Open access Valvular heart disease Open Heart: first published as 10.1136/openhrt-2020-001485 on 11 January 2021. Downloaded from http://openheart.bmj.com/ on April 11, 2023 at Sant Paul Hospital Consortia. Protected Management of patients with severe aortic stenosis in the TAVI-­era: how recent recommendations are translated into clinical practice Alexander Lauten,1 Tanja K Rudolph,2 David Messika-­Zeitoun ‍ ‍,3 Jeetendra Thambyrajah,4 Antonio Serra,5 Eberhard Schulz,6 Norbert Frey,7 Jiri Maly,8,9 Marco Aiello,10 Guy Lloyd,11 Alessandro Santo Bortone,12 Alberto Clerici,13 Georg Delle-­Karth,14 Johannes Rieber,15 Ciro Indolfi,16 Massimo Mancone,17 Loic Belle,18 Martin Arnold,19 Berto J Bouma,20 Matthias Lutz,7 Cornelia Deutsch,21 Jana Kurucova,22 Martin Thoenes,23 Peter Bramlage ‍ ‍,21 Richard Paul Steeds ‍ ‍24 To cite: Lauten A, Rudolph TK, ABSTRACT Messika-­Zeitoun D, et al. Key questions Objective Approximately 3.4% of adults aged >75 years Management of patients with suffer from aortic stenosis (AS). Guideline indications severe aortic stenosis in the What is already known about this subject? for aortic valve replacement (AVR) distinguish between TAVI-­era: how recent ►► In 2012, the European Society of Cardiology pro- recommendations are translated patients with symptomatic and asymptomatic severe duced guidelines that included a class I recommen- into clinical practice. Open Heart AS. The present analysis aims to assess contemporary dation for aortic valve replacement in all patients 2021;8:e001485. doi:10.1136/ practice in the treatment of severe AS across Europe presenting with symptomatic aortic stenosis (AS). by copyright. openhrt-2020-001485 and identify characteristics associated with treatment These guidelines were updated in 2017 to include decisions, namely denial of AVR in symptomatic patients all patients with symptomatic AS with high-­gradient and assignment of asymptomatic patients to AVR. Received 13 October 2020 AS or low-­flow, low-­gradient AS, a reduced left ven- Methods Participants of the prospective, multinational Revised 2 December 2020 tricular ejection fraction and evidence of contractile IMPULSE database of patients with severe AS were Accepted 21 December 2020 reserve. grouped according to AS symptoms, and stratified into subgroups based on assignment to/denial of AVR. What does this study add? Results Of 1608 symptomatic patients, 23.8% did not ►► Our study assessed the contemporary decision-­ undergo AVR and underwent medical treatment. Denial making process for the treatment of patients with was independently associated with multiple factors, severe AS across European treatment centres. We including severe frailty (p=0.024); mitral (p=0.002) showed that 23.8% of patients with symptomatic AS or tricuspid (p=0.004) regurgitation grade III/IV, and did not undergo treatment and treatment denial was the presence of renal impairment (p=0.017). Of 392 associated with severe patient frailty, mitral/tricus- asymptomatic patients, 86.5% had no prespecified pid regurgitation grade III/IV and renal impairment. indication for AVR. Regardless, 36.3% were assigned to Conversely, 36.3% of patients with no prespecified valve replacement. Those with an indexed aortic valve indication for aortic valve replacement were as- area (AVA; p=0.045) or left ventricular ejection fraction signed treatment. (LVEF; p<0.001) below the study median; or with a left ventricular end systolic diameter above the study median How might this impact on clinical practice? (p=0.007) were more likely to be assigned to AVR. ►► There appears to be discrepancies between Conclusions There may be considerable discrepancies guideline-­based recommendations and clinical between guideline-­based recommendations and clinical practice decision-­making for treatment of patients practice decision-­making in the treatment of AS. It appears with severe AS and a significant percentage of © Author(s) (or their that guidelines may not fully capture the complete clinical symptomatic patients with severe AS are not being employer(s)) 2021. Re-­use spectrum of patients with AS. Thus, there is a need to offered life-­saving treatment. Guidelines may not permitted under CC BY-­NC. No fully capture the complete clinical spectrum of pa- find ways to increase their acceptance and the rate of commercial re-­use. See rights adoption. tients with AS. Thus, there is a need to find ways to and permissions. Published by BMJ. increase their acceptance and the rate of adoption. For numbered affiliations see end of article. INTRODUCTION patients with symptomatic and asympto- Correspondence to Dr Peter Bramlage; ​peter.​ Recent recommendations on the treatment matic severe AS. The 2012 European Society bramlage@​ippmed.