Abstract
Background.
Prior studies demonstrated that female sex is associated with an increased mortality after orthotopic heart transplantation (OHT). The impact of sex on OHT outcomes after bridging with newer-generation durable left ventricular assist devices (LVADs) remains unclear.
Methods.
The United Network for Organ Sharing database was queried to study OHT recipients bridged with a newer-generation LVAD (ie, HeartMate III or HeartWare) between 2010 and 2018. The primary outcome was mortality at 30 and 90-days and 1-year. Secondary outcomes included rates of posttransplant complications. Propensity score matching and Cox multivariable analysis were used to assess comorbidity-adjusted sex differences in outcomes.
Results.
A total of 3010 patients (76.7% male) bridged with newer-generation LVADs underwent OHT. After adjusting for relevant covariates, both age and heart failure etiology, but not sex, were independent predictors of mortality. In the matched cohorts, sex did not affect posttransplant outcomes, including renal failure, cerebrovascular events, allograft rejection, functional status, or mortality (all P > .05). Survival at 1-year after OHT was 90.5% in males and 92.8% in females (P = .058).
Conclusions.
Among 3010 OHT recipients, matched females bridged with newer-generation HeartWare or HeartMate III LVADs have comparable posttransplant outcomes compared with males. Furthermore, survival at 1-year follow-up was not affected by sex; instead, it was driven by well-established risk factors including increased age, worse preoperative renal function, and heart failure etiology. These data suggest that considerable progress has been made in mitigating sex differences in heart failure outcomes in the modern era.
Left ventricular assist device (LVAD) implantation in end-stage heart failure patients provides enhanced circulatory support that allows for preservation of distal organ perfusion and improvements in quality of life in those awaiting orthotopic heart transplantation (OHT). Substantial progress in device design, including the evolution from pulsatile to centrifugal pumps, has decreased the rates of major LVAD-related events and enhanced the success of bridge-to-transplant (BTT) strategies. Despite this, prior studies demonstrated sex differences in both LVAD and OHT outcomes, with women commonly faring worse than men.1–3 In one study, females undergoing LVAD bridging displayed worse survival after OHT when observed up to 10 years.1 When considering the risks associated with mechanical circulatory support (MCS) alone, females display a higher risk for stroke and worse 1-year survival after LVAD implantation compared with males.1,3 Nevertheless, a study4 suggested that females may actually gain more benefit from newer-generation LVADs than males. Because the use of newer-generation (ie, centrifugal) LVADs may be associated with improved survival with lower complication rates,5,6 we sought to investigate the relationship between sex and OHT outcomes among patients bridged with a HeartWare (Medtronic, Minneapolis, MN) (HVAD) or HeartMate III (Abbott, Lake Bluff, IL) (HM3) device.
Patients and Methods
Data Source
Data were obtained from the United Network for Organ Sharing (UNOS) registry, which provides information on all solid organ transplants in the United States. This study was approved by the Institutional Review Board at the University of Pittsburgh.
Study Population
Adults (aged ≥18 years) who underwent implantation of a newer-generation (ie, centrifugal), durable LVAD as a bridge to OHT between January 1, 2010 and December 31, 2018 were included. Newer-generation LVADs included either an HM3 or HVAD device. We excluded all patients receiving concurrent support with other ventricular assist device (VAD) models as well as patients bridged with other types of MCS including a total artificial heart, extracorporeal membrane oxygenation, and temporary VADs. The resulting cohort of patients was stratified by sex for all analyses.
Statistical Analysis
Baseline characteristics are presented as frequency (percentage) for categorical variables and mean (SD) or median (interquartile range) for continuous variables as appropriate based on normality. For categorical variables, Pearson chi-square test was used for categorical comparisons, whereas for continuous variables, Student t test was employed. Multivariable Cox regression analysis was used to obtain adjusted hazards for mortality at 30 and 90 days and 1 year after OHT. To account for differences in baseline characteristics, propensity scores were obtained with probit regression using the Stata pscore package; matching with 1:1 pairing was performed employing the following variables: age, sex, race, VAD type, heart failure etiology, diabetes, creatinine level, pulmonary capillary wedge pressure, panel reactive antibody (PRA), ABO blood type, functional status, sex matching, and cytomegalovirus matching. Males and females were matched using nearest-neighbor matching with a caliper distance of 0.20 the SD of the logit of the propensity score. Appropriateness of matching was confirmed by an absolute standardized mean difference of less than 0.10. In the matched cohort, univariate Cox analysis was used to obtain the hazard ratio (HR) associated with sex for mortality. We carried out Kaplan-Meier analysis to compare survival in both the matched and unmatched cohorts.
