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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. 348 Hsich et al. JACC: HEART FAILURE VOL. 2, NO. 4, 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, and the donor of illness (3). However criteria for OHT pools are distinguished by age (3). 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. UNOS status 1A includes patients rate despite known sex differences in cause (7–9), requiring ventricular assist device (VAD), total artifi- HF = heart failure cardiac remodeling (10–12), response to ther- cial heart (TAH), extracorporeal membrane oxygena- apy (13–16), and prognosis (17–19). Therefore, tion (ECMO), intra-aortic balloon pump (IABP), pump advanced HF therapies such as OHT or me- mechanical ventilation, continuous intravenous high- LVAD = left ventricular assist chanical circulatory support may be recom- dose inotropes, 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. UNOS status 1B is the transplantation are not recognized and utilized. 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. UNOS status 2 is the ing OHT, 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. that stratifies patients into categories based on severity of illness: United Network for Organ Sharing (UNOS) status 1A for high-risk patients; UNOS status 1B for intermediate-risk patients; and UNOS status 2 for lower risk, ambulatory patients. To account for the limited mechanical circulatory support available to rescue women prior to April 2008, when the U.S. Food and Drug OUTCOME MEASURES. The primary endpoint was all-cause mortality, assessed as a right-censored time to death, with follow-up censored at the time of transplantation. SRTR mortality data are maintained by the transplantation centers and verified with the U.S. Social Security Administration Death Master File which was available until November 30, 2011. Administration approved a smaller device called STATISTICAL ANALYSIS. Sex-specific baseline char- HeartMate II (Thoratec Corp., Pleasanton, California) acteristics were reported according to UNOS status that could be implanted in petite patients (body at the time of listing for OHT. Continuous variables surface area: <1.5 m 2), we also assessed the impor- were expressed as means, and categorical variables tance of the era before and after that date to look for were expressed as frequencies. Chi-square and Wil- any sex interaction. coxon rank-sum tests were used for group comparisons. Sex-specific survival analysis was performed METHODS for UNOS status 1A, 1B, and 2 patients, using the Kaplan-Meier method with censoring for OHT. The SCIENTIFIC REGISTRY OF TRANSPLANT RECIPIENTS. 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, waitlisted candidates, were included in the primary analysis. 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, using the Fine and and Transplantation Network (OPTN) and has been Gray method (21). Cox proportional hazard models described elsewhere (20). The U.S. 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. Two models were created. activities of OPTN and SRTR contractors. Human er- Model 1 was adjusted for the following characteristics ror in collecting data is minimized by edit checks, at time of listing: age, diabetes mellitus status, dial- validation of data at time of entry, and internal veri- ysis, body mass index, previous OHT, race (white, fication, when there are outliers. PATIENT POPULATION AND UNOS black, Hispanic, Asian, other), history of cerebral STATUS. We vascular accident and tobacco use, inotrope use, included all adult patients in the SRTR database who glomerular filtration rate (GFR), ventilator status, were placed on the waiting list for OHT from January insurance (private, Medicare/Medicaid, other), type 1, 2000, to December 31, 2010. Follow-up data were of ventricular assist device (left ventricular assist available until November 30, 2011. 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 Hsich et al. JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:347–55 Mortality on the Heart Transplant Waiting List circulatory device), antiarrhythmia, previous cardiac prevalence of blacks among women than among men surgery, hypertension, malignancy, peripheral va- in all subgroups. Women were younger and had a scular disease, ECMO, IABP, era, cardiac diagnosis lower body mass index than men at time of listing for (dilated cardiomyopathy, ischemic cardiomyopathy, OHT in each subgroup. Most patients had an idio- congenital heart disease, hypertrophic cardiomyopa- pathic dilated cardiomyopathy with slightly more thy, restrictive cardiomyopathy, valvular cardiomy- congenital heart disease, hypertrophic cardiomyopa- opathy, and other), ABO blood type, defibrillator, thy, restrictive cardiomyopathy, and valvular disease pulmonary artery mean, mean pulmonary capillary among women than among men in all subgroups. wedge pressure (PCWP), total albumin, and cardiac Previous cardiac surgery and tobacco abuse were output with dummy variables for missing GFR, pul- more likely in men than in women, whereas history monary artery mean pressure, PCWP, cardiac output, of malignancy was more common in women than in and albumin. Model 2 was performed as a sensitivity men in all subgroups. Defibrillators were more likely analysis that excluded variables with ahigh propor- to be present in men than in women at time of listing, tion of “missingness” (>10% that included cardiac with UNOS status 1A patients having a lower per- output [12% “missingness”]), albumin (15% “miss- centage of patients with a defibrillator at time of ingness”), pulmonary pressure (11% “missingness”), listing than UNOS status 1B or 2 patients. Among and PCWP pressure (13% “missingness”) and in- UNOS status 1A patients, 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, LVAD missing data. In both models, we imputed mean support, or an IABP. Most UNOS status 1B patients values for missing values and included an interaction were receiving inotropes at the time of listing, with a term between coronary artery disease and sex. similar percentage of women and men. In all UNOS In order to understand the association between status subgroups, women had slightly lower peak VO 2 baseline parameters (at the time of placement on values than men. 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 gen- 1A patients, with no sex differences except for lower erated a propensity score. The propensity score was cardiac output among women than among men in all derived from a multivariate logistic model that subgroups. ABO blood types, previous cerebral included the full study population and all parame- vascular accident, and history of peripheral vascular ters previously described, with the exