Abstract
Background:
Higher donor sequence numbers (DSNs) might spark provider concern about poor donor quality. We evaluated characteristics of high DSN offers used for transplant and compared outcomes of high and low DSN transplants.
Materials and Methods:
Adult isolated heart transplants between 1/1/2015 and 12/31/2022 were identified from the Organ Procurement and Transplantation Network database and stratified into high (≥42) and low (<42) DSN. Post-operative outcomes, including pre-discharge complications, hospital length of stay, and survival at 1 and 3 years, were evaluated using multivariable regressions.
Results:
A total of 21,217 recipients met inclusion criteria, with 2,131 (10.0%) classified as high DSN. Donor factors associated with greater odds of high DSN at acceptance included older age, higher creatinine, diabetes, hypertension, and lower left ventricular ejection fraction. Recipients accepting high DSN offers were older and more likely to be female, of blood type O, and have lower status at transplant. High and low DSN transplants had similar likelihood of stroke (3.2% vs. 3.5%; p=0.97), dialysis (12.3% vs. 13.5%; p=0.12), and pacemaker implant (2.3% vs. 2.1%; p=0.64), and had similar lengths of stay (16 [12-24] vs. 16 [12-25] days, p=0.38) and survival at 1 (91.6% vs. 91.6%; aHR 0.85 [0.72-1.02], p=0.08) and 3 years (84.2% vs. 85.1%; aHR 0.91 [0.79-1.05], p=0.21) post-transplant.
Conclusions:
High DSN (≥42) was not an independent risk factor for post-transplant mortality and should not be the sole deterrent to acceptance. Accepting high DSN organs may increase access to transplantation for lower-status candidates.
Keywords: donor sequence number, heart transplant, outcomes, risk factors
INTRODUCTION
Heart transplantation has long been limited by the availability of “suitable” donor hearts, leading to efforts to expand the donor pool. While the annual number of heart transplants has increased in recent years, it has not kept pace with the increase in new candidate listings.1,2 Despite the growing need for donor grafts, the percentage of accepted donor offers has remained fairly low, with less than 50% of offers being accepted for transplantation as of 2018.3 The criteria for a “suitable” donor graft lack standardization, leading to rejection of many potentially viable donor hearts.4,5
Donor sequence number (DSN) indicates the number of prior recipients to whom an organ has been offered. While higher DSN has been associated with factors such as donor age and lower left ventricular function, there are concerns that high DSN itself might be considered an indication of poor allograft quality.6 However, studies in lung and kidney transplantation have found non-inferior outcomes for recipients of organs with high and low DSN.7-9 This has also been demonstrated in pediatric heart transplant recipients.10 In the adult population, Baran et al. investigated a national cohort of heart transplant recipients between 2007 and 2014 and found that high DSN was not associated with inferior survival. More recently, DSN has only been explored in single-center populations, with studies from Baylor demonstrating no significant differences in primary graft dysfunction or 1-year mortality between high and low DSN recipients.11,12 However, there have been no recent national studies on the association between DSN and heart transplant outcomes. Additionally, no studies have investigated DSN changes associated with the 2018 United Network for Organ Sharing (UNOS) heart allocation policy change.
Therefore, we used national registry data to evaluate whether high DSN was an independent risk factor for post-transplant outcomes in heart recipients. We compared post-transplant outcomes, including post-transplant complications, hospital length of stay, and mortality at 1 and 3 years, among recipients of organs with high vs. low DSN. We also characterized donor and recipient factors associated with high DSN transplants.
MATERIALS AND METHODS
Study Population
Adult (≥18 years) heart transplant recipients transplanted between January 1, 2015 to December 31, 2022 in the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN) database were included. Multiorgan transplants and retransplants were excluded. Recipients were categorized based on donor sequence number at acceptance, with the top 10th percentile being categorized as high DSN (≥42) and all others being categorized as low DSN (<42). Recipients were followed until they had the outcome of interest or were administrative censored on 6/30/2023. This study was approved by the Johns Hopkins Institutional Review Board (IRB00352819) with a waiver of informed consent.
Baseline donor and recipient characteristics
Baseline donor and recipient characteristics were compared between low DSN and high DSN transplants. Normality of all variables in this study were evaluated using Shapiro-Wilk testing and histogram visualization. Parametric continuous variables were compared using t-tests and reported as mean (standard deviation). Nonparametric continuous variables were compared using Wilcoxon rank-sum tests and reported as median (interquartile range, IQR). Categorical variables were assessed using Chi-squared testing and reported as number (percentage).
Donor refusal reasons
For high DSN transplants, data on reasons for declined offers from the OPTN Potential Transplant Recipient dataset were utilized and categorized into donor age or quality, donor size or weight, operational/logistic/recipient issues, organ-specific donor issues, donor infectious concerns, human leukocyte antigen issues, multiple organ transplant, and other.
Donor and recipient factors associated with high DSN
Donor characteristics associated with having a high DSN were identified using multivariable logistic regression adjusting for variables with p<0.1 on univariate analysis. Covariates included in the donor model were donor age, sex, race, cause of death, blood type, body mass index (BMI), creatinine, total bilirubin, diabetes, hypertension, left ventricular ejection fraction (LVEF), >20 pack-year smoking history, >2 drinks per day of alcohol, cocaine use, other drug use, hepatitis C (HCV) positivity (defined as testing positive on either HCV antibody test or HCV nucleic acid test), Public Health Service increased risk donor, and ischemic time.
