Sex‐Related Differences in the Management and Outcomes of Patients Across the Spectrum of Aortic Stenosis

Abstract

Background

There are conflicting data on sex differences in patients with aortic stenosis (AS). We aimed to investigate sex differences in management and outcomes across the spectrum of outpatients with AS.

Methods

Between 2016 and 2017, consecutive all‐comer outpatients with mild (peak aortic velocity=2.5–2.9 m/s), moderate (3–3.9 m/s), or severe (≥4 m/s) native AS were included by 117 cardiologists and followed up for 5 years for aortic valve replacement (AVR) and cause of death. Outcomes were compared by sex using inverse probability of treatment weighting adjustment.

Results

Among the 2704 patients, 1257 (46.5%) were women. Women were more symptomatic (New York Heart Association class ≥2, 67.7% versus 54.6%; P<0.001) and had a higher proportion of severe AS (17.5% versus 14.3%, P=0.02) at inclusion. During follow‐up (median, 5.0 [interquartile range, 3.4–5.5]) years, 993 AVRs (488 surgical and 505 transcatheter) and 1098 deaths occurred. After inverse probability of treatment weight adjustment, women had better survival (adjusted hazard ratio [HR], 0.81 [95% CI, 0.71–0.93]; P=0.003) but similar cardiovascular death (P=0.99) compared with men. Interestingly, the higher survival in women was observed only in mild AS (adjusted HR, 0.71 [95% CI, 0.56–0.90]; P=0.005). The inverse probability of treatment weight–adjusted cumulative incidence of AVR by AS severity revealed no significant differences between women and men among patients across the AS spectrum. Cumulative incidence of surgical AVR was lower in women than in men (P=0.02).

Conclusions

Women had a similar referral rate for AVR (versus men), with a lower proportion undergoing SAVR, allowing similar outcomes between women and men with moderate and severe AS. The lower mortality rate in women was restricted to mild AS presentation.

Nonstandard Abbreviations and Acronyms

AS

aortic stenosis

AVR

aortic valve replacement

IMPULSE

Study to Improve Outcomes in Aortic Stenosis: International, Multicenter, Prospective, Observation, and Interventional Cohort Registry

IPTW

inverse probability of treatment weighting

PARTNER II S3

Placement of Aortic Transcatheter Valves II–S3

RHEIA

Randomized Research in Women All Comers With Aortic Stenosis

SAVR

surgical aortic valve replacement

TAVR

transcatheter aortic valve replacement

VALVENOR

Follow‐Up of a Cohort of Patients With Valvular Aortic Stenosis in the Nord‐Pas‐de‐Calais Region

Clinical Perspective.

What Is New?

• Our study provides insights into sex‐specific variations across the entire aortic stenosis spectrum in a broad and unselected population.

What Are the Clinical Implications?

• Our findings suggest with similar referral rates for aortic valve replacement, comparable survival could be achieved in patients with severe aortic stenosis.

• This should prompt community clinicians to refer women for echocardiography or aortic valve replacement without delay if indicated.

Aortic stenosis (AS) is the most frequent valvular heart disease in Western countries, ¹ affecting ≈5% of individuals aged >65 years. ² Its burden is expected to rise in the next years due to the aging of the population. ³ Recent studies have highlighted important sex disparities in initial clinical presentation, ⁴ , ⁵ progression of the disease, ⁶ adaptive response to AS‐related pressure overload, ⁷ , ⁸ and management of AS, including fewer echocardiograms. ⁹ , ¹⁰

However, the only sex‐based difference in the latest guidelines on the management of valvular heart disease concerns the assessment of calcium burden using cardiac computed tomography. The thresholds for defining a likely severe AS are >2000 Agatston units for men and >1200 for women. ¹¹ , ¹² , ¹³ Additionally, data on clinical outcomes before and after aortic valve replacement (AVR) showed inconsistencies when analyzed by sex. ⁴ , ⁶ , ¹⁰ , ¹⁴

Overall, sex differences in valvular heart disease are poorly explored. Most studies focused on outcome differences following surgical or transcatheter treatments, while more recent studies have explored the epidemiology and pathophysiology of valvular heart disease. Notably, most of the studies investigating sex differences in AS were based on data from a limited number of patients, were restricted to severe AS, or were based on tertiary centers or specialized heart valve clinics. ⁴ , ⁵ , ⁸ , ⁹

Understanding sex‐specific differences across the entire spectrum of AS in a broader population is of main importance for optimizing personalized treatment strategies. Therefore, the present study, based on the VALVENOR (Suivi d'une cohorte de patients présentant une sténose valvulaire aortique en région Nord‐Pas‐de‐Calais [Follow‐Up of a Cohort of Patients With Valvular Aortic Stenosis in the Nord‐Pas‐de‐Calais Region]) registry, aimed to evaluate the impact of sex on (1) clinical presentation, (2) management, and (3) patient survival, using a large cohort of all‐comer patients with different degrees of AS severity.

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study Population and Design

The VALVENOR is a multicenter registry that enrolled 2830 outpatients with native valvular AS between May 2016 and December 2017. ¹⁵ Patients with a peak aortic jet velocity ≥2.5 m/s on transthoracic echocardiography were prospectively included by 117 cardiologists from the Nord‐Pas‐de‐Calais region (≈4 million inhabitants) in France during outpatient visits. Patients aged <18 years or with a documented history of AVR were excluded. Participating physicians were selected on the basis of their geographic distribution to provide a representative sample of the current practice of cardiology care in the region, including university public hospitals, nonuniversity public hospitals, and private practices. At the initial visit, the investigators (ie, cardiologists) prospectively completed a case record form containing information on demographic, clinical, and echocardiographic details of the patients.

This study was approved by the French medical data protection committee (Advisory Committee on Information Processing in Health Research) and authorized by the Commission Nationale de l'Informatique et des Libertés for the treatment of personal health data. All patients consented to the study after being informed in writing of the study's objectives and treatment of the data, as well as on their rights to object and rights of access and rectification.

Transthoracic Echocardiography

Transthoracic echocardiography was performed at inclusion as part of routine clinical practice using commercially available systems. Peak aortic jet velocity was derived from transaortic flow, recorded with continuous‐wave Doppler. According to current diagnostic criteria, ¹⁶ patients were categorized as follows: mild AS (peak velocity, 2.5–2.99 m/s), moderate AS (peak velocity, 3–3.99 m/s), and severe AS (peak velocity, ≥4 m/s). Left ventricular ejection fraction (LVEF) was estimated by the Simpson biplane method. Aortic and mitral regurgitation were also assessed as previously described. ¹⁷

Follow‐Up

Patients were followed up by their treating cardiologists. The number of outpatient visits was at the discretion of the treating cardiologists. Protocol‐specified follow‐up was performed at 5 years using a standardized case record form to report clinical events. To minimize follow‐up bias, general practitioners and patients were contacted by a research technician in the case of missing information. The identification of patients with events for adjudication was based on interviews with patients/relatives during outpatient visits, discharge summaries for hospitalization during follow‐up, and information obtained by the research technician.

All clinical events were adjudicated by 2 investigators blinded to each other. A third investigator joined the adjudication in case of disagreement according to prespecified definitions. A consensus was then reached. Cardiovascular causes of death included congestive heart failure, sudden death, AVR procedures, stroke, myocardial infarction, limb ischemia, and other cardiovascular death. Noncardiovascular causes of death included cancer, sepsis, renal failure, respiratory failure, or accident, and other noncardiovascular death. Deaths by an unknown cause were kept as a separate category. The definitions for adjudication of the causes of death were published previously. ¹⁸

Statistical Analysis

Patients were divided into 2 groups according to sex (ie, women and men). Categorical variables were reported as numbers and corresponding proportions and compared with the χ² test with continuity correction or the Fisher exact test, as appropriate. Continuous variables were described as mean±SD or as median (interquartile range) and compared with a 2‐sided Student's t test (parametric test) or the Wilcoxon rank‐sum test (nonparametric test), according to their distribution.

A propensity score methodology with inverse probability of treatment weighting (IPTW) was performed to limit selection bias and balance baseline characteristics between women and men. ¹⁹ , ²⁰ The covariates used to balance baseline characteristics were AS severity grades; LVEF; angina at inclusion; age; New York Heart Association class; previous coronary event; diabetes; history of hypertension; previous myocardial infarction; previous coronary artery bypass graft surgery; previous percutaneous coronary intervention; atrial fibrillation; previous hospitalization for heart failure; previous stroke; antiplatelet therapy; and use of β blockers, angiotensin‐converting enzyme inhibitor or angiotensin receptor blockers, and statins.

Propensity scores predicting each patient's probability of being in the male or female group were estimated using logistic regression. Propensity scores were used to compute stabilized weights. IPTW was used to maintain the numbers of patients in both cohorts, contrary to traditional propensity matching that requires trimming both groups to create a balanced match. The balance of measured covariance between groups was compared by generating a standardized difference, and the optimal balance was determined with a value of ≤10%. Subsequent survival analyses were weighted by IPTW.

Freedom from death was estimated using the Kaplan–Meier method and compared using the log‐rank test. Hazard ratios (HRs) and 95% CIs were determined using Cox proportional hazards regression. The proportional hazards assumption was formally tested using Schoenfeld residuals, and no significant violations were detected. Multicollinearity was assessed using variance inflation factors, confirming the absence of concerning collinearity among covariates. The incidence of AVR was estimated using the cumulative incidence function accounting for death as competing risk (P value calculated using Gray's test).

A 2‐sided P value of <0.05 was considered statistically significant. Statistics were performed using R version 4.1.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline and Procedural Characteristics

Among the 2704 patients (99.4%) who completed follow‐up (median, 5.0 [interquartile range, 3.4–5.5]) years, 1257 (46.5%) were women. Baseline characteristics stratified by sex are shown in Table 1. Compared with men, women were older (78.5±10.4 versus 73.8±10.7 years, P<0.001), had a lower prevalence of diabetes (26.7% versus 33.5%, P<0.001) and of prior coronary events (11.2% versus 24.4%, P<0.001) but a higher prevalence of hypertension (80.2% versus 73.1%, P<0.001) and higher LVEF (65.1% versus 62.7%, P<0.001). There were no significant differences in the prevalence of atrial fibrillation (P=0.53) or previous stroke (P=0.27). Despite similar mean peak aortic jet velocity, women had a higher proportion of severe AS (17.5% versus 14.3%, P=0.02).

Table 1.

Baseline Characteristics

	All patients (n=2704)	Men (n=1447)	Women (n=1257)	P value
Age, y	76±10.8	73.8±10.7	78.5±10.4	<0.001
Diabetes	820 (30.3)	484 (33.5)	336 (26.7)	<0.001
History of hypertension	2066 (76.4)	1058 (73.1)	1008 (80.2)	<0.001
Previous coronary event	494 (18.3)	353 (24.4)	141 (11.2)	<0.001
Previous myocardial infarction	252 (9.3)	173 (12)	79 (6.3)	<0.001
Previous coronary artery bypass grafting	126 (4.7)	98 (6.8)	28 (2.2)	<0.001
Previous percutaneous coronary intervention	351 (13)	253 (17.5)	98 (7.8)	<0.001
Atrial fibrillation	604 (22.3)	330 (22.8)	274 (21.8)	0.53
Previous hospitalization for heart failure	269 (10)	142 (9.8)	127 (10.1)	0.80
Previous stroke	230 (8.5)	131 (9.1)	99 (7.9)	0.27
New York Heart Association class at inclusion*
1	1061 (39.5)	652 (45.4)	409 (32.8)
2	1292 (48.2)	650 (45.3)	642 (51.5)	<0.001
3–4	330 (12.3)	134 (9.3)	196 (15.7)
Angina at inclusion	109 (4)	50 (3.5)	59 (4.7)	0.10
Peak aortic jet velocity, m/s	3.27±0.65	3.26±0.63	3.29±0.68	0.20
AS severity
Mild	1156 (42.7)	611 (42.2)	545 (43.4)
Moderate	1121 (41.5)	629 (43.5)	492 (39.1)	0.02
Severe	427 (15.8)	207 (14.3)	220 (17.5)
LVEF,† %	63.8±8.9	62.7±9	65.1±8.5	<0.001
ß blocker	1210 (44.8)	651 (45)	559 (44.5)	0.79
ACE‐I or ARB	1779 (65.8)	978 (67.6)	801 (63.7)	0.04
Statin	1493 (55.2)	892 (61.6)	601 (47.8)	<0.001
Antiplatelet	1221 (45.2)	735 (50.8)	486 (38.7)	<0.001
Oral anticoagulant	580 (21.5)	305 (21.1)	275 (21.9)	0.61

Data are mean±SD or n (%). P values compare men vs women.

ACE‐I indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin 2 receptor antagonist; AS, aortic stenosis; and LVEF, left ventricular ejection fraction.

^*Missing data in 21 patients.

^† Missing data in 2 patients.

Regarding the initial clinical presentation, although there was no difference in previous heart failure hospitalization (P=0.80) or angina at inclusion (P=0.10), women were more likely to be symptomatic (New York Heart Association class ≥2, P<0.001).

Sex‐Related Unadjusted Outcomes

There were 1098 deaths during follow‐up (cardiovascular death, n=452; noncardiovascular death, n=500; death from unknown cause, n=146). There was no difference between men and women for all‐cause death (unadjusted HR, 1.03 [95% CI, 0.91–1.16]; P=0.67) or cardiovascular death (unadjusted HR, 1.16 [95% CI, 0.96–1.39]; P=0.12; Figure S1). A total of 993 patients underwent AVR (564 in men and 429 in women). The 5‐year cumulative incidence of AVR was significantly higher in men (41.6% [95% CI, 39–44]) compared with women (35.9% [95% CI, 33–39]; P=0.02; Figure 1).

Figure 1. Cumulative incidence of AVR and death according to sex.

The 5‐y cumulative incidence of AVR was significantly higher in men (41.6% [95% CI, 39–44]) compared with women (35.9% [95% CI, 33–39]; P=0.02) accounting for death as competing risk. P value by Gray's test. AVR indicates aortic valve replacement; and CIR, cumulative incidence rate.

Sex‐Related Outcomes After IPTW Adjustment

After IPTW adjustment, baseline characteristics of the weighted groups were more balanced between male and female patients, in particular with regard to age (75.9±10.4 years versus 75.1±13.1 years; standardized difference, 6.3%), diabetes (30.9% versus 30.0%; standardized difference, 1.8%), history of hypertension (76.0% versus 74.5%; standardized difference, 3.6%), prior coronary event (18.4% versus 17.6%; standardized difference, 1.9%), LVEF (63.7% versus 63.6; standardized difference, 0.8%), and NHYA class at inclusion (standardized difference, 1.5%); Table 2; Figures S2 and S3). No significant differences persisted in the baseline characteristics of the weighted groups.

Table 2.

Weighted Patient Characteristics by Sex (Men Versus Women Group)

	Men (n=1440)	Women (n=1257)	P value	Standardized difference, %
Age, y	75.86 (10.40)	75.12 (13.05)	0.26	6.3
Diabetes	444.3 (30.9)	382.7 (30.0)	0.67	1.8
History of hypertension	1094.5 (76.0)	949.7 (74.5)	0.45	3.6
Previous coronary event	264.2 (18.4)	224.5 (17.6)	0.69	1.9
Previous myocardial infarction	134.5 (9.3)	113.8 (8.9)	0.75	1.4
Previous coronary artery bypass grafting	68.0 (4.7)	62.9 (4.9)	0.87	1
Previous percutaneous coronary intervention	186.3 (12.9)	159.2 (12.5)	0.78	1.4
Atrial fibrillation	324.2 (22.5)	290.0 (22.7)	0.90	0.5
Previous hospitalization for heart failure	148.4 (10.3)	147.0 (11.5)	0.45	3.9
Previous stroke	119.0 (8.3)	109.3 (8.6)	0.80	1.1
New York Heart Association class at inclusion*			0.94	1.5
1	561.8 (39.3)	502.7 (39.7)
2	687.9 (48.1)	610.6 (48.2)
3–4	180.3 (12.6)	153.6 (12.1)
Angina at inclusion	59.0 (4.1)	51.6 (4.0)	0.95	0.3
Peak aortic jet velocity, m/s	3.27 (0.64)	3.27 (0.66)	0.82	1
AS severity			0.89	2.1
Mild	615.5 (42.8)	555.4 (43.6)
Moderate	601.9 (41.8)	519.8 (40.8)
Severe	222.3 (15.4)	199.8 (15.7)
LVEF,† %	63.68 (8.77)	63.61 (9.02)	0.87	0.8
ß blocker	637.0 (44.2)	562.5 (44.1)	0.95	0.3
ACE‐I or ARB	944.0 (65.6)	818.2 (64.2)	0.50	2.9
Statin	794.4 (55.2)	685.6 (53.8)	0.52	6.3
Antiplatelet	640.9 (44.5)	555.1 (43.5)	0.65	1.8
Oral anticoagulant	311.2 (21.6)	277.4 (21.8)	0.94	3.6

Data are n (%). P values compare men vs women.

