Transcatheter aortic valve replacement in women

Abstract

This review examines the treatment options for women with severe aortic stenosis. It is known that female sex is associated with poorer outcomes after surgical aortic valve replacement. With the introduction and adoption of transcatheter aortic valve replacement as an alternative to surgical aortic valve replacement, there are emerging data about the potential impact of female sex‐specific characteristics on clinical outcomes after transcatheter aortic valve replacement. These data provide an insight into female‐specific aspects of the treatment of aortic stenosis. The data can help guide patient selection, choice of intervention method, and evaluation of risk to help improve long‐term follow‐up of patients with aortic stenosis.

In the developed world, severe aortic stenosis (AS) is the most common form of valvular abnormality. It accounts for 40% of native valvular disease and has equal prevalence in men and women.1 Historically, aortic valve replacement (AVR) has been the gold standard of treatment for symptomatic severe calcific aortic stenosis (AS).2 The introduction and adoption of transcatheter AVR (TAVR) as an alternative to surgical aortic valve replacement (SAVR) has evolved and is established in some patient subsets, and several studies have assessed the impact of sex on outcome.3, 4, 5

Existing data show that not only do women undergo SAVR for aortic stenosis less frequently than men, but when they do, they have worse outcomes with SAVR than do men.6 SAVR in women has been associated with worse in‐hospital mortality and higher cost compared with men. Chaker et al6 reviewed sex‐related differences in SAVR utilization, patient risk profile, and in‐hospital outcomes using the Nationwide Inpatient Sample. A total of 166 809 patients (63% male, 37% female) who underwent SAVR between 2003 and 2014 were identified, and 48.5% had an additional cardiac surgery procedure. Their data showed that when compared with male patients, female patients were older and had more comorbidities, such as hypertension, diabetes mellitus (DM), pulmonary disease, and atrial fibrillation and flutter, but less coronary and peripheral arterial disease. In this study, the in‐hospital mortality after SAVR was significantly higher in women (5.6% vs 4%; P < 0.001), along with vascular complications and blood transfusion (6% vs 5.6%, P = 0.027; and 40.4% vs 33.9%, P < 0.001, respectively). Although the length of stay was similar in men and women, women were more likely to be discharged to a nursing home or intermediate‐care facility compared with men (27.9% vs 19.6%; P < 0.001).

TAVR is now a well‐established treatment option in patients with AS who are of intermediate and high risk or inoperable for severe AS.3, 4, 5 It is interesting to note that unlike coronary artery disease trials, where women are historically underrepresented, women are better represented in TAVR studies.7, 8, 9, 10 The adaptive mechanism in particular in women with AS is mostly left ventricular hypertrophy rather than dilation, preserved systolic function, and low prevalence of concurrent coronary artery disease, all of which delays their symptom onset; thus, symptomatic women are older, and this can influence the decision for a TAVR.

The landmark Placement of Aortic Transcatheter Valves (PARTNER) trial compared the accepted standard therapy for high‐risk and inoperable patients with TAVR and established its safety and efficacy. In PARTNER 1, cohort A, TAVR was demonstrated to be a noninferior treatment strategy for patients at high risk for SAVR. More recently, the PARTNER‐2 and Nordic Aortic Valve Intervention Trial (NOTION) demonstrated noninferiority in intermediate‐risk patients with TAVR vs SAVR with results up to 2 years following valve implantation.5, 11, 12 Several meta‐analyses have substantiated the noninferior outcomes with TAVR compared with SAVR13, 14, 15 in both high‐ and intermediate‐risk patient groups. Additionally, it has been shown that the durability of TAVR is acceptable at 5 years.16, 17

In the PARTNER A (high‐risk surgical patients) trial, women (42.9%) who had TAVR had lower 12‐month mortality with SAVR compared with men (18.4% vs 28.0%; P = 0.05).4 The PARTNER subanalysis also showed that women randomized to TAVR had lower mortality rates than those randomized to SAVR at 2 years' follow‐up, whereas such a mortality difference was not observed in men.

