Int J Surg Res Pract ISSN: 2378-3397

• Abstract
• Introduction
• Methods
• Results
• Discussion
• Disclosures
• Figure 1
• Table 1
• Table 2
• Table 3
• Table 4
• Table 5
• Table 6
• References

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International Journal of Surgery Research and Practice

Toronto General Hospital, University Health Network, Canada

Abstract

Background: Studies have demonstrated gender differences in adverse events after cardiac surgery, with men experiencing more favorable outcomes. The scarce gender-focused literature in the left ventricular assist device (LVAD) population has failed to find consistent differences. It has also been suggested that women experience longer transplant wait times due to higher PRA values.

Methods: A retrospective chart review was conducted of 28 women and 75 men who received an LVAD from 2006-2015. Chi squares, T tests, nonparametric tests, regression and Kaplan-Meier analysis were used as appropriate to compare event rates between groups. Re-admissions were categorized using the INTERMACS Appendix.

Results: Before and after correction for gender size differences, women on LVAD support were shown to wait longer for transplant (p = 0.02, p = 0.006). On average, women waited for 562 ± 374 days versus 279 ± 207 days for men. During LVAD support, mortality rates were 25% in men and 39% in women (p > 0.05). There were no differences in outcomes, re-admissions, or time spent in hospital (p > 0.05). While women have higher PRA values than men (p = 0.04, p = 0.04), patients' PRA values at discharge did not relate to transplant wait time (p = 0.13).

Patients maximum PRAs throughout LVAD support showed a statistically significant but mild relationship to transplant wait time (p = 0.04, R² = 0.07).

Conclusions: Since men and women spend similar amounts of time in-hospital, this suggests that the longer support times observed in women are not associated with increased adverse events. Gender differences in PRAs were not sufficient to explain women's longer transplant wait times.

Introduction

In Canada, 40,000 women are newly diagnosed with heart failure (HF) every year [1]. While the prevalence and incidence of HF is comparable among genders, women exhibit a unique risk factor profile [1,2]. While some reports claim that women with HF experience increased adverse events and higher mortality rates, [3-9] others have shown that women present with fewer comorbidities and preserved ejection fractions, reducing total mortality [10-13]. End-stage heart failure requires intervention, which could include medical therapy, mechanical circulatory support, or cardiac transplantation. Cardiac transplantation is still considered the ideal treatment for advanced HF, but donor heart shortages have led to increasing numbers of patients being bridged with left ventricular assist devices (LVAD).

Women were underrepresented in most multi-center, randomized controlled trials for mechanical circulatory support (MCS). Further, it has been shown that women recovering from cardiac surgeries, including coronary artery bypass grafting, aortic valve repair, and cardiac transplantation, have poorer outcomes then men [14,15]. The literature is scarce regarding gender-related LVAD outcomes and complications. Studies from the pulsatile era found that women experienced increased mortality and higher incidences of bleeding and neurological events [3,9,16]. Studies from the non-pulsatile era examining gender differences in LVAD support have generally found no differences in mortality [8,17-19].

When it comes to post-LVAD transplantation, women tend to receive fewer cardiac transplants and wait longer to receive them [8]. Lower rates of transplantation may be explained by higher titres of panel reactive antibodies (PRAs) in parous women. Additionally, women may be at higher risk of antibody-mediated rejection of donor allograft [19]. Studies have also shown an increase in sensitization post LVAD implantation [20]. The primary objective of the present study is to analyze sex-related outcomes post-LVAD implantation, with a special interest in transplant wait times, re-admissions, and PRA differences.

Methods

The present study is a retrospective chart review of 103 patients who received continuous flow LVADs at Toronto General Hospital from June 2006 until May 2015. All patients who received a Heart Mate II, Heart Ware, Dura heart, and Heart Mate III device were included in the analysis. Re-admissions were used as a surrogate marker for overall patient morbidity. Patient wait-times were based on date of LVAD implant. Length and etiology of readmissions as categorized using INTERMACS 2015 Adverse Events Definitions were recorded. The institutional research ethics board approved the project.

Complete records were obtained of patients' panel reactive antibody testing history. Class I antibody values were collected and used for analyses as these values have the greatest bearing on transplant assessments at our centre. Test results collected included general PRA class I percentages as well as calculated PRAs (cPRAs) from single antigen specificity assays. For each member of the study population, two PRA values were obtained. These included the measurement after surgery, which was taken closest to time of discharge, and the highest value obtained during time on LVAD support. PRA levels were not assessed in those LVAD recipients who were not transplant eligible. However, in those patients who were eventually transplanted, PRA values were available in 100% of cases.

Statistical analysis was conducted using SAS 9.4 and SPSS software. An alpha level of p = 0.05 was set for all analyses and all tests conducted were two-sided. Categorical variables were analyzed using chi-squared tests. Continuous variables were assessed using unpaired T-tests. Variables that did not exhibit normal distributions were analysed using nonparametric tests. Linear regression analysis was conducted to assess the relationships between PRAs and patients' LVAD support time, the time spent outside of hospital, and waiting time for transplant.

