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JACC: HEART FAILURE

VOL. 2, NO. 4, 2014

ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 2213-1779/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jchf.2014.03.008

Does the UNOS Heart Transplant
Allocation System Favor
Men Over Women?
Eileen M. Hsich, MD,*y Randall C. Starling, MD, MPH,*y Eugene H. Blackstone, MD,*yz Tajinder P. Singh, MD, MSC,xk
James B. Young, MD,* Eiran Z. Gorodeski, MD, MPH,* David O. Taylor, MD,* Jesse D. Schold, PHDz

ABSTRACT
OBJECTIVES The aim of this paper was to identify sex differences in survival of patients awaiting orthotopic heart
transplantation (OHT).
BACKGROUND Women have a higher mortality rate while awaiting OHT than men, and the reason has not been
fully determined.
METHODS We included all adult patients in the Scientific Registry of Transplant Recipients (SRTR) placed on the OHT
waiting list from 2000 to 2010. The primary endpoint was all-cause mortality before receiving OHT, analyzed using timeto-event analysis. Multivariate Cox proportional hazards models were used to evaluate sex differences in survival, with
data stratified by United Network for Organ Sharing (UNOS) status at time of listing.
RESULTS There were 28,852 patients (24% women) awaiting OHT. This cohort included 6,163 UNOS status 1A
(25% women), 9,168 UNOS status 1B (25% women), and 13,521 UNOS status 2 (24% women) patients. During a median
follow-up of 3.7 years, 1,290 women and 4,286 men died. Female sex was associated with a significant risk of death
among UNOS status 1A (adjusted hazard ratio [HR]: 1.20; 95% confidence interval [CI]: 1.05 to 1.37, p ¼ 0.01) after
adjusting for more than 30 baseline variables. In contrast, female sex was significantly protective for time to death
among UNOS status 2 patients (adjusted HR: 0.75; 95% CI: 0.67 to 0.84, p < 0.001). No sex differences were noted
among UNOS status 1B patients.
CONCLUSIONS There are sex differences in survival between women and men awaiting heart transplantation, and the
current UNOS transplant criteria do not account for this disparity. (J Am Coll Cardiol HF 2014;2:347–55) © 2014 by the
American College of Cardiology Foundation.

W

omen in the United States have a higher

awaiting OHT during a 12-month follow-up. After

mortality rate than men while awaiting

adjusting for age, heart failure survival score, serum

orthotopic heart transplantation (OHT)

creatinine, inpatient status, cardiac index, low voca-

(1), which has not been fully evaluated. Based on pub-

tional level, smoking, and low emotional support at

licly available Scientific Registry of Transplant Recip-

time of transplant listing, female sex was still associ-

ients (SRTR) data, the median OHT wait time for

ated with a higher risk of death/deterioration (hazard

women during this same time period was shorter

ratio [HR]: 2.3; 95% confidence interval [CI]: 1.04 to

than for men (1), suggesting it was not due to availabil-

5.12; p ¼ 0.04) (2). What remains unknown is whether

ity of donors. In 1 small European study (58 women,

sex differences in waitlist mortality also exist in the

260 men), more women (17%) than men (12%) died

United States after adjusting for baseline risk factors.

From the *Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio; yCleveland Clinic, Lerner College of Medicine of Case
Western Reserve University School of Medicine, Cleveland, Ohio; zDepartment of Quantitative Health Sciences, Cleveland Clinic,
Cleveland, Ohio; xDepartment of Cardiology, Boston Children’s Hospital, Boston, Massachusetts; and the kHarvard Medical
School, Boston, Massachusetts. This research was funded by Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
Dr. Schold is a member of the Scientific Registry of Transplant Recipients Technical Advisory Committee. All other authors have
reported that they have no relationships relevant to the contents of this paper to disclose.
Manuscript received February 7, 2014; revised manuscript received February 24, 2014, accepted March 7, 2014.