Recipient factors associated with accepting a high DSN offer were similarly assessed. Given that the 2018 allocation policy change resulted in significant differences in recipient statuses, separate recipient models were constructed for recipients transplanted prior to (“pre-2018”) and after the 2018 allocation policy change (“post-2018”). Covariates included in the recipient models were recipient age, sex, race, diagnosis, status at transplant, blood type, creatinine, total bilirubin, pre-transplant mechanical ventilation, pre-transplant mechanical circulatory support (MCS, categorized into none, durable ventricular assist device [VAD], intra-aortic balloon pump [IABP], and temporary VAD or extracorporeal membrane oxygenation [ECMO]), and time on waitlist.
Post-transplant outcomes
Pre-discharge acute rejection (either treated or untreated), dialysis, stroke, and pacemaker implant were compared using Chi-squared testing and multivariable logistic regression. Hospital length of stay was evaluated using Wilcoxon rank-sum testing. For post-transplant survival, time-to-event analysis was performed, and outcomes were visualized using Kaplan-Meier curves. Univariate and multivariable Cox regression were used to compare post-transplant survival at 30 days, 1 year, and 3 years post-transplant. Covariates in the post-transplant survival models included donor age, race, cause of death, body mass index, diabetes, and hypertension; recipient age, race, diagnosis, status, body mass index, creatinine, total bilirubin, diabetes, pre-transplant mechanical ventilation, and pre-transplant MCS; and ischemic time.
Subgroup analysis of DCD transplants
A subgroup analysis of DCD transplants was performed. For this analysis, DCD recipients were categorized based on DSN at acceptance, with the top 10th percentile of DCD DSNs being categorized as high DSN (≥33) and all others being categorized as low DSN (<33). Baseline characteristics and post-transplant outcomes were assessed as described above. Given the novelty of DCD heart transplants, 3-year survival could not be assessed for this subgroup analysis.
Subgroup analysis by donor age
Subgroup analyses by donor age were performed. Within low volume centers, transplants utilizing donors <50 years were compared to those utilizing donors ≥50 years. Baseline characteristics and post-transplant outcomes of low DSN transplants utilizing donors <50 and ≥50 years were compared as described above. Similarly, within high volume centers, transplants utilizing donors <50 years were compared to those utilizing donors ≥50 years. Baseline characteristics and post-transplant outcomes of high DSN transplants utilizing donors <50 and ≥50 years were compared as described above.
Subgroup analysis by center volume
Subgroup analyses by center volume were performed. Centers with ≥40 transplants per year during the study period were considered high volume centers, and all other centers were considered low volume centers. Among low volume centers, baseline characteristics and post-transplant outcomes of high and low DSN transplants were compared as described above. Similarly, among high volume centers, baseline characteristics and post-transplant outcomes of high and low DSN transplants were compared as described above. All statistics were performed using StataSE 18 (StataCorp, College Station, Texas).
RESULTS
Study population
A total of 21,217 recipients met inclusion criteria, of which 19,086 (90.0%) were low DSN and 2,131 (10.0%) were high DSN. Median age of the study population was 57 years (IQR: 46-64 years), and 73.2% of the population was male. Median follow-up time for the entire cohort was 3.0 years (IQR: 1.0-5.0 years). Median donor sequence numbers in the low and high DSN cohorts were 4 (IQR: 2-10) and 79 (IQR: 55-127) respectively. The median number of centers that declined low and high DSN donors before final acceptance of the offer was 2 (IQR: 1-6) and 25 (IQR: 17-33) centers (p<0.001), respectively.
Donor characteristics
High DSN donors had higher median age (38 [29-47] vs. 31 [23-39] years, p<0.001) and were more likely to die of anoxia (53.0% vs. 39.9%, p<0.001) and have blood type O (60.9% vs. 50.0%, p<0.001), diabetes (6.1% vs. 3.2%, p<0.001), or hypertension (28.7% vs 14.4%, p<0.001; Table 1). High DSN donors were also more likely to have a history of smoking >20 pack-years (17.7% vs. 11.0%, p<0.001) and alcohol use (>2 drinks per day; 29.6% vs. 25.4%, p<0.001), but they were less likely to have other drug use (56.7% vs. 61.3%, p<0.001). High DSN donors also had higher ischemic times (3.6 [3.0-4.2] vs. 3.3 [2.5-3.9] hours, p<0.001) and distances from recipient center (296 [137-428] vs. 152 [27-338] nautical miles, p<0.001).
