Sex-Based Disparities in Waitlist and Posttransplant Outcomes Under the Previous and Revised United States Heart Allocation Systems

Abstract

Background:

In October 2018, the heart transplant (HT) allocation system in the United States was revised to address limitations of the prior model. Changes included more granular patient population stratifications and expansion of geographic boundaries. While the revised allocation system has improved transplant access for critically ill patients, limited data exist regarding its impact on sex-based disparities in waitlist and posttransplant outcomes.

Objective:

To evaluate the impact of the revised HT allocation system on sex-based differences on waitlist and posttransplant outcomes.

Methods:

We conducted a retrospective study of adult patients listed for HT in the Organ Procurement and Transplantation Network database between January 1, 2014 and December 31, 2021. Patients were stratified by sex and allocation system era. Waitlist outcomes were analyzed using competing risks methodology. Posttransplant outcomes were analyzed using Kaplan–Meier and Cox proportional hazards models.

Results:

Of 26,876 patients, 16,053 (59.7%) were listed under the previous system and 10,823 (40.3%) under the current system. A total of 4,216 (26.2%) were women in the previous system and 2,882 (26.6%) were women in the current system. In both allocation systems, women had a significantly higher cumulative incidence of transplantation at 1 year compared with men (old: 60.4% versus 54.1%; new: 72.4% versus 66.6%, p < 0.001). Among 18,725 transplant recipients, adjusted 1-year posttransplant survival was significantly lower for women compared with men in both systems (old: 91.2% versus 93.3%, p < 0.001; new: 89.7% versus 91.4%, p = 0.036). Female sex remained an independent predictor of lower adjusted survival despite increased access to transplantation.

Conclusion:

The updated allocation system has improved transplant access for women without increasing waitlist mortality. However, women continue to experience worse adjusted posttransplant survival compared with men. These disparities likely reflect a combination of immunological, clinical, and system sex-based factors. Ongoing investigation is needed to address sex-based inequities in transplant outcomes.

Keywords

heart transplantation sex-based disparities waitlist outcomes posttransplant survival United Network for Organ Sharing (UNOS)Organ Procurement and Transplantation Network (OPTN)

Introduction

In October 2018, the heart transplant (HT) allocation system in the United States was revised to improve over the shortcomings of the previous system. The changes in the allocation included a more granular stratification of patients on the waitlist and extending geographic boundaries.

Implementation of the current allocation system led to profound changes in clinical practice, aiming to prioritize organ allocation for the most critically ill patients, particularly those ineligibles for durable mechanical support.¹ Overall, the current system has had the intended effect on patients with cardiogenic shock supported by temporary mechanical circulatory support devices and those with restrictive cardiomyopathies.^2–4 However, the new system has also resulted in unintended consequences for patients with low socioeconomic status, who experienced an increased frequency of death or being delisted due to worsening clinical status and a decreased posttransplant survival. This disadvantage was not present in the previous allocation system.⁵

Sex-based disparities in clinical outcomes have previously been reported in cardiovascular disease. After an acute cardiovascular event, females are more likely to face mortality than males.⁶ Sex predicts higher mortality for females who experience ST-segment elevation myocardial infarction compared with males.⁷ Previous reports suggest that females have worse transplant outcomes; however, most of these studies were referred to the previous allocation system. Data regarding the impact of the implementation of the new HT allocation system on waitlist and posttransplant outcomes of females are limited. Existing literature on sex-based disparities in heart transplantation has primarily consisted of studies comparing allocation systems or center-level decision-making, narrative reviews, and 6-month follow-up outcomes.^8–11 Our study addresses this critical gap by providing a 1-year post allocation, patient-level quantitative analysis, employing competing-risk and multivariable survival models to assess outcomes.

Our objective was to determine the impact of the new HT allocation system on outcomes of females on the waitlist and after heart transplantation. The data reported here were supplied by the United Network for Organ Sharing (UNOS) as the contractor for the Organ Procurement and Transplantation Network (OPTN). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the OPTN or the U.S. Government.

Methods

Study population

Adult patients over the age of 18 registered for HT in the OPTN database between January 1, 2014, and December 31, 2021, were included in the study. Follow-up data were available through July 22, 2024. Patients categorized for multi-organ transplants, retransplantation, or co-listed for transplants other than heart transplantation were excluded from the study. The Corewell Health Institutional Review Board approved this research as exempt determination. Patients were classified into the “previous” or “current” system depending on whether they were listed or transplanted before and after October 18, 2018. In addition, patients were categorized according to sex.

This study used data from the OPTN database. The OPTN data system includes data on all donors, wait-listed candidates, and transplant recipients in the United States submitted by the members of the OPTN. The Health Resources and Services Administration, U.S. Department of Health and Human Services provides oversight to the activities of the OPTN contractor.