Men in the study population weighed significantly more than women (85 ± 20 vs. 62 ± 10 kg, Table 1). Consequently, support times, time spent outside of hospital, and waiting time for transplant were also re-assessed after size adjustment with additional unpaired T-tests. Patients of a larger stature are expected to wait longer to have a donor heart that is able to adequately perfuse their body become available. This size adjustment excluded patients who had weights greater than 80 kg from subsequent T-tests to control for the effects of patient size on likelihood of transplantation. Survival comparisons were completed using the Kaplan-Meier method, censoring transplanted patients. Mantel-Cox log-rank test was used to compare differences in survival.

Results

Seventy-five men and 28 women were included in the analysis (Table 1). There was a significant difference in heart failure etiology between the 2 groups with most men having an ischemic cardiomyopathy diagnosis and most women having a dilated cardiomyopathy diagnosis (p = 0.03, Table 1). Men had significantly higher preoperative weight, body mass index, and body surface area. These differences likely played a key role in the difference which was also observed in the type of device implanted, with the majority of men receiving a Heart Mate II and the majority of women receiving a Heart Ware HVAD (p = 0.005).

There were no significant differences in rates of transplantation and stroke, or in length of hospital stay and support times between the 2 groups (Table 2). Women waited for transplant for an average of 562 ± 374 days versus 279 ± 207 days for men (p = 0.02, Table 2). After size adjustment, these gender differences in wait times remained significant, with this cohort's wait times being 625 ± 345 days versus 273 ± 238 days for women and men, respectively (p = 0.006, Table 3).

Women were found to have significantly higher class 1 PRA values throughout LVAD support (60% vs. 24% p = 0.04) and prior to discharge (49% vs. 17% p = 0.04) (Table 4). More specifically, women were more likely to be classified as highly sensitized (class 1 PRA > 90%) throughout LVAD support and at discharge (p = 0.0004 and p = 0.04, p = 0.0004, Table 5). Classification of patients as highly sensitized enables them to be listed for transplant as status 4S when applicable. A modest but statistically significant relationship was observed between patients' maximum PRAs on LVAD support and their transplant waiting time (p = 0.04, R2 = 0.07) (Table 5). Despite observed gender differences in each of these variables, patients' PRAs at discharge from hospital were not found to relate linearly to transplant wait times (p = 0.13, Table 5).

There were no differences in total number of readmissions or reason for admission between the 2 groups (p = 0.18, p > 0.05, Table 6). While there were no significant differences, women experienced double the incidence of bleeding in comparison to their male counterparts. Additionally, while the average number of readmissions between the genders did not reach significance, it is clear that women tended to be readmitted more and there was a wide variance in the group (SD = 4.6).

Figure 1 shows a Kaplan-Meier survival curve for men and women. There was no difference in perioperative, one year and 2-year mortality between the 2 groups (p = 0.611). Women exhibited higher mortality rates in each of the above-mentioned time points. While differences in overall mortality on LVAD support between genders did not reach significance, it is important to note that women experienced higher rates of mortality at 39.3% versus 25.3% for men (p = 0.17, Table 6). There were no significant gender differences in all-cause mortality (p = 0.32).

Discussion

The findings from the present study have shown that on average, women have lower overall weight, BMI and BSA than their male counterparts. Further, men have significantly higher incidence of ischemic cardiomyopathy and are implanted with Heart Mate 2 versus their female counterparts who largely receive Heart Ware. Most importantly, women on LVAD support wait longer for transplant than men. Differences in transplant wait times were still present after correction for gender size differences, meaning that difficulties with size-matching donor hearts were not sufficient to explain observed wait times. Although women showed higher PRA values than men, it is not our opinion that these differences fully explained the gender discrepancy in transplant wait times either. A regression plotting patients' maximum PRAs with their transplant wait times did reach statistical significance, but with an R2 value of 0.07, this relationship can hardly be said to be linear. Although differences in mortality and readmissions between genders did not reach significance, the present study yielded observations which warrant further examination of these variables.

The finding that women on LVAD support have higher PRAs than their male counterparts is neither novel nor unexpected given the impact of pregnancies. The present study determined that the influence of these differences on transplant wait times may not be as straightforward as we expected. PRAs of women receiving LVAD support have consistently been shown to be higher than those of their male counterparts [21,22]. The relationship between PRAs and transplant wait times for people receiving LVAD support is less clear. A recent multi-center study which included earlier data from our own centre found that increased PRAs reduced odds of transplant, but had no significant impact on wait time [21]. When assessed categorically, authors have found that highly sensitized patients (class 1 or 2 > 25%) have longer wait times [22]. While the present study observed only a very mild relationship between PRAs and transplant waiting time, we cannot negate the impact which PRAs are known to have on transplantation decisions. It is now important that we consider which other variables could have influenced this pattern of data. We have two theories as to why this may have occurred. For women receiving LVAD support, the risks associated with transplantation may appear to outweigh the benefits more frequently, with the converse occurring more frequently for men. Our second theory for why women on LVAD support wait longer for transplant concerns the impact of clinicians' expectations of the impact of PRAs on transplant wait times. There is a chance that women are simply expected to wait longer due to their higher PRAs, so their care providers are not surprised or concerned when longer wait times are observed, hindering interventions to alter this trend.

