of valvular pathophysiology (from Johnson NP, Zelis JM, Tonino PAL, Houthuizen P, Bouwman RA, Brueren GRG, Johnson DT, Koolen JJ, Korsten HHM, Wijnbergen IF, Zimmermann FM, Kirkeeide RL, Pijls NHJ, Gould KL. Pressure gradient vs. flow relationships to characterize the physiology of a severely stenotic aortic valve before and after transcatheter valve implantation. See pages 2646–2655). Patients with aortic stenosis may develop right ventricular dysfunction, particularly with longstanding and severe disease. Thus, in their article ‘The incidence and prognostic implications of worsening right ventricular function after surgical or transcatheter aortic valve replacement: insights from PARTNER IIA’ Paul Cremer and colleagues from the Cleveland Clinic in Ohio, USA sought to determine in 1376 patients from PARTNER IIA whether aortic valve replacement is associated with worsening right ventricular function and mortality in patients randomized to TAVI or surgical valve replacement.16 While only 8.3% of those undergoing TAVI had worsening right ventricular function, this was notable in 24.7% of those treated surgically. In a multivariable model, surgical aortic valve replacement, a dilated right ventricle, and more than mild tricuspid regurgitation were associated with worsening right ventricular function. These patients had a doubling of all-cause mortality, with no mortality difference between TAVI and surgery. The development of moderate or severe right ventricular dysfunction from a baseline normal function almost tripled risk. Thus, worsening right ventricular function is associated with bad outcome and is particularly common in those with right ventricular dilation, more than mild tricuspid regurgitation and in those treated surgically. Patients with left-sided heart valve replacement are considered at high risk of infective endocarditis.17,18 In their article entitled ‘Incidence and factors associated with infective endocarditis in patients undergoing left-sided heart valve replacement’,19 Lauge Klement Moltke Østergaard and colleagues from the Rigshospitalet in Copenhagen, Denmark identified 18 041 patients in Danish administrative registries patients who underwent left-sided heart valve replacement over a 10-year period. The cumulative risk of endocarditis at 10 years follow-up was 5.2% after both mitral and aortic valve replacement. In patients with mitral valve replacement, male gender, bioprosthetic valve, and heart failure were associated with an increased risk of infective endocarditis. After aortic valve replacement, male gender, bioprosthetic valve,20 and cardiac implantable electronic devices21 were associated with an increased risk. Thus, infective endocarditis after left-sided heart valve replacement is not uncommon and occurs in ∼1 in 20 patients over 10 years. These clinically important fidings are further discussed in an Editorial by Thomas Cahill from the Oxford University Hospitals NHS Foundation Trust in the UK.22 While TAVI is to become standard care, transcatheter mitral valve implantation is still an experimental approach.23–25 Dominique Himbert and colleagues from the Bichat Hospital in Paris, France report their prospectively collected experience in 91 patients in their article ‘Clinical and haemodynamic outcomes of balloon-expandable transcatheter mitral valve implantation: a 7-year experience’.26 All patients were at high risk for surgery with a median EuroSCORE II of 9.6%. Indications for transcatheter mitral valve implantation were bioprosthesis or annuloplasty failure and severe mitral annulus calcification. With a trans-septal approach and balloon-expandable valves, a technical success was achieved in 85% of the patients, with one dying during the procedure and left ventricular outflow tract obstruction in three patients. The mean transmitral gradient decreased from 9.3 mmHg at baseline to 6.0 mmHg at discharge without changes up to 1 year. At 30 days, 7.7% of patients had died and 2.2% had a major stroke, without differences between groups. The cumulative rates of all-cause mortality at 1 and 2 years were 21.0% and 35.7%, respectively, with a higher late mortality in those with mitral annulus calcification. The 2-year rates of re-intervention and valve thrombosis were 8.8% and 14.4%, respectively. Thus, in selected patients with bioprosthesis or annuloplasty failure or severe annular calcification, transcatheter mitral valve implantation using balloon-expandable valves is associated with a low rate of periprocedural complications and acceptable long-term outcomes. The editors hope that this issue of the European Heart Journal will be of interest of to its readers.