Outcome analysis

The outcomes in the waitlist and posttransplant survival were compared between sexes both before and after the change in the allocation system. All clinical characteristics were obtained from the OPTN datasets. Continuous variables are presented as mean ± standard deviation or median with interquartile range. Discrete variables are expressed as counts and percentages. Comparisons among groups were performed using the t-test, chi-square, Wilcoxon test, or Fisher exact test, as appropriate. Differences were considered statistically significant at p < 0.05. Missing values in the data were imputed using multiple imputations by chained equations assuming missingness occurred randomly. All analyses were performed using R statistical software (version 4.3.2).

For patients listed for HT, competing outcomes methodology was used to estimate the time-related probability of mutually exclusive outcomes in the waitlist (death/delisting due to worsening clinical status, transplantation, or alive in the waitlist) at 1 year after listing. At any time point, the sum of probabilities for all mutually exclusive outcomes equaled 100%. Competing outcomes curves were compared using the Fine–Gray test. Patients in the previous allocation system who continued waiting for HT on October 18, 2018 were censored as alive. The cumulative incidence of transplantation and death/delisting was calculated for each group. Subdistribution univariate analyses for the outcomes in the waitlist (transplantation or death/delisting) were performed. Variables with a p value < 0.15 were included in the multivariate analysis. A subdistribution hazard model was performed, and variables which were independently associated with the outcome were kept in the model (Supplementary Tables S1 and S2).

For patients who underwent HT, 1-year posttransplant survival was calculated for each group using Kaplan–Meier curves. Differences in survival according to sex within each allocation system were compared using the log-rank test. Patients were censored at the last follow-up or at 365 days. Univariate Cox proportional hazards analysis was performed to identify variables associated with 1-year survival. Variables with a p value <0.15 in the univariate analysis were supplied to the multivariate analysis. Adjusted survival curves were subsequently calculated and compared (Supplementary Table S3).

Results

A total of 26,876 patients were listed for HT during the study period, of these, 16,053 (59.7%) were listed under the previous system and 10,823 (40.3%) under the current system (Fig. 1A). A total of 4,216 (26.2%) and 2,882 (26.6%) patients were female in the previous and current systems, respectively (Fig. 1A). There was no difference in the proportion of females listed between the previous and current systems (p = 0.514). In summary, listed female patients in the previous and current systems were younger, more likely to be Black, and more likely to have nonischemic cardiomyopathy than male patients. In addition, female patients had a lower frequency of left ventricular assist devices (LVAD) utilization at listing (Table 1; Supplementary Table S4). In the current system, nonischemic cardiomyopathy remained the most common etiology of heart failure among female patients, whereas other etiologies were less frequent than ischemic cardiomyopathy (Table 1).

FIG. 1.

Study cohort and patient outcomes according to heart transplant allocation era and sex. (A) Flow diagram of adult patients listed for heart transplantation in the Organ Procurement and Transplantation Network between January 1, 2014 and December 31, 2021, stratified by allocation era (previous versus current system), sex, and 1-year waitlist outcomes (transplantation, death/removal from the waitlist due to worsening clinical status, or remaining on the waitlist). (B) Flow diagram of heart transplant recipients stratified by allocation era, sex, and 1-year posttransplant outcomes (alive or deceased).

Table 1.

Characteristics of Patients Listed for Heart Transplant

Variables at the time of listing	Previous system			Current system
Variables at the time of listing	Female (n = 4,216)	Male (n = 11,837)	p	Female (n = 2,882)	Male (n = 7,941)	p
Age (years)	51.3 ± 13	54.3 ± 11.9	<0.001	51 ± 13.4	54.2 ± 12.3	<0.001
Ethnicity, n (%)			<0.001			<0.001
White	2,463 (58.42)	7,818 (66.05)		1,613 (55.97)	4,975 (62.65)
Black	1,211 (28.72)	2,509 (21.2)		879 (30.5)	1,796 (22.62)
Other	542 (12.86)	1,510 (12.76)		390 (13.53)	1,170 (14.73)
BMI (kg/m²)	27.21 ± 5.384	28.1 ± 4.747	<0.001	27.8 ± 5.4	28.3 ± 4.8	<0.001
Etiology of HF, n (%)			<0.001			<0.001
Nonischemic	2,802 (66.46)	6,139 (51.86)		1,832 (63.57)	4,242 (53.42)
Ischemic	723 (17.15)	4,532 (38.29)		470 (16.31)	2,671 (33.64)
Other	691 (16.39)	1,166 (9.85)		580 (20.12)	1,028 (12.95)
Recipient blood group, n (%)			0.002			0.367
A	1,492 (35.39)	4,507 (38.08)		1,034 (35.88)	2,981 (37.54)
AB	184 (4.36)	586 (4.95)		127 (4.41)	345 (4.34)
B	627 (14.87)	1,620 (13.69)		434 (15.06)	1,119 (14.09)
O	1,913 (45.37)	5,124 (43.29)		1,287 (44.66)	3,496 (44.02)
Status at listing, n (%)			<0.001
OLD-1A	984 (23.34)	2,856 (24.13)
OLD-1B	1,868 (44.31)	5,719 (48.31)
OLD-2	1,253 (29.72)	3,025 (25.56)
Inactive	111 (2.63)	237 (2)
Status at listing, n (%)						0.013
NEW-1				113 (3.92)	341 (4.29)
NEW-2				578 (20.06)	1,816 (22.87)
NEW-3				322 (11.17)	904 (11.38)
NEW-4				1,109 (38.48)	2,971 (37.41)
NEW-6				724 (25.12)	1,802 (22.69)
Inactive				36 (1.25)	107 (1.35)
Days in waitlist^a	119 (31, 368.2)	168 (45, 472)	<0.001	45 (11–215)	60 (13–291)	<0.001
Cause of death, n (%)			0.076			0.785
Cardiovascular	72 (1.71)	261 (2.2)		36 (1.25)	88 (1.11)
Cerebrovascular	44 (1.04)	107 (0.9)		7 (0.24)	26 (0.33)
Hemorrhage	4 (0.09)	26 (0.22)		3 (0.1)	5 (0.06)
Infection	11 (0.26)	62 (0.52)		5 (0.17)	11 (0.14)
Malignancy	1 (0.02)	0 (0)		0 (0)	1 (0.01)
Pulmonary	6 (0.14)	25 (0.21)		2 (0.07)	7 (0.09)
Other causes	82 (1.94)	287 (2.42)		25 (0.87)	88 (1.11)
Missing	3,996 (94.78)	11,069 (93.51)		2,804 (97.29)	7,715 (97.15)
Creatinine (mg/dL)	1.1 ± 0.5	1.3 ± 0.5	<0.001	1 ± 0.4	1.3 ± 0.4	<0.001
Diabetes, n (%)	1,032 (24.48)	3,721 (31.44)	<0.001	676 (23.46)	2,429 (30.59)	<0.001
Dialysis, n (%)	24 (0.57)	74 (0.63)	0.776	12 (0.42)	43 (0.54)	0.418
HCV status, n (%)	61 (1.45)	178 (1.5)	0.851	50 (1.73)	121 (1.52)	0.436
PRA (%)	21.1 ± 32	7.1 ± 17.3	<0.001	19.8 ± 30.8	6.3 ± 16.3	<0.001
On LVAD, n (%)	992 (23.53)	4,016 (33.93)	<0.001	634 (22)	2,396 (30.17)	<0.001
On ECMO, n (%)	81 (1.92)	141 (1.19)	0.001	95 (3.3)	253 (3.19)	0.774
On IABP, n (%)	226 (5.36)	589 (4.98)	0.349	375 (13.01)	1,120 (14.1)	0.145
On ventilator, n (%)	65 (1.54)	195 (1.65)	0.692	48 (1.67)	124 (1.56)	0.702
On inotropes, n (%)	1,463 (34.7)	3,673 (31.03)	<0.001	915 (31.75)	2,381 (29.98)	0.078
PAP mean (mm Hg)	27.7 ± 10	28.7 ± 10.4	<0.001	26.6 ± 10.1	27.8 ± 10.4	<0.001
PCWP (mm Hg)	17.9 ± 8.6	19 ± 9	<0.001	17.4 ± 8.6	18.5 ± 9	<0.001
Cardiac output (L/min)	3.8 ± 1.2	4.5 ± 1.3	<0.001	3.8 ± 1.2	4.4 ± 1.3	<0.001

Characteristic is summarized by median (interquartile range).

BMI, body mass index; ECMO, extracorporeal membrane oxygenation; HCV, hepatitis C virus; HF, heart failure; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; PAP, pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; PRA, panel reactive antibody.

There were significant sex-based disparities in competing outcomes in both the previous and current systems. In the previous system, females had a higher cumulative incidence of transplantation at 1 year (60.4%) when compared with males (54.1%) (p < 0.001) (Fig. 2A). The cumulative incidence of death or removal from the waitlist due to worsening clinical status was similar between females (9.6%) and males (10.5%) (Fig. 2B). In the current allocation system, females had a higher 1-year cumulative incidence of transplantation than males (72.4% vs. 66.6% p < 0.001) (Fig. 2A), whereas the cumulative incidence of death/delisting due to worsening status of was similar between males and females (5.5% vs 6.4%,p = 0.127) (Fig. 2B).

