Open access Valvular heart disease Open Heart: first published as 10.1136/openhrt-2020-001443 on 8 January 2021. Downloaded from http://openheart.bmj.com/ on April 12, 2023 by guest. Protected by copyright. IMPULSE: the impact of gender on the presentation and management of aortic stenosis across Europe Richard Paul Steeds ‍ ‍,1 David Messika-­Zeitoun ‍ ‍,2 Jeetendra Thambyrajah,3 Antonio Serra,4 Eberhard Schulz,5 Jiri Maly,6,7 Marco Aiello,8 Tanja K Rudolph,9 Guy Lloyd,10 Alessandro Santo Bortone,11 Alberto Clerici,12 Georg Delle-­Karth,13 Johannes Rieber,14 Ciro Indolfi,15 Massimo Mancone,16 Loic Belle,17 Alexander Lauten,18 Martin Arnold,19 Berto J Bouma,20 Matthias Lutz,21 Cornelia Deutsch,22 Jana Kurucova,23 Martin Thoenes,24 Peter Bramlage ‍ ‍,22 Norbert Frey,21 On behalf of the IMPULSE registry group To cite: Steeds RP, ABSTRACT Messika-­Zeitoun D, Key questions Aims There is an increasing awareness of gender-­related Thambyrajah J, et al. IMPULSE: differences in patients with severe aortic stenosis and their the impact of gender on the What is already known about this subject? outcomes after surgical aortic valve replacement (SAVR) presentation and management ►► There is an increasing awareness of gender-­related of aortic stenosis across Europe. and transcatheter aortic valve implantation (TAVI). differences in the characteristics of patients diag- Open Heart 2021;8:e001443. Methods Data from the IMPULSE registry were analysed. nosed with severe aortic stenosis (AS) and their doi:10.1136/ Patients with severe aortic stenosis (AS) were enrolled outcomes after surgical aortic valve replacement openhrt-2020-001443 between March 2015 and April 2017 and stratified by (SAVR) and transcatheter aortic valve implantation gender. A subgroup analysis was performed to assess the (TAVI). impact of age. Received 10 September 2020 Results Overall, 2171 patients were enrolled, and 48.0% Revised 9 November 2020 What does this study add? were female. Women were characterised by a higher rate ►► We investigated gender-­related patient profiles at Accepted 1 December 2020 of renal impairment (31.7 vs 23.3%; p<0.001), were at the time of diagnosis and the associated treatment higher surgical risk (EuroSCORE II: 4.5 vs 3.6%; p=0.001) decisions, leading to the provision of SAVR or TAVI. and more often in a critical preoperative state (7.0vs Both disease presentation and treatment approach- 4.2%; p=0.003). Men had an increased rate of previous es were found to differ between women and men cardiac surgery (9.4 vs 4.7%; p<0.001) and a reduced with severe AS. left ventricular ejection fraction (4.9 vs 1.3%; p<0.001). ►► Women were generally older and more symptomat- Concomitant mitral and tricuspid valve disease was ic, despite a lesser degree of concentric LV remod- substantially more common among women. Symptoms elling. TAVI was more commonly assigned to women were highly prevalent in both women and men (83.6 vs than to men, with the inverse true of SAVR. 77.3%; p<0.001). AVR was planned in 1379 cases. Women ►► These decisions appear to be appropriate in princi- were more frequently scheduled to undergo TAVI (49.3 vs ple given the increased risk for women undergoing 41.0%; p<0.001) and less frequently for SAVR (20.3 vs surgery. 27.5%; p<0.001). Conclusions The present data show that female patients How might this impact on clinical practice? with severe AS have a distinct patient profile and are ►► The findings of this study may help to guide treat- managed in a different way to males. Gender-­based ment decisions for patients with severe AS. differences in the management of patients with severe ►► Future studies, such as RHEIA (NCT04160130), have AS need to be taken into account more systematically to been initiated to explore the benefits and risks of improve outcomes, especially for women. TAVI and SAVR in men versus women. © Author(s) (or their employer(s)) 2021. Re-­use permitted under CC BY-­NC. No filtration rates and at higher surgical risk INTRODUCTION commercial re-­use. See rights Gender differences in the presentation and than their male counterparts, while men and permissions. Published management of patients with severe aortic are frequently affected by the consequences by BMJ. For numbered affiliations see stenosis (AS) and their outcomes after an of ischaemic heart disease.2–4 Furthermore, end of article. intervention have received increasing atten- female hearts and their aortic annuli tend tion in recent years.1 At the time of diagnosis, to be smaller which may predispose them to Correspondence to women tend to be older, more frail, more procedure-­ related complications and poor Dr Peter Bramlage; ​peter.​ bramlage@​ippmed.