Downloaded From: http://onlinejacc.org/ by Kendra Marsh on 01/05/2016

continuous intravenous high- LVAD = left ventricular assist chanical circulatory support may be recom- dose inotropes. Human er- Model 1 was adjusted for the following characteristics ror in collecting data is minimized by edit checks. Department of were created to assess for the association between Health and Human Services Health Resources and female sex and death according to initial UNOS Services Administration provides oversight of the status at time of listing. coxon rank-sum tests were used for group comparisons.S. UNOS status 1B for intermediate-risk patients. The goal of next highest status for OHT and includes patients PCWP = pulmonary capillary this study was to further evaluate sex dif- receiving continuous intravenous doses of inotrope ferences in mortality for HF patients await- support and stable VAD patients. or an exemption for critical illness such device mended with no evidence-based expectations as ventricular tachycardia or complications with me- OHT = orthotopic heart if sex differences in prognostic risk factors chanical circulatory support. history of cerebral STATUS. when there are outliers. Asian. using the Kaplan-Meier method with censoring for OHT. and categorical variables tance of the era before and after that date to look for were expressed as frequencies. and the donor of illness (3). Sex-specific survival analysis was performed METHODS for UNOS status 1A. PATIENT POPULATION AND UNOS black. response to ther- cial heart (TAH). previous OHT. To account for the limited mechanical circulatory support available to rescue women prior to April 2008. dial- validation of data at time of entry. Chi-square and Wil- any sex interaction.S. Medicare/Medicaid.org/ by Kendra Marsh on 01/05/2016 . However criteria for OHT pools are distinguished by age (3). JACC: HEART FAILURE VOL. Two models were created. UNOS status 1A includes patients rate despite known sex differences in cause (7–9). UNOS status 2 is the ing OHT. activities of OPTN and SRTR contractors. race (white. diabetes mellitus status. included all adult patients in the SRTR database who glomerular filtration rate (GFR). Food and Drug OUTCOME MEASURES. and prognosis (17–19).. other). Therefore. and internal veri- ysis. 1B. 2011. The SCIENTIFIC REGISTRY OF TRANSPLANT RECIPIENTS. that stratifies patients into categories based on severity of illness: United Network for Organ Sharing (UNOS) status 1A for high-risk patients. listing and heart failure (HF) survival models Data were stratified according to UNOS status at (4–6) do not distinguish women from men time of waitlisting. Pleasanton. assessed as a right-censored time to death. We vascular accident and tobacco use.348 Hsich et al. Administration approved a smaller device called STATISTICAL ANALYSIS. using our current allocation system least urgent status for patients actively waiting for IABP = intra-aortic balloon wedge pressure SRTR = Scientific Registry of Transplant Recipients OHT and is reserved for patients receiving standard SEE PAGE 356 TAH = total artificial heart UNOS = United Network for Organ Sharing VAD = ventricular assist device medical therapy. 2010. 4. type 1. using the Fine and and Transplantation Network (OPTN) and has been Gray method (21). Hispanic. The U. California) acteristics were reported according to UNOS status that could be implanted in petite patients (body at the time of listing for OHT. inotrope use. ambulatory patients. 2011. SRTR mortality data are maintained by the transplantation centers and verified with the U. other). 2014 AUGUST 2014:347–55 Mortality on the Heart Transplant Waiting List ABBREVIATIONS AND ACRONYMS ECMO = extracorporeal membrane oxygenation GFR = glomerular filtration The current OHT allocation system in the UNOS criteria for listing pediatric patients differs United States is based primarily on severity from that for patients who are adults. 2.5 m 2). tion (ECMO). and 2 patients. we also assessed the impor- were expressed as means. requiring ventricular assist device (VAD). and UNOS status 2 for lower risk. Continuous variables surface area: <1. NO. pump advanced HF therapies such as OHT or me- mechanical ventilation. at time of listing: age.S. were placed on the waiting list for OHT from January insurance (private. were included in the primary analysis. Cox proportional hazard models described elsewhere (20). fication. ventilator status. to December 31. intra-aortic balloon pump (IABP). body mass index. 2000. The cumula- and transplantation recipients in the United States tive incidence of transplantation and death was submitted by members of the Organ Procurement estimated as competing risks. total artifi- HF = heart failure cardiac remodeling (10–12). Follow-up data were of ventricular assist device (left ventricular assist available until November 30. waitlisted candidates. extracorporeal membrane oxygena- apy (13–16). Patients were device [LVAD] or right ventricular assist device with excluded if they were <18 years of age because the or without LVAD or TAH/unspecified mechanical Downloaded From: http://onlinejacc. primary analysis was based on intent to treat such This study used data from SRTRs. The SRTR database that deaths following removal from the waiting list includes data for all donors. The primary endpoint was all-cause mortality. when the U. UNOS status 1B is the transplantation are not recognized and utilized. with follow-up censored at the time of transplantation. Sex-specific baseline char- HeartMate II (Thoratec Corp. Social Security Administration Death Master File which was available until November 30.