​de of aortic stenosis (AS) distinguish between of Cardiology guidelines featured a class-­ I Lauten A, et al. Open Heart 2021;8:e001485. doi:10.1136/openhrt-2020-001485 1 Open Heart Open Heart: first published as 10.1136/openhrt-2020-001485 on 11 January 2021. Downloaded from http://openheart.bmj.com/ on April 11, 2023 at Sant Paul Hospital Consortia. Protected recommendation for aortic valve replacement (AVR; On a centre basis, consecutive patients aged over 18 either surgical aortic valve replacement (SAVR) or tran- years being diagnosed with severe AS (symptomatic or scatheter aortic valve implantation (TAVI)) in all patients asymptomatic) defined as an aortic valve area (AVA)<1 presenting with symptoms.1 This was updated in 2017 to cm2, indexed AVA<0.6 cm2/m2, Vmax >4 m/s, or mean include all symptomatic patients with high-­gradient AS transvalvular gradient >40 mm Hg following echocar- or low-­flow, low-­gradient AS, a reduced left ventricular diography were included. Prior AVR recipients were ejection fraction (LVEF) and evidence of contractile excluded. reserve.2 A class IIa recommendation remains for those Details were documented by each centre (echocardiog- with low-­flow, low-­gradient AS, a reduced LVEF and no rapher or a nurse under their supervision) and included flow reserve, and those with a paradoxical low-­flow low-­ patient demographics, medical history, disease character- gradient AS.2 In patients with asymptomatic AS, AVR istics and symptoms at presentation (chest pain, shortness should be performed in patients with a LVEF <50% and a of breath and/or dizziness on exertion/syncope) were pathological exercise test.1 2 AVR is also recommended in entered into an electronic case report form. Canadian asymptomatic patients with a peak transvalvular velocity Cardiovascular Society-­defined angina class III/IV and (Vmax) of >5.5 m/s1 2 and/or severe pulmonary hyper- New York Heart Association (NYHA) functional class III/ tension.2 Generally, a careful risk–benefit analysis by IV were also recorded. Patients were defined ‘symptom- the heart team is advocated prior to AVR in any asymp- atic’ if they presented with either chest pain, shortness tomatic individual due to recent evidence of a potential of breath and/or dizziness on exertion/syncope. Echo- benefit of AVR versus medical therapy in asymptomatic cardiographic parameters (eg, mean pressure gradient patients.3 While guidelines recommend best clinical prac- (MPG) and AVA) were documented for each patient, as tice according to the available evidence, real-­world devi- was the presence of concomitant valve disease or regur- ations are known to occur. Furthermore, contemporary gitation. As an indicator of surgical risk, a EuroSCORE II data on the real-­world management of patients with AS value was calculated for each patient. Frailty was defined are scarce. Historical data demonstrated that 33%–41% as ‘none’ (able to walk five metres in under 6 s plus inde- of patients did not undergo SAVR in the past—despite pendent activities of daily living (ADL) – wash, dress, severe symptomatic AS.4 5 Recently, the widespread availa- feed, toilet), “mild”(unable to walk 5 m in under 6 s or bility of TAVR has opened a less invasive treatment option fails to perform one ADL) or ‘severe’ (indicated by an inability to perform two or more ADL).9 Heart teams by copyright. for higher risk patients and the process of decision-­ making within the heart team approach has changed in were involved in the AVR decision in the participating many European centres. It is timely, therefore, to assess centres, respectively. These teams were established by the contemporary practice of decision-­making in patients each centre leveraging the expertise of cardiologists, with severe AS in centres across Europe in the era of inter- cardiac surgeons, imaging specialists, anaesthesiologists disciplinary TAVI treatment. The present analysis aims to and other if needed. explore the characteristics of patients with severe AS with Data are presented descriptively, with continuous vari- unusual treatment decisions, namely severe symptomatic ables given as means with SD and categorical variables patients did not undergo AVR and asymptomatic patients presented as absolute values with percentages (%). assigned to AVR, and to identify potential reasons for it. Group comparisons were made using a Pearson’s χ2 or Fisher’s exact test for categorical variables and a t-­test or Mann-­ Whitney-­ Wilcoxon test for continuous variables. Separate logistic regression analyses were carried out to METHODS determine baseline variables associated with AVR denial Originally designed as part of a quality-­ of-­ care initia- in symptomatic patients and AVR assignment in asymp- tive, IMPULSE is a prospective, multinational registry of tomatic patients. In the former case and according to the patients with severe AS across Europe. It was funded by findings of the univariate analysis, multivariateOR, 95% Edwards Lifesciences (Nyon, Switzerland) and sponsored CI and p values were adjusted for age, severe frailty, renal by the Institute for Pharmacology and Preventive Medi- insufficiency, chronic obstructive pulmonary disease cine (Cloppenburg, Germany). The authors are solely (COPD), Vmax, mean AV gradient, LVEF, mitral regur- responsible for the design and conduct of this study, all gitation grade III/IV and tricuspid regurgitation grade study analyses and drafting and editing of the paper. III/IV. In the latter case, these parameters were adjusted The rationale and methodology of the registry has for age, diabetes, atrial fibrillation, mean AV gradient, been previously described.6–8 Patients were enrolled LVEF, pulmonary artery systolic pressure (PASP), aortic between March 2015 and April 2017 at 23 centres across regurgitation grade III/IV and mitral regurgitation grade nine European countries (Austria, Czech Republic, III/IV. All continuous variables were converted to binary France, Germany, Italy, the Netherlands, Spain, Switzer- predictors for regression analysis, taking the median of land and the UK). All sites offered the full range of treat- the overall study population as a cut-­off. ment options for AS, including surgical and transcatheter All statistical analysis was performed using SPSS V.24.0 procedures. All patients provided their written informed (IBM Corp.), with a p value of <0.05 considered statisti- consent to participate. cally significant. 