​de often symptomatic, with lower glomerular surgical outcomes. Steeds RP, et al. Open Heart 2021;8:e001443. doi:10.1136/openhrt-2020-001443 1 Open Heart Open Heart: first published as 10.1136/openhrt-2020-001443 on 8 January 2021. Downloaded from http://openheart.bmj.com/ on April 12, 2023 by guest. Protected by copyright. These gender differences translate into a differential AS-­attributed symptoms (chest pain, shortness of breath risk profile for surgical aortic valve replacement (SAVR) and dizziness on exertion/syncope). Surgical risk was and transcatheter aortic valve implantation (TAVI). calculated using logistic EuroSCORE I and EuroSCORE Indeed, recent large meta-­analyses5–8 and a large retro- II risk-­stratification tools, with frailty determined by the spective study from the STS/ACC TVT registry9 demon- inability to walk 5 m in ≤6 s and/or to perform activities strated improved survival in female versus male patients of daily living.16 Stroke volume and flow rate were not with AS undergoing TAVI despite their advanced age calculated. The decision on which treatment approach and increased rates of major peri-­ procedural vascular to take (TAVI, SAVR, balloon aortic valvuloplasty (BAV), complications, bleeding events and strokes. In the recent watchful waiting or active decision not-­to-­treat) and the PARTNER 3 trial,10 which compared surgery with SAVR time between assignment to AVR and its performance in low-­risk patients, subgroup analyses of the primary were then documented. All data were subject to auto- endpoint at 1 year showed no heterogeneity of treatment matic checks for plausibility and completeness. effect by gender (p=0.27), but for women the endpoint rate for SAVR was 18.5% (men 13.8%) and 8.1% for Statistics TAVI (men 8.7%), showing a clear trend for an increased Following descriptive analysis, continuous variables are benefit of women undergoing TAVI instead of SAVR (rate presented as means with SDs, with categorical varia- difference −10.4%; 95% CI −18.3% to −2.5%). bles presented as absolute values with percentages (%). These observations have triggered an investigation Comparisons between men and women were made using into gender-­related patient profiles at the time of diag- Pearson’s χ2 or Fisher’s exact test for categorical variables nosis and into the treatment decisions made, leading to and a t-­test or Mann-­Whitney-­Wilcoxon U test for contin- the provision of SAVR or TAVI. The analyses are based uous variables. All statistical analysis was performed using on the prospective IMPULSE database,11 which enrolled SPSS V.24.0 and a p value of <0.05 was considered statis- patients at the time of diagnosis in the echo laboratory tically significant. and followed them for 3 months. RESULTS METHODS A total of 2171 patients were enrolled in the registry of The design of the prospective IMPULSE database has which 48.0% were women (n=1130) and 52.0% men been previously described.11–15 The European registry (n=1130) (figure 1). Patient characteristics, symptoms, spanned 23 TAVI/SAVR-­equipped centres across 9 coun- echocardiographic variables and treatment decisions tries (Austria, Czech Republic, France, Germany, Italy, were compared. As for many of these variables age was a the Netherlands, Spain, Switzerland and the UK) and was potential confounder, analyses were repeated for the age set up as part of a quality of care initiative for improving group of patients over 80 years (women n=571, mean age the management of patients with severe AS. Enrolment 85.5 years; men n=435, mean age 85.5 years; p=0.256). took place between March 2015 and April 2017, with each patient providing written informed consent to partici- Patient characteristics pate. Neither patients nor the public were not involved In patients diagnosed with severe AS (table 1), women were in the design, conduct, reporting or dissemination of our approximately 3 years older (79.5 vs 76.4 years; p<0.001), research. had a higher degree of renal impairment (31.7 vs 23.3%; p<0.001), had a higher surgical risk (EuroSCORE II: 4.5 Patients vs 3.6%; p=0.001) and more often in a critical preop- Patients aged 18 years or older who were diagnosed with erative state (7.0 vs 4.2%; p=0.003). Men, on the other severe AS (symptomatic or asymptomatic; defined as hand, had an increased rate of previous cardiac surgery aortic valve area (AVA) <1 cm2, indexed AVA <0.6 cm2/ (9.4 vs 4.7%; p<0.001) and a reduced left ventricular ejec- m2, maximum jet velocity (Vmax) >4 m/s or mean trans- tion fraction ((LVEF) EF <30% 4.9 vs 1.3%; p<0.001). As valvular gradient >40 mm Hg) after being referred for many of these differences were potentially age related, we echocardiography at one of the participating sites were performed a sensitivity analysis for age. In patients older included in the registry. Recruitment was consecutive on than 80 years, we essentially confirmed all of the observed a centre level based on the patient’s willingness to partic- differences between women and men, although the ipate. For the purposes of the present analysis, the study difference in haematological disorders and liver disease population was divided into two groups according to lost statistical significance. On the other hand, chronic gender. A subanalysis comparing males and females aged obstructive pulmonary disease, which was borderline over 80 years was also carried out. more frequent in men for the total population, became significantly more frequent in men versus women over 80 Data collection years (15.2 vs 9.2%; p=0.003). An electronic case report form was used to collect data, which was entered by a dedicated study nurse. Patient Echocardiographic parameters demographics, echocardiographic parameters and Aortic valve–related parameters, such as the indexed medical history were recorded at baseline, alongside AVA and the mean AV gradient were largely identical 2 Steeds RP, et al. Open Heart 2021;8:e001443. doi:10.1136/openhrt-2020-001443 Valvular heart