whereas history monary artery mean pressure. restrictive cardiomyopathy. defibrillator. The outcome vari- tients were undergoing dialysis. ischemic cardiomyopathy. women were more likely cluding dummy variables when needed for missing than men to be on a ventilator and require inotrope variables among characteristics that had <10% of or ECMO support and less likely to have a TAH. able of this model was whether patients were listed as status 1A. IABP. JACC: HEART FAILURE VOL. Model 2 was performed as a sensitivity men in all subgroups. In all UNOS In order to understand the association between status subgroups. ABO blood types. antiarrhythmia. LVAD missing data.org/ by Kendra Marsh on 01/05/2016 349 . There were 1. and other). ECMO. similar percentage of women and men. 9. wedge pressure (PCWP). initially listed as UNOS status 1B. 2. Few pa- initial status and candidate sex. listed as UNOS status 1A was associated with lower A p value of <0. except for the mortality curve Downloaded From: http://onlinejacc. hypertension. There were no significant sex differ- RESULTS ences in competing outcomes between transplantation and death among patients awaiting OHT as STUDY POPULATION. Defibrillators were more likely analysis that excluded variables with ahigh propor- to be present in men than in women at time of listing. The propensity score was cardiac output among women than among men in all derived from a multivariate logistic model that subgroups. tality in women than in men initially listed as UNOS status 2 was associated with higher likelihood for OHT (Fig. and valvular disease pulmonary artery mean. Most patients had an idio- congenital heart disease. 1) but a better survival than men 2-sample t-test) to understand whether sex was when listed as UNOS status 2 (Fig. All analyses were performed using SAS version Higher mortality in women than in men initially 9. 2). cardiac output. Among and PCWP pressure (13% “missingness”) and in- UNOS status 1A patients. and cardiac Previous cardiac surgery and tobacco abuse were output with dummy variables for missing GFR. Right-heart catheterization showed the waiting list) and the likelihood of being placed slightly better hemodynamics for UNOS status 2 than on the waiting list as a status 1A patient. We then compared the average survival than men when initially listed for OHT as probabilities between men and women (using a UNOS status 1A (Fig. 3B). 4.852 adult HF patients (24% women) awaiting OHT men in all UNOS subgroups had the highest mortality are shown in Table 1.7 placed as status 1A as predicted by the set of cova- years. 2014 AUGUST 2014:347–55 Mortality on the Heart Transplant Waiting List circulatory device). There were no associated with greater predicted likelihood of status significant sex differences in survival for patients 1A placement.163 and transplantation rate within the first year after UNOS status 1A (25% women). pulmonary pressure (11% “missingness”). we WAITLIST MORTALITY. PCWP.286 men who died during a median follow-up of 3. with no sex differences except for lower erated a propensity score. Based on the output of this model. total albumin. with a higher years after listing. There was a plateau in the mortality and (25% women). Both women and 28. 3C). Women were younger and had a scular disease. This cohort included 6. OHT in each subgroup. malignancy. of malignancy was more common in women than in and albumin.290 women and evaluated the probability that a patient would be 4. valvular cardiomy- congenital heart disease. ABO blood type. thy.521 UNOS status 2 (24% women) transplantation curves around the second and third patients. In both models. Women had a statistically significant worse riates in the model. and history of peripheral vascular ters previously described. hypertrophic cardiomyopa- pathic dilated cardiomyopathy with slightly more thy. albumin (15% “miss- centage of patients with a defibrillator at time of ingness”). women had slightly lower peak VO 2 baseline parameters (at the time of placement on values than men. cardiac diagnosis lower body mass index than men at time of listing for (dilated cardiomyopathy. hypertrophic cardiomyopa- opathy.168 UNOS status 1B listing. or an IABP. peripheral va- in all subgroups. era. restrictive cardiomyopathy. mean pulmonary capillary among women than among men in all subgroups. we gen- 1A patients. previous cardiac prevalence of blacks among women than among men surgery. North Carolina). Cary. we imputed mean support.05 was considered statistically likelihood for undergoing OHT (Fig 3A). tion of “missingness” (>10% that included cardiac with UNOS status 1A patients having a lower per- output [12% “missingness”]). Lower mor- significant. Baseline characteristics of UNOS status 1B patients (Fig. with a term between coronary artery disease and sex. with the exception of disease were similar among all subgroups. NO.2 software (SAS Institute. pul- more likely in men than in women. Most patients were white. and 13. previous cerebral included the full study population and all parame- vascular accident.Hsich et al. listing than UNOS status 1B or 2 patients. Most UNOS status 1B patients values for missing values and included an interaction were receiving inotropes at the time of listing.

