Epidemiology
The reported prevalence of AS among the elderly population is 12.4%, while the prevalence of severe AS in the same population is 3.4%. Under the current indications, approximately 290,000 elderly patients with severe AS are TAVR candidates [
41]. However, there continues to be a disparity between male and female sex in diagnosis, treatment, and management of the disease. Extensive echocardiographic data shows that men are twice as likely to develop aortic stenosis compared to women [
44]. Several studies have reported a higher utilization of surgical aortic valve replacement (SAVR) in men compared to women [
45‐
48]. This may be because women with aortic stenosis had unfavorable preoperative baseline characteristics, and were thus less likely to be referred for surgical treatment [
44]. Interestingly, this disparity in referral for valve replacement is not seen with the current TAVR practice [
49,
50]. Since TAVR became commercially available in the United States in 2011, women have been referred more often for TAVR compared to men [
49]. Women are often older when they develop symptomatic AS, which may explain the increase in TAVR referral initially [
51].
Differences in Anatomy/Surgical Technique
When assessing a patient for possible SAVR or TAVR, both anatomic and clinical considerations, such as surgical risk, should be considered. The choice of access site and valve type depends on several factors, including presence of peripheral disease and aortic arch anatomy. Specifically, there is a higher likelihood of aortic valve area-gradient discordance due to smaller left ventricular outflow tract dimensions and more frequent paradoxical low-flow, low-gradient severe aortic stenosis in women compared to men [
52]. Buellesfeld et al. evaluated TAVR-related multi-detector computed tomography imaging findings among 97 women and 80 men with severe symptomatic aortic stenosis and found smaller annular and left ventricular outflow tract dimensions in women, but similar ascending aortic dimensions [
53]. The smaller aortic annuli in women are associated with use of smaller transcatheter heart valves compared to men. Although implications of small valve size historically relate to some elderly women falling out of range of available devices, this has become less of problem since the induction of smaller transcatheter heart valves sizes, as well as self-expanding and balloon-expandable platforms. Patients with a smaller annulus had lower rates of severe prosthetic valve regurgitation compared to patients with a large annulus [
52]. Proper assessment of the aortic annulus is important for valve sizing. The width of the sinuses of Valsalva and the height of the coronary arteries, specifically the left main, are crucial for proper assessment as well. Women generally have smaller body surface areas compared to men, therefore these aortic root structures tend to differ in size as well [
54]. The smaller vessel size in women is not limited to the aortic arch; women have smaller diameter peripheral vessels that are suboptimal or prohibitive for femoral access [
1].
Given the innumerable differences discussed above, thoughtful consideration should be given to procedural technique. Specifically, the access site (transfemoral, transaxillary, transapical, or direct aortic access) and the use of self-expanding or balloon-expanding valves should be given extra attention. Lack of appreciation of these differences (valve size, height of coronary arteries) can lead to suboptimal valve implantation, leading to catastrophic complications (Table
1) such as coronary obstruction or annular rupture that are known to occur more frequently in women [
54].
Table 1
Differences in complications post-transcatheter aortic valve replacement
↓ Pacemaker implantation |
↑ Coronary obstruction |
↑ Likelihood of patient–prosthesis mismatch |
↑ Peripheral vascular complications (i.e., bleeding) |
↑ Annular rupture |
Review of Outcomes
The landmark TAVR trials assessed outcomes in patients who were felt to have prohibitive risk for SAVR. Since safety data have shown equivalent outcomes, more recent studies have focused on low and intermediate-risk groups. Along the lines of safety, there is evidence of notable differences in adverse outcomes based on sex. Post-procedurally, women have demonstrated increased risk of annular rupture, coronary obstruction, peripheral vascular complications, and possible risk of patient–prosthesis mismatch [
52]. In contrast, the need for permanent pacemaker implantation post-TAVR was lower in women compared to men (Table
1) [
51].
Patient–Prosthesis mismatch Patient–prosthesis mismatch occurs when the effective orifice area of an inserted prosthetic valve is too small relative to body size, resulting in higher than expected gradients in otherwise normally functioning prosthetic valves. Patient–prosthesis mismatch is a concern in patients with small aortic annulus size undergoing SAVR but has not been problematic with TAVR. Recent studies have shown that despite the need for smaller valve sizes in women, they do not appear to be at increased risk of patient–prosthesis mismatch [
55]. A recent trial performed by Popma et al. found that in patients with severe aortic stenosis who were low surgical risk, TAVR with a self-expanding supra-annular bioprosthesis was not inferior to SAVR with respect to death from any cause at 24 months [
56]. This suggests an increased utility of TAVR in those who are surgical candidates, but who also have smaller annular dimensions [
57]. Extrapolating further, this suggests that TAVR should be the preferred intervention in women with severe AS [
55]. Further studies are needed to directly compare TAVR versus SAVR in this cohort, however, to assess possible impact of patient–prosthesis mismatch on long-term clinical outcomes.
