Sex-Related Differences in Outcomes After Percutaneous Balloon Aortic Valvuloplasty

Abstract: Objectives. We aimed to evaluate sex-related differences in short-term and long-term outcomes of patients undergoing balloon aortic valvuloplasty (BAV) for severe aortic stenosis (AS). Methods. A total of 112 patients with severe AS underwent 114 BAV procedures as palliative procedure, bridge to definitive treatment, or before urgent non-cardiac surgery. Patients were followed for 24 months. Results. Of the 112 patients, 70 (62.5%) were women. Women were older, and had a higher STS score and higher prevalence of chronic kidney disease and arterial hypertension. Indications for BAV did not differ by gender. Women had a higher risk of vascular complications than men (15.7% vs 0.0%; P=.01), but with a similar rate of major periprocedural complications (17.1% vs 9.5%; P=.40). Transcatheter aortic valve implantation (TAVI) was performed in 22.8% of women and 26.2% of men (P=.61) and surgical aortic valve replacement in 10% of women and 11.9% of men (P=.70). Women and men treated finally with TAVI/aortic valve replacement had lower mortality as compared with conservative treatment (P<.01). No difference in in-hospital and 24-month mortality between women and men was observed (11.4% vs 4.9% [P=.26]; 63.3% vs 39.0% [P=.22], respectively). In a multivariable Cox model, STS score above 9.8% (hazard ratio, 2.29; 95% confidence interval, 1.09-4.83; P=.03) was an independent predictor of all-cause death only in women. Conclusion. Despite the presence of sex-related differences in baseline and procedural characteristics as well as in the risk of vascular complications, no difference in major procedural complications and long-term mortality was confirmed for patients with severe AS undergoing BAV.

J INVASIVE CARDIOL 2017;29(6):188-194.

Key words: aortic stenosis, transcatheter aortic valve implantation, valvuloplasty

Balloon aortic valvuloplasty (BAV) still retains its place in the management of severe aortic stenosis (AS). Despite the introduction of transcatheter aortic valve implantation (TAVI), physicians still encounter clinical dilemmas concerning patients with AS ineligible for any definitive treatment. In those high-risk patients, BAV can either serve as a stand-alone palliative procedure or as a bridge to TAVI or surgical aortic valve replacement (AVR).¹ In addition, in less frequent cases, BAV allows patients with severe AS to undergo an urgent non-cardiac surgery. On the other hand, the long-term clinical and hemodynamic outcomes of BAV are proved to be rather poor.^2-4 However, taking into account acceptable procedural risk and favorable hemodynamic changes, BAV seems to be sufficient as a bridge therapy or to relieve symptoms of heart failure. Importantly, in the previous studies on the treatment of AS, women are often an over-represented group of patients.^1,5-7 It is well known that women have longer life expectancy, leading to advanced age, which correlates with the prevalence of severe AS. This may explain characteristics of treated populations. Moreover, female sex itself is considered a risk factor in the Society of Thoracic Surgeons (STS) predicted risk of mortality and Logistic EuroScore II predictive models. However, its impact on the total risk profile needs to be further investigated, and there are still limited data on sex-related differences in periprocedural, short-term, and long-term outcomes of patients undergoing transcatheter procedures including TAVI and BAV. In addition, results of the published studies in this field are inconsistent.^8-10 Thus, we sought to assess sex-related differences in baseline and procedural characteristics as well as long-term outcomes of patients undergoing BAV for severe AS.

Methods

Patients and data collection. We included 112 consecutive patients with severe symptomatic AS (aortic valve area [AVA] <1 cm², indexed AVA <0.6 cm²/m² body surface area) who underwent BAV between October 2012 and July 2015 in two Polish centers experienced in diagnostics and interventional treatment of AS.¹ The decision to perform BAV was carried out by an interdisciplinary group of specialists (heart team) after careful consideration of total risk, possible profits, and further planned treatment. The study was approved by the institutional review board and all eligible patients signed informed written consent. Data were collected prospectively using hospital records, outpatient visits, and telephone interviews. While awaiting TAVI or AVR, some patients became ineligible for their planned procedures due to exacerbating comorbidities, frailty, dementia, or diagnosis of cancer with life expectancy <1 year. On the other hand, some patients remaining in ambulatory care were requalified for further definitive treatment of AS after observation of significant symptomatic/left ventricular ejection fraction (LVEF)/comorbidity improvements resulting in diminishing procedural risk of TAVI or AVR.