Results
Baseline Characteristics
A total of 3010 patients were included in the analysis, 2310 of whom were male (76.7%). Mean age was significantly higher in males (53 versus 49.7 years; P < .001) (Table 1). There were no significant sex differences in the type of LVAD used; approximately 85% of patients received a HVAD device and the remaining patients were supported with an HM3 device (P = .12). Males were more likely to have ischemic cardiomyopathy (38.8% versus 19.7%) whereas nonischemic dilated cardiomyopathy was more common among females (72.9% versus 55.5%) (P < .001). Mean calculated panel reactive antibody percentage was significantly higher among females (26.6% versus 8%; P < .001). Males were more likely to undergo transplantation with a same-sex donor (84.7% versus 63.3%; P < .001) and less likely to have a cytomegalovirus-matched donor (51.1% versus 56.5%; P = .012). Propensity score matching resulted in a well-matched cohort of 648 males and females with similar baseline characteristics (Table 2). Of note, 95.2% of OHTs (n = 617) occurred before the 2018 UNOS allocation policy change.
Table 1.
Characteristics of Patients Undergoing Orthotopic Heart Transplantation After Bridging With Newer-Generation Left Ventricular Assist Devices, Stratified by Sex
| Characteristics | Males (N = 2310 [76.7%]) | Females (N = 700 [23.3%]) | P |
|---|---|---|---|
| Age, y (mean [SD]) | 53 (11.8) | 49.7 (13.3) | <.001 |
| Race, n (%) | <.001 | ||
| Caucasian | 1550 (67.4) | 417 (59.6) | |
| African American | 484 (21) | 203 (29) | |
| Hispanic | 168 (7.3) | 52 (7.4) | |
| Other | 98 (4.3) | 26 (3.7) | |
| Body mass index, kg/m2 (mean [SD]) | 27.9 (4.8) | 27.4 (5.5) | .183 |
| Temporary support device, n (%) | .122 | ||
| HeartWare | 1962 (84.9) | 611 (87.3) | |
| HeartMate III | 348 (15.1) | 89 (12.7) | |
| Smoking history, n (%) | 1215 (52.6) | 272 (38.9) | <.001 |
| Etiology of heart failure, n (%) | <.001 | ||
| Nonischemic dilated cardiomyopathy | 1283 (55.5) | 510 (72.9) | |
| Ischemic cardiomyopathy | 897 (38.8) | 138 (19.7) | |
| Congenital | 29 (1.3) | 3 (0.4) | |
| Valvular | 12 (0.5) | 7(1) | |
| Hypertrophic cardiomyopathy | 21 (0.9) | 14 (2) | |
| Restrictive cardiomyopathy | 20 (0.9) | 12 (1.7) | |
| Failed primary heart transplant | 6 (0.3) | 0 | |
| Other/unknown | 42 (1.8) | 16 (2.3) | |
| Intraaortic balloon pump, n (%) | 130 (5.6) | 42 (6) | .710 |
| Inotropes, n (%) | 626 (27.1) | 200 (28.6) | .445 |
| Dialysis, n (%) | 46 (2) | 7 (1) | .423 |
| Diabetes mellitus, n (%) | 728 (31.5) | 168 (24) | <.001 |
| Serum creatinine, mg/dL | 1.33 (0.66) | 1.08 (0.55) | <.001 |
| Pulmonary artery pressure, mm Hg (mean [SD]) | 30.4 (10.3) | 29.7 (10.2) | .146 |
| Pulmonary capillary wedge pressure, mm Hg (mean [SD]) | 20.4 (9.2) | 19.5 (9) | .037 |
| Calculated panel reactive antibodies (%) (mean [SD]) | 8.0 (18.6) | 26.6 (36.0) | <.001 |
| Blood type, n (%) | .02 | ||
| A | 906 (39.2) | 226 (32.3) | |
| AB | 92 (4) | 31 (4.4) | |
| B | 327 (14.2) | 106 (15.1) | |
| O | 985 (42.6) | 337 (48.1) | |
| Functional status, n (%) | .014 | ||
| Moribund | 1294 (56) | 435 (62.1) | |
| Moderate assistance | 683 (29.6) | 190 (27.1) | |
| No assistance | 264 (11.4) | 56 (8) | |
| Unknown | 69 (3) | 19 (2.7) | |
| Same-sex donor/recipient, n (%) | 1957 (84.7) | 443 (63.3) | <.001 |
| Cytomegalovirus matched, n (%) | 1173 (51.1) | 393 (56.5) | .012 |
| Human leukocyte antigen mismatch, n (%) | 1741 (84.6) | 511 (84.9) | .883 |
| ABO match, n (%) | 2087 (90.3) | 621 (88.7) | .208 |
Table 2.