Table 1:
Baseline characteristics of low and high DSN donors.
| Variable, n (%) | Low DSN (n=19,086) |
High DSN (n=2,131) |
p-value |
|---|---|---|---|
| Donor sequence number, median (IQR) | 4 (2-10) | 79 (55-127) | <0.001 |
| Age (years), median (IQR) | 31 (23-39) | 38 (29-47) | <0.001 |
| Male sex | 14,144 (74.1%) | 949 (44.5%) | <0.001 |
| Race | <0.001 | ||
| White | 12,092 (63.4%) | 1,390 (65.2%) | |
| Black | 3,089 (16.2%) | 387 (18.2%) | |
| Hispanic | 3,337 (17.5%) | 295 (13.8%) | |
| Other | 568 (3.0%) | 59 (2.8%) | |
| Cause of death | <0.001 | ||
| Anoxia | 7,607 (39.9%) | 1,130 (53.0%) | |
| Stroke | 2,517 (13.2%) | 476 (22.3%) | |
| Head trauma | 8,481 (44.4%) | 457 (21.4%) | |
| Other | 479 (2.5%) | 68 (3.2%) | |
| Blood type | <0.001 | ||
| O | 9,550 (50.0%) | 1,297 (60.9%) | |
| A | 6,898 (36.1%) | 719 (33.7%) | |
| B | 2,205 (11.6%) | 115 (5.4%) | |
| AB | 433 (2.3%) | 0 (0.0%) | |
| Comorbidities | |||
| BMI (kg/m2), median (IQR) | 26.6 (23.4-30.8) | 28.3 (24.4-33.2) | <0.001 |
| Creatinine (mg/dL), median (IQR) | 1.0 (0.8-1.5) | 1.0 (0.7-1.9) | 0.01 |
| Total bilirubin (mg/dL), median (IQR) | 0.7 (0.5-1.1) | 0.6 (0.4-1.0) | <0.001 |
| Diabetes | 656 (3.5%) | 157 (7.4%) | <0.001 |
| Hypertension | 2,716 (14.4%) | 602 (28.7%) | <0.001 |
| LVEF | 60 (56-65) | 60 (55-65) | <0.001 |
| Substance use | |||
| Smoking history (>20 pack-year) | 2,054 (11.0%) | 367 (17.7%) | <0.001 |
| Alcohol use (>2 drinks/day) | 4,853 (25.9%) | 614 (29.6%) | <0.001 |
| Cocaine use | 3,400 (18.4%) | 411 (19.8%) | 0.10 |
| Other drug use | 11,551 (61.3%) | 1,189 (56.7%) | <0.001 |
| Donation after circulatory death | 546 (2.9%) | 40 (1.9%) | 0.009 |
| Hepatitis C positive | 1,471 (7.8%) | 182 (8.7%) | 0.17 |
| PHS increased risk donor | 5,693 (29.8%) | 663 (31.1%) | 0.22 |
| Ischemic time (hours), median (IQR) | 3.3 (2.5-3.9) | 3.6 (3.0-4.2) | <0.001 |
| Distance (nautical miles), median (IQR) | 152 (27-338) | 296 (137-482) | <0.001 |
Abbreviations: BMI, body mass index; DSN, donor sequence number; IQR, interquartile range; LVEF, left ventricular ejection fraction; PHS, Public Health Services.
Donor factors associated with high DSN
On adjusted analysis, donor factors independently associated with having a high DSN were higher age, Black race, higher BMI, higher creatinine, diabetes, hypertension, cocaine use, or greater ischemic times (Table 2). Donor factors associated with lower odds of high DSN included male sex, stroke or head trauma (vs. anoxia) cause of death, blood type A, B, or AB (vs. O), greater LVEF, and hepatitis C positivity. The most common refusal reasons for high DSN donors were donor age/quality (44.8%), followed by donor size/weight (26.6%), organ-specific donor issues (11.2%), and operational/logistic/recipient issues (9.9%).
Table 2:
Multivariable logistic regression of donor factors associated with high DSN.
| Covariate | aOR | 95% confidence interval | p-value |
|---|---|---|---|
| Age (per 5 years) | 1.23 | 1.20-1.27 | <0.001 |
| Male sex | 0.30 | 0.27-0.34 | <0.001 |
| Race (ref=White) | |||
| Black | 1.35 | 1.18-1.55 | <0.001 |
| Hispanic | 0.92 | 0.79-1.06 | 0.25 |
| Other | 0.97 | 0.72-1.31 | 0.85 |
| Cause of death (ref=anoxia) | |||
| Stroke | 0.79 | 0.68-0.91 | 0.001 |
| Head trauma | 0.52 | 0.45-0.59 | <0.001 |
| Other | 0.99 | 0.74-1.32 | 0.93 |
| Blood type (ref=O) | |||
| A | 0.83 | 0.75-0.93 | 0.001 |
| B | 0.38 | 0.30-0.47 | <0.001 |
| AB | - | - | - |
| Comorbidities | |||
| BMI | 1.01 | 1.00-1.02 | 0.002 |
| Creatinine | 1.07 | 1.05-1.10 | <0.001 |
| Total bilirubin | 1.00 | 0.96-1.03 | 0.79 |
| Diabetes | 1.25 | 1.02-1.55 | 0.03 |
| Hypertension | 1.30 | 1.15-1.48 | <0.001 |
| LVEF (per 10%) | 0.76 | 0.71-0.82 | <0.001 |
| Substance use | |||
| Smoking history (>20 pack-year) | 1.12 | 0.97-1.29 | 0.14 |
| Alcohol use (>2 drinks/day) | 1.00 | 0.87-1.14 | 0.96 |
| Cocaine use | 1.14 | 1.01-1.29 | 0.04 |
| Other drug use | 0.89 | 0.79-1.00 | 0.06 |
| Hepatitis C positive | 0.73 | 0.60-0.88 | 0.001 |
| PHS increased risk donor | 1.11 | 0.98-1.26 | 0.11 |
| Ischemic time (per hour) | 1.43 | 1.37-1.49 | <0.001 |
Abbreviations: aOR, adjusted odds ratio; BMI, body mass index; LVEF, left ventricular ejection fraction; PHS, Public Health Services.