Procedure. A detailed description of the BAV technique as well as procedural data were previously published.¹ In brief, the aortic valve was reached from femoral retrograde approach under echocardiographic and fluoroscopic guidance. Different balloon sizes were used for each patient depending on annulus diameter measured by transthoracic echocardiography or transesophageal echocardiography. Exact positioning of the balloon was obtained by rapid ventricular pacing from endocavitary electrode placed in the right ventricle. Vascular accesses were closed with Angio-Seal (St. Jude Medical) vascular closure device or with manual compression. The only contraindication for BAV was a baseline severe aortic regurgitation (AR) determined by transthoracic echocardiography. In-hospital major complications were defined as severe AR, tamponade, permanent pacemaker implantation, need for transfusion of ≥2 units red blood cells, stroke, complete atrioventricular block requiring pacing, myocardial infarction, renal failure, and serious vascular complication requiring intervention and/or transfusion.

Echocardiographic data. Pre-BAV, post-BAV, and 1-month, 6-month, and 12-month follow-up echocardiograms were performed by the same experienced echocardiographers using measurements of AVA (continuity equation), peak aortic valve gradient (pAVG), and mean aortic valve gradient (mAVG); degree of AR and LVEF were based on M-mode, Doppler, and two-dimensional conventional echocardiography.¹¹

Statistical methods. Continuous variables were expressed as mean ± standard deviation or median (interquartile range [IQR] or minimum/maximum value) and categorical variables were expressed as number (percentage). Normality was checked by the Shapiro-Wilk test. Continuous variables were compared with unpaired and paired Student’s t-tests when normally distributed and by the Mann-Whitney U-test or Wilcoxon signed-rank test when not normally distributed, as appropriate. The Pearson’s Chi² test or Fisher’s exact test were used to compare the category frequencies. Kaplan-Meier curves for women and men were constructed and compared by the log-rank test. Univariate Cox regression analysis was performed on each of the variables to estimate the hazard ratio (HR) and 95% confidence interval (CI). Multivariable Cox regression analysis was performed to identify the independent predictors of long-term mortality. The significance level was set at P<.05. Statistical analyses were performed with Statistica version 12 (Statsoft, Inc).

Results

Baseline characteristics. Data on 112 patients with severe symptomatic AS undergoing BAV were collected. Women comprised the majority of included patients treated with BAV (n = 70; 62.5%). As compared to men, women were high-risk individuals with older age, higher STS score, and more frequent presence of chronic kidney disease and arterial hypertension (Table 1). On the contrary, men were more likely to undergo previous percutaneous coronary intervention (PCI) despite similar prevalence of coronary artery disease. There was no difference in indications for BAV between women and men (P>.05): bridge for TAVI 48.6% vs 57.1% (n = 34, n = 24); bridge for AVR 3.0% vs 4.2% (n = 3, n = 3); bridge to non-cardiac surgery 7.1% vs 9.5% (n = 5, n = 4); and palliative treatment 37.7% vs 26.2% (n = 26, n = 11).

Echocardiographic data. In echocardiographic data (Table 2), men were characterized with higher AVA at baseline, directly after BAV, and at 1-month, 6-month, and 12-month follow-up than women (+0.12 cm², +0.22 cm², +0.14 cm², +0.16 cm², and +0.18 cm², respectively; P<.05 for all). The favorable effect of increased AVA in women after BAV in comparison with baseline remained statistically significant only directly after BAV and at 1 month (+0.21 cm² and +0.14 cm², respectively; P<.05 for all). In men during all time points of 1-year follow-up after BAV, AVA hasn’t reached baseline values (+0.31 cm², +0.16 cm², +0.06 cm², and +0.07 cm², respectively; P<.05 for all). At baseline, men had lower mAVG than women (-7.6 mm Hg; P<.05 for all); in both groups, we observed a decrease in pAVG and mAVG directly after BAV and at 1 month and 6 months (women: pAVG, -27.7 mm Hg, -20.6 mm Hg, and -6.7 mm Hg; mAVG, -16.9 mm Hg, -10.8 mm Hg, and -2.7 mm Hg, respectively [P<.05 for all]; men: pAVG, -25.6 mm Hg, -21.8 mm Hg, and -9.9 mm Hg; mAVG, -15.6 mm Hg, -10.7 mm Hg, and -4.0 mm Hg, respectively [P<.05 for all]). In our study, men were characterized by lower LVEF at baseline and at all follow-up points than women (P<.05 for all). In men, we observed increase in LVEF after 1 month (+10.5%; P<.05) and in women after 6 and 12 months (+5 and +10%, respectively; P<.05 for all). In the subgroup of patients with LVEF <40%, only women showed an increase in LVEF after 1 month (+23%; P<.05), and this effect was stable up to 6 months after BAV.