ACE‐I indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin 2 receptor antagonist; AS, aortic stenosis; and LVEF, left ventricular ejection fraction.

^*Missing data in 21 patients.

^† Missing data in 2 patients.

After IPT weighting, Kaplan–Meier analyses showed a better overall survival in women than in men (adjusted HR, 0.81 [95% CI, 0.71–0.93]; P=0.003; Figure 2A) but similar cardiovascular death (adjusted HR, 1.00 [95% CI, 0.80–1.25]; P=0.99; Figure 2B) compared with men. There was no difference between women and men in the cumulative incidence of AVR (P=0.92; Figure 2C). Of note, the IPTW‐adjusted cumulative incidence of surgical AVR (SAVR) was higher in men than in women (20.6% versus 16.5%, P=0.02), and that of transcatheter AVR (TAVR) tended to be higher in women than in men without reaching statistical significance (21.8% versus 18.5%, P=0.10; Figure 3).

Figure 2. Clinical outcomes according to sex after IPTW.

A, After IPTW adjustment, Kaplan–Meier analysis showed a higher overall survival in women compared with men at 5 years (adjusted HR, 0.81 [95% CI, 0.71–0.93]; P=0.003). B, No difference was observed for cardiovascular death (P=0.99). C, No difference was observed on the cumulative incidence function for aortic valve replacement accounting for death as competing risk (P=0.92). HR indicates hazard ratio; and IPTW, inverse probability of treatment weighting.

Figure 3. Cumulative incidence of (A) SAVR and (B) TAVR according to sex after IPTW.

After IPTW adjustment, Kaplan–Meier analyses showed that while the IPTW‐adjusted cumulative incidence of SAVR was higher in men than in women (20.6% vs 16.5%, P=0.02) (A), the cumulative incidence of TAVR showed a tendency to be higher in women than in men (21.8% vs 18.5%, P=0.10) (B). IPTW indicates inverse probability of treatment weighting; SAVR, surgical aortic valve replacement; and TAVR, transcatheter aortic valve replacement.

Finally, among patients who met criteria for AVR but remained untreated, there was a trend for a higher proportion of treatment refusals in women compared with men without reaching statistical significance (57% versus 47%, P=0.12; Figure S4). After excluding patients who refused AVR, overall survival remained better in women than in men (adjusted HR, 0.81 [95% CI, 0.70–0.93]; P=0.004; Figure S5A).

Outcomes According to AS Severity

After IPT weighting, Kaplan–Meier analyses showed a better overall survival in women than in men in mild AS (adjusted HR, 0.71 [95% CI, 0.56–0.90]; P=0.005) but not in moderate AS (adjusted HR, 0.90 [95% CI, 0.74–1.11]; P=0.34) and in severe AS (adjusted HR, 0.87 [95% CI, 0.63–1.19]; P=0.39; Figure 4). Similar findings were observed after excluding patients who refused AVR (Figures S5B through S5D).

Figure 4. Kaplan–Meier curves of all‐cause death after IPTW according to sex and AS severity.

After IPTW adjustment, Kaplan–Meier analyses showed a higher overall survival in women than in men in (A) mild AS (adjusted HR, 0.71 [95% CI, 0.56–0.90]; P=0.005) but not in (B) moderate AS (adjusted HR, 0.90 [95% CI, 0.74–1.11]; P=0.34) and in (C) severe AS (adjusted HR, 0.87 [95% CI, 0.63–1.19]; P=0.39). AS indicates aortic stenosis; HR, hazard ratio; and IPTW, inverse probability of treatment weighting.

The IPT‐weighted cumulative incidence of AVR by AS severity revealed no significant differences between women and men among patients with mild AS (P=0.37), moderate AS (adjusted HR, P=0.55), and severe AS (adjusted HR, P=0.28; Figure 5).

Figure 5. IPTW‐adjusted cumulative incidence of AVR according to sex and AS severity.