Recipient characteristics
Recipients of high DSN donors were older (59 [50-65] vs. 56 [46-63] years, p<0.001) and less likely to be male (58.7% vs. 74.9%, p<0.001), status 1A in the pre-2018 era (52.9% vs. 68.3%, p<0.001), status 1 (0.1% vs. 10.4%, p<0.001) or 2 (4.2% vs. 54.4%, p<0.001) in the post-2018 era, and supported with pre-transplant IABP (4.4% vs. 19.3%, p<0.001) or tVAD/ECMO (3.6% vs. 11.9%, p<0.001; Table 3). Recipients of high DSN donors more likely to be White (66.1% vs. 61.9%, p<0.001) and have blood type O (49.7% vs. 38.9%, p<0.001). The percent of total heart transplants that utilized high DSN donors varied by UNOS region and ranged from 2.0% (region 6) to 14.5% (region 2). Regions in the Northeast had a higher proportion of high DSN transplants (Figure 1).
Table 3:
Baseline characteristics of recipients accepting low and high DSN offers.
| Variable, n (%) | Low DSN (n=19,086) |
High DSN (n=2,131) |
p-value |
|---|---|---|---|
| Age (years), median (IQR) | 56 (46-63) | 59 (50-65) | <0.001 |
| Male sex | 14,288 (74.9%) | 1,250 (58.7%) | <0.001 |
| Race | 0.001 | ||
| White | 11,816 (61.9%) | 1,408 (66.1%) | |
| Black | 4,484 (23.5%) | 458 (21.5%) | |
| Hispanic | 1,844 (9.7%) | 185 (8.7%) | |
| Other | 942 (4.9%) | 80 (3.8%) | |
| Diagnosis | <0.001 | ||
| Ischemic cardiomyopathy | 5,598 (29.3%) | 680 (31.9%) | |
| Nonischemic dilated cardiomyopathy | 10,711 (56.1%) | 1,103 (51.8%) | |
| Restrictive cardiomyopathy | 765 (4.0%) | 104 (4.9%) | |
| Hypertrophic cardiomyopathy | 586 (3.1%) | 101 (4.7%) | |
| Congenital | 648 (3.4%) | 61 (2.9%) | |
| Other | 778 (4.1%) | 82 (3.8%) | |
| Status at transplant | <0.001 | ||
| Pre-2018* | |||
| Status 1A | 5,864 (68.3%) | 416 (52.9%) | |
| Status 1B | 2,549 (29.7%) | 280 (35.6%) | |
| Status 2 | 168 (2.0%) | 91 (11.6%) | |
| Post-2018** | <0.001 | ||
| Status 1 | 1,093 (10.4%) | 1 (0.1%) | |
| Status 2 | 5,718 (54.4%) | 57 (4.2%) | |
| Status 3 | 1,805 (17.2%) | 264 (19.6%) | |
| Status 4 | 1,530 (14.6%) | 736 (54.8%) | |
| Status 5 | 4 (0.0%) | 2 (0.1%) | |
| Status 6 | 355 (3.4%) | 284 (21.1%) | |
| Blood type | <0.001 | ||
| O | 7,419 (38.9%) | 1,060 (49.7%) | |
| A | 7,565 (39.6%) | 821 (38.5%) | |
| B | 3,022 (15.8%) | 206 (9.7%) | |
| AB | 1,080 (5.7%) | 44 (2.1%) | |
| Comorbidities | |||
| BMI (kg/m2), median (IQR) | 27.5 (24.1-31.3) | 27.9 (24.5-31.7) | <0.001 |
| Creatinine (mg/dL), median (IQR) | 1.1 (0.9-1.4) | 1.1 (0.9-1.4) | 0.03 |
| Total bilirubin (mg/dL), median (IQR) | 0.7 (0.5-1.1) | 0.6 (0.4-0.9) | <0.001 |
| Diabetes | 5,379 (28.2%) | 588 (27.6%) | 0.55 |
| Mechanical ventilation | 302 (1.6%) | 10 (0.5%) | <0.001 |
| Pre-transplant MCS | <0.001 | ||
| None | 6,609 (34.6%) | 1,214 (57.0%) | |
| Durable VAD | 6,516 (34.1%) | 748 (35.1%) | |
| IABP | 3,684 (19.3%) | 93 (4.4%) | |
| Temporary VAD or ECMO | 2,277 (11.9%) | 76 (3.6%) | |
| Time on waitlist (days), median (IQR) | 56 (14-233) | 83 (23-293) | <0.001 |
| UNOS region | <0.001 | ||
| 1 | 952 (5.0%) | 149 (7.0%) | |
| 2 | 1,892 (9.9%) | 320 (15.0%) | |
| 3 | 2,293 (12.0%) | 184 (8.6%) | |
| 4 | 1,883 (9.9%) | 157 (7.4%) | |
| 5 | 3,177 (16.6%) | 166 (7.8%) | |
| 6 | 695 (3.6%) | 14 (0.7%) | |
| 7 | 1,619 (8.5%) | 215 (10.1%) | |
| 8 | 1,345 (7.0%) | 104 (4.9%) | |
| 9 | 1,298 (6.8%) | 199 (9.3%) | |
| 10 | 1,458 (7.6%) | 197 (9.2%) | |
| 11 | 2,474 (13.0%) | 426 (20.0%) |
Abbreviations: BMI, body mass index; DSN, donor sequence number; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; IQR, interquartile range; MCS, mechanical circulatory support; VAD, ventricular assist device.