Procedural data. Detailed procedural data stratified by gender are shown in Table 3. We noticed some differences between genders concerning equipment used during BAV. The sheath and balloon sizes were larger and the procedures were longer in men than women (all P<.05). Women received a higher amount of contrast media (P<.05) and had longer hospital stays (P<.05). Concomitant coronary angiography during BAV was performed in 7 men and 14 women; moreover, 2 men (4.8%) and 8 women (11.4%) underwent concomitant PCI. 

BAV complications and mortality. Patients were followed for a median of 513 days (IQR, 246-799 days) with no difference between the gender groups: 474 days (IQR, 272-769 days) for women and 642 days (IQR, 231-850 days) for men; P>.05. In-hospital outcomes for both groups are shown in Table 4. Women had numerically higher in-hospital mortality than men; however, statistical significance was not reached (11.4% vs 4.9%; P=.26). We recorded 3 intraprocedural deaths (2 caused by tamponade, 1 due to complete atrioventricular block). No cases of stroke or myocardial infarction after BAV were observed.

Women had a higher risk of vascular complications than man (15.7% vs 0.0%; P<.01) with similar risk of major periprocedural complications (17.1% vs 9.5%; P=.40). Vascular complications resulted in 1 unplanned surgical repair of the femoral artery and 1 retroperitoneal bleeding with open surgery. Within the follow-up period, a total of 16 women (22.8%) and 11 men (26.2%) received TAVI (P=.61), whereas 7 women (10.0%) and 5 men (11.9%) received AVR (P=.70). Periprocedural, in-hospital, and 24-month mortality rates before definitive treatment were comparable between women and men (2.9% vs 2.4% [P>.99]; 11.4% vs 4.9% [P=.26]; and 63.3% vs 39.0% [P=.22], respectively). In a multivariable Cox model, STS >9.8% (HR, 2.29; 95% CI, 1.09-4.83; P=.03) was an independent predictor of all-cause mortality only in women. STS score >9.8% offered the best overall sensitivity, specificity, and positive and negative predictive values (60.0%, 75.6%, 64.3%, and 72.1%, respectively) (Figure 1). The area under the curve for the STS score was 0.693 (95% CI, 0.569-0.817). Figure 2A illustrates the Kaplan-Meier survival curves for women and men after stand-alone BAV procedure and after BAV as a bridge to TAVI or AVR. Furthermore, women and men treated with TAVI or AVR had lower mortality rates when compared with the group who underwent conservative management of their symptoms (P<.01) (Figure 2B). 

Discussion 

The main finding of this study is that despite higher risk profile of women (STS score), no differences were observed in major procedural complications or long-term mortality between women and men undergoing BAV. On the contrary, more vascular complications were noted in women than in men. These findings are consistent with previous studies on the treatment of AS,^12,13 with similarly higher prevalence of vascular complications and bleeding reported in women.^5,14,15 Complication rates after BAV varied in different studies. Data from the NHLBI and Mansfield registry showed high total complication rates above 20%, and the NHLBI registry reported a vascular complication rate of 34%.^2,16 Interestingly, after the introduction of TAVI, the number of complications associated with BAV has tended to decrease,^6,17,18 which could be explained by improved BAV techniques, with smaller sheaths, vascular closure devices, and more experienced operators. On the other hand, patients qualified for BAV are all at high surgical risk and often have low ejection fraction, concomitant severe valve disease, pulmonary hypertension, advanced frailty, hemodynamic instability, and severe comorbidities. These facts increase risk of complications and might affect the worse prognosis of any invasive treatment of severe AS.

The larger amount of vascular complications in women undergoing BAV may result from the presence and susceptibility of smaller-lumen vessels to injury while achieving arterial access. Additionally, it can be related to the use of relatively large arterial sheaths as compared to actual size of the vessel, as well as to concomitant peripheral arterial disease. Procedural risk was also increased by the relatively higher-risk profile of women due to more advanced age and more frequent chronic kidney disease. Importantly, we did not observe any stroke after BAV, contrary to other studies.^6,18,19 Despite a higher number of periprocedural complications among women than men, periprocedural risk seemed to be acceptable for both genders; however, the overall complication rate was quite high for the treated population. 

Furthermore, recent studies suggest the usefulness of BAV in patients ineligible for TAVI/AVR at the time of BAV, providing information about the hemodynamic and clinical response concerning recovery of low ejection fraction, functional recovery, reduction in the magnitude of mitral valve regurgitation, and pulmonary artery systolic pressure.¹⁹ In our study, hemodynamic outcomes of BAV as assessed by echocardiography were generally comparable between both genders; nevertheless, women at baseline and after BAV presented with lower AVA than man. Christodoulidis et al similarly reported lower AVA and higher mAVG in women before BAV.⁸ Despite the fact that men had significantly lower LVEF at baseline than women, in the subgroup of patients with LVEF <40%, only women benefited in terms of LVEF improvement at 1 month after BAV. On the other hand, Saia et al¹⁹ and Kefer et al²⁰ showed no difference in baseline characteristics including gender in patients with reduced LVEF with or without significant LVEF improvement after BAV.An increase in LVEF may be crucial in reducing procedural risk and requalifying for final treatment of severe AS as it may confirm the presence of LV contractility reserve, particularly in patients with low-flow, low-gradient AS. Barbash et al²¹ demonstrated that BAV predicted LVEF improvement after TAVI better than dobutamine stress echocardiography, while recovery of LVEF post TAVI was confirmed in numerous previous studies.^22-25 Baseline gender differences were also reported in LV remodeling adaptation to severe AS with different patterns of myocardial fibrosis.²⁶ 

The observed higher contrast load during BAV in women compared with men could result from more frequent concomitant coronary angiography/PCI in women. It is important to note that female sex is a risk factor for contrast-induced nephropathy in patients with renal impairment undergoing TAVI.²⁷ The amount of contrast used for standalone BAV is very limited, as it is used mainly to prepare the aortic balloon. No cases of contrast-induced nephropathy after BAV were observed, which makes BAV appropriate in patients with renal impairment. 

There are still ambiguous data concerning sex-related differences in outcomes of invasive treatment of coronary artery and valvular heart diseases. Published data on female patients undergoing isolated AVR showed no increased risk of early and late mortality as compared with men.²⁸ Undergoing TAVI after BAV has significantly improved outcomes as compared with stand-alone BAV procedure.^6,29 Similarly, our study confirms higher survival in patients finally scheduled for TAVI/AVR than in patients remaining on conservative treatment. However, this difference may be driven not only by the beneficial effects of TAVI/AVR, but foremost by the presence of comorbidities and frailty features in patients treated conservatively after BAV. O’Connor et al¹⁴ reported that female sex was an independent predictor of late survival after TAVI.In contrast, we failed to confirm any impact of gender on long-term mortality after BAV. The survival depended only on baseline risk profile (STS score) in women. Other predictors of mortality in patients undergoing BAV from different studies included reduced LVEF, NYHA class, cardiogenic shock, or emergent status at the time of the procedure.^17,18,30

Study limitations. The present study has several limitations. A relatively small sample size didn’t allow the definitive confirmation/exclusion of the relationship between gender and outcomes in patients with AS undergoing BAV. On the other hand, this is one of the largest prospective studies addressing this issue. The lack of follow-up echocardiograms after BAV resulted from a low compliance with outpatient follow-up visits. 

Conclusion

Despite the presence of significant sex-related differences in baseline and procedural characteristics, as well as in the risk of vascular complications, no difference in major procedural complications and long-term mortality was confirmed for patients with severe AS undergoing a BAV procedure. 

References

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From the ¹2nd Department of Cardiology, Institute of Cardiology, Jagiellonian University Medical College, University Hospital, Krakow, Poland; and ²Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University Medical College, The John Paul II Hospital, Krakow, Poland.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted December 19, 2016, provisional acceptance given December 31, 2016, final acceptance given February 3, 2017.

Address for correspondence: Dariusz Dudek, MD, PhD, FESC, Department of Interventional Cardiology, Jagiellonian University Medical College, 17 Kopernika Street, 31-501 Krakow, Poland. Email: mcdudek@cyfronet.pl