Pulling data from >23 000 patients (49.9% women), several large meta‐analyses2, 18, 19, 20 and a large retrospective study from the Society of Thoracic Surgeons/American College of Cardiology (STS/ACC) Transcatheter Valve Therapy (TVT) Registry21 also showed improved survival in women as compared with men with AS who undergo TAVR, despite their older age and higher rates of vascular complications, bleeding events, and strokes.

The mortality benefit for women with TAVR has been reported in multiple other studies, including a recent meta‐analysis by Siontis et al.22 They showed that TAVR, when compared with SAVR, was associated with a significant 13% relative risk reduction in 2‐year mortality, a benefit more pronounced among females and patients undergoing transfemoral TAVR. In another meta‐analysis looking at female‐specific survival advantage from TAVR vs SAVR, Panoulas et al1 analyzed gender‐specific results in 4 randomized controlled trials of TAVR vs SAVR for severe AS, reporting 1‐ and/or 2‐year survival totaling 3758 patients (1706 women and 2052 men). The women who underwent TAVR had significantly lower mortality than male SAVR recipients at 1 and 2 years (31% reduction at 1 year and 26% reduction at 2 years). In the 2052 men, there was no difference in mortality between TAVR and SAVR at 1 year or 2 years. The difference in treatment effect between sexes, the relative mortality advantage of TAVR vs SAVR, was statistically significant at both 1 year and 2 years (P _interaction = 0.02 and P _interaction = 0.04, respectively).

Thus, the sex‐specific mortality risk in TAVR is lower in women than in men, which is the opposite result from SAVR. There has been much speculation on potential mechanisms of why women and not men have a survival benefit from TAVR over SAVR. There may be many factors that explain the improved long‐term survival after TAVR in women.

One factor that has been mentioned is that female patients treated with TAVR had lower rates of acute kidney injury, a complication that can increase the risk of postoperative mortality >4‐fold.23

A second factor may have to do with the fact that women have a lower risk of moderate/severe aortic regurgitation after TAVR, a well‐known risk factor for cardiovascular mortality.1, 24 Women are known to have smaller annular size, which reduces the chance of prosthesis undersizing compared with men, who tended to receive undersized valves and thus experience more paravalvular leaks.24, 25 Studies have also shown that women were more likely to receive balloon‐expandable valves, whereas men were more likely to receive self‐expanding valves.25 Prior to the introduction of the 29‐mm SAPIEN valve (Edwards Lifesciences, Irvine, CA), only self‐expanding valves were used for larger annular sizes. At the time of the PARTNER trial, the only available valve sizes were 23 mm and 26 mm.24 Given their larger annulus sizes and limited options with regards to valve sizing, a subset of men undergoing TAVR may have received an undersized valve, resulting in a greater paravalvular leak. And now with newer‐generation devices, larger sizes are available, which could potentially decrease some of the paravalvular leak seen in men. Using more balloon‐expandable valves (sutureless anchoring across the annulus) in women could have contributed to more favorable stent frame expansion and less moderate/severe aortic regurgitation compared with men.26 This knowledge could therefore lead to improved outcomes for men.

Interestingly, Saad et al25 reported that the increased number of self‐expanding valves implanted in men compared with women led to a lower risk of permanent pacemaker (PPM) placement in women vs men (10.4% vs 17.6%) after TAVR in their study, which analyzed 17 studies including 8 TAVR registries (47 188 patients, 49.4% of them women). Prior studies have demonstrated a lower risk of PPM placement with balloon‐ vs self‐expanding valves.27 The Women's International Transcatheter Aortic Valve Implantation (WIN‐TAVI) study, which utilized 47.1% self‐expanding valves vs 41.7% balloon‐expandable stent, reported any arrhythmia or conduction disturbance in 21.9% of their female patients after TAVR, and a PPM in 12.1% of patients. In the secondary analysis of data from the PARTNER trials utilizing only the balloon‐expandable stent, PPM was reported in 15.8% of women vs 26.6% of men, but this was not a randomized comparison, thus limiting any conclusions.

There are currently no conclusive data about differences in long‐term outcomes with TAVR based on the type of valve implanted. In the PARTNER trial, balloon‐expandable stents, the Edwards SAPIEN transcatheter aortic valves were used in all patients. A study of patients having TAVR with a different transcatheter heart valve, the Medtronic CoreValve (Medtronic, Minneapolis, MN), a self‐expandable stent, showed a trend toward mortality benefit for women compared with men.28

Another factor for the sex‐based difference is that men have significantly worse baseline vascular disease and comorbidities, including hypertension, DM, coronary artery disease, prior revascularization, and lower left ventricular ejection fraction (LVEF) compared with women.7, 21, 25

Saad et al25 looked at long‐term outcomes with TAVR in women compared with men, evidence from a meta‐analysis of 17 studies. They showed that regardless of the fact that women were older and had fewer comorbidities, after TAVR they had better 1‐year and long‐term survival compared with men, despite a higher risk of early postoperative (30 days) bleeding and vascular complications and a higher long‐term risk of stroke. Data from Saad et al. are similar to other studies also reporting that women undergoing TAVR are typically older than men and experience more frequent vascular complications and bleeding events,25 which in part may be explained by their frailty. Older age, anatomical factors such as lower body surface area, smaller‐caliber vessels, and hormonal influences on vascular biology likely contribute to this finding. Additionally, with newer devices that require smaller sheath sizes for implantation, vascular complications may decrease. New‐generation TAVR devices are smaller and are associated with more favorable outcomes than conventional devices, with fewer complications and lower incidence of mortality.5 At this time, there are no reports of difference in clinical outcomes between men and women using these new devices.

To examine sex‐specific outcomes in patients undergoing TAVR, a secondary analysis of the randomized and nonrandomized patients of the PARTNER trial that included 2559 (1220 women and 1339 men) high‐risk and inoperable patients with AS undergoing TAVR was undertaken.24 In this analysis, the women had lower rates of hyperlipidemia, DM, renal disease, peripheral vascular disease, and coronary heart disease, with fewer histories of myocardial infarction and coronary artery bypass grafting, but they had higher STS Predicted Risk of Mortality scores (12% vs 11%, respectively). They noted that on the average, women have smaller aortic valve areas, smaller annular dimensions, and higher average LVEF. The transfemoral approach was more common in men compared with women (62% vs 54%, respectively). After TAVR, women had more postprocedural major bleeding and vascular complications (17.3% vs 10.0%; P < 0.001) and postprocedure major bleeding (10.5% vs 7.7%; P = 0.012), but less frequent moderate and severe paravalvular regurgitation (6.0% vs 14.3%; P < 0.001) and improved 1‐year survival than men. After 1 year, all‐cause mortality was significantly lower in women than in men (19.0% vs 25.9%; P < 0.001). Women also had lower re‐hospitalization rates, at 16% vs 19% for men (P = 0.043).

Another meta‐analysis evaluating sex‐specific outcomes looked at 47, 188 patients also found that women who underwent TAVR had higher 30‐day risk of bleeding, vascular complications, and long‐term risk of stroke, but better 1‐year and long‐term survival, compared with men.25

Studies also noted2, 18, 19, 20, 21 that women had lower rates of transfemoral access, probably due to the use of older‐generation devices, which were generally larger. Conceivably, now with smaller and improved TAVR devices, a transfemoral approach may be utilized in women, which could reduce the risk of procedural complications. Of note, males undergoing TAVR were more frequently burdened by extensive atherosclerotic disease, as noted by their higher rates of previous percutaneous coronary interventions, coronary artery bypass procedures, strokes, and peripheral vascular disease.21 It is postulated that the protective effects of estrogen might mitigate the progression of atherosclerosis in women. Despite the differences in clinical and procedural characteristics, with women experiencing more major bleeds and vascular complications, these data showed that female sex is an independent predictor of lower 1‐year mortality after TAVR.