disease Open Heart: first published as 10.1136/openhrt-2020-001443 on 8 January 2021. Downloaded from http://openheart.bmj.com/ on April 12, 2023 by guest. Protected by copyright. Figure 1 Patient flow. AVR, aortic valve replacement; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation. between women and men (table 2). While the p value Treatment decisions for the mean AV gradient was below 0.05, the means did Of the 2000 patients with a documented treatment deci- not show a potentially clinically relevant difference. The sion, AVR was planned in 1379 cases (69%), with BAV, heart of women was, on the one hand, smaller (LV mass medical management or watchful waiting planned in the 128.9 g/m2 vs 135.9 g/m2; p=0.001). On the other hand, remaining 621 patients (31%). This split was uniform there was an increased relative wall thickness (0.56 vs 0.50; across genders (69.5% in women vs 68.5% in men; p<0.001). Concomitant mitral and tricuspid valve disease p=0.614). However, the type of AVR planned differed was substantially more common among women than significantly, with women more frequently being sched- men, with increased rates of grade III/IV mitral (12.5 vs uled to undergo TAVI (49.3 vs 41.0%; p<0.001) and less 9.0%; p=0.010) and tricuspid regurgitation (10.4 vs 5.5%; frequently for SAVR (20.3 vs 27.5%; p<0.001) (figure 3; p<0.001). In a sensitivity analysis for age, the pattern of table 3). A higher proportion of women also underwent differences between women and men persisted, while the TAVI within 3 months of the treatment decision (41.3 difference in the mean AV gradient as described earlier vs 35.0%; p=0.004). Conversely, a higher proportion of lost its statistical significance. men underwent SAVR within 3 months compared with women (19.9 vs 16.5%; p=0.047). The mean time to AVR (33.0±34.7 days) was comparable between gender Symptom presentation groups, with the same true for TAVI (29.2±34.2) and Symptoms were defined as any of chest pain, shortness of SAVR (40.7±34.5 days) considered separately. The breath and dizziness/syncope in this registry (figure 2). gender-­related trends observed in the overall population Symptoms overall were common in both women and were also seen in the subset of patients aged >80 years men but more frequent by approximately 6% in women (figure 3; table 3). (83.6 vs 77.3%; p<0.001). This was largely due to more frequent shortness of breath (77.4 vs 67.5%; p<0.001) and dizziness (27.4 vs 21.4%; p<0.01) in women, while DISCUSSION chest pain was equally common in either gender. The In the present analysis, both disease presentation and sensitivity analysis revealed that the difference in the rate treatment approach were found to differ between women of dizziness/syncope was affected by age (resulting in no and men with severe AS. Women were generally older and difference in patients over 80 years; 28.3 vs 28.2%), while more symptomatic, despite a lesser degree of concentric other differences persisted. LV remodelling. Although the proportion of patients Steeds RP, et al. Open Heart 2021;8:e001443. doi:10.1136/openhrt-2020-001443 3 Open Heart Open Heart: first published as 10.1136/openhrt-2020-001443 on 8 January 2021. Downloaded from http://openheart.bmj.com/ on April 12, 2023 by guest. Protected by copyright. Table 1 Patient characteristics Total population Population >80 years Women Men Women Men   n=1041 n=1130 P value n=571 n=435 P value Age (years) 79.5±9.5 76.4±10.2 <0.001 85.8±3.7 85.5±3.6 0.256 BMI 27.3±5.9 27.5±4.7 0.563 26.1±5.0 26.2±3.9 0.607 Comorbidities  Haematological disorder 6.8 4.5 0.022 8.2 6.0 0.176  Liver disease 1.5 2.9 0.024 0.9 1.4 0.543  Extra-­arterial pathology 10.0 12.3 0.093 10.6 11.3 0.712  Renal impairment* 31.7 23.3 <0.001 42.9 34.2 0.009  Diabetes requiring insulin 8.2 8.8 0.633 5.6 6.2 0.696  COPD 10.3 12.4 0.128 9.2 15.2 0.003  Pulmonary hypertension† 8.6 8.4 0.854 10.6 10.6 1.000  Endocarditis 0.5 0.5 0.872 0.4 0.5 1.000 Cardiac history  Recent MI 3.1 2.9 0.824 3.9 3.5 0.729  LVEF <30% 1.3 4.9 <0.001 1.3 7.3 <0.001  Previous cardiac surgery 4.7 9.4 <0.001 4.0 9.7 <0.001 Critical preoperative status 7.0 4.2 0.003 8.5 3.9 0.004 Frailty (severe) 6.0 4.3 0.067 8.5 7.5 0.583 Logistic EuroSCORE I (%) 16.5±13.5 14.7±14.2 0.056 21.9±14.4 20.4±15.5 0.305 EuroSCORE II (%) 4.5±5.3 3.6±4.7 0.001 5.6±6.0 4.7±5.1 0.023 Values are reported as mean with SDs or as percentage. *Defined as creatinine clearance <50 mL/min or dialysis. †Defined as pulmonary systolic pressure >55 mm Hg. BMI, body mass index; COPD, chronic obstructive pulmonary disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction. scheduled for AVR was largely comparable between Alternatively, it may be partly reflective of differences in genders, TAVI was more commonly assigned to females physical activity levels, which are reportedly higher in men than to males, with the inverse true of SAVR. While these than in women.20 As such, women could describe or be decisions appear to be appropriate in principle given the perceived to have more shortness of breath due to a natu- increased risk for women undergoing surgery, the degree rally lower exercise tolerance. Indeed, dyspnoea but not of this location shift may be questioned in the absence dizziness/syncope remained significantly more common of additional benefit of TAVI in women compared with in women than men aged over 80 years, despite compa- men. rable mean ages. Activity-­dependent gender subjectivity may thus be a driver for the apparently higher frequency Gender and symptomatic presentation of symptoms in women. Finally, the higher frequency of Cardiac symptoms were more common in women concomitant tricuspid/mitral valvular disease in women compared with men. This trend is consistent with the may have impacted on symptoms, given that shortness of observations of prior studies,3 17 and was primarily driven breath is also a manifestation of both of these valvular by shortness of breath and dizziness/syncope. Neverthe- conditions.21 22 Regardless of the underlying explanation, less, a lesser degree of concentric remodelling was seen in our data support the previously reported trend towards a women at echocardiography. A similar trend was recently greater likelihood of symptomatic presentation in women observed by Singh et al in their study into the relationship compared with men with severe AS.17 Considering that between LV remodelling and AS symptom onset in men symptomatic onset is a key consideration when deter- and women,17 with other studies also reporting women to mining the timing of AVR,23 this difference has important have a higher relative wall thickness, a smaller LV cavity implications for treatment decisions. and a lower LV mass index than men in the context of AS chronic pressure overload.18 19 Singh et al have suggested Gender and treatment decision that, in the context of these diverse pathophysiolog- Early AVR is strongly recommended in all severe sympto- ical profiles, the higher symptomatic burden in women matic patients with AS, unless the intervention is unlikely may be due to higher wall stress and filling pressures.17 to improve quality of life/survival or the patient has a 4 Steeds RP, et al. Open Heart 2021;8:e001443. doi:10.1136/openhrt-2020-001443 Valvular heart disease Open Heart: first published as 10.1136/openhrt-2020-001443 on 8 January 2021. Downloaded from http://openheart.bmj.com/ on April 12, 2023 by guest. Protected by copyright. Table 2 Echocardiographic parameters Total population Population >80 years Women Men Women Men   n=1041 n=1130 P value n=571 n=435 P value AV parameters  Indexed AVA (cm2/m2) 0.39±0.11 0.40±0.11 0.274 0.40±0.11 0.39±0.11 0.471  Mean AV gradient (mm Hg) 47.8±15.2 46.5±14.2 0.031 47.1±14.7 45.7±14.7 0.148  Aortic regurgitation grade III/IV 7.6 8.5 0.467 6.2 8.1 0.252  LVEF (%) 57.9±11.0 54.0±12.8 <0.001 57.4±11.1 52.6±13.5 <0.001 Left ventricle parameters  LV hypertrophy* 62.5 61.8 0.748 64.0 64.6 0.849  LV-E­ SD (mm) 29.0±9.0 33.3±10.5 <0.001 29.0±9.0 33.3±10.5 <0.001  LV-­EDD (mm) 44.4±8.4 49.1±8.3 <0.001 44.4±8.4 49.1±8.3 <0.001  IVS (mm) 13.9±2.7 14.0±2.6 0.895 13.9±2.7 14.0±2.6 0.895  PW (mm) 12.2±2.3 12.3±2.4 0.837 12.2±2.3 12.3±2.4 0.837  RWT† (cm) 0.56±0.16 0.50±0.13 <0.001 0.58±0.16 0.52±0.14 <0.001  LV mass (g) 219.1±72.3 261.6±75.7 <0.001 219.2±68.5 256.9±78.9 <0.001  Indexed LV mass (g/m2) 128.9±42.0 135.9±39.5 0.001 133.5±41.2 140.0±43.7 0.055 Other valve parameters  Mitral regurgitation III/IV 12.5 9.0 0.010 17.9 13.1 0.041  Mitral stenosis III/IV 2.2 1.5 0.267 2.2 1.5 0.431  Tricuspid regurgitation III/IV 10.4 5.5 <0.001 13.0 8.6 0.032 Values are reported as mean with SD or as percentage. *Defined as LV wall thickness >12 mm. †Calculated as 2×PW/LV−EDD. AV, aortic valve; AVA, aortic valve area; LVEF, left ventricular ejection fraction; LV, left ventricular; ESD, end-­systolic dimension; EDD, end-­ diastolic dimension; IVS, interventricular septal thickness at end-­diastole; PW, posterior wall thickness at end diastole; RWT, relative wall thickness. life expectancy of less than 1 year.23 Therefore, given that scores, the older age of our female patients and a smaller symptomatic presentation was more common in women, valvular anatomy/aortic annulus which are favouring it is surprising that the proportion of patients assigned patient prosthesis mismatch in women.28–30 The factors to AVR did not differ according to gender. This may be are also favouring TAVI over SAVR according to European partly explained by the counterbalancing effect of a more guidelines.23 More specifically, the higher prevalence of severely reduced LVEF in men, which is an independent renal impairment in women (apparent both overall and indication for AVR in asymptomatic patients.23 Regard- in the elderly subgroup) is likely to have been a strong less, nearly two-­thirds of the present study population deterrent for cardiac surgery, given that it has been were denied a life-­saving AVR intervention. This rate is previously associated with increased in-­hospital mortality similar to that reported by the Euro Heart Survey prior and length of hospital/ICU stay in individuals under- to the widespread diffusion of TAVI.24 Consequently, it going SAVR.31 This association has not been observed would appear that this minimally invasive alternative to in patients undergoing TAVI,31 strengthening the argu- SAVR is being used as an approach to risk reduction in ment for this minimally invasive alternative in individuals patients previously considered for surgery, but not as a with kidney disease. A further consideration is the higher novel option in those considered inoperable. As such, prevalence of coronary