Pre-2018: n=7,503 for low DSN; n=1,865 for high DSN
Post-2018: n=8,571 for low DSN; n=3,278 for high DSN
Figure 1:
Percent of total heart transplants that utilized high DSN donors, by UNOS region.
DSN and allocation policy
DSN was significantly higher in the post-2018 (median: 7 [IQR: 3-17]) vs. pre-2018 (median: 3 [IQR: 1-11]) era (p<0.001). In the pre-2018 era, 8.4% of overall transplants were high DSN transplants; this percentage ranged from 6.6% of status 1A recipients to 35.1% of status 2 recipients (Supplemental Table 1). In the post-2018 era, 11.3% of transplants were high DSN transplants, with just 0.1% of status 1 recipients receiving a high DSN donor. Even though DSNs were higher in the post-2018 era, median days on the waitlist was significantly lower in the post-2018 era compared to the pre-2018 era (32 [9-162] vs. 110 [31-317] days, p<0.001).
Recipient factors associated with acceptance of high DSN offers
Given the status changes that resulted from the 2018 allocation policy change, recipient factors associated with acceptance of high DSN donors were separately investigated in the pre-2018 and post-2018 eras. In both eras, factors associated with greater odds of accepting high DSN offers included older age, female sex, blood type O, lower time on the waitlist, and lower status at transplant. In the pre-2018 era (Table 4), Hispanic race (vs. White race) was associated with lower odds, but this association were not observed in the post-2018 era. In the post-2018 era (Table 5), durable VAD (vs. no MCS) was associated with higher odds of accepting high DSN offers.
Table 4:
Multivariable logistic regression of recipient factors associated with acceptance of high DSN offers in the pre-2018 allocation policy era.
| Covariate | aOR | 95% confidence interval | p-value |
|---|---|---|---|
| Age (per 5 years) | 1.08 | 1.05-1.12 | <0.001 |
| Male sex | 0.57 | 0.49-0.68 | <0.001 |
| Race (ref=White) | |||
| Black | 0.99 | 0.82-1.20 | 0.93 |
| Hispanic | 0.66 | 0.49-0.89 | 0.007 |
| Other | 0.76 | 0.52-1.13 | 0.17 |
| Diagnosis (ref=nonischemic dilated CM) | |||
| Ischemic cardiomyopathy | 1.13 | 0.95-1.35 | 0.18 |
| Restrictive cardiomyopathy | 1.35 | 0.94-1.95 | 0.11 |
| Hypertrophic cardiomyopathy | 0.99 | 0.65-1.51 | 0.96 |
| Congenital | 0.85 | 0.52-1.40 | 0.52 |
| Other | 1.03 | 0.69-1.52 | 0.89 |
| Status at transplant (ref=status1A) | |||
| Status 1B | 1.64 | 1.39-1.95 | <0.001 |
| Status 2 | 9.36 | 6.82-12.85 | <0.001 |
| Blood type (ref=O) | |||
| A | 0.59 | 0.49-0.69 | <0.001 |
| B | 0.51 | 0.40-0.65 | <0.001 |
| AB | 0.15 | 0.09-0.26 | <0.001 |
| Comorbidities | |||
| Creatinine | 0.95 | 0.82-1.11 | 0.52 |
| Total bilirubin | 1.02 | 0.98-1.07 | 0.29 |
| Mechanical ventilation | 2.01 | 0.97-4.16 | 0.06 |
| Pre-transplant MCS (ref=none) | |||
| Durable VAD | 0.86 | 0.72-1.04 | 0.12 |
| IABP | 1.16 | 0.85-1.58 | 0.34 |
| Temporary VAD or ECMO | 1.10 | 0.81-1.48 | 0.54 |
| Time on waitlist (per 10 days) | 0.996 | 0.994-0.998 | 0.001 |
Abbreviations: aOR, adjusted odds ratio; CM, cardiomyopathy; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; IQR, interquartile range; VAD, ventricular assist device.
Table 5:
Multivariable logistic regression of recipient factors associated with acceptance of high DSN offers in the post-2018 allocation policy era.
| Covariate | aOR | 95% confidence interval | p-value |
|---|---|---|---|
| Age (per 5 years) | 1.04 | 1.01-1.07 | 0.01 |
| Male sex | 0.67 | 0.58-0.78 | <0.001 |
| Race (ref=White) | |||
| Black | 1.11 | 0.92-1.32 | 0.26 |
| Hispanic | 0.84 | 0.66-1.06 | 0.15 |
| Other | 0.82 | 0.57-1.17 | 0.28 |
| Diagnosis (ref=nonischemic dilated CM) | |||
| Ischemic cardiomyopathy | 1.02 | 0.87-1.20 | 0.82 |
| Restrictive cardiomyopathy | 0.87 | 0.63-1.21 | 0.42 |
| Hypertrophic cardiomyopathy | 1.13 | 0.80-1.58 | 0.49 |
| Congenital | 0.76 | 0.51-1.13 | 0.17 |
| Other | 0.69 | 0.48-1.01 | 0.054 |
| Status at transplant (ref=status 2) | |||
| Status 1 | 0.09 | 0.01-0.66 | 0.02 |
| Status 3 | 17.4 | 12.0-25.4 | <0.001 |
| Status 4 | 68.4 | 47.2-99.0 | <0.001 |
| Status 5 | 73.1 | 11.4-471.2 | <0.001 |
| Status 6 | 122.4 | 81.3-184.2 | <0.001 |
| Blood type (ref=O) | |||
| A | 0.31 | 0.27-0.37 | <0.001 |
| B | 0.14 | 0.11-0.18 | <0.001 |
| AB | 0.08 | 0.05-0.11 | <0.001 |
| Comorbidities | |||
| Creatinine | 1.02 | 0.90-1.15 | 0.78 |
| Total bilirubin | 1.00 | 0.95-1.05 | 0.94 |
| Mechanical ventilation | 0.64 | 0.08-5.16 | 0.67 |
| Pre-transplant MCS (ref=none) | |||
| Durable VAD | 0.84 | 0.71-0.999 | 0.049 |
| IABP | 0.75 | 0.49-1.16 | 0.20 |
| Temporary VAD or ECMO | 0.97 | 0.54-1.73 | 0.92 |
| Time on waitlist (per 10 days) | 0.997 | 0.996-0.999 | 0.003 |
Abbreviations: aOR, adjusted odds ratio; CM, cardiomyopathy; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; IQR, interquartile range; VAD, ventricular assist device.
Post-transplant outcomes
High DSN and low DSN transplants had similar likelihood of experiencing pre-discharge stroke (3.2% vs. 3.5%; aOR 1.01 [0.76-1.33], p=0.97), dialysis (12.3% vs. 13.5%; aOR 0.88 [0.76-1.03], p=0.12), and pacemaker implant (2.3% vs. 2.1%; aOR 1.08 [0.78-1.51], p=0.64), as well as similar median hospital lengths of stay (16 [12-24] vs. 16 [12-25] days, p=0.38; Table 6). High DSN recipients were more likely to experience pre-discharge acute rejection (22.2% vs. 19.4%; aOR 1.21 [95% CI: 1.07-1.37], p=0.003) but had similar likelihood of experiencing pre-discharge acute rejection requiring treatment (11.6% vs. 11.1%; aOR 1.06 [95% CI: 0.90-1.24], p=0.51).
Table 6:
Post-transplant outcomes of low vs. high DSN transplants in the United States, 2015-2022.
| Variable, n (%) | Low DSN (n=19,086) |
High DSN (n=2,131) |
aOR/HR (95% CI) | p-value |
|---|---|---|---|---|
| Pre-discharge acute rejection | 3,708 (19.4%) | 474 (22.2%) | 1.21 (1.07-1.37) | 0.003 |
| Post-transplant dialysis | 2,574 (13.5%) | 261 (12.3%) | 0.88 (0.76-1.03) | 0.12 |
| Post-transplant stroke | 659 (3.5%) | 69 (3.2%) | 1.01 (0.76-1.33) | 0.97 |
| Post-transplant pacemaker | 391 (2.1%) | 49 (2.3%) | 1.08 (0.78-1.51) | 0.64 |
| Hospital length of stay (days), median (IQR)* | 16 (12-25) | 16 (12-24) | -- | 0.38 |
| 30-day survival | 97.0% | 97.2% | 0.77 (0.57-1.05) | 0.09 |
| 1-year survival | 91.6% | 91.6% | 0.85 (0.72-1.02) | 0.08 |
| 3-year survival | 85.1% | 84.2% | 0.91 (0.79-1.05) | 0.21 |
Abbreviations: aHR, adjusted hazards ratio; aOR, adjusted odds ratio; DSN, donor sequence number; IQR, interquartile range.
Unadjusted analysis performed.
Recipients of offers from high vs. low DSN donors had similar survival at 30 days (97.2% vs. 97.0%; aHR 0.77 [0.57-1.05], p=0.09), 1 year (91.6% vs. 91.6%; aHR 0.85 [0.72-1.02], p=0.08) and 3 years (84.2% vs. 85.1%; aHR 0.91 [0.79-1.05], p=0.21) post-transplant (Figure 2).
Figure 2:
Three-year post-transplant survival of low vs. high DSN transplants in the United States, 2015-2022.
Subgroup analysis of DCD transplants
A subgroup analysis of DCD transplants was performed. Baseline donor and recipient characteristics of high- and low-DSN transplants are shown in Supplemental Tables 2 and 3, respectively. Recipients of high- and low-DSN transplants had similar likelihood of pre-discharge acute rejection (17.5% vs. 17.6%; aOR 1.18 [95% CI: 0.53-2.61], p=0.69), dialysis (16.1% vs. 17.6%; aOR 1.18 [95% CI: 0.53-2.65], p=0.69), stroke (3.2% vs. 3.4%; aOR 0.49 [95% CI: 0.10-2.45], p=0.38), and pacemaker implant (1.6% vs. 0.6%; aOR 2.19 [95% CI: 0.16-29.64], p=0.56). Recipients of high- and low-DSN transplants also had similar post-transplant hospital lengths of stay (16 [12-25] vs. 16 [12-24] days, p=0.96), 30-day survival (96.6% vs. 97.7%; aHR 0.93 [95% CI: 0.14-6.42], p=0.95), and 1-year survival (91.0% vs. 92.8%; aHR 1.25 [95% CI: 0.39-4.01], p=0.71; Supplemental Figure 1).
Subgroup analysis by donor age
Of the 19,086 low DSN transplants, 1,149 (6.0%) utilized donors ≥50 years. Baseline donor and recipient characteristics of low DSN transplants by donor age are shown in Supplemental Tables 4 and 5, respectively. Of the 2,131 high DSN transplants, 367 (17.2%) utilized donors ≥50 years. Baseline donor and recipient characteristics of low DSN transplants by donor age are shown in Supplemental Tables 6 and 7, respectively.
Among low DSN transplants, donor age ≥50 years was associated with worse survival at 1 (88.2% vs. 91.9%; aHR 1.35 [95% CI: 1.12-1.63], p=0.002) and 3 years (80.8% vs. 85.4%; aHR 1.28 [95% CI: 1.09-1.49], p=0.002) post-transplant (Supplemental Table 8). Among high DSN transplants, donor age ≥50 years was not associated with worse survival at 1 (91.3% vs. 91.7%; aHR 0.84 [95% CI: 0.55-1.29], p=0.42) or 3 years (82.8% vs. 84.5%; aHR 0.88 [95% CI: 0.63-1.23], p=0.45) post-transplant (Supplemental Table 9).
Subgroup analysis by center volume
Overall, transplants at high compared to low volume centers had higher median DSN (6 [2-19] vs. 5 [2-14], p<0.001). Transplants at high compared to low volume centers were more likely to be high DSN (12.3% vs. 9.2%, p<0.001). Among the 15,339 total transplants performed at a low volume center, 1,410 (9.2%) were high DSN. Baseline donor and recipient characteristics of transplants at low volume centers Supplemental Tables 10 and 11, respectively. At low volume centers, transplant using high DSN donors was not associated with differences in post-transplant outcomes, including survival out to 3 years (Supplemental Table 12).
Among the 5,878 total transplants performed at a high volume center, 721 (12.3%) were high DSN. Baseline donor and recipient characteristics of transplants at low volume centers Supplemental Tables 13 and 14, respectively. At high volume centers, transplant using high DSN donors was associated with higher risk of all pre-discharge acute rejection (30.5% vs. 21.4%; aOR 1.88 [95% CI: 1.53-2.30], p<0.001), higher risk of treated pre-discharge acute rejection (13.3% vs. 9.5%; aOR 1.60 [95% CI: 1.22-2.10], p=0.001), and lower risk of dialysis (10.6% vs. 12.8%; aOR 0.73 [95% CI: 0.55-0.98), p=0.03), but no differences in survival out to 3 years (Supplemental Table 15).
DISCUSSION
In this national retrospective analysis, we found that recipients who received high DSN grafts had similar survival to recipients who recipients low DSN grafts out to 3 years post-transplant, despite many high DSN offers being refused due to concerns about donor quality or age. We found this to be true at both low volume and high volume heart transplant centers and on subgroup analysis of just DCD transplants. We identified a number of donor characteristics associated with higher DSN, including older age, diabetes, hypertension, and longer ischemic time. We also identified recipient characteristics associated with acceptance of high DSN grafts, including female sex and lower waitlist status. Finally, we found that recipients with status 1 and 2 recipients under the new allocation guidelines were less likely to accept high DSN grafts than status 1A recipients under the old guidelines.
Our finding that outcomes were similar for recipients of high and low DSN grafts is consistent with reports from single-institution studies.11,12 At the national level, we confirmed these results and found that outcomes for high DSN recipients remain similar to those of low DSN recipients at 3 years post-transplant, at both low volume and high volume heart transplant centers. In the short term, recipients who received high DSN grafts did just as well as recipients who received low DSN grafts, despite over 40% of refusals for high DSN grafts being due to donor age or quality reasons. We also assessed post-operative complications and found that high and low DSN recipients were at similar risk for post-transplant dialysis, stroke, and pacemaker use. Although high DSN recipients were at increased risk for acute rejection during the transplant hospitalization, high DSN was not associated with differences in overall survival in the short or long term. These findings are also consistent with reports in the pediatric heart transplant population and amongst recipients of other organs.10,13 The association of high DSN on lung transplant outcomes has been well-studied, and similarly found increased rates of rejection in high DSN recipients with no difference in overall survival at 1 year.7 While it is still important to carefully assess any graft prior to accepting it for transplant, our findings underscore that high DSN offers should not be rejected solely on the grounds of prior refusals.
A number of donor characteristics were identified as having increased odds of high DSN. Specifically, we found an association between higher DSN and older donor age, hypertension, diabetes, and lower LVEF. Notably, however, we demonstrated that donor age ≥50 was not associated with worse outcomes among high DSN transplants, despite donor age ≥50 being associated with worse survival among low DSN transplants. It is possible that older donors with high DSNs accepted for transplant were healthier in other ways, as demonstrated by the lower creatinine and higher LVEF as compared to younger donors with high DSNs. However, further studies should continue to investigate the interaction between donor age and other donor risk factors. Squiers et al. who reported on the Baylor experience found no difference in LVEF between high and low DSN donors, though they did not perform adjusted analysis and their sample sizes were significantly smaller.11 This difference may also potentially reflect center-level differences in acceptance patterns; while some centers may not heavily weigh LVEF, our results suggest that, at the national level, lower LVEF is associated with increased odds of high DSN. While older donor age and longer ischemic time have been associated with worse post-transplant heart survival, donor diabetes and hypertension have not been found to be independent risk factors for post-transplant mortality.14-16 The associations between donor diabetes or hypertension and high DSN have not been identified in other populations, including lung or pediatric heart transplant, suggesting that adult heart transplant providers may be uniquely concerned about these donor factors.7,10 Providers may be weighing donor diabetes and hypertension in their decision to accept an offer, despite minimal data to support the association of these factors on post-transplant outcomes.
We further identified recipient characteristics associated with acceptance of high DSN offers. We found that female sex was associated with greater acceptance of high DSN grafts. This may be due to concerns about sex- or size-mismatch, as high DSN grafts were more likely to come from female donors and studies have shown that male recipients of female donors have worse post-transplant outcomes.17-19 A prior study investigating transplants before 2014 also found that female donor to male recipient was associated with greater odds of high DSN.6 Importantly, we also found an association between status at transplant and acceptance of high DSN grafts. Across both allocation eras, the greatest factor associated with acceptance of high DSN grafts was lower status at transplant, consistent with what has been demonstrated with single-center studies from prior to the allocation policy change.11 Similarly, prior studies in lung transplantation have found that lower recipient lung allocation score (LAS) at transplant was associated with greater odds of accepting high DSN grafts.7 These results suggest that high DSN grafts may be increasing access to transplantation for lower waitlist status candidates.
Since the 2018 change to the heart allocation guidelines, DSNs have increased overall. The 2018 policy change replaced Donation Service Areas (DSAs) for organ sharing with a 500-mile radius in order to promote broader geographic sharing of allografts, resulting in increased sharing of heart allografts across DSAs.20,21 Our findings of increased DSNs in the post-2018 era may reflect an increase in the number of candidates geographically qualifying for an offer. Despite the overall increase in DSNs, the average time candidates spent on the waitlist decreased since the 2018 policy change,22 reflecting an improvement in organ prioritization. The distribution of DSNs based on waitlist status of recipients has also changed under the new guidelines. Status 1A recipients under the prior allocation policy were significantly more likely to receive a high DSN graft compared to a status 1 or 2 recipient under the new allocation policy. However, over a third of status 3 recipients and over a half of status 4-6 recipients in the post-2018 have received high DSN grafts. Taken together, these findings suggest that higher status recipients may have a greater number of offers as a result of the increased stratification of candidates, and providers may be more comfortable declining a marginal offer for this candidate population. These more marginal donor offers are in turn going to lower status candidates, who may otherwise have to wait longer before receiving another offer.
Our study was limited by its retrospective nature and the data available in the UNOS database. As with any database, some data may be inaccurate or missing, and there may be additional donor or recipient covariates that were not captured in the UNOS database. Additionally, the cohort of high DSN donors in our study included only donors that ultimately were accepted for heart transplant. Data on donors that were offered but ultimately not accepted for transplant were not available, which introduces selection bias and limits generalizability of our findings to all high DSN offers. Furthermore, although we were able to quantify the number of refusals for donor quality/age, we did not have additional granularity on specific concerns regarding donor quality to further explore reasons for decline. Lastly, the UNOS database lacks granularity on variables that assess post-transplant longer-term morbidity and functional status assessment, which could therefore not be studied.
CONCLUSIONS
In conclusion, we found that recipients who received high DSN grafts had similar post-transplant survival out to 3 years as recipients who received low DSN grafts. This was true at both low and high volume heart transplant centers. Higher DSN grafts were more readily accepted by recipients with lower waitlist status. Overall, our results underscore that DSN alone is not an indicator of organ quality and can result in excellent outcomes and increased access to transplant for lower status candidates.
Supplementary Material
ACKNOWLEDGEMENTS
We would like to acknowledge the Pozefsky Scholars Program for supporting this work.
Sources of funding:
F32AG067642 from the National Institute on Aging (PI: Ruck).
Footnotes
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IRB: This study was approved by the Johns Hopkins Institutional Review Board (IRB00352819).
DISCLOSURES
None.
Conflicts of interest: None
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