467 (45) Other Prior cardiac surgery Prior OHT 137 (9. l/min 3.035 (44) 1.039 (22) 141 (6) 440 (6) 32 (1) Ventilator 10 (8.197 (41) B 234 (15) 651 (14) 325 (14) 931 (14) 398 (12) 1.034 (55) 288 (4) 261 (8) 427 (4) 239 (4) 69 (2) 368 (4) 49 (3) 173 (4) 92 (4) 313 (5) 114 (4) 374 (4) 428 (33) 1.9) 4.6 (3.5.6) PVO2.621 (49) 2.83) 66 (50.3.5 (2.4.13) 10 (8.8) 57 (2.7. 2000–Mar 31.4.9 (3. mm Hg 20 (18.9) 1.917) 55 (45.157 (35) eGFR.6) 3.61) UNOS Status 2 Female (n ¼ 3. 2008 1. mm Hg 30 (26.328 (52) 408 (27) 2.4.13) 11 (9.218 (47) 1.81) Mean PAP.5.260 (39) 4.295 (33) 772 (24) 2226 (22) A 561 (37) 1842 (40) 807 (36) 2.647 (38) 1.2.014 (45) 3.83) 66 (47.0) Hypertension 425 (32) 1. g/dl 3.114 (40) 30–34 213 (14) 986 (21) 441 (20) 1.5.488 (66) 4. ml/kg/min 11 (9.4.672 (36) 1. NO.9.9.937 (58) Medicare/Medicaid 569 (37) 1.764 (44) Tobacco usage 312 (34) 1.046 (78) Apr 1.5.0) 3.38) 28 (20. 27) 20 (15.0) 3.7) 3.12) 11 (9. kg/m2 14–19 181 (12) 196 (4) 236 (11) 243 (4) 20–24 561 (37) 1.3) 28 (21.551 (78) Black 351 (23) 767 (17) 686 (31) 1.58) 54 (45.025 (46) 2933 (42) 1.478 (46) 4.334 (72) 1.9 (3.288 (49) Hypertrophic CMP 30 (2) 60 (1) 47 (2) 75 (1) 133 (4) 166 (2) Restrictive CMP 43 (3) 51 (1) 60 (3) 99 (1) 140 (4) 208 (2) 240 (2) Valvular CMP 47 (3) 89 (2) 68 (3) 143 (2) 107 (3) 155 (10) 277 (6) 79 (4) 183 (3) 200 (6) 518 (5) ICD 547 (37) 2.82) Serum albumin. 4.58) Male (n ¼ 10.417 (21) 820 (22) 1.34) 66 (51.org/ by Kendra Marsh on 01/05/2016 .61) Race White 983 (64) 3.25) 20 (17.1) 4.272) 56 (48.634) 49 (36.14) 307 (20) 686 (15) 57 (3) 137 (2) 18 (1) 69 (1) Inotrope 912 (60) 2594 (56) 1461 (65) 4.807 (39) 1.925 (42) 1.) 275 (19) 1101 (23) Dialysis at listing 70 (5) 196 (4) 33 (1) 143 (2) 60 (2) 178 (2) 278 (31) 1.251) 51 (39.3.396 (64) 180 (6) 624 (6) LVAD 189 (12) 733 (16) 207 (9) 786 (11) 38 (1) 149 (2) RVAD or RVAD þ LVAD 342 (22) 1.5) 163 (5.477 (76) 8.752 (38) 655 (29) 2.25) 20 (19.251 (22) 801 (8) Insurance Other 135 (1) Era Jan 1.342 (29) 735 (33) 1.5.6.4.529) Male (n ¼ 4.7 (2.2.13) 12 (10.32) PCWP.8.491 (53) 617 (35) 3.676 (41) 762 (37) 2.73 m2 64 (43.658 (52) 6.22) 19 (13.174 (43) 468 (31) 1.763 (27) 35–40 92 (6) 274 (6) 153 (7) 498 (7) 249 (8) Private 910 (60) 2.747 (69) 2.990 (29) 972 (30) 233 (2) 25–29 441 (29) 1.24) CO.740 (37) 550 (31) 2.9) 3.622 (67) 2.248 (62) Diabetes mellitus 104 (17) 438 (23) 141 (20) 513 (23.37) 30 (24. 2010 427 (28) 1258 (27) 763 (34) 2.102 (72) 3.791 (60) 1.542 (22) 725 (22) 2.072 (44) 719 (22) 5.334 (60) 4. JACC: HEART FAILURE VOL.5 (3. 2.226 (12) O 666 (44) 1.6 (3.6 (3.6.244 (38) 4.61) UNOS Status 1B Female (n ¼ 2.618 (41) 636 (33) 2.4 (3.5) 176 (2.35) 30 (27.484 (34) 328 (3) 487 (22) 3.376 (73) 1.4.249) 51 (39.7) 4.58) Male (n ¼ 6.0 (3.438 (43) AB 68 (5) 216 (5) 105 (5) 304 (4) 129 (4) 823 (54) 1.392 (51) 608 (40) Malignancy 118 (8) 171 (4) 227 (10) 41 (3) 127 (3) 58 (3) PVD Prior CVA Antiarrhythmic 270 (5.0) 503 (4.564 (37) 993 (31) 4.426 (63) 23 (2) 62 (1) ABO blood type 411 (4) Diagnosis Dilated CMP Congenital CAD 3.85) 65 (48.333 (12) Hispanic 131 (9) 346 (8) 185 (8) 552 (8) 316 (8) 705 (7) Asian 48 (3) 151 (3) 47 (2) 155 (2) 77 (2) 210 (2) Other 16 (1) 36 (1) 29 (1) 46 (1) 45 (1) 116 (1) 260 (8) BMI.200 (41) 50 (3) 171 (4) 48 (2) 159 (2) 39 (1) 2.304 (58) 4.4 (2.36) 31 (26.0. 2008–Dec 31.314 (39) 805 (29) 3.729 (53) 84 (4) 127 (2) 221 (7) 3.204 (49) 1.13) 118 (1) Continued on the next page Downloaded From: http://onlinejacc.950 (60) 5.178 (52) 3825 (55) 1.6.9) 4.151 (39) 4.350 Hsich et al.82) 67 (49.27) 18 (12.2) 3. ml/min/1.8 (3.524 (67) 8.2.624 (68) 1. 2014 AUGUST 2014:347–55 Mortality on the Heart Transplant Waiting List T A B L E 1 Sex Differences in Baseline Characteristics While Awaiting OHT UNOS Status 1A Variable Age (yrs) Female (n ¼ 1.

33% males were status 1A at end of study. We then assessed females vs. PVO2 ¼ peak oxygen consumption. 1% males (17% females vs. body 1A at end of study. When the cohort Figure 4 demonstrates that female sex was still was limited to only those who underwent trans- associated with a significant risk of death among plantation.0001). Again more men be a woman versus a man. NO.2% females vs. 17% study (censored at time of transplantation. 2% fe- sex and presence of coronary artery disease (p value males vs. we created a underwent transplantation. p ¼ 0. have a higher UNOS status at the end of the study 17% males were status 1B.0001). ECMO ¼ extracorporeal membrane oxygenation. p ¼ 0. ICD ¼ implantable cardioverter-defibrillator. p < 0. 42% males.251) Male (n ¼ 6. 22% females last day of study while on waiting list). In contrast. or 2. 0. CMP ¼ cardiomyopathy. To evaluate whether women were sicker than men When the cohort was limited to only those who at time of listing as UNOS status 1A. Among vs. 36% patients initially listed as UNOS status 1A. OHT ¼ orthotopic heart transplant. 81% males were status founding factors including age.917) Female (n ¼ 3. only significant interaction we found was between 55% females vs. 16% females vs. 40% males were status 1A at end of study.05 to 1. To further evaluate sex differences in outcome Among patients initially listed as UNOS status 2.0001). or males were status 1A at end of study. type of than men who initially did not have mechanical VAD.87). the likelihood that a patient listed as status 1A would 1% males were status 2. we analyzed changes in status at end of status at the end of the study (12% females vs. and 19% females vs. but fewer women mass index. 2% females vs. PVD ¼ peripheral vascular disease. 15% males were rise with time. The males vs.249) Male (n ¼ 10. 15% males were inactive status 7. p < 0. Similar results were there were slightly fewer women than men who were obtained when data were reanalyzed for women and at a higher status at the end of the study (26% fe- men without dummy variables for missing data.001). among UNOS status 2 patients. 59% males were status 1B.0001).org/ by Kendra Marsh on 01/05/2016 351 .029 (22) 55 (2) 173 (3) 20 (1) 96 (1) Values are median (interquartile range) or n (%).529) Male (n ¼ 4. BMI ¼ body mass index.67 to females vs. female sex was signifi- circulatory support at the time of listing received a cantly protective for time to death among UNOS VAD or TAH at the time of transplantation (31% status 2 patients (adjusted HR: 0.272) * * 33 (1) * * * ECMO 71 (5) 100 (2) * * * * IABP 313 (21) 1. vs. LVAD ¼ left ventricular assist device.20. 44% females vs. p < 0.84. CAD ¼ coronary artery disease. 51% males were status 1B. MCS ¼ mechanical circulatory support. vs. p < 0. 20. CVA ¼ cerebral vascular accident.001). When the urgent status and more women temporarily inactive cohort was limited to only those who underwent on UNOS waiting list (63% females vs. among patients initially listed as UNOS status 1A. p < 0. TAH ¼ total artificial heart. p < 0. 23% males were slightly fewer women than men remaining at were inactive status 7.9% or TAH at the time of transplantation (21% females males. RVAD ¼ right ventricular assist device. 95% CI: among the percentages of patients who were UNOS 1. death.0001). 2. and 16% females for interaction ¼ 0. and 22% females vs. *Frequency <10 patients. among UNOS status 1B patients. 26% males were status 1A at end of Downloaded From: http://onlinejacc. 2014 AUGUST 2014:347–55 Mortality on the Heart Transplant Waiting List T A B L E 1 Continued UNOS Status 1A Variable TAH or unspecified MCS Female (n ¼ 1. defibrillator. JACC: HEART FAILURE VOL. No sex differences were noted Among patients initially listed as UNOS status 1B. GFR. 2% males were status 2.37. IABP. 24% males were status 1B. 95% CI: 0. IABP ¼ intra-aortic balloon pump. 2% females vs. which continued to were status 2. inactive status 7. using the entire OHT vs. p < 0. p < 0. 65% cohort in SRTR from 2000 to 2010. PAP ¼ pulmonary arterial pressure. there were no significant sex differences UNOS status 1A patients (adjusted HR: 1. 67% males transplantation.75.Hsich et al.03). CO ¼ cardiac output. ABO blood type. We found women slightly than women who did not initially have mechanical more likely than men to have the characteristics of circulatory support at time of listing had either a VAD a UNOS status 1A patient (22. eGFR ¼ estimated glomerular filtration rate.0001). and era. ECMO. women were less likely than men to have a higher 1B. there males were status 2.634) UNOS Status 1B UNOS Status 2 Female (n ¼ 2.01 after adjusting for >30 con- status 1A (82% females vs. women were less likely model to determine the most likely characteristics of to be UNOS status 1A and more likely to be UNOS patients listed as UNOS status 1A with all variables status 1B at the time of transplantation (33% females excluding sex and UNOS status. 30% males. women were less likely than men to remained status 1A at end of study. 4.