artery disease generally seen in there may be considerable scope for increasing the rate men compared with women,26 32 which may have resulted of AVR in clinical practice. in a tendency towards the performance of more AVR/ The type of AVR planned differed significantly between coronary artery bypass graft hybrid interventions in men, genders. In line with previous studies, women were less increasing the overall proportion undergoing SAVR. frequently assigned to SAVR25 26; however, contrary to the Unfortunately, data to support this speculation were not existing literature suggesting that comparable propor- available in the present analysis. Finally, assuming that tions of men and women undergo TAVI,9 27 a higher rate the physicians responsible for treatment decisions were of TAVI was observed in the latter. This reciprocal trend familiar with contemporary real-­world AVR studies, they may be partly explained by the slightly higher surgical risk may have been aware of data suggesting women to have Steeds RP, et al. Open Heart 2021;8:e001443. doi:10.1136/openhrt-2020-001443 5 Open Heart Open Heart: first published as 10.1136/openhrt-2020-001443 on 8 January 2021. Downloaded from http://openheart.bmj.com/ on April 12, 2023 by guest. Protected by copyright. comparable mean ages. Thus, the observed differences in TAVI/SAVR assignment cannot be explained purely as a function of age. Gender and time to intervention The waiting time between referral for AVR and its perfor- mance appeared to be unrelated to gender, averaging at approximately 30 days in both males and females. This is longer than the 20.3 days reported by a 2014 study,35 perhaps reflecting the temporal trend towards an increasing prevalence of severe AS in the ageing popula- tion, which in turn places a higher burden on healthcare providers.36 TAVI waiting times were shorter than SAVR waiting times in both males and females, with no significant differences between gender groups. This suggests that the urgency of the intervention is not sex dependent and largely is restricted by procedure availability. The differences in Figure 2 Cardiac symptoms at baseline in (A) all patients and (B) those aged >80 years. **p<0.01, ***p<0.001. NYHA class III or IV: female 441/1024 (43.1) vs male 418/1118 (37.4); p=0.007. Angina class III or IV: female 43/909 (4.7) vs male 48/992 (4.8); p=0.912. superior long-­term outcomes and achieve a greater clin- ical benefit after TAVI compared with SAVR,33 34 with greater survival compared with men undergoing this minimally invasive procedure.5 9 This may also have contributed to the gender-­related disparity in preferred AVR type. Interestingly, several of the factors highlighted in contemporary guidelines as instrumental for choosing between TAVI and SAVR were significantly different between gender groups, but appeared to have little influence on clinical decision-­ making. For example, significantly more men than women had previously undergone cardiac surgery, which is a characteristic in favour of TAVI,23 yet fewer men underwent this interven- Figure 3 Treatment decision in (A) all patients and (B) those tion. Furthermore, age >75 years is another guideline-­ aged >80 years. AVR, aortic valve replacement; M, months; recommended factor favouring TAVI.23 Although there SAVR, surgical aortic valve implantation; TAVI, transcatheter was a nominally higher rate of TAVI and lower rate of aortic valve implantation. *p< 0.05, ***p<0.001. †Balloon SAVR in elderly compared with all patients, the sex-­ aortic valvuloplasty, medical management or watchful waiting dependent differences in treatment decision persisted, planned. Values are proportional to the number of patients with relatively fewer men undergoing TAVI, despite with known treatment decisions. 6 Steeds RP, et al. Open Heart 2021;8:e001443. doi:10.1136/openhrt-2020-001443 Valvular heart disease Open Heart: first published as 10.1136/openhrt-2020-001443 on 8 January 2021. Downloaded from http://openheart.bmj.com/ on April 12, 2023 by guest. Protected by copyright. Table 3 Treatment decision and time to intervention Total population Population >80 years Women Men Women Men   n=954 n=1046 P value n=509 n=390 P value Decision to perform AVR 69.5 68.5 0.614 67.2 64.9 0.466  AVR performed in 3 months 57.8 54.9 0.195 55.4 54.4 0.755  Time to intervention (days) 33.3±34.1 32.8±35.2 0.825 30.5±33.8 27.8±34.0 0.374 Decision made for TAVI 49.3 41.0 <0.001 60.7 53.9 0.039  TAVI performed in 3 months 41.3 35.0 0.004 50.3 45.4 0.144  Time to intervention (days) 30.2±34.2 28.1±34.1 0.389 29.4±33.5 26.6±35.0 0.382 Decision made for SAVR 20.3 27.5 <0.001 6.5 11.1 0.015  SAVR performed in 3 months 16.5 19.9 0.047 5.1 9.0 0.022  Time to intervention (days) 40.8±32.8 40.7±35.8 0.991 40.9±35.4 34.1±27.7 0.387 Decision not to perform AVR* 30.5 31.5 0.614 32.8 35.1 0.466 Values are reported as mean with SD or as percentage. *Balloon aortic valvuloplasty, medical management or watchful waiting planned instead. AVR, aortic valve replacement; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve replacement. the proportions of male and female patients who under- important in women than in men, as the benefits of went TAVI and SAVR within 3 months of the treatment TAVI are pronounced in women: A meta-­analysis of decision are likely to reflect general differences in AVR randomised trials compared TAVI with SAVR and assignment. Indeed, when expressed as a proportion of found that TAVI was associated with a survival benefit patients initially assigned to the procedure, the rate of compared with SAVR in women but not men.37 38 A TAVI performance within 3 months was the same in men further meta-­analysis found TAVI to be associated with and women. A slight sex-­dependent disparity may exist reduced mortality compared with SAVR in women at in terms of SAVR, with only 72% of the assigned males both 1 (OR 0.68, 95% CI 0.50 to 0.94) and 2 years of undergoing the procedure within 3 months compared follow-­up (OR 0.74, 95% CI 0.58 to 0.95), whereas with 81% of the assigned females (p=0.026). Specula- tively, this may be related to the lower rate of symptoms there was no difference among men at either time in males, making them lower priority for such an invasive point.38 The difference in treatment effect between procedure. This merits further investigation. the sexes was significant at both 1 (p=0.02) and 2 years Limitations (p=0.04). In the recent PARTNER 3 trial,10 which is The principal limitation in the present analysis is the lack pivotal in showing the benefits of TAVI over SAVR in of adjustment for confounding variables when comparing low-­risk patients, subgroup analyses of the primary genders. This means that it is difficult to determine sex-­ endpoint at 1 year showed no heterogeneity of treat- specific trends from those influenced by the particular ment effect by gender (p=0.27). However, apart from characteristics of male and female patients with AS. On this non-­ significant p value, the endpoint rate in the other hand, adjustment for gender-­specific variables SAVR-­treated women was 18.5% (vs 13.8% in men) would abolish the clear difference between both gender, and 8.1% for TAVI (vs 8.7% in men), showing a clear making conclusions of the gender impact impossible. As trend for an increased benefit of women undergoing the two are closely linked, the present data provide an TAVI instead of SAVR (rate difference −10.4%; 95% CI overview of the multifactorial gender-­related influences −18.3% to −2.5%). To shed further light on the poten- that are relevant to clinical practice. While the wide tial benefits of TAVI in women, there is an ongoing range of countries included is a strength of the registry, our findings may not be generalisable to regions outside clinical trial (​ ClinicalTrials.​ gov: NCT04160130), of Europe. The interventional portion of the quality of which compares either strategy in women undergoing care initiative did not take place until month 3, so did not TAVI. Women with severe symptomatic aortic stenosis, influence the data presented. with any but prohibitive surgical risk status, will be Clinical implications and perspectives randomised 1:1 to undergo aortic valve intervention There is an ever growing number of patients for whom with either transfemoral TAVR with the SAPIEN 3 or TAVI is preferred over SAVR, which is due to growing SAPIEN 3 Ultra device or SAVR and followed up for body of evidence for a benefit of TAVI over SAVR in 1 year. The authors pursue non-­inferiority, but the trial high and prohibitive surgical risk, and also interme- is also powered to show superiority of this approach in diate and even risk patients. This trend is even more women.39 Steeds RP, et al. Open Heart 2021;8:e001443. doi:10.1136/openhrt-2020-001443 7 Open Heart Open Heart: first published as 10.1136/openhrt-2020-001443 on 8 January 2021. Downloaded from http://openheart.bmj.com/ on April 12, 2023 by guest. Protected by copyright. CONCLUSION Provenance and peer review Not commissioned; externally peer reviewed. The present contemporary data from major treatment Data availability statement Data are available on reasonable request. centres across Europe show that female patients with Open access This is an open access article distributed in accordance with the severe AS have a distinct patient profile and are managed Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which in a different way to males with the same condition. permits others to distribute, remix, adapt, build upon this work non-­commercially, and license their derivative works on different terms, provided the original work is Gender-­based differences in the management of patients properly cited, appropriate credit is given, any changes made indicated, and the use with severe AS need to be taken into account more system- is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. atically to improve outcomes, especially for women. ORCID iDs Richard Paul Steeds http://​orcid.​org/​0000-​0001-​5687-​2535 Author affiliations 1 David Messika-­Zeitoun http://​orcid.​org/​0000-​0002-​6278-​5670 Queen Elizabeth Hospital & Institute of Cardiovascular Sciences, University of Peter Bramlage http://​orcid.​org/​0000-​0003-​4970-​2110 Birmingham, Birmingham, UK 2 University of Ottawa Heart Institute, Ottawa, Ontario, Canada 3 James Cook University Hospital, Middlesbrough, UK 4 Interventional Cardiology Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, REFERENCES Spain 1 Caponcello MG, Banderas LM, Ferrero C, et al. Gender differences in 5 Cardiology Department, AKH Celle, Celle, Germany aortic valve replacement: is surgical aortic valve replacement riskier 6 Department of Cardiovascular Surgery, Institute for Clinical and Experimental and transcatheter aortic valve replacement safer in women than in Medicine, Prague, Czech Republic men? J Thorac Dis 2020;12:3737–46. 