FIG. 2.

Competing-risk analysis of waitlist outcomes according to sex and allocation system. (A) Cumulative incidence of heart transplantation among female and male candidates listed under the previous and current heart transplant allocation systems. Females demonstrated a higher cumulative incidence of transplantation in both allocation eras. (B) Cumulative incidence of death or removal from the waitlist due to worsening clinical status among female and male candidates. Comparisons between groups were performed using Gray’s test.

In the multivariate subdistribution hazard models, female sex was associated with an increased frequency of transplantation both in the previous (HR: 1.16 [1.1–1.23], p < 0.001) and current (HR: 1.13 [1.07–1.19], p < 0.001) allocation systems (Table 2). Female sex was not associated with an increased risk of mortality or delisting due to worsening clinical status in either the previous or current allocation system (Table 3).

Table 2.

Multivariate Subdistribution Hazard Model for Heart Transplant

Variable	Previous system			Current system
Variable	Estimate	p	HR (95% CI)	Estimate	p	HR (95% CI)
Sex = F	0.151	<0.001	1.16 (1.1–1.23)	0.122	<0.001	1.13 (1.07–1.19)
Age, year	0.006	<0.001	1.01 (1.006–1.01)	0.0024	0.016	1 (0.998–1.001)
BMI, kg/m²	−0.0318	<0.001	0.969 (0.964–0.973)	−0.0304	<0.001	0.97 (0.965–0.975)
Ethnicity
Black versus White	−0.119	<0.001	0.89 (0.838–0.94)	−0.145	<0.001	0.86 (0.814–0.92)
Other versus White	0.126	<0.001	1.13 (1.06–1.21)	−0.0123	0.74	0.988 (0.919–1.06)
Creatinine, mg/dL	−0.0448	0.11	0.956 (0.904–1.01)	—	—	—
Diabetes	—	—	—	−0.0528	0.062	0.949 (0.897–1)
Heart failure cause
Nonischemic versus other	−0.0851	0.021	0.918 (0.854–0.987)	—	—	—
Ischemic versus other	−0.169	<0.001	0.84 (0.78–0.915)	—	—	—
Blood group
AB versus A	0.555	<0.001	1.74 (1.58–1.92)	0.328	<0.001	1.39 (1.25–1.54)
B versus A	0.0127	0.71	1.01 (0.948–1.08)	−0.0045	0.9	0.995 (0.926–1.07)
O versus A	−0.557	<0.001	0.57 (0.545–0.602)	−0.482	<0.001	0.62 (0.585–0.652)
PAP mean, mm Hg	−0.0078	<0.001	0.992 (0.99–0.994)	0.0054	0.028	1.01 (1.009–1.013)
PCWP, mm Hg	—	—	—	0.0116	<0.001	1.01 (1.006–1.02)
On ventilator	−0.573	<0.001	0.56 (0.447–0.712)	—	—	—
On inotropes	0.375	<0.001	1.45 (1.38–1.53)	0.4	<0.001	1.49 (1.41–1.58)
On LVAD	0.101	<0.001	1.11 (1.05–1.16)	−0.183	<0.001	0.83 (0.785–0.883)
On ECMO	−0.273	0.024	0.76 (0.6–0.964)	0.92	<0.001	2.51 (2.07–3.05)
Cardiac output, L/min	−0.0422	<0.001	0.959 (0.94–0.978)	−0.0441	<0.001	0.957 (0.936–0.978)

HR, Hazard Ratio; CI, confidence interval.

Table 3.

Multivariate Subdistribution Hazard Model for Death/Removal in Waitlist

Variable	Previous system			Current system
Variable	Estimate	p	HR (95% CI)	Estimate	p	HR (95% CI)
Sex = F	0.0202	0.74	1.02 (0.906–1.15)	0.0054	0.96	1.01 (0.832–1.22)
Age, year	0.0185	<0.001	1.02 (1.01–1.02)	0.0144	<0.001	1.01 (1.01–1.02)
Ethnicity
Black versus white	—	—	—	0.243	0.01	1.28 (1.06–1.54)
Other versus white	—	—	—	0.237	0.038	1.27 (1.01–1.59)
Creatinine, mg/dL	0.111	<0.001	1.12 (1.06–1.18)	0.439	<0.001	1.55 (1.35–1.79)
Diabetes	0.156	0.004	1.17 (1.05–1.3)	0.196	0.021	1.22 (1.03–1.44)
PAP mean, mm Hg	0.0133	0.004	1.01 (1.009–1.02)	0.0182	<0.001	1.02 (1.01–1.03)
PCWP, mm Hg	0.013	0.014	1.01 (1–1.02)	—	—	—
On ventilator	0.721	<0.001	2.06 (1.52–2.79)	0.838	0.002	2.31 (1.36–3.94)
On inotropes	0.196	<0.001	1.22 (1.09–1.36)	0.177	0.043	1.19 (1.01–1.42)
On dialysis	1.12	<0.001	3.08 (2.02–4.69)	—	—	—
On IABP	0.403	<0.001	1.5 (1.24–1.81)	—	—	—
On ECMO	1.35	<0.001	3.85 (2.85–5.19)	0.457	0.05	1.58 (0.999–2.5)