level. women initially listed as UNOS status 1A or 1B had a higher risk than men for death/delisting due to severity of illness and a lower chance than men for transplantation. and low emotional support at the DISCUSSION time of transplantation listing (HR: 2.27. there has been no significant change in the number of OHTs in the United States annually despite a high waitlist mortality (25). national transplantation registry. we found women and men to have a similar profile at time of listing (22. 2. inpatient status. 34% males were status 1B. Our study adds to this literature suggesting that a sex-specific disparity exists in waitlist survival. Our study adds to the growing concern that the current OHT allocation system needs to be refined (22–24).0001). variables. p < European study noted women had a higher mortality 0. The authors concluded that women benefited from being listed as UNOS status 2 and that removing this status would result in a larger sex disparity (30). and status 1A upon listing for heart transplantation. However.153 OHT candi- sex differences in mortality while patients awaited dates listed from 2003 to 2008 to determine effec- OHT. No sex differences were noted among UNOS status 1B patients. Based on status 2 upon listing for heart transplantation. which remained after time of transplantation (7% females vs. low vocational level. HF survival score. NO. One small 53% females vs. 2014 AUGUST 2014:347–55 Mortality on the Heart Transplant Waiting List risk of death among patients listed initially as UNOS status 1A. the current transplantation allocation system was based primarily on severity of illness. JACC: HEART FAILURE VOL. The disparity in survival rates between women and men is of concern given the limited number of donor hearts available every year and the limited F I G U R E 2 Sex Differences in Survival in Heart Failure Patients Initially research in this field to further evaluate cause. even after multivariate analysis accounting for >30 possible confounders. serum creatinine p <0.0001) and less likely to have VAD or TAH at the rate than men awaiting OHT. 4.04 to 5. 15% males. For Listed As UNOS Status 2 patients initially listed as UNOS status 1A.28). appropriateness of elective 30-day UNOS status Kaplan-Meier survival curves for women and men initially listed as UNOS 1A time for patients with an LVAD (24. UNOS ¼ United Network for Organ Sharing. mortality while patients await OHT (2. 30% females vs.3. more Kaplan-Meier survival curves for women and men initially listed as UNOS women than men died on the waiting list. reF I G U R E 1 Sex Differences in Survival in Heart Failure Patients Initially Listed As UNOS Status 1A cent studies raise concern regarding racial disparity (26). 95% CI: 1. status 1A patients. whereas the opposite was true for UNOS status 2 patients. adjusting for age. To minimize death on the waiting list.30). cardiac index. Censored for heart trans- the characteristics available that identified UNOS plantation. female sex was associated with a higher Patients were stratified by UNOS status.04) (2). UNOS ¼ United Network for Organ Sharing. Our study found similar sex differences in mortality while patients awaited OHT as UNOS status 1A and 2 patients. 40% males were status 2. Censored for heart trans- transplantation of stable UNOS status 2 HF patients plantation. After we adjusted for possible confounding tiveness of transplanting UNOS status 2 patients. A larger study in the United In a large. Few studies have evaluated sex differences in study. p ¼ 0. smoking.2% Downloaded From: http://onlinejacc.12.352 Hsich et al. and based on univariate logistic regression models. (29). we found States using UNOS data analyzed 14.org/ by Kendra Marsh on 01/05/2016 . Over the last decade. and male sex was associated with a higher risk of death among patients listed initially as UNOS status 2.