The IPTW‐adjusted cumulative incidence of AVR by AS severity revealed no significant differences between women and men among patients with (A) mild AS (P=0.37), (B) moderate AS (P=0.55), and (C) severe AS (P=0.28). Cumulative incidence function was obtained accounting for death as competing risk. AS indicates aortic stenosis; and AVR, aortic valve replacement; and IPTW, inverse probability of treatment weighting.

Discussion

Exploring 2704 outpatients across the spectrum of AS included in a prospective regionwide registry, followed‐up for 5 years and compared by sex using IPTW, we observed the following: (1) women exhibited more symptoms and had a higher proportion of severe AS before IPTW; (2) after IPTW, a lower mortality rate in women was observed exclusively among patients with mild AS; and (3) although AVR rates were similar between women and men, the cumulative incidence of SAVR was higher in men.

Symptoms According to Sex

The clinical presentation of AS may vary between men and women. ²¹ In a study of 3632 patients with at least mild‐to‐moderate AS at a single tertiary center, Bienjonetti‐Boudreau et al reported that women were more likely to experience AS‐related symptoms, including dyspnea (New York Heart Association class ≥II), angina, presyncope, or syncope (76.22% versus 72.15%, P=0.008). ²² In patients with severe AS, Tribouilloy et al found that at presentation, women were older, had fewer comorbidities, and were more frequently symptomatic than men. ⁴ Similarly, we found that women were more likely to be classified as New York Heart Association class ≥II (P<0.001), though there was no difference in prior heart failure hospitalizations or angina at inclusion.

This discrepancy may be attributed to the higher prevalence of severe AS and the older age of women compared with men. Notably, we observed that although the mean peak aortic jet velocity was similar, a higher proportion of women had severe AS. This finding may be attributed to differences in LVEF and flow rates between sexes.

Additionally, there are differences in the adaptive response to AS‐related pressure overload with more concentric remodeling and thus diastolic dysfunction in women, as well as a higher prevalence of heart failure with preserved ejection fraction, may result in high flow rates and higher gradients. This could explain why, during follow‐up, women experience a faster decline in functional status despite having the same AS progression. ²³

Although men have a higher prevalence of coronary artery disease and related interventions, there was no difference in angina at inclusion, possibly due to the higher proportion of coronary microcirculation dysfunction in women.

Sex‐Related Differences in Outcomes

Tribouilloy et al showed that after adjusting for age, women with severe AS had lower 5‐year survival rates than men, despite having a longer life expectancy in the general population. ⁴ Likewise, Bienjonetti‐Boudreau et al found that, after accounting for key confounders—including age, diabetes, hypertension, renal and coronary disease, chronic pulmonary disease, symptoms, aortic valve area, mean gradient, and indexed stroke volume—women had a higher mortality rate. ²² Notably, these studies are limited to severe AS or conducted in tertiary centers with specialized heart valve clinics. Conversely, recent data from the European Society of Cardiology EURObservational Research Programme Valvular Heart Disease II survey reported no significant sex‐related differences in survival at 6‐month follow‐up among patients with severe AS. ¹⁰

To our knowledge, only a few studies have prospectively evaluated outcomes by sex across a broad spectrum of AS severity in a region‐wide population. After carefully balancing baseline characteristics, we observed similar outcomes between women and men with moderate and severe AS. Differences in survival in women and men were restricted to mild AS presentation, with better outcomes in women. The more favorable outcomes observed in patients with mild AS may be attributable to noncardiovascular causes, with lower survival in men potentially related to lifestyle factors not captured in our analysis, such as smoking, obesity, or physical inactivity.

Sex‐Related Differences in AS Management

Female sex has often been linked to higher 30‐day and long‐term mortality rates following SAVR ²⁴ that is attributed to several anatomic characteristics, including worse preoperative risk profile, smaller aortic annuli leading to a higher incidence of prosthesis–patient mismatch, more concentric left ventricular remodeling, and increased myocardial fibrosis. ²⁵ Data from the IMPULSE (Study to Improve Outcomes in Aortic Stenosis: International, Multicenter, Prospective, Observation, and Interventional Cohort Registry) registry showed that female patients with severe AS exhibit a distinct patient profile with higher surgical risk and are managed differently than males patients, being more frequently offered TAVR and less undergoing SAVR. ²⁶