2 Lauten A, et al. Open Heart 2021;8:e001485. doi:10.1136/openhrt-2020-001485 Valvular heart disease Open Heart: first published as 10.1136/openhrt-2020-001485 on 11 January 2021. Downloaded from http://openheart.bmj.com/ on April 11, 2023 at Sant Paul Hospital Consortia. Protected Figure 1 Patient flow. AS, aortic stenosis; AVR, aortic valve replacement (surgical or transcatheter). *Symptomatic defined as having ≥1 of the following (presumed to be AS-­related): chest pain, shortness of breath, dizziness on exertion/ by copyright. syncope.†According to 2017 European guideline recommendations. SAVR, surgical aortic valve replacement. RESULTS cardiologist in 50.9% and requested by the patient in A total of 2171 patients were enrolled in the registry, of 15.4%. A heart team was involved in a ‘no AVR’ decision which 1743 were symptomatic and 428 asymptomatic at in 17.8% of cases (figure 2). Conversely, the decision to presentation (figure 1). perform AVR in symptomatic patients was made by the Symptomatic patients who were assigned to medical heart team in the majority of cases (68.2%). The propor- treatment were slightly older and had a higher mean tion of symptomatic patients with a class I (95.0% vs EuroSCORE II compared with those assigned to AVR, 94.4%) or class II (5.0% vs 5.6%) indication for AVR did with a higher proportion being severely frail and assessed not differ between those that did not undergo and those to have a reduced life expectancy at baseline (table 1). assigned to AVR (p=0.168). In a multivariate analysis, Renal insufficiency and COPD were also more common the referral by a cardiologist, shortness of breath, NYHA among those that did not undergo AVR. In symptom- class III/IV and indexed AVA≤0.39 cm2/m2, an LVEF atic patients, shortness of breath was the most common ≤58% were associated with a reduced rate of AVR denial symptom recorded with slightly higher rates in those (table 3). On the other hand, age >80 years, severe frailty, with an AVR (92.7%) than in those without (86.2%). renal impairment, mitral regurgitation grade III/IV, Other symptoms, such as dizziness/syncope and chest tricuspid regurgitation grade III/IV and interventricular pain, were equally frequent in those with or without an septum >13.3 mm were all associated with an increased intervention (figure 2A). Medically treated symptom- risk of AVR denial. atic patients had a larger indexed AVA, lower Vmax, lower The baseline characteristics of asymptomatic patients mean AV gradient and higher LVEF; however, mitral and assigned to AVR were comparable to those assigned to tricuspid regurgitation grade III/IV were more frequent medical treatment (table 1). In patients undergoing among those that did not undergo AVR, as was the combi- medical treatment, diabetes was more frequent but nation of an AVA<1 cm2 plus a mean AV gradient <40 it did not reach statistical significance. Asymptomatic mm Hg (table 2). A definitive decision for either medical patients assigned to AVR had a smaller indexed AVA and treatment or AVR was made in 1608 (92.3%) of symp- a higher Vmax (table 2). Mean LVEF was slightly lower tomatic patients: 1225 of these patients were assigned to (although still within the normal range) and PASP was any AVR (810 TAVI and 415 SAVR) and the rest assigned significantly higher in patients assigned to medical treat- to medical treatment (figure 1). The decisions not to ment. A definitive treatment decision was made in 392 perform AVR despite symptomatic AS were made by a asymptomatic patients (91.6%); 52 of these 392 patients Lauten A, et al. Open Heart 2021;8:e001485. doi:10.1136/openhrt-2020-001485 3 Open Heart Open Heart: first published as 10.1136/openhrt-2020-001485 on 11 January 2021. Downloaded from http://openheart.bmj.com/ on April 11, 2023 at Sant Paul Hospital Consortia. Protected Table 1 Baseline characteristics Symptomatic* patients with treatment Asymptomatic* patients with treatment decision (n=1608) decision (n=392) Assigned to Assigned to AVR Denied AVR No AVR AVR n=1225 n=383 n=238 n=154   n (%) or n (%) or n (%) or n (%) or   mean±SD mean±SD P value mean±SD mean±SD P value Age (years) 77.7±9.4 79.8±9.9 <0.001 75.4±11.3 74.8±10.7 0.633 Female gender 600/1225 (49.0) 198/383 (51.7) 0.353 93/238 (39.1) 63/154 (40.9) 0.717 BMI (kg/m2) 27.6±5.2 27.1±5.8 0.116 27.3±5.0 26.7±5.2 0.206 Severe frailty 41/1221 (3.4) 28/371 (7.5) 0.001 10/229 (4.4) 4/154 (2.6) 0.366 EuroSCORE II (%) 4.1±4.5 4.8±6.2 0.047 1.9±1.7 2.2±2.6 0.243 Comorbidity  Renal insufficiency† 287/1109 (25.9) 126/341 (37.0) <0.001 39/204 (19.1) 21/145 (14.5) 0.258  COPD 138/1225 (11.3) 60/383 (15.7) 0.022 9/236 (3.8) 8/154 (5.2) 0.514  Diabetes‡ 108/1225 (8.8) 35/383 (9.1) 0.847 18/236 (7.6) 5/154 (3.2) 0.073  AF 173/1140 (15.2) 59/337 (17.5) 0.301 21/208 (10.1) 19/144 (13.2) 0.368  Endocarditis 4/1225 (0.3) 