Characteristics of Patients Undergoing Orthotopic Heart Transplantation After Bridging With Newer-Generation Left Ventricular Assist Devices, Stratified by Sex After Propensity Score Matching
| Males (N = 324) | Females (N = 324) | P | Standardized Mean Difference | |
|---|---|---|---|---|
| Age, y (mean [SD]) | 50.8 (12.5) | 51 (12.8) | .879 | 0.042 |
| Race, n (%) | .090 | 0.095 | ||
| Caucasian | 189 (58.3) | 208 (64.2) | ||
| African American | 79 (24.4) | 81 (25) | ||
| Hispanic | 30 (9.3) | 22 (6.8) | ||
| Other | 26 (8) | 13 (4) | ||
| Body mass index, kg/m2 (mean [SD]) | 27.9 (4.8) | 27.9 (5.6) | .998 | 0.005 |
| Temporary support device, n (%) | .916 | 0.019 | ||
| HeartWare | 271 (83.6) | 270 (83.3) | ||
| HeartMate III | 53 (16.4) | 54 (16.7) | ||
| Smoking history, n (%) | 122 (37.7) | 131 (40.4) | .469 | 0.085 |
| Etiology of heart failure, n (%) | <.001 | 0.041 | ||
| Nonischemic dilated cardiomyopathy | 198 (61.1) | 233 (71.9) | ||
| Ischemic cardiomyopathy | 107 (33) | 66 (20.4) | ||
| Congenital | 7 (2.2) | 0 | ||
| Valvular | 1 (0.3) | 4 (1.2) | ||
| Hypertrophic cardiomyopathy | 2 (0.6) | 9 (2.8) | ||
| Restrictive cardiomyopathy | 2 (0.6) | 6 (1.9) | ||
| Failed primary heart transplant | 1 (0.3) | 0 | ||
| Other/unknown | 6 (1.9) | 6 (1.9) | ||
| Intraaortic balloon pump, n (%) | 11 (3.4) | 17 (5.3) | .246 | 0.106 |
| Inotropes, n (%) | 85 (26.2) | 84 (25.9) | .929 | 0.020 |
| Dialysis, n (%) | 0 | 4 (1.2) | .045 | 0.168 |
| Diabetes mellitus, n (%) | 89 (27.5) | 85 (26.2) | .723 | 0.021 |
| Serum creatinine, mg/dL | 1.1 (0.3) | 1.1 (0.5) | .708 | 0.030 |
| Pulmonary artery pressure, mm Hg (mean [SD]) | 28.9 (10.5) | 29.4 (10.5) | .560 | 0.078 |
| Pulmonary capillary wedge pressure, mm Hg (mean [SD]) | 19.1 (9) | 19.3 (9) | .750 | 0.036 |
| Calculated panel reactive antibodies (%) (mean [SD]) | 21.2 (29.5) | 16.5 (28.6) | .039 | 0.153 |
| Blood type, n (%) | .466 | 0.050 | ||
| A | 100 (30.9) | 107 (33) | ||
| AB | 11 (3.4) | 16 (4.9) | ||
| B | 47 (14.5) | 53 (16.4) | ||
| O | 166 (51.2) | 148 (45.7) | ||
| Functional status, n (%) | .560 | 0.095 | ||
| Moribund | 202 (62.4) | 195 (60.2) | ||
| Moderate assistance | 85 (26.2) | 92 (28.4) | ||
| No assistance | 24 (7.4) | 29 (9) | ||
| Unknown | 13 (4) | 8 (2.5) | ||
| Same-sex donor/recipient, n (%) | 201 (62) | 212 (65.4) | .369 | 0.060 |
| Cytomegalovirus matched, n (%) | 182 (56.5) | 175 (54.2) | .550 | 0.053 |
| Human leukocyte antigen mismatch, n (%) | 247 (87.3) | 243 (85) | .425 | 0.063 |
| ABO match, n (%) | 290 (89.5) | 282 (87) | .329 | 0.078 |
Posttransplant Outcomes
In the unmatched cohort, male patients spent significantly longer on the waiting list (224 versus 194 days; P = .003) and were more likely to develop posttransplant renal failure (13.6% versus 9%; P < .001) (Table 3). In the matched cohorts, there were no significant sex differences in median length of hospital stay (16 days in both; P = .688) or rejection within 1 year (21% of males versus 23.2% of females; P = .586), stroke (2.2% versus 3.1%; P = .282), and renal failure (12.4% versus 11.1%; P = .625). Functional status in males and females was also comparable after transplant (P = .65). There were no significant differences in short-term (30- or 90-day) or longer-term (1-year) mortality between sexes (all P > .05). After matching, there were only 9 males and 9 females with graft failure. Of those, there was a significant difference in etiology; most males (88.9%) had primary graft nonfunction, whereas among females, the causes were evenly split among primary nonfunction, acute rejection, and other causes (P = .043).