7 Department of Cardiovascular Surgery, Second Faculty of Medicine, Charles 2 Szerlip M, Gualano S, Holper E, et al. Sex-­specific outcomes of transcatheter aortic valve replacement with the SAPIEN 3 valve: University, Prague, Czech Republic 8 insights from the PARTNER II S3 high-­risk and intermediate-­risk Department of Cardiothoracic Surgery, Foundation IRCCS Policlinico S.Matteo, cohorts. JACC Cardiovasc Interv 2018;11:13–20. Pavia, Italy 3 Fuchs C, Mascherbauer J, Rosenhek R, et al. Gender differences in 9 Department of Cardiology, Heart and Diabetes Center Bad Oeynhausen, Ruhr-­ clinical presentation and surgical outcome of aortic stenosis. Heart University of Bochum, Bad Oeynhausen, Germany 2010;96:539–45. 10 St Bartholomew's Hospital, London, UK 4 Wong SC, Yeo I, Bergman G, et al. The influence of gender on 11 in-­hospital clinical outcome following isolated mitral or aortic heart University of Bari, Bari, Italy 12 valve surgery. Cardiovasc Revasc Med 2019;20:468–74. University of Turin, Turin, Italy 5 O'Connor SA, Morice M-­C, Gilard M, et al. Revisiting sex 13 4th Medical Department, Hietzing Hospital, Vienna, Austria equality with transcatheter aortic valve replacement outcomes: a 14 Herzkatheterlabor Nymphenburg and Department of Cardiology, University of collaborative, patient-­level meta-­analysis of 11,310 patients. J Am Munich, Munich, Germany Coll Cardiol 2015;66:221–8. 15 Division of Cardiology and URT CNR of IFC, University Magna Graecia, Catanzaro, 6 Zhao Z-­G, Liao Y-­B, Peng Y, et al. Sex-­related differences in outcomes after transcatheter aortic valve implantation: a systematic Italy review and meta-­analysis. Circ Cardiovasc Interv 2013;6:543–51. 16 Sapienza University of Rome, Rome, Italy 7 Conrotto F, D'Ascenzo F, Presbitero P, et al. Effect of gender after 17 Centre Hospital d’Annecy, Annecy, France transcatheter aortic valve implantation: a meta-­analysis. Ann Thorac 18 Department for Cardiology, Helios Erfurt Clinic, Erfurt, Germany Surg 2015;99:809–16. 19 Department of Cardiology, University of Erlangen, Erlangen, Germany 8 Stangl V, Baldenhofer G, Laule M, et al. Influence of sex on outcome 20 University of Amsterdam, Amsterdam, Netherlands following transcatheter aortic valve implantation (TAVI): systematic 21 review and meta-­analysis. J Interv Cardiol 2014;27:531–9. Department of Cardiology and Angiology, University of Kiel, Kiel, Germany 9 Chandrasekhar J, Dangas G, Yu J, et al. Sex-­based differences in 22 Institute for Pharmacology and Preventive Medicine, Cloppenburg, Germany outcomes with transcatheter aortic valve therapy: TVT registry from 23 Edwards Lifesciences, Prague, Czech Republic 2011 to 2014. J Am Coll Cardiol 2016;68:2733–44. 24 Edwards Lifesciences, Nyon, Switzerland 10 Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aortic-­valve replacement with a balloon-­expandable valve in low-­risk patients. N Engl J Med 2019;380:1695–705. Twitter Richard Paul Steeds @Richard.Steeds, Antonio Serra @none and Matthias 11 Frey N, Steeds RP, Serra A, et al. Quality of care assessment Lutz @MJLutz and improvement in aortic stenosis – rationale and design of a Acknowledgements Data were captured using the s4trials Software provided by multicentre registry (IMPULSE). BMC Cardiovasc Disord 2017;17:5. 12 Frey N, Steeds RP, Rudolph TK, et al. Symptoms, disease severity Software for Trials Europe GmbH, Berlin, Germany. and treatment of adults with a new diagnosis of severe aortic Contributors All authors have participated in the work. RPS, DM-­Z, NF, JK, MT and stenosis. Heart 2019;105:1709–16. PB were involved in the conception and design of the project. PB and RPS drafted 13 Steeds RP, Lutz M, Thambyrajah J, et al. Facilitated data relay and the manuscript and all other authors revised the article for important intellectual effects on treatment of severe aortic stenosis in Europe. J Am Heart content. All authors gave final approval and agree to be accountable for all aspects Assoc 2019;8:e013160. 14 Lutz M, Messika-­Zeitoun D, Rudolph TK, et al. Differences in the of work ensuring integrity and accuracy. presentation and management of patients with severe aortic stenosis Funding This work was supported by a research grant from Edwards Lifesciences in different European centres. Open Heart 2020;7:e001345. (Nyon, Switzerland), awarded to the Sponsor, the Institute for Pharmacology and 15 Rudolph TK, Messika-­Zeitoun D, Frey N, et al. Impact of selected Preventive Medicine (IPPMed, Cloppenburg, Germany). comorbidities on the presentation and management of aortic stenosis. Open Heart 2020;7:e001271. Competing interests PB is the representative of the IPPMed, Cloppenburg, 16 Katz S, Downs TD, Cash HR, et al. Progress in development of the Germany. NF, RPS and DM-­Z have received honoraria for advisory board meetings index of ADL. Gerontologist 1970;10:20–30. and TKR speakers’ honoraria from Edwards Lifesciences. The institutions of these 17 Singh A, Chan DCS, Greenwood JP, et al. Symptom onset in aortic three and those of the remaining authors representing study centres have received stenosis: relation to sex differences in left ventricular remodeling. funding for employing a study nurse. JK and MT are employees of the funder of this JACC Cardiovasc Imaging 2019;12:96–105. 