4/383 (1.0) 0.098 2/236 (0.8) 0/154 (0.0) 0.521 Previous cardiac surgery 88/1225 (7.2) 34/383 (8.9) 0.275 14/237 (5.9) 4/154 (2.6) 0.127 2-­year life expectancy <25%§ 80/817 (9.8) 41/275 (14.9) 0.019 4/150 (2.7) 5/104 (4.8) 0.493 *Symptomatic defined as having ≥1 of the following (presumed to be AS-­related): chest pain, shortness of breath, dizziness on exertion/ syncope. †Creatinine clearance rate <50 mL/min or dialysis. by copyright. ‡Insulin dependent. §2-­yearlife expectancy <25% was assessed by the dedicated nurses and physicians. AF, atrial fibrillation; AVR, aortic valve replacement; BMI, body mass index; COPD, chronic obstructive pulmonary disease. had an indication for AVR according to guideline-­based DISCUSSION criteria (2017: LVEF <50%, Vmax >5.5 m/s, pulmonary In the present study, almost a quarter (23.8%) of patients hypertension >60 mm Hg), though such a procedure was with severe symptomatic AS did not undergo AVR. Age>80 planned in just 30 cases (22 were scheduled for TAVI, 8 years, severe frailty and the comorbidities renal impair- for SAVR) (figure 1). Of the remaining 339 patients with ment (CCR <50 mL/min or dialysis) and concomitant no prespecified indication for AVR, 123 were assigned to mitral/tricuspid valve regurgitation were all found to be TAVI or SAVR. The heart team was responsible for the independent deterrents for AVR in this subpopulation. majority of AVR assignments in asymptomatic patients Further, the absence of dyspnoea and a larger AVA, lower (53.9%), while cardiologists were responsible for the MPG and lower Vmax despite severe AS were associated majority of the decisions not to perform AVR (68.5%) with a medical treatment decision. Interestingly, symp- tomatic patients with a lower surgical risk were also less (figure 3). Patients undergoing AVR had a guideline-­ likely to be assigned to AVR. Conversely, over one-­third confirming indication in 18.3% (guidelines from 2012) (36.3%) of asymptomatic individuals with no predesig- and 19.6% (guidelines from 2017) of cases. LVEF <50% nated indication for AVR were assigned to undergo treat- was the most common reason (15.3%) named as a reason ment (with TAVI planned in over half of these cases); very for the intervention. Conversely, this means that between few variables were associated with this treatment decision. 80.4% and 81.7% of those undergoing AVR had no Treatment denial and not adhering to guideline guideline-­based indication. On the other hand, 8.4% and recommendations for patients with symptomatic AS is 9.2% patients not undergoing AVR had a guideline-­based not uncommon (range 21%–41%),4 5 10 and our results indication. An indexed AVA, a LVEF below the median support these findings. Fortunately, the number of of the study population, or a left ventricular end systolic patients not being treated has reduced over time, which diameter (LV-­ESD) above the median were predictive for may be attributed to the adoption of TAVI as a treat- AVR assignment (table 4). Conversely, renal impairment ment option for high-­risk patients, as well as changes in reduced the likelihood of an asymptomatic patient being decision-­making by the heart team in many centres.11 assigned to AVR. Nevertheless, it is crucial to understand the variables 4 Lauten A, et al. Open Heart 2021;8:e001485. doi:10.1136/openhrt-2020-001485 Valvular heart disease Open Heart: first published as 10.1136/openhrt-2020-001485 on 11 January 2021. Downloaded from http://openheart.bmj.com/ on April 11, 2023 at Sant Paul Hospital Consortia. Protected by copyright. Figure 2 Impact of (A) symptoms in symptomatic* patients and (B) guideline recommendations in asymptomatic* patients on the decision to perform aortic valve replacement (AVR). CCS, Canadian Cardiovascular Society; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; Vmax, peak aortic valve (AV) jet velocity. *Symptomatic defined as having ≥1 of the following (presumed to be AS-­related): chest pain, shortness of breath, dizziness on exertion/syncope. †Vmax >5.5 m/s and/or LVEF<50%. §Vmax>5.5 m/s and/or LVEF<50% and/or PASP>60 mm Hg. associated with an active decision not to perform AVR in with symptomatic AS enrolled in the Euro Heart Survey,4 almost one-­quarter of symptomatic patients, especially likely due to the higher surgical risk associated with inter- as the survival prospects associated with this strategy are ventions in these patients.13 While this study found that poor.12 age was associated with AVR denial, both a smaller AVA Older age and more severe left ventricular dysfunction and a lower LVEF appeared to increase the likelihood of were found to be key drivers of SAVR denial in patients intervention by nearly twofold. This is probably a result Lauten A, et al. Open Heart 2021;8:e001485. doi:10.1136/openhrt-2020-001485 5 Open Heart Open Heart: first published as 10.1136/openhrt-2020-001485 on 11 January 2021. Downloaded from http://openheart.bmj.com/ on April 11, 2023 at Sant Paul Hospital Consortia. Protected Table 2 Echocardiographic parameters Symptomatic* patients with treatment Asymptomatic* patients with treatment decision decision (n=1608) (n=392) Assigned to AVR Denied AVR No AVR Assigned to AVR n=1225 n=383 n=238 n=154   n (%) or n (%) or n (%) or n (%) or   mean±SD mean±SD P value mean±SD mean±SD P value 2 2 Indexed AVA (cm /m ) 0.38±0.10 