However, in a large cohort of patients with AS, Bienjonetti‐Boudreau et al found no difference between sexes in terms of aortic valve intervention rates and survival after intervention among patients with severe AS. ²² However, in patients with discordant low‐gradient AS, women were less referred to intervention and experienced a higher mortality rate. Recent analyses from the PARTNER II S3 (Placement of Aortic Transcatheter Valves II–S3) study ²⁷ and the CENTER (Cerebrovascular EveNts in patients undergoing TranscathetER aortic valve implantation with balloon‐expandable valves versus self‐expandable valves) collaboration, ²⁸ both reflecting contemporary management strategies, found no significant sex‐specific differences in survival following TAVR after multivariable adjustments.

We found that although overall AVR rates were comparable between women and men, the cumulative incidence of SAVR was higher in men. Differences in referral patterns between TAVR and SAVR may be partly explained by the less favorable periprocedural outcomes observed in women undergoing surgery, including higher risks of death, bleeding complications, acute kidney injury, and severe prosthesis–patient mismatch. ²⁹ , ³⁰ Recently, the RHEIA (Randomized Research in Women All Comers With Aortic Stenosis) trial, which randomized 443 women across 48 European centers, reported that in women with severe AS, TAVR was associated with a lower 1‐year incidence of the composite outcome of death, stroke, or rehospitalization compared with surgery. ³¹ However, more follow‐up is needed to assess long‐term clinical outcomes and valve durability following TAVI versus surgery in women.

Clinical Perspectives

Sex‐based differences had been reported in both the clinical presentation and management of AS, with conflicting data on outcomes often influenced by patient selection biases. For the first time, our study provides insights into sex‐specific variations across the entire AS spectrum in a broad and unselected population. Importantly, our findings suggest that with similar referral rates for AVR, comparable survival could be achieved in patients with severe AS. This underlines the importance of ensuring equitable access to diagnostic evaluation and treatment, encouraging community clinicians to promptly refer women for echocardiography or AVR without delay if indicated. Beyond referral practices, these findings emphasize the importance of greater awareness of potential sex‐related differences in symptom perception, disease progression, and clinical decision making. Current guidelines do not systematically account for sex‐specific variations in AS, particularly on patient selection and timing of intervention. Future studies are warranted to investigate whether incorporating sex‐specific diagnostic thresholds, risk stratification strategies, or treatment algorithms could help optimize outcomes in patients with AS.

Study Limitations

The primary aim of our registry was to compile data on outcomes of patients with AS cared for in various clinical settings. To provide a clinically applicable message while aligning with current cardiology practices, we categorized AS severity solely on the basis of peak aortic jet velocity, whose prognostic value has been reported in several studies. ³² We acknowledge, however, that relying exclusively on peak aortic jet velocity may lead to erroneous classification of AS severity in cases of low‐flow AS, with patients classified as moderate instead of severe. We also acknowledge that rapid advances in device technology and the expansion of TAVR indications may limit the applicability of our results to current practice.

Additionally, the number of outpatient visits and the individual decisions to perform or contraindicate patients for AVR was left to treating cardiologists and local heart teams. Our data reflect the practice in a regional area of France, and thus further investigation is warranted to determine whether these findings are generalizable and representative of practices in other parts of the world. Finally, although several statistical methods, such as propensity IPTW, have been applied, we cannot exclude the impact on outcomes of unknown/unmeasured variables that could not be corrected.

Conclusions

Among all‐comer outpatients across the spectrum of AS, women had a similar referral rate for AVR (versus men), with a lower proportion undergoing SAVR, allowing similar outcomes between women and men with moderate and severe AS. The lower mortality rate in women was restricted to mild AS presentation in our cohort.

Sources of Funding

This study was supported by a grant from Fédération Française de Cardiologie. Dr Montaigne is supported by grants from Agence Nationale pour la Recherche (ANR‐10‐LABX‐0046, ANR TOMIS‐Leukocyte: ANR‐CE14‐0003‐01, and ANR CALMOS: ANR‐18‐CE17‐0003‐02), the Leducq Foundation LEAN Network (16CVD01), and the National Center for Precision Diabetic Medicine—PreciDIAB (ANR‐18‐IBHU‐0001; 20001891/NP0025517; 2019_ESR_11).

Disclosures

None.

Supporting information

Figures S1–S5

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