18 Dobson LE, Musa TA, Uddin A, et al. Gender influences left registry. As this is a disease registry, neither the type of intervention (SAVR, TAVI or ventricular remodelling in the setting of aortic stenosis but does not medical management) nor on the valves to be used was pre-­specified. appear to impact on reverse remodelling following transcatheter Patient consent for publication Not required. aortic valve implantation. J Cardiovasc Magn Reson 2015;17:P332. 19 Bech-­Hanssen O, Wallentin I, Houltz E, et al. Gender differences Ethics approval The study was carried out in accordance with the Declaration in patients with severe aortic stenosis: impact on preoperative left of Helsinki and was approved by the independent ethical review board at each ventricular geometry and function, as well as early postoperative participating institution. morbidity and mortality. Eur J Cardiothorac Surg 1999;15:24–30. 8 Steeds RP, et al. Open Heart 2021;8:e001443. doi:10.1136/openhrt-2020-001443 Valvular heart disease Open Heart: first published as 10.1136/openhrt-2020-001443 on 8 January 2021. Downloaded from http://openheart.bmj.com/ on April 12, 2023 by guest. Protected by copyright. 20 Rosenfeld CS. Sex-­dependent differences in voluntary physical 32 Chiha J, Mitchell P, Gopinath B, et al. Gender differences in the activity. J Neurosci Res 2017;95:279–90. severity and extent of coronary artery disease. Int J Cardiol Heart 21 O'Rourke RA, Crawford MH. Mitral valve regurgitation. Curr Probl Vasc 2015;8:161–6. Cardiol 1984;9:1–52. 33 Williams M, Kodali SK, Hahn RT, et al. Sex-­related differences in 22 Andersen MJ, Nishimura RA, Borlaug BA. The hemodynamic basis outcomes after transcatheter or surgical aortic valve replacement of exercise intolerance in tricuspid regurgitation. Circ Heart Fail in patients with severe aortic stenosis: insights from the PARTNER 2014;7:911–7. Trial (placement of aortic transcatheter valve). J Am Coll Cardiol 23 Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines 2014;63:1522–8. for the management of valvular heart disease. Eur Heart J 34 Skelding KA, Yakubov SJ, Kleiman NS, et al. Transcatheter aortic 2017;38:2739–91. valve replacement versus surgery in women at high risk for surgical 24 Iung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on aortic valve replacement (from the CoreValve us high risk pivotal Valvular Heart Disease. Eur Heart J 2003;24:1231–43. trial). Am J Cardiol 2016;118:560–6. 25 Elhmidi Y, Piazza N, Mazzitelli D, et al. Sex-­related differences in 35 Malaisrie SC, McDonald E, Kruse J, et al. Mortality while waiting for 2197 patients undergoing isolated surgical aortic valve replacement. aortic valve replacement. Ann Thorac Surg 2014;98:1564–71. J Card Surg 2014;29:772–8. 36 Ersboll M, Samad Z, Al Enezi F, et al. Temporal trends in disease 26 Chaker Z, Badhwar V, Alqahtani F, et al. Sex differences in the severity and predicted surgical risk at the time of referral for utilization and outcomes of surgical aortic valve replacement for echocardiography in patients diagnosed with aortic stenosis. Crit severe aortic stenosis. J Am Heart Assoc 2017;6. doi:10.1161/ Pathw Cardiol 2015;14:103–9. JAHA.117.006370. [Epub ahead of print: 21 Sep 2017]. 37 Siontis GCM, Praz F, Pilgrim T, et al. Transcatheter aortic valve 27 Hayashida K, Morice M-­C, Chevalier B, et al. Sex-­related differences implantation vs. surgical aortic valve replacement for treatment of in clinical presentation and outcome of transcatheter aortic severe aortic stenosis: a meta-­analysis of randomized trials. Eur valve implantation for severe aortic stenosis. J Am Coll Cardiol Heart J 2016;37:3503–12. 2012;59:566–71. 38 Panoulas VF, Francis DP, Ruparelia N, et al. Female-­specific survival 28 Rodés-­Cabau J, Pibarot P, Suri RM, et al. Impact of aortic advantage from transcatheter aortic valve implantation over surgical annulus size on valve hemodynamics and clinical outcomes after aortic valve replacement: meta-­analysis of the gender subgroups of transcatheter and surgical aortic valve replacement: insights from the randomised controlled trials including 3758 patients. Int J Cardiol PARTNER Trial. Circ Cardiovasc Interv 2014;7:701–11. 2018;250:66–72. 29 Fallon JM, DeSimone JP, Brennan JM, et al. The incidence and consequence of prosthesis-­patient mismatch after surgical aortic 39 Eltchaninoff H, Bonaros N, Prendergast B, et al. Rationale and valve replacement. Ann Thorac Surg 2018;106:14–22. design of a prospective, randomized, controlled, multicenter study 30 Kuten D, Krajcer Z. Transcatheter aortic valve replacement in to evaluate the safety and efficacy of transcatheter heart valve women. Tex Heart Inst J 2017;44:341–4. replacement in female patients with severe symptomatic aortic 31 Nguyen TC, Babaliaros VC, Razavi SA, et al. Impact of varying stenosis requiring aortic valve intervention (Randomized researcH degrees of renal dysfunction on transcatheter and surgical aortic in womEn all comers wIth Aortic stenosis [RHEIA] trial). Am Heart J valve replacement. J Thorac Cardiovasc Surg 2013;146:1399–407. 2020;228:27–35. Steeds RP, et al. Open Heart 2021;8:e001443. doi:10.1136/openhrt-2020-001443 9