0.41±0.12 <0.001 0.44±0.11 0.40±0.10 0.001 Vmax (m/s) 4.33±0.67 4.23±0.68 0.014 4.29±0.56 4.42±0.62 0.034 Mean AV gradient (mm Hg) 48.0±14.6 44.6±15.4 <0.001 47.0±12.7 48.8±14.4 0.211 LVEF (%) 54.9±12.0 57.1±12.5 0.002 61.4±9.5 57.1±10.8 <0.001 PASP (mm Hg) 39.9±12.9 39.4±14.1 0.613 35.0±10.8 37.6±10.7 0.047 2 AVA <1 cm and mean AV gradient 280/1199 (23.4) 119/373 (31.9) 0.001 48/236 (20.3) 26/152 (17.1) 0.429 <40 mmHg Aortic regurgitation grade III/IV 82/1166 (7.0) 28/367 (7.6) 0.699 27/224 (12.1) 10/149 (6.7) 0.091 Mitral regurgitation grade III/IV 109/1199 (9.1) 65/371 (17.5) <0.001 19/224 (8.5) 6/153 (3.9) 0.081 Mitral stenosis grade III/IV 19/1137 (1.7) 5/348 (1.4) 0.762 5/208 (2.4) 3/146 (2.1) 1.000 Tricuspid regurgitation grade III/IV 76/1157 (6.6) 45/358 (12.6) <0.001 13/221 (5.9) 6/149 (4.0) 0.428 LVH† 759/1214 (62.5) 227/367 (61.9) 0.817 136/231 (58.9) 88/152 (57.9) 0.849 Relative wall thickness 0.52±0.15 0.55±0.16 0.011 0.53±0.15 0.52±0.14 0.383 LV mass (g) 243.2±75.9 232.8±82.5 0.047 237.7±72.6 252.2±76.6 0.091 2 Indexed LV mass (g/m ) 131.3±39.9 133.0±44.3 0.546 129.8±39.0 137.0±39.1 0.121 LV-­ESD (mm) 33.0±11.3 29.9±9.2 <0.001 28.2±6.2 31.2±8.3 0.001 by copyright. LV-­EDD (mm) 48.8±9.9 46.0±7.9 <0.001 46.5±7.0 48.4±7.9 0.022 IVS (mm) 13.6±2.5 13.8±2.8 0.320 13.9±2.8 13.9±2.5 0.984 PW (mm) 12.1±2.3 12.1±2.7 0.979 12.0±2.2 12.1±2.2 0.759 LVEF <30% 40/1168 (3.4) 9/365 (2.5) 0.363 2/229 (0.9) 4/144 (2.8) 0.211 LVEF ≥50% and PASP <55 mm Hg 743/1094 (67.9) 238/340 (70.0) 0.470 189/211 (89.6) 108/138 (78.3) 0.004 *Symptomatic defined as having ≥1 of the following (presumed to be AS related): chest pain, shortness of breath, dizziness on exertion/ syncope. †>12 mm in thickness. AV, aortic valve; AVA, aortic valve area; IVS, interventricular septum; LV, left ventricular; LV-­EDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; LV-­ESD, left ventricular end systolic diameter; PASP, pulmonary artery systolic pressure; PW, posterior wall; Vmax, peak AV jet velocity. of recent evidence demonstrating the substantial func- as an independent predictor of AVR denial in symp- tional recovery and mortality benefit from AVR interven- tomatic patients, likely because pre-­ existing chronic tions in patients with poor left ventricular function,13 14 kidney disease is strongly associated with worse outcomes with TAVI shown to be particularly safe in this popula- following TAVI.20 In contrast to medical management, tion.15 16 In this context and given the often exacerbated AVR in haemodialysis patients has been shown to result in symptoms in patients with a lower LVEF,17 poorer echo- a significantly lower long‐term mortality risk.21 Further- cardiographic valve parameters may actually be viewed more, TAVI may improve renal function,22 and reduce as an incentive for AVR, with a greater improvement in rates of in-­hospital mortality compared with SAVR.23 The quality of life to be gained for the interventional risk and presence of concomitant valvular disease is a substantial a better risk–benefit ratio. This is supported by the fact factor influencing the decision to deny TAVI.24 25 Signif- that dyspnoea appeared to be a major driver of a posi- icant concomitant mitral/tricuspid valve regurgitation tive AVR decision. However, waiting for a deterioration were identified as independent predictors of AVR denial in echocardiographic parameters and symptoms before in symptomatic patients in our study. Both mitral and scheduling AVR treatment increases the risk of sudden tricuspid regurgitation are known to affect functional cardiac death.18 status and prognosis in patients with AS undergoing More recently, comorbidity has been highlighted as a AVR.26 27 There is little evidence, however, to support reason for non-­assignment of symptomatic patients to combined or sequential procedures to address concom- SAVR.19 In this study, renal impairment was identified itant valve conditions and modify this risk.2 27 As such, 6 Lauten A, et al. Open Heart 2021;8:e001485. doi:10.1136/openhrt-2020-001485 Valvular heart disease Open Heart: first published as 10.1136/openhrt-2020-001485 on 11 January 2021. Downloaded from http://openheart.bmj.com/ on April 11, 2023 at Sant Paul Hospital Consortia. Protected Table 3 Baseline predictors of AVR denial in symptomatic* patients with decision (N=1608)   Univariate OR (95% CI) Univariate p value Multivariate† OR (95% CI) Multivariate† p value Referring by cardio (vs other referring 0.791 (0.605 to 1.034) 0.086 0.594 (0.426 to 0.828) 0.002 physician) Age > versus ≤80 years 1.562 (1.240 to 1.968) <0.001 1.390 (1.041 to 1.858) 0.026 Severe frailty 2.349 (1.432 to 3.855) 0.001 2.036 (1.096 to 3.781) 0.024 EuroSCORE II> versus ≤2.39% 1.051 (0.833 to 1.327) 0.676 0.673 (0.487 to 0.930) 0.016 Comorbidities  Renal impairment‡ 1.679 (1.297 to 2.172) <0.001 1.466 (1.071 to 2.007) 0.017  COPD 1.463 (1.055 to 2.030) 0.023 1.450 (0.955 to 2.202) 0.081  Diabetes§ 1.040 (0.697 to 1.551) 0.847 1.343 (0.828 to 2.178) 0.232  Endocarditis 3.222 (0.802 to 12.943) 0.099 2.198 (0.476 to 10.157) 0.313 2-­year life expectancy <25%¶ 1.614; (1.078 to 2.418) 0.020 0.779 (0.439 to 1.382) 0.393 Cardiac-­related symptoms  Chest pain 0.831 (0.640 to 1.081) 0.168 0.780 (0.566 to 1.076) 0.130  Shortness of breath 0.493 (0.343 to 0.710) <0.001 0.568 (0.358 to 0.900) 0.016  Dizziness on