A total of 18,725 patients received heart transplantation during the study period, including 9,674 (51.7%) in the previous system and 9,051 (48.3%) in the current system. A total of 2,628 (27.2%) and 2,454 (27.1%) were female recipients in the previous and current systems, respectively. Overall, transplanted female patients were younger, more likely to be Black, had lower creatinine levels and lower rates of diabetes mellitus (DM), had higher Panel Reactive Antibody (PRA) levels, had higher distance from the donor hospital, and received fewer undersized hearts than male patients (Table 4; Supplementary Table S5).

Table 4.

Characteristics of Heart Transplanted Patients

Variables	Previous system			Current system
Variables	Female (n = 2,628)	Male (n = 7,046)	p	Female (n = 254)	Male (n = 697)	p
Recipient characteristics at time of HT
Age (year)	52 ± 13	55.1 ± 11.8	<0.001	51.5 ± 13.3	54.7 ± 12.3	<0.001
Ethnicity, n (%)			<0.001			<0.001
White	1,571 (59.78)	4,651 (66.01)		1,428 (58.19)	4,240 (64.27)
Black	709 (26.98)	1,420 (20.15)		705 (28.73)	1,392 (21.1)
Other	348 (13.24)	975 (13.84)		321 (13.08)	965 (14.63)
BMI (kg/m²)	26.9 ± 5.3	27.8 ± 4.6	<0.001	27.6 ± 5.4	28 ± 4.9	<0.001
Etiology of HF, n (%)			<0.001			<0.001
Nonischemic	1,743 (66.32)	3,698 (52.48)		1,553 (63.28)	3,536 (53.6)
Ischemic	442 (16.82)	2,659 (37.74)		390 (15.89)	2,188 (33.17)
Other	443 (16.86)	689 (9.78)		511 (20.82)	873 (13.23)
Recipient blood group, n (%)			0.011			0.357
A	1,028 (39.12)	2,921 (41.46)		936 (38.14)	2,637 (39.97)
AB	143 (5.44)	465 (6.6)		117 (4.77)	329 (4.99)
B	427 (16.25)	1,061 (15.06)		377 (15.36)	999 (15.14)
O	1,030 (39.19)	2,599 (36.89)		1,024 (41.73)	2,632 (39.9)
Status at Tx, n (%)			<0.001
OLD-1A	1,543 (58.71)	4,960 (70.39)
OLD-1B	939 (35.73)	1,942 (27.56)
OLD-2	146 (5.56)	144 (2.04)
Status at Tx, n (%)						<0.001
NEW-1				162 (6.6)	607 (9.2)
NEW-2				985 (40.14)	3,266 (49.51)
NEW-3				440 (17.93)	1,248 (18.92)
NEW-4				666 (27.14)	1,191 (18.05)
NEW-6				201 (8.19)	285 (4.32)
Retransplant, n (%)	14 (0.53)	22 (0.31)	0.163	11 (0.45)	13 (0.2)	0.066
Cause of death at Tx, n (%)			0.156			0.031
Cardiovascular	90 (3.42)	244 (3.46)		45 (1.83)	105 (1.59)
Cerebrovascular	34 (1.29)	79 (1.12)		34 (1.39)	49 (0.74)
Graft failure	71 (2.7)	142 (2.02)		21 (0.86)	69 (1.05)
Hemorrhage	15 (0.57)	26 (0.37)		7 (0.29)	17 (0.26)
Infection	70 (2.66)	200 (2.84)		55 (2.24)	139 (2.11)
Malignancy	29 (1.1)	118 (1.67)		2 (0.08)	24 (0.36)
Pulmonary	33 (1.26)	83 (1.18)		19 (0.77)	50 (0.76)
Other	199 (7.57)	532 (7.55)		84 (3.42)	256 (3.88)