Coronary obstruction risk Women also have a higher risk of coronary occlusion/obstruction due to lower coronary heights and smaller sinuses of Valsalva [
10]. These dimensions are inversely related to left main obstruction post-implantation [
58]. A higher proportion (> 80%) of patients who developed coronary obstruction were women despite equal sex representation in their registries [
58]. In such cases, novel techniques such as BASILICA, a technique involving intentional laceration of the native or bioprosthetic leaflet to prevent iatrogenic coronary artery obstruction, may be considered to reduce the risk of coronary obstruction.
Permanent pacemaker implantation Permanent pacemaker placement is a known risk of TAVR, with risk related to valve type and underlying conduction disease. A 2019 study looking at sex differences in outcomes among the CENTER collaboration data for trans-femoral TAVR procedures noted that the need for permanent pacemaker implantation was lower for females compared to males (12.2 vs. 16.7%, RR 0.7, 95% CI 0.7–0.8%,
p < 0.001) [
51]. This difference was seen with both self-expandable and balloon-expandable valves, though pacemaker implantation rates were higher in both sexes among the self-expandable valve group [
51]. This finding may be due to anatomical and sizing discrepancies seen among the sexes, but warrants further investigation to characterize the mechanism.
Peripheral vascular complications The overall risk of peripheral vascular complications has declined with advances in technology allowing the use of lower-profile delivery systems. However, this risk has not been eliminated and is known to vary by sex, with women having more vascular complications (6–20% vs. 2–14%) and higher bleeding rates (10–44% vs. 8–25%) compared to their male counterparts compared to their male counterparts, see Table 3 [
59]. A 2019 study looking at the CENTER collaboration data in transfemoral TAVR procedures also found elevated risk of bleeding in women by about 50% (6.7 vs. 4.4%, RR 1.5; 95% CI 1.3–1.8,
p < 0.001) [
51]. Interestingly, bleeding risk appeared to correlate inversely with body mass index (BMI) in females (lowest BMI bleeding rate 7.7%, middle BMI group 7.1%, and highest BMI group 5.5%), with no particular correlation in the male cohort [
51]. These findings were true for both early and newer generation TAVR valves. Large sheath-to-femoral-artery ratio, increased vessel tortuosity, and significant vascular calcification specifically contributing to these findings [
51]. Previously described differences in femoral diameter between sexes may explain the elevated rate of vascular complications in women, as they appear to undergo TAVR via transfemoral access more frequently [
1]. Appropriate use of pre-TAVR imaging assessments of iliofemoral vasculature is therefore particularly important in women [
52]. This further supports the need for more evidence on antithrombotic therapy post-TAVR, as well as potential adjunctive options in those with higher bleeding risk. In late 2019, Saito et al. published a review on adjunctive antithrombotic regimens post-TAVR and found that single antiplatelet therapy (SAPT) may be safer than dual antiplatelet therapy [
60]. Additionally, they suggested that an oral anticoagulant alone may be superior to oral anticoagulation plus SAPT in those patients requiring full anticoagulation. Future trials are underway that may provide clarity on this issue, and may be particularly beneficial in women who have demonstrated increased risk of bleeding [
60].
Overall morbidity and mortality In a meta-analysis of 23 publications, women had fewer pre-existing co-morbidities and better survival (range of hazard ratio [95% CI] = 0.27 [0.09–0.84] to 0.91 [0.75–1.10]) with TAVR compared to SAVR [
59]. More recent data looking at over 12,000 patients found higher baseline prevalence of hypertension and renal failure in females, but lower prevalence of common cardiovascular comorbidities like coronary artery disease, prior PCI or coronary artery bypass graft, diabetes mellitus, stroke, and peripheral arterial disease [
51]. While some previous studies outline a lower mortality rate in women due to more favorable baseline characteristics and lower rates of significant paravalvular aortic regurgitation, others suggest that both sexes have similar mortality outcomes, at least in the 30-day period [
51,
52,
59,
61]. Overall mortality and stroke rates 30 days post-TAVR were found to be similar in males and females in the CENTER collaboration dataset, despite the increase in bleeding complications for females mentioned above [
51]. The 30-day mortality was lower in both sexes by at least 50% over the last 10 years, with overall mortality rates between 2007 and 2018, the data collection period, decreasing further in males over time compared to females [
51]. Stroke rates, however, did not change over time in either sex [
51]. Outcomes of TAVR versus SAVR in women, particularly in the low-risk population, have yet to be thoroughly examined. In high-risk and inoperable patients, females may have a survival benefit of up to 2 years with TAVR compared to SAVR [
62]. In similar populations in the PARTNER 3 trial, the rate of death, stroke, or re-hospitalization at 1 year was actually found to be lower with TAVR than with surgery [
63]. More sex-specific analyses are needed to analyze these differences, and to help clarify conflicting evidence in the literature.