exertion/syncope 0.961 (0.736 to 1.254) 0.770 0.788 (0.566 to 1.096) 0.157  NYHA class III/IV 0.484 (0.381 to 0.615) <0.001 0.452 (0.333 to 0.613) <0.001  Angina class III/IV 1.090 (0.665 to 1.785) 0.733 1.068 (0.582 to 1.959) 0.832 Echocardiographic parameters  Indexed AVA ≤versus>0.39 cm2/m2 0.604 (0.471 to 0.775) <0.001 0.566 (0.416 to 0.771) <0.001  Vmax >versus≤4.3 m/s 0.813 (0.637 to 1.037) 0.096 1.207 (0.795 to 1.832) 0.378  Mean AV gradient >versus≤45.0 mm 0.738 (0.584 to 0.931) 0.010 0.776 (0.511 to 1.178) 0.234 by copyright. Hg  LVEF ≤versus>58% 0.828 (0.655 to 1.048) 0.116 0.511 (0.382 to 0.683) <0.001  PASP >versus ≤37.0 mm Hg 1.146 (0.894 to 1.468) 0.282 0.898 (0.664 to 1.214) 0.485  AVA <1 cm2 and mean AV gradient 1.538 (1.191 to 1.985) 0.001 1.371 (0.915 to 2.054) 0.126 <40 mm Hg  Aortic regurgitation grade III/IV 1.092 (0.699 to 1.706) 0.699 0.886 (0.520 to 1.509) 0.656  Mitral regurgitation grade III/IV 2.124 (1.524 to 2.961) <0.001 1.995 (1.299 to 3.064) 0.002  Tricuspid regurgitation grade III/IV 2.045 (1.385 to 3.019) <0.001 2.029 (1.246 to 3.304) 0.004  LV-­ESD >versus ≤30.0 mm 0.586 (0.440 to 0.782) <0.001 0.693 (0.476 to 1.009) 0.056  LV-­EDD >versus ≤47.0 mm 0.606 (0.471 to 0.780) <0.001 0.773 (0.564 to 1.059) 0.108  IVS>versus ≤13.3 mm 1.202 (0.937 to 1.542) 0.148 1.350 (1.003 to 1.817) 0.048  PW >versus ≤12.0 mm 0.957 (0.733 to 1.249) 0.745 0.850 (0.622 to 1.163) 0.311  Relative wall thickness >versus ≤0.51 1.183 (0.908 to 1.541) 0.214 1.063 (0.778 to 1.454) 0.701  LV mass >versus ≤233.9 g 0.777 (0.596 to 1.012) 0.061 1.047 (0.760 to 1.443) 0.778  LV mass indexed >versus ≤126.3 g/m2 1.149 (0.870 to 1.518) 0.327 1.330 (0.956 to 1.851) 0.091  LVEF <50% and PASP ≥55 mm Hg 0.907 (0.696 to 1.182) 0.470 0.815 (0.560 to 1.188) 0.288 All continuous variables were converted to binary predictors using the median of the overall study population as a cut off. *Symptomatic defined as having ≥1 of the following (presumed to be AS related): chest pain, shortness of breath, dizziness on exertion/ syncope. †Adjusted for age, severefrailty, renal insufficiency, COPD, Vmax, mean AV gradient, LVEF, mitral regurgitation grade III/IV and tricuspid regurgitation grade III/IV. ‡Creatinine clearance rate <50 mL/min or dialysis. §Insulin dependent. ¶2-­year life expectancy< 25% was assessed by the dedicated nurses and physicians. AV, aortic valve; AVA, aortic valve area; AVR, aortic valve replacement; COPD, chronic obstructive pulmonary disease; IVS, interventricular septum; LV, left ventricular; LV-­EDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; LV-­ESD, left ventricular end systolic diameter; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; PW, posterior wall; Vmax, peak AV jet velocity. Lauten A, et al. Open Heart 2021;8:e001485. doi:10.1136/openhrt-2020-001485 7 Open Heart Open Heart: first published as 10.1136/openhrt-2020-001485 on 11 January 2021. Downloaded from http://openheart.bmj.com/ on April 11, 2023 at Sant Paul Hospital Consortia. Protected Figure 3 Entity responsible for treatment decision. AVR, aortic valve replacement; int. cardiol, interventional cardiologist. by copyright. *Symptomatic defined as having ≥1 of the following (presumed to be aortic stenosis related): chest pain, shortness of breath, dizziness on exertion/syncope. it is natural that mitral and tricuspid regurgitation are compared with AVR.30 Patient preference is likely to be current deterrents to AVR. Existing knowledge gaps need influenced by the responsible practitioner, cardiologist to be addressed. Frailty is consistently associated with and heart team. Strikingly, over half of the decisions not death and disability after TAVI and SAVR,28 and this study to perform AVR in symptomatic patients were taken by showed that severe frailty was independently associated a cardiologist, with the heart team involved in just 18% with AVR denial in symptomatic patients. Indeed, both of cases. This is a clear deviation from guideline recom- 2012 and 2017 guidelines identify this variable as a key mendations, which state that the heart team should be consideration for SAVR versus TAVI decision-­making.1 2 integral to the clinical decision-­making process.2 Indeed, Guidelines recognise the limitations and inaccuracies over two-­thirds of positive AVR decisions were made by of classical surgical risk scores when assessing a patient the heart team, suggesting that a comprehensive expert for either intervention, although highlighting the utility and multidisciplinary review took place, which may have of scores to predict general trends in outcomes. Inter- resulted in a higher proportion of symptomatic patients estingly, after adjustment for potentially confounding not undergoing AVR being assigned to such an inter- variables, a lower surgical risk score appeared to trans- vention. Increasing the awareness of the importance of late into a higher likelihood of AVR denial in the present the heart team’s perspective, therefore, may increase the population. This appears paradoxical, especially given proportion of patients benefitting from AVR. that prior studies have noted a clear and logical associ- According to 2017 guidelines, AVR is only indicated ation between higher EuroSCORE II values and poorer in asymptomatic patients under specific circumstances2; postinterventional outcomes.29 Given