Table 3.
Sex-Based Characteristics and Outcomes of Patients Bridged With Newer-Generation Left Ventricular Assist Devices in Unmatched and Matched Cohorts
| Unmatched Cohort | Matched Cohort | |||||
|---|---|---|---|---|---|---|
| Males (N = 2310 [76.7%]) | Females (N = 700 [23.3%]) | P | Males (N = 324 [50%]) | Females (N = 324 [50%]) | P | |
| Characteristics | ||||||
| Reason for removal from waiting list | .93 | .317 | ||||
| Transplanted | 2307 (99.9) | 699 (99.9) | 324 (100) | 323 (99.7) | ||
| Died during transplant | 3 (0.1) | 1 (0.1) | 0 | 1 (0.3) | ||
| Days on waiting list | 224 (101–458) | 194 (86–392) | .003 | 232 (97.5–483) | 186.5 (74.5–353) | .010 |
| Days at status 1A | 31 (11–64) | 25 (5–51) | <.001 | 30 (10–67.5) | 23 (2–47.5) | .003 |
| Ischemic time, h | 3.1 (1.1) | 3.1 (1) | .700 | 3.1 (1) | 3 (1) | .280 |
| Distance from hospital, miles | 70 (10–222) | 95 (11–286) | .003 | 81 (16–214.5) | 88.5 (10–269) | .775 |
| Outcomes | ||||||
| New-onset dialysis | 314 (13.6) | 63 (9) | <.001 | 40 (12.4) | 36 (11.1) | .625 |
| Cerebrovascular accident | 94 (4.1) | 18 (2.6) | .179 | 7 (2.2) | 10 (3.1) | .282 |
| Pacemaker | 61 (2.6) | 19 (2.7) | .469 | 11 (3.4) | 4 (1.2) | .113 |
| Median length of stay, d | 16 (11–24) | 16 (11–25) | .865 | 16 (12–24) | 16 (12–26) | .688 |
| Rejection requiring treatment within 1 y | 301 (18.9) | 109 (22.2) | .10 | 45 (21) | 49 (23.2) | .586 |
| Mortality | ||||||
| 30-d | 83 (3.6) | 20 (2.9) | .348 | 9 (2.8) | 8 (2.5) | .806 |
| 90-d | 138 (6.0) | 33 (4.7) | .207 | 15 (4.6) | 14 (4.3) | .849 |
| 1-y | 204 (8.8) | 46 (6.7) | .058 | 19 (5.9) | 26 (8) | .279 |
| Functional status at most recent follow-up | .518 | .650 | ||||
| Moribund | 363 (15.7) | 108 (15.4) | 169 (52.2) | 176 (54.3) | ||
| Moderate assistance | 1420 (61.5) | 450 (64.3) | 83 (25.6) | 84 (25.9) | ||
| No assistance | 418 (18.1) | 112 (16) | 52 (16.1) | 51 (15.7) | ||
| Unknown | 109 (4.7) | 30 (4.3) | 20 (6.2) | 13 (4) | ||
| Cause of graft failure | .321 | .043 | ||||
| Primary nonfunction | 55 (55) | 17 (50) | 8 (88.9) | 3 (33.3) | ||
| Acute rejection | 16 (16) | 7 (20.6) | 0 | 3 (33.3) | ||
| Chronic rejection/atherosclerosis | 15 (15) | 2 (5.9) | 0 | 0 | ||
| Other | 14 (14) | 8 (23.5) | 1 (11.1) | 3 (33.3) | ||
Survival Analysis
Multivariable Cox analysis of mortality demonstrated the influence of age, heart failure etiology, and pretransplant creatinine levels on outcomes. Increasing age was associated with an increased hazard for mortality at all time points (30 days: HR = 1.02, P = .028; 90 days: HR = 1.02, P = .002; 1 year: HR = 1.02, P = .003) (Table 4). The presence of a valvular etiology of heart failure was significantly associated with mortality for all time points (all P < .05). In addition, at 1 year, the pretransplant diagnosis of ischemic cardiomyopathy was associated with an increased hazard for death (HR = 1.37; P = .027). The HRs for female sex in each model demonstrated no adverse effect of sex on OHT outcomes after bridging with a newer-generation LVAD (30 days: HR = 0.85, P = .529; 90 days: HR = 0.92, P = .694; 1 year: HR = 0.89, P = .484). Univariate Cox models using the matched cohorts also demonstrated independence between sex and mortality (Table 4). Survival at 30 and 90 days and 1 year in the matched cohorts was 96.5%, 93.9%, and 90.5%, respectively in males compared with 97.1%, 95.1%, and 92.8%, respectively in females (all P > .05) (Figure 1).
Table 4.
Predictors of Mortality After Orthotopic Heart Transplantation by Univariate and Multivariate Cox Regression Analysis Among Patients Bridged With Newer-Generation Left Ventricular Assist Devicesa