Missing	2,087 (79.41)	5,622 (79.79)		2,187 (89.12)	5,888 (89.25)
Creatinine (mg/dL)	1.1 ± 0.4	1.3 ± 0.4	<0.001	1.1 ± 0.4	1.3 ± 0.4	<0.001
Diabetes, n (%)	633 (24.09)	2157 (30.61)	<0.001	570 (23.23)	1928 (29.23)	<0.001
On dialysis, n (%)	40 (1.52)	140 (1.99)	0.155	38 (1.55)	120 (1.82)	0.433
Total bilirubin^a (mg/dL)	0.6 (0.4, 0.9)	0.7 (0.5, 1.1)	0.003	0.6 (0.4, 0.9)	0.7 (0.5, 1.1)	<0.001
HCV status, n (%)	59 (2.25)	151 (2.14)	0.82	52 (2.12)	148 (2.24)	0.781
PRA (%)	20.4 ± 31.3	7 ± 16.8	<0.001	20.6 ± 31.6	6.6 ± 16.9	<0.001
On LVAD, n (%)	900 (34.25)	3501 (49.69)	<0.001	647 (26.37)	2453 (37.18)	<0.001
On ECMO, n (%)	23 (0.88)	50 (0.71)	0.481	107 (4.36)	356 (5.4)	0.053
On IABP, n (%)	209 (7.95)	540 (7.66)	0.667	624 (25.43)	1875 (28.42)	0.005
On ventilator, n (%)	19 (0.72)	53 (0.75)	0.987	38 (1.55)	145 (2.2)	0.062
On inotropes, n (%)	1120 (42.6)	2458 (34.9)	<0.001	942 (38.4)	2504 (37.9)	0.726
PAP mean (mm Hg)	26.1 ± 9.3	26.7 ± 9.9	0.014	26.1 ± 9.6	27.3 ± 10.3	<0.001
PCWP (mm Hg)	16.6 ± 8.3	17.5 ± 8.7	<0.001	16.9 ± 8.5	18.2 ± 8.9	<0.001
Cardiac output (L/min)	4 ± 1.3	4.7 ± 1.4	<0.001	4 ± 1.3	4.6 ± 1.5	<0.001
Deceased donor variables
Age (year)	32.6 ± 11.6	32.1 ± 10.9	0.059	32.4 ± 10.6	32.7 ± 10.4	0.344
Male gender, n (%)	942 (35.84)	5709 (81.02)	<0.001	905 (36.88)	5611 (85.05)	<0.001
Ejection fraction (%)	61.8 ± 6.6	61.6 ± 6.5	0.089	61.8 ± 6.8	61.5 ± 6.6	0.155
Total bilirubin (mg/dL)	0.7 (0.4, 1.1)	0.7 (0.5, 1.2)	0.05	0.6 (0.4, 1)	0.7 (0.5, 1.1)	0.075
Cardiac index (L/min)	4 ± 1.2	4.4 ± 1.7	0.018	4 ± 1.4	4.4 ± 1.5	0.07
DCD donor, n (%)	—	—	—	69 (2.81)	265 (4.02)	0.008
Recipient/Donor Relationship
Distance: donor hosp. to Tx CTR^a (naut. mile)	95 (13, 299)	68 (11, 222)	<0.001	232 (89, 413)	223 (87, 401)	0.06
Ischemic time (h)	3.1 ± 1	3.1 ± 1	0.1	3.4 ± 1	3.5 ± 1.1	0.036
Gender mismatch, n (%)	942 (35.84)	1,337 (18.98)	<0.001	905 (36.88)	986 (14.95)	<0.001
Height mismatch, n (%)			0.004			0.025
Undersize (R/D < 0.8)	4 (0.15)	1 (0.01)		2 (0.08)	0 (0)
Normal (0.8 ≤ R/D ≤ 1.2)	2,623 (99.81)	7,031 (99.79)		2,447 (99.71)	6,591 (99.91)
Oversize (R/D > 1.2)	1 (0.04)	14 (0.2)		5 (0.2)	6 (0.09)
Weight mismatch, n (%)			<0.001			<0.001
Undersize (R/D < 0.8)	558 (21.23)	922 (13.09)		500 (20.37)	1,020 (15.46)
Normal (0.8 ≤ R/D ≤ 1.2)	1,598 (60.81)	4,493 (63.77)		1,490 (60.72)	4,084 (61.91)
Oversize (R/D > 1.2)	468 (17.81)	1,630 (23.13)		464 (18.91)	1,490 (22.59)
Missing	4 (0.15)	1 (0.01)		0 (0)	3 (0.05)

Characteristic is summarized by median (interquartile range).

DCD, donation after circulatory death; HT, heart transplant; Tx CTR, Transplant Center.

Regarding posttransplant outcomes in the previous system, females had a 1-year posttransplant survival rate of 91.5%, which was similar to that of males (92.5%, p = 0.125) (Fig. 3A). After adjustment for independent risk factors (age, body mass index, creatinine, extracorporeal membrane oxygenation requirement, ventilator requirement, ischemic time, days on waiting list, heart failure etiology, and donor age), the 1-year adjusted survival probability was statistically significantly lower for females compared with males, both in the previous (91.2% versus 93.3%, p < 0.001) and current (89.7% versus 91.4%, p = 0.036) allocation systems (Fig. 3C,D; Table 5).

FIG. 3.

One-year posttransplant survival according to sex and allocation system. (A) Unadjusted Kaplan–Meier survival curves for female and male heart transplant recipients in the previous allocation system. (B) Unadjusted Kaplan–Meier survival curves for female and male heart transplant recipients in the current allocation system. (C) Adjusted survival curves for female and male recipients in the previous allocation system. (D) Adjusted survival curves for female and male recipients in the current allocation system.

Table 5.

Multivariate Cox Proportional Hazards Model for Posttransplant 1 Year Mortality

Variable	Previous system			Current system
Variable	Estimate	p	HR (95% CI)	Estimate	p	HR (95% CI)
Sex = F	0.301	<0.001	1.35 (1.149–1.59)	0.186	0.036	1.2 (1.012–1.432)
Age at Tx, year	0.014	<0.001	1.01 (1.007–1.02)	0.0237	<0.001	1.02 (1.017–1.031)
Race
Black versus White	−0.22	0.024	0.8 (0.66–0.97)	—	—	—
Other versus White	0.136	0.198	1.15 (0.93–1.41)	—	—	—
Recipient BMI, kg/m²	0.0303	<0.001	1.03 (1.015–1.05)	0.0327	<0.001	1.03 (1.017–1.05)
Creatinine, mg/dL	0.456	<0.001	1.58 (1.34–1.86)	0.301	<0.001	1.35 (1.14–1.604)
Days on waiting list	—	—	—	0.0004	<0.001	1.003 (1.002–1.006)
Patient on ECMO	0.795	0.01	2.21 (1.21–4.05)	0.412	0.014	1.51 (1.1–2.1)
On ventilator	0.88	0.002	2.41 (1.37–4.24)	0.726	<0.001	2.07 (1.35–3.16)
Etiology of heart failure	—	—	—
Nonischemic versus Other	—	—	—	−0.356	<0.001	0.7 (0.57–0.86)
Ischemic versus Other	—	—	—	−0.144	0.206	0.86 (0.69–1.08)
Ischemic time, h	0.138	<0.001	1.15 (1.073–1.22)	0.094	0.004	1.1 (1.03–1.17)
Age donor, year	0.0079	0.013	1.01 (1.001–1.014)	—	—	—

Race was significantly associated with posttransplant mortality in the previous system, but not in the current system (Table 5). In the previous system, Black patients had a lower risk of posttransplant mortality compared with White patients (HR: 0.8 [0.66–0.97], p ≤ 0.024). A multivariate model was used to determine whether there was an association between posttransplant mortality and the interaction of sex and race. There was no significant the interaction between sex and race in either system, suggesting that the effect of sex on posttransplant mortality was consistent across racial groups.

Discussion

Our study showed that after implementation of the current allocation system: (1) the proportion of female patients being listed or transplanted has remained constant, (2) female patients on the waitlist have an increased cumulative incidence of transplantation when compared with males, with similar waitlist mortality/delisting. However, females had worse posttransplant survival after adjustment for risk factors (Tables 1 and 3).

Across the globe, cardiovascular disease is the most common cause of death in females.¹² Despite this high prevalence, disparities between care in males and females remain widespread. Females have higher rates of mortality following acute cardiovascular events compared with males.⁶ Despite knowledge of unique risk factors for cardiovascular disease faced by females, they continue to face lack of recognition, treatment lags, and decreased cardiac rehabilitation.^13,14 While global cardiovascular disparities provide context, our findings are specifically focused on inequities in advanced heart failure therapies. Looking to previous literature, describing sex differences in such therapies may guide us toward explanation. LVADs are commonly utilized to bridge patients to HT. Although there are similar rates of survival between males and females using LVAD, females are less likely to have an LVAD compared with males at the time of transplantation.¹⁵ Potential explanations include a higher burden of comorbidities in females, such as renal disease, which may limit eligibility for LVAD placement and influence transplant decisions.^16,17 Anatomical factors, including smaller body and heart size, as well as social factors such as differences in referral patterns and implicit bias in selection processes, may also contribute.¹⁸

When examining the baseline characteristics of patients, more males had higher statuses of listing compared with females in both eras, suggesting that males were more likely to be listed at a further advanced stage of disease (old: 24.13% versus 23.34%, p ≤ 0.001; New 1: 4.29% versus 3.92%; and New 2: 22.87% versus 20.06%, p = 0.013). This difference in illness severity at the time of listing may partly explain why, among waitlisted patients, women demonstrated a higher cumulative incidence of transplantation at 1 year in both allocation systems. Because this pattern remained consistent across eras, the observed sex differences in transplantation rates among waitlisted patients may reflect differences in clinical status at the time of listing rather than a direct effect of the revised allocation policy itself. Additionally, there was no significant difference in waitlist mortality or delisting due to clinical deterioration between sexes in either era, further supporting this interpretation.

Importantly, our analysis of race alongside sex provides additional context for addressing these disparities. Black female transplant recipients were significantly younger than White female recipients at the time of transplantation (Supplementary Table S6; 52.61 versus 51.11, p ≤ 0.001). This difference in age at transplantation may reflect earlier disease onset, differences in access to care, or variations in referral patterns, and may partially influence the posttransplant outcomes observed between groups. These findings are consistent with prior literature suggesting that Black female patients represent a disadvantaged group in advanced heart failure care, likely reflecting biological, clinical, and systemic inequities.⁸

In this study, we demonstrate in the postallocation era, females had an increased cumulative incidence of transplantation. This may lead us to believe the postallocation system has created a path toward improved outcomes for females in need of transplantation. However, the adjusted outcome of significant lower survival for females compared with males in both eras presents further concern. Posttransplant survival among female recipients did not improve in the current allocation system compared with the previous era, suggesting persistent disparities despite policy changes. This outcome reflects previous research demonstrating females had higher mortality rates compared with males in the most urgent categories of the prior allocation system.^19,20

The underlying causes of these posttransplant disparities are multifold and complex. Stronger immune systems and increased autoimmune disease prevalence may explain females’ increased likelihood to experience allograft rejection, acute rejection, and earlier production of anti-Human Leukocyte Antigen (anti-HLA)antibodies after transplantation.^21,22 As mentioned before, certain comorbidities, such as diabetes and renal disease, are more common in females compared with males with heart failure, which may also contribute to differences in mortality outcomes. In addition, systemic causes of sex-based health disparities in the American healthcare system may play a role in transplant outcomes. Widespread assumptions about sex and cardiovascular disease, such as the common perception that females are less likely to develop heart disease than their male counterparts, may cause females to seek cardiovascular care less frequently, resulting in underdiagnosis and undertreatment.²³ More generally, there is evidence revealing physicians hold implicit bias against female patients across many health care fields.²⁴ Such biases may result in differences in posttransplant care quality. These theories may explain why our data showed females had worse posttransplant survival when adjusted for risk factors in the current allocation system.

It is important to consider that although the 1-year adjusted survival probability was statistically lower for females compared with males in both previous (91.2% versus 93.3%, p < 0.001) and current (89.7% versus 91.4%, p = 0.036) allocation systems, the survival probabilities for females (91.2% and 89.7%) are still considered reasonably successful (Fig. 3C, D). The possibility to eliminate the disparity and improve outcomes for males and females still exists.

Limitations

The limitations of our study are reflected in the characteristics of retrospective analysis in a national database, which are susceptible to data entry errors and missing data. Additionally, our study analyzed data recorded during the waitlist and transplant periods. Future changes in the status of patients are not reflected in our analysis. Finally, as heart allocation systems progress and change with time, specific center practice modifications may not be applicable to our analysis.

Conclusion

The implementation of the current HT allocation system has increased the access of females to heart transplantation. Although actuarial survival after heart transplantation was similar between females and males, when adjusted for risk factors, females have worse survival. A plethora of causes may contribute to the differences in survival rates, including long-held, widespread beliefs regarding sex and cardiovascular health among both patients and providers. As in many fields of cardiology, further research is needed to understand this persistent disadvantage for female patients in transplantation.

Supplemental Material

sj-docx-1-jwh-10.1177_15409996261460415 — Supplemental material for Sex-Based Disparities in Waitlist and Posttransplant Outcomes Under the Previous and Revised United States Heart Allocation Systems

Supplemental material, sj-docx-1-jwh-10.1177_15409996261460415 for Sex-Based Disparities in Waitlist and Posttransplant Outcomes Under the Previous and Revised United States Heart Allocation Systems by Anjali Purohit, Dana Marsy, Nabin K. Shrestha, Renzo Loyaga-Rendon, and Milena Jani

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

The authors would like to express gratitude for support from the DeVos Cardiovascular Research Program.

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