the large number present data support the use of SAVR when a patient of variables entered into the regression, this finding may has a LVEF <50%; a Vmax >5 m/s or pressure difference merely represent a statistical error, which merits further of >60 mm Hg; an abnormal exercise test; rapid AS exploration. progression; or progressively increasing brain natriuretic In this study, the patient was responsible for the treat- peptide values.31 Furthermore, only SAVR and not TAVI ment decision in 15% of symptomatic cases not assigned is advocated in this population, given only very minimal to AVR. It is assumed that all patients were fully informed evidence for the latter intervention.32 Despite this, one-­ when making such a choice, but education programmes third of asymptomatic individuals with no predesignated should stress the relative futility of medical management indication for AVR were assigned to treatment, over half 8 Lauten A, et al. Open Heart 2021;8:e001485. doi:10.1136/openhrt-2020-001485 Valvular heart disease Open Heart: first published as 10.1136/openhrt-2020-001485 on 11 January 2021. Downloaded from http://openheart.bmj.com/ on April 11, 2023 at Sant Paul Hospital Consortia. Protected Table 4 Baseline predictors of AVR assignment in asymptomatic* patients with decision (N=392) Univariate OR Univariate p Multivariate† OR Multivariate†   (95% CI) value (95% CI) p value Referring by cardio (vs other referring physician) 1.213 (0.735 to 2.002) 0.450 1.226 (0.678 to 2.216) 0.501 Age >versus≤80 years 0.833 (0.546 to 1.271) 0.396 0.695 (0.409 to 1.178) 0.176 Severe frailty 0.584 (0.180 to 1.897) 0.371 0.586 (0.129 to 2.655) 0.488 EuroSCORE II>versus≤2.39% 0.914 (0.526 to 1.588) 0.749 0.899 (0.431 to 1.872) 0.775 Comorbidities  Renal impairment‡ 0.717 (0.401 to 1.279) 0.259 0.451 (0.204 to 0.998) 0.049  COPD 1.382 (0.521 to 3.663) 0.515 1.588 (0.484 to 5.210) 0.445  Diabetes§ 0.406 (0.148 to 1.119) 0.081 0.404 (0.119 to 1.378) 0.148  Endocarditis n.a. n.a. n.a. n.a. 2-­year life expectancy <25%¶ 1.843 (0.483 to 7.035) 0.371 0.897 (0.169 to 4.768) 0.899 Echocardiographic parameters  Indexed AVA ≤versus>0.39 cm2/m2 2.169 (0.398 to 3.366) 0.001 1.709 (1.012 to 2.886) 0.045  Vmax >versus≤4.3 m/s 1.592 (1.045 to 2.426) 0.030 1.227 (0.630 to 2.392) 0.547  Mean AV gradient >versus≤45.0 mm Hg 1.493 (0.992 to 2.247) 0.055 1.434 (0.741 to 2.774) 0.285  LVEF ≤versus>58% 1.758 (1.152 to 2.681) 0.009 2.815 (1.698 to 4.666) <0.001  PASP >versus≤37.0 mm Hg 1.463 (0.917 to 2.333) 0.110 1.593 (0.910 to 2.789) 0.103 2  AVA <1 cm and mean AV gradient <40 mm Hg 0.808 (0.477 to 1.370) 0.429 0.960 (0.452 to 2.040) 0.915  Aortic regurgitation grade III/IV 0.525 (0.246 to 1.119) 0.095 0.612 (0.235 to 1.592) 0.314  Mitral regurgitation grade III/IV 0.440 (0.172 to 1.130) 0.088 0.460 (0.143 to 1.480) 0.193  Tricuspid regurgitation grade III/IV 0.671 (0.249 to 1.808) 0.430 0.821 (0.211 to 3.194) 0.776 by copyright.  LV-­ESD >versus≤30.0 mm 2.251 (1.361 to 3.723) 0.002 2.303 (1.256 to 4.223) 0.007  LV-­EDD >versus≤47.0 mm 1.691 (1.096 to 2.610) 0.018 1.358 (0.807 to 2.286) 0.249  IVS>versus≤13.3 mm 1.007 (0.649 to 1.563) 0.976 0.839 (0.496 to 1.421) 0.514  PW >versus≤12.0 mm 1.140 (0.718 to 1.810) 0.577 1.187 (0.679 to 2.076) 0.547  Relative wall thickness >versus≤0.51 0.820 (0.522 to 1.289) 0.390 0.917 (0.537 to 1.565) 0.750  LV mass >versus≤233.9 g 1.486 (0.942 to 2.345) 0.088 1.122 (0.658 to 1.914) 0.673  LV mass indexed >versus≤126.3 g/m2 1.364 (0.858 to 2.168) 0.190 1.043 (0.609 to 1.784) 0.879  LVEF <50% and PASP ≥55 mm Hg 2.386 (1.311 to 4.343) 0.004 1.543 (0.689 to 3.455) 0.292 All continuous variableswere converted to binary predictors using the median of the overall studypopulation as a cut off. *Symptomatic defined as having ≥1 of the following (presumed to be AS related): chest pain, shortness of breath, dizziness on exertion/ syncope. †Adjusted for age, diabetes,atrial fibrillation, mean AV gradient, LVEF, PASP, aortic regurgitation grade III/IV, and mitral regurgitation grade III/ IV. ‡Creatinine clearance rate <50 mL/minor dialysis. §Insulin dependent. ¶2-­year life expectancy< 25% was assessed by the dedicated nurses and physicians. AS, aortic stenosis; AV, aortic valve; AVA, aortic valve area; AVR, aortic valve replacement; COPD, chronic obstructive pulmonary disease; IVS, interventricular septum; LV, left ventricular; LV-­EDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; LV-­ESD, left ventricular end systolic diameter; PASP, pulmonary artery systolic pressure; PW, posterior wall. of which were TAVI procedures. In terms of indepen- that would influence a positive AVR decision in asymp- dent predictors, a lower AVA indexed and LVEF, a higher tomatic patients. LV-­ESD and an absence of renal impairment were associ- ated with AVR assignment. While only LVEF is specifically stated in guidelines within the context of AS, LV-­ESD is LIMITATIONS an indicator for intervention in various other valve-­related Due to the post-­hoc nature of the present analysis, several conditions.1 2 The role of kidney insufficiency deterring factors that may potentially have contributed to treatment invasive procedures has already been discussed.20 As such, decisions were not available. Exercise testing, markedly our data suggest that there are few specific characteristics elevated natriuretic