| Hazard Ratio | 95% Confidence Interval | P | ||
|---|---|---|---|---|
| 30-d | Univariate analysis | |||
| Sex | ||||
| Male | Reference | Reference | Reference | |
| Female | 0.96 | 0.57–1.63 | .888 | |
| Multivariate analysis | ||||
| Sex | ||||
| Male | Reference | Reference | Reference | |
| Female | 0.85 | 0.52–1.40 | .529 | |
| Age | 1.02 | 1.0–1.04 | .028 | |
| Etiology of heart failure, n (%) | ||||
| Nonischemic dilated cardiomyopathy | Reference | Reference | Reference | |
| Ischemic cardiomyopathy | 0.86 | 0.55–1.36 | .527 | |
| Congenital | 4.10 | 1.24–13.52 | .20 | |
| Valvular | 7.24 | 2.62–20.04 | <.001 | |
| Hypertrophic cardiomyopathy | 0 | 0 | >.999 | |
| Restrictive cardiomyopathy | 0.94 | 0.12–6.80 | .951 | |
| Failed primary heart transplant | 0 | 0 | >.999 | |
| Other/unknown | 1.71 | 0.54–5.47 | .365 | |
| 90-d | Univariate analysis | |||
| Sex | ||||
| Male | Reference | Reference | Reference | |
| Female | 0.83 | 0.55–1.25 | .380 | |
| Multivariate analysis | ||||
| Sex | ||||
| Male | Reference | Reference | Reference | |
| Female | 0.92 | 0.62–1.37 | .694 | |
| Age | 1.02 | 1.01–1.04 | .002 | |
| Etiology of heart failure, n (%) | ||||
| Nonischemic dilated cardiomyopathy | Reference | Reference | Reference | |
| Ischemic cardiomyopathy | 1.14 | 0.82–1.61 | .44 | |
| Congenital | 3.01 | 0.93–9.71 | .07 | |
| Valvular | 6.16 | 2.49–15.21 | <.001 | |
| Hypertrophic cardiomyopathy | 0.57 | 0.08–4.09 | .576 | |
| Restrictive cardiomyopathy | 0.61 | 0.08–4.36 | .620 | |
| Failed primary heart transplant | 0 | 0 | >.999 | |
| Other/unknown | 1.87 | 0.76–4.60 | .175 | |
| Creatinine | 1.23 | 1.05–1.43 | .012 | |
| 1-y | Univariate analysis | |||
| Sex | ||||
| Male | Reference | Reference | Reference | |
| Female | 1.02 | 0.81–1.30 | .845 | |
| Multivariate analysis | ||||
| Sex | ||||
| Male | Reference | Reference | Reference | |
| Female | 0.89 | 0.64–1.24 | .484 | |
| Age | 1.02 | 1.01–1.03 | .003 | |
| Etiology of heart failure, n (%) | ||||
| Nonischemic dilated cardiomyopathy | Reference | Reference | Reference | |
| Ischemic cardiomyopathy | 1.37 | 1.04–0.81 | .027 | |
| Congenital | 2.66 | 0.97–7.32 | .058 | |
| Valvular | 4.45 | 1.82–10.92 | .001 | |
| Hypertrophic cardiomyopathy | 0.41 | 0.06–2.94 | .375 | |
| Restrictive cardiomyopathy | 0.87 | 0.22–3.53 | .849 | |
| Failed primary heart transplant | 0 | 0 | >.999 | |
| Other/unknown | 1.61 | 0.71–3.66 | .253 | |
| Creatinine | 1.19 | 1.04–1.37 | .012 |
Variables included in multivariate models were age, sex, race, body mass index, ventricular assist device type, smoking history, etiology of heart failure, intraaortic balloon pump use, inotrope use, dialysis, diabetes, creatinine level, mean pulmonary artery pressure, pulmonary capillary wedge pressure, panel of reactive antibodies percentages, ABO group, functional status, transplant year, same-sex pair, human leukocyte antigen mismatch, cytomegalovirus match, and ABO match.
Figure 1.
Kaplan-Meier survival curves for unmatched cohort (A) and matched cohort (B) after orthotopic heart transplantation, stratified by sex.
Comment
Outcomes after OHT in patients bridged with a newer-generation LVAD have yet to be clearly defined. Prior studies examining either LVAD or OHT patients were contradictory, demonstrating either inferior outcomes in females or no differences based on sex.1,2 Given the advances in LVAD design and postimplant critical care in the modern era, we sought to compare outcomes in males and females undergoing OHT who were bridged with either an HM3 or HVAD. Among 3010 patients in the UNOS database, the use of a newer-generation LVAD was associated with comparable 30- and 90-day and 1-year survival and posttransplant complications among propensity-matched males and females. Furthermore, this study emphasizes that age, renal function, and etiology of heart failure are the major drivers of mortality in the modern era, rather than sex. These data suggest that newer-generation, durable LVADs may serve to mitigate disparities in OHT outcomes between the sexes, and furthermore, that these LVADs can be safely used for BTT in both males and females.
The primary end point of this study was posttransplant mortality, which we found to be comparable between the sexes. This contrasts with a retrospective cohort study of 410 patients undergoing OHT between 1993 and 2009, which demonstrated a substantial effect of sex on survival among those undergoing VAD bridging.1 Survival was notably lower after OHT among females bridged with an LVAD, whereas there was no difference between the sexes among those who did not require VAD support before.1 However, the 2010 study did not reflect clinical use of the HVAD and HM3 devices which received premarket approval in 2012 and 2017, respectively, and thus the current comparable sex-stratified mortality outcomes may be attributable to a benefit ascribed to newer technology as well as enhancements in postimplant care. Because we have no evidence to suggest differential improvements in VAD patient care between the sexes, we attribute the current findings to the use of these centrifugal VADs. Two more recent studies explored the role of sex in VAD outcomes. Tsiouris and colleagues4 studied 130 patients undergoing VAD implantation as a BTT or a destination therapy and found that although females had a lower cardiac index and were more likely to be receiving other MCS at the time of LVAD implantation, survival was equivalent between the sexes at up to 2 years. In another study of patients bridged with either a HeartMate II or HVAD between 2007 and 2013, the authors found comparable overall survival among patients awaiting OHT.7 However, those studies did not specifically address survival after transplant, and thus it is unclear whether these comparable pretransplant outcomes translate into equivalent post-OHT mortality. Nevertheless, the current study’s 1-year survival rates of 90.5% and 92.8% in matched males and females, respectively, are consistent with a prior report of 1-year outcomes in patients bridged with an HVAD device demonstrating a survival rate of 90% after OHT.8
One essential sex difference noted in the current full cohort was differences in calculated PRA values (26.2% in females versus 8% in males). Although LVAD implantation may be a sensitizing event, females are predisposed to higher PRA levels as a result of multiparity as well as hormonal influences.9–11 This allosensitization is particularly important because of the associated risk for OHT rejection. Prior work associated sensitization in BTT patients with higher rates of antibody-mediated rejection.12 Furthermore, those authors found that sensitization was associated with posttransplant mortality12; thus, the combined effects of device-related sensitization and sex-related sensitization may be concerning for worse survival among females. After matching for PRA, however, we detected no significant sex differences in rejection at 1 year. The finding of equivalent outcomes in the full cohort and comparable survival between the sexes also argues against a negative impact of these higher PRA levels as a contributor to outcomes in female BTT patients.
Although we found no sex differences in the use of either an HM3 or HVAD, these LVADs differ in size and pericardial-related placement, which may potentially influence the choice of device for a male or female patient. An examination of Interagency Registry for Mechanically Assisted Circulatory Support registry patients managed with continuous-flow LVADs between 2008 and 2013 found no differences in overall survival or outcomes compared with those with a body surface area (BSA) of 1.5 m2 of less, as opposed to those with a BSA greater than 1.5 m2.13 Over two-thirds of the 231 patients in the lower-BSA group were female, which supports the safety of the use of these devices in smaller adults.13 Although those authors did not specify the model of devices used, a similar publication reported on 526 patients undergoing HeartMate II or HVAD implantation between 2003 and 2016. There, Volkovicher and colleagues14 found conversely that a smaller BSA (<1.5 m2) was associated with lower survival up to 24 months and was an independent predictor of postoperative mortality. However, neither study stratified patients based on device indication; thus, the BTT population may demonstrate distinct patterns in size-based outcomes as opposed to destination therapy LVAD patients, for example. Because female patients tend to be smaller, directed inquiry will be necessary to determine whether body size alone should dictate the selection of newer-generation LVADs to optimize outcomes.
This study had several limitations. Retrospective review of prospectively collected data introduces inherent bias into the study population, in that analyses depend on thorough and accurate data entry. However, the UNOS database captures all transplant patients within the United States, and thus is the most comprehensive data set for this type of study. Nevertheless, this limits our study only to patients who survived to the time of transplant, and thus we are unable to draw conclusions regarding the relationship between newer-generation LVAD use and sex-specific mortality while wait-listed. Further studies will be necessary to explore outcomes among males and females awaiting OHT who are bridged with an HVAD or HM3 to improve understanding of wait-list mortality, recovery, and clinical deterioration precluding transplant. In addition, owing to a lack of information regarding posttransplant complications within the UNOS data registry, we were unable to account fully for all posttransplant complications, aside from mortality, that could have influenced outcomes. Finally, although we found that the etiology of heart failure influenced post-OHT survival, because of the distribution of etiologies within our matched cohorts, we were unable to account fully for the interaction between sex and heart failure etiology on post-OHT outcomes.
Although prior studies on sex-based outcomes yielded conflicting evidence, we report equivalent 30- and 90-day and 1-year survival after OHT among matched males and females bridged with newer-generation HVAD or HM3 LVAD devices. These data suggest that newer-generation LVADs can be safely used for BTT therapy without incurring a sex-associated risk for adverse posttransplant outcomes. Furthermore, evidence of comparable outcomes after OHT indicates that the use of newer-generation LVADs may mitigate some of the adverse sex-specific outcomes that were previously reported in OHT recipients bridged with some of the older-generation LVADs.
Acknowledgments
This work was supported by the National Institutes of Health, grant 5T32HL098036 (LVH) and the Thoracic Surgery Foundation (LVH). Dr. Huckaby received support from the National Institutes of Health (grant 5T32HL098036) (Principal Investigator Edith Tzeng, MD) and the Thoracic Surgery Foundation.
References
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