21. 2. pulmo- vival. the higher mortality rate in women than in men was less likely due to sex differences in severity of illness at time of listing. Objective evidence to support this is limited in the SRTR database as there was a high rate of missing important variables like hemodynamics. mechanical ventilation.org/ by Kendra Marsh on 01/05/2016 model includes variables like oxygen 353 . Therefore. it is important to mention that the risk of survival for women did not change even after adjusting for >30 variables including mechanical circulatory support and era pre. so that as variables for an individual change. the level Sex differences in survival while awaiting OHT is of risk is adjusted. it is supported by status 2 (C). NO.Hsich et al. best example. Therefore. and despite not identifying the cause. The data remain limited. UNOS status 1A women were less likely than men to be bridged with VAD or TAH support at time of transplantation and more likely than men to be temporarily inactivated. preventing capture of any change in variable that affects prognosis but not UNOS status. 2014 AUGUST 2014:347–55 Mortality on the Heart Transplant Waiting List predicted vs.and post-FDA approval of HeartMate II. which might have been due to fewer women than men being eligible for devices or fewer women than men who consented to devices. However. 4. whereby regression models are used to a solution to reduce mortality must be found. We also did not have information as to why fewer women received mechanical circulatory support. UNOS ¼ United Network for Organ Sharing. and data were only available at discrete time points (time of listing. perceived differences in survival of ambulatory patients may be due to premature listing of women as UNOS status 2 when peak oxygen consumption values are similar to F I G U R E 3 Competing Outcomes for Women and Men on those in men. As for UNOS status 2 patients. even in the cohort heart transplantation as UNOS status 1A (A). The lung transplant waitlist allocation system to a “survival model-based” allo- survival cation system to account for sex differences in sur- dependency at rest. UNOS status 1B (B). 6-min walk distance. JACC: HEART FAILURE VOL.8% actual females and 20.33). Unfortunately. the differences in survival between women and men likely has to do with a lack of sex-specific OHT guidelines for peak oxygen consumption (31). this hypothesis cannot Heart Transplant Waiting List be explored because data for peak oxygen consumption were missing from approximately 50% of Sex-specific competing outcomes are shown for patients listed initially for patients in the SRTR database. and UNOS listed as UNOS status 2. We balance differences and assign a weight score that propose changing a “rule-based” heart transplant is used to rank patients.9% predicted vs. The lung allocation system is the a concern. the fact that women had better survival than men on the waiting list despite fewer women receiving VAD or TAH support at time of transplantation and fewer women than men at higher status at time of OHT.2% actual males were UNOS status 1A at time of listing). and Downloaded From: http://onlinejacc. We also propose making the process dynamic nary artery pressures. 21. time of transplantation. However. We and others have shown that women tend to live longer than men with the same peak oxygen consumption value (32. and change in status). but these findings raise concern that women were not successfully bridged to transplantation while they remained at high status and were inactivated due to worsening condition.