peptide levels or combined severe valve Lauten A, et al. Open Heart 2021;8:e001485. doi:10.1136/openhrt-2020-001485 9 Open Heart Open Heart: first published as 10.1136/openhrt-2020-001485 on 11 January 2021. Downloaded from http://openheart.bmj.com/ on April 11, 2023 at Sant Paul Hospital Consortia. Protected calcification and a rate of Vmax progression ≥0.3 m/s/year 19 Department of Cardiology, University Hospital Erlangen, Erlangen, Bayern, may also have resulted in a class I or IIa indication for AVR Germany 20 University of Amsterdam, Amsterdam, Netherlands in asymptomatic patients,1 2 though this information was not 21 Institut für Pharmakologie und Präventive Medizin GmbH, Cloppenburg, Germany systematically recorded. This may explain a large number 22 Edwards Lifesciences, Prague, Czech Republic of the asymptomatic patients assigned to AVR (including 23 Edwards Lifesciences, Nyon, Switzerland TAVI). Moreover, we did not capture specific reasons for the 24 Queen Elizabeth Hospital & Institute of Cardiovascular Sciences, University of denial of AVR in extreme risk or inoperable patients which Birmingham, Birmingham, UK would have required a specific questionnaire. Furthermore, Twitter Antonio Serra @none, Matthias Lutz @MJLutz and Richard Paul Steeds @ a large number of factors were considered in the regression Richard.Steeds analyses; while this is defensible given that our aim was to Acknowledgements Data were captured using the s4trials Software provided by provide a comprehensive view of the characteristics contrib- Software for Trials Europe GmbH (Berlin, Germany). Funding provided by Edwards uting to AVR decision-­making, it also increases the poten- Lifesciences (Nyon, Switzerland) is acknowledged. tial for overfitting. Finally, while the Europe-­wide nature of Contributors All authors have participated in the work. RPS, DM-­Z, NF, JK, MT and the present study is a clear strength, our findings may not PB were involved in the conception and design of the project. AL and PB drafted be generalisable to other countries or regions outside of the manuscript and all other authors revised the article for important intellectual Europe, or to centres where not all AS management options content. All authors gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. are available. Nevertheless, the data provide an interesting Funding This work was supported with a research grant provided by Edwards snapshot into some of the behaviours and parameters likely Lifesciences (Nyon, Switzerland) to the Institute for Pharmacology and Preventive contributing to treatment decisions in severe AS. Medicine (IPPMed), Cloppenburg, Germany. Competing interests Peter Bramlage received research funding from Edwards CONCLUSION Lifesciences, Nyon, Switzerland. Norbert Frey, Rick Steeds and David Messika-­ Zeitoun have received honoraria for advisory board meetings and Tanja Rudolph The present results illustrate that almost one-­quarter of speakers’ honoraria from Edwards Lifesciences. The institutions of these three and patients with symptomatic severe AS with guideline indica- those of the remaining authors representing study centres have received funding tions for AVR did not undergo valve replacement, despite for employing a study nurse. the poor prognosis associated with a lack of intervention. Patient consent for publication Not required. In contrast, over one-­third of asymptomatic patients were Ethics approval The study was approved by the independent ethics review board assigned to AVR, with very few specific characteristics at each participating institution and carried out in accordance with the Declaration by copyright. associated with this choice. We conclude that there may of Helsinki. be a considerable discrepancy between guideline-­based Provenance and peer review Not commissioned; externally peer reviewed. recommendations and clinical practice decision-­making Data availability statement Data are available from the corresponding author in the treatment of AS. It appears as if guidelines may not upon reasonable request. fully capture the clinical spectrum of AS presentation and Open access This is an open access article distributed in accordance with the the individual patient need for an intervention or that Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-­commercially, unrequired AVRs may be being performed. and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use Author affiliations is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. 1 Department for Cardiology, Helios Clinic, Erfurt, Germany 2 Department of Cardiology, Hear and Diabetes Center Bad Oeynhausen, Ruhr-­ ORCID iDs University of Bochum, Bad Oeynhausen, Germany David Messika-­Zeitoun http://​orcid.​org/​0000-​0002-​6278-​5670 3 University of Ottawa Heart Institute, Ottawa, Ontario, Canada Peter Bramlage http://​orcid.​org/​0000-​0003-​4970-​2110 4 James Cook University Hospital, Middlesbrough, UK Richard Paul Steeds http://​orcid.​org/​0000-​0001-​5687-​2535 5 Interventional Cardiology Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Catalunya, Spain 6 Cardiology Department, AKH Celle, Celle, Niedersachsen, Germany 7 Department of Cardiology and Angiology, University of Kiel, Kiel, Schleswig-­ REFERENCES Holstein, Germany 1 Vahanian A, Alfieri O. 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