The increase in bleeding and vascular complications in women did not decrease the long‐term survival benefit compared with men. The findings of favorable outcomes following TAVR in female patients might be affected by the fact that females have less comorbidity and tend to have smaller annular size and higher LVEF before TAVR, as well as less aortic regurgitation after the procedure. These differences probably lead to better preoperative preservation of left ventricular function and improved hemodynamics in women after the procedure. Additionally, lifetime hormonal influences may have a role in arterial stiffness and diastolic dysfunction, consequently impacting on AS and post‐TAVR outcomes, but further study is needed to prove this. Another possible explanation is the sex‐related difference in myocardial remodeling in response to pressure or volume overload.

The influence of factors such as frailty, osteoporosis, history of pregnancy, and age of menopause on TAVR outcomes is unknown. Although frailty and osteoporosis have been linked with poor postoperative recovery, osteoporosis and vertebral fractures may change cardiac rotation, which may impact device implantation.2, 21, 25

Although female sex is associated with a better long‐term survival after TAVR compared with men, there is documented potential increased risk of stroke.25 Some studies demonstrated a similar stroke risk at 30 days10, 21, 24 and 1 year.29 One meta‐analysis showed that women had more strokes compared with men at 30 days post‐TAVR.2 Chieffo et al30 looked at acute and 30‐day outcomes in women after TAVR, results from the WIN‐TAVI Real‐World Registry, a prospective, observational registry of women undergoing TAVR for aortic stenosis. They found an increased 30‐day risk of stroke/transient ischemic attack in women and that such risk remains significantly higher in women at long‐term follow‐up (mean follow‐up of 1.4 years). They noted that despite the long‐term survival advantage of TAVR in women compared with men, the increased risk of stroke should be carefully considered and stroke‐reduction therapies utilized.

In a report from the STS/ACC TVT Registry, female sex was associated with increased risk of stroke at 1 year.25, 31 Given that men have worse baseline vascular comorbidities, it is unclear why women are at higher risk of stroke after TAVR. One theory suggests that, in women, who are typically smaller than men, the risk lies in the valve delivery systems, which would be bulkier in the ascending aorta and the aortic arch compared with men.21 Chieffo et al. hypothesized that the greater use of balloon‐expandable valves in women could also explain the increased risk of stroke.30 They postulated that “cerebral hypoperfusion caused by rapid ventricular pacing and transient outflow tract obstruction during balloon‐expandable valve implantation may increase the risk of watershed infarcts.”30 It is postulated that for female patients, avoidance of balloon aortic valvuloplasty, minimal ventricular pacing, limiting post‐dilatation to underexpanded valves only, and judicious size selection for the valve may reduce both ischemic and embolic stroke post‐TAVR.

In conclusion, women have worse outcomes with SAVR when compared with men. Women undergoing TAVR had improved survival at 1 year compared with men, despite higher rates of postprocedural vascular complications and bleeding events at 30 days, as well as higher risk of stroke. It may be that having lower periprocedural mortality, lower rates of acute kidney injury, better long‐term recovery of LV function and larger postprocedural AVA with a better patient prosthesis match as seen in women for TAVR (in comparison with SAVR) may mitigate the vascular complications and the higher rate of moderate paravalvular leak. This “TAVR survival benefit,” as labeled by Panoulas et al.,1 has not been noted in males, who have more comorbidities, including atherosclerotic burden along with increased paravalvular aortic regurgitation. The TAVR sex data to date illustrate important differences for men and women that should be considered with regard to patient selection, choice of intervention method, and evaluation of risk to help improve long‐term follow‐up.

Conflicts of interest

The authors declare no potential conflicts of interest.

Itchhaporia D. Transcatheter aortic valve replacement in women. Clin Cardiol. 2018;41:229–232. 10.1002/clc.22912