In the general heart failure population, women have been shown to have worse outcomes waiting for transplant. In Morris, et al. examination of all adults listed for cardiac transplant in the United States from 2000-2014, women were shown to in fact spend fewer days on the transplant list, but have an increased mortality risk while waiting [23]. Furthermore, women were less likely to receive LVAD support than men [23]. Women were also at increased risk for removal from the transplant list for death or deterioration in The Waiting for a New Heart Study [24]. Although significant survival differences were not observed in our study population, these observations still provide incentive to further examine causes for increased transplant wait times their effects.

While the majority of baseline characteristics examined in the present study did not display gender differences, differences were observed in size, device, diagnosis, and presence of hypertension. Women in the present study were found to be significantly smaller than men with respect to weight, BMI, and BSA. Not unexpectedly, this has been true of other examinations of patients on LVAD support [8,25]. These size differences impact LVAD patients' courses of care through numerous avenues. Smaller patients are more frequently implanted with a Heart Ware HVAD due to its compact design, and larger patients are more frequently implanted with a Heart Mate device due to its power capabilities. It is also likelier that transplanted individuals receive hearts from oversized donors than undersized donors to accommodate for any residual pulmonary hypertension in the recipient. This makes our finding of increased transplant wait times for women all the more significant, since one might expect women to in fact receive acceptable hearts faster due to their smaller sizes. Our study also observed higher incidence of hypertension and ischemic etiology in men. Other authors have observed comparable gender differences for these variables in their LVAD patient populations [8,25] although this is not always the case [18].

The present study found no difference in all-cause mortality between women and men on continuous flow LVAD support. The literature examining gender differences in mortality post LVAD implantation is conflicting. Large, multicenter trials including one reporting findings from the INTERMACS database found no gender differences in LVAD patients' mortality [8,17,18,25]. Smaller studies did observe increased risk in women for mortality and right heart failure [3,26]. We are happy to note that the present study is in agreement with INTERMACS findings. Of note, most of the mortality observed in the present study was contained within the postoperative time point of index admission (19 patients, 63% of deaths) which is agreement with literature [8,18]. The sixth INTERMACS Annual Report described 1 and 2 year LVAD mortality rates at 20% and 31%, respectively. We observed comparable mortality rates of 23% at 1-year and 26% at 2-years. Interestingly, while INTERMACS reported a 30-day mortality of 5%, our center experienced rates nearing 18% [27]. This difference in mortality rates warrants further analysis at our center and might reflect center-specific practices such as discharge to external care facilities [18,25].

With an increasing population of longitudinally supported LVAD patients, it is important to monitor and reduce re-admissions to increase patients' quality of life and lower the financial burden on our healthcare system. While there were no statistically significant gender differences between the average numbers of readmissions, women had a higher number on average with a large variance. Of note, the patients that had the three highest numbers of readmissions [13,14,17] were all women. Unlike other centers [25], time spent in the hospital was not found to differ significantly between genders at our center. However, women spent more time hospitalized on average, with high variances. Interestingly, there were no significant differences in etiology for readmissions between the genders, which is promising considering women have been shown to be at higher risk of bleeding episodes post implantation. There does seem to be increased incidence of bleeding events in women, supporting findings at other centers [28,29]. While increased incidence of bleeding presents a concern independently, these adverse events were not associated with increased PRA values (p > 0.05 for all analyses).

The bulk of the present study's limitations center on its retrospective nature. More specifically, baseline characteristics that were not controlled for at the outset of the study may have impacted its results. Our sample size was relatively small, and we were not able to correct for repeated analysis on this sample. The present study also may not be widely generalizable due to the fact that it was a single-centre study. This being said, our centre serves a wide catchment area and is the largest LVAD center in the country.

The present study supports existing literature on gender differences in transplant wait times while questioning our assumptions regarding the reasons for these differences. Contrary to commonly held beliefs that patients' PRAs independently predict their time to transplant, we have not observed this relationship in our patient population. We are happy to report that there were no significant gender differences for actuarial mortality or readmissions.

Disclosures

Vivek Rao MD is a consultant to Terumo Corp (Tokyo), Thoratec Corp (Plesanton, Calif), and Heart Ware International Inc (Framingham, Mass). All other authors have nothing to disclose.

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