of medical support does not match the severity Eileen M. However. Prognostic risk factors can calculated using an individual’s weight. we found sex differences there are still likely database errors. current UNOS transplant criteria does not account for this disparity. Our study has several impor- tant limitations. It is also important to mention that the database is not inclusive of all objective data. the po- Awaiting OHT tential for this incomplete data to alter the qualitaThe risk of being female while initially listed as UNOS status 1A. However. For instance.1%). but there is vary based on the category that defines a patient’s no requirement to use lean body mass despite sex underlying lung disease. The validity of the data is dependent on accuracy upon data entry. Nonetheless. 4. Cleveland. national registry. JACC: HEART FAILURE VOL. Thus. OHT ¼ orthotopic heart transplantation. 2. and time of status change. estimated determine whether there are possible interactions vs.5%. NO. men ¼ 6. and internal verification when there are outliers. The cause are patients on mechanical ventilation (women ¼ remains unknown but should raise concern as the 0. determined by the individual center. men ¼ 0. Hemodynamics and serum laboratory with other variables. men ¼ 1. of illness defined by UNOS status.6%. In a large. valida- change the status of the patient are not routinely updated.354 Hsich et al. To create a similar strategy differences in body composition. men ¼ 0. tive findings of the study should be minimal but does prevent further understanding of sex differences in waitlist survival. A system that depends on awaiting transplantation. SRTR data are assessed by edit checks. Ohio 44195. but it will also improve database available with which to study patients our current registry. To minimize human error. indi- Heart and Vascular Institute.5%).2%. panel of reactive antibody and cardiac index. there is no define the variables associated with mortality and to requirement as to how to calculate it (i. Furthermore. We would also propose chang- values should be provided at the time of listing. it captures only informa- entering essential variables will be properly updated tion at given time points such as time of listing. For instance.org. Another important limitation is the fact that baseline data entered may not be standardized. These appear to be errors as the level REPRINT REQUESTS AND CORRESPONDENCE: Dr. more research will be needed to further body mass is used to calculate peak VO2 . HR ¼ hazard ratio. measured). Cleveland Clinic. This not only will provide a better alloca- despite the fact that the SRTR database is the best tion system for the patients. 2014 AUGUST 2014:347–55 Mortality on the Heart Transplant Waiting List these are actual database errors or patients intentionally labeled at lower status to prevent OHT while ill. CI ¼ confidence interval. peak VO 2 (ml/kg/min) is underlying lung disease. variables that affect prognosis but do not STUDY LIMITATIONS. other abbreviations as in Figure 1. missing data. Downloaded From: http://onlinejacc. but ing the system to a dynamic process where variables which values are entered if more than 1 is obtained is.org/ by Kendra Marsh on 01/05/2016 . risk score. CONCLUSIONS tion of data at time of entry. vidual centers may list at a lower UNOS status than 9500 Euclid Avenue. so it remains unknown whether Hsiche@ccf.e.. use of LVADs (women ¼ 1. and use of IABPs (women ¼ 0. Finally. in survival among patients awaiting OHT even after among ambulatory stable UNOS status 2 candidates rigorous multivariable risk adjustment. The lack of these variables. Therefore. E-mail: clinically indicated. if lean for OHT. time with information and likely have a lower rate of of transplantation. the low percent of “possible errors” would not be expected to alter the data significantly. it is unlikely that the proporF I G U R E 4 Cox Proportional Hazards Analyses of Female Sex and Mortality While tion of missing data elements was systematically and markedly different by candidate sex. which were not available. inotropes therapy (women ¼ 5. for the purpose of this study. Hsich.9%). Kaufman Center for Heart Failure.6%. In our multivariate analysis some important variables were not utilized such as natriuretic peptides. J3-4. and 2 are shown as unadjusted and multivariate adjusted data. 1B. can be updated daily to change an individual’s again. Despite these attempts.7%). limits the analysis not only for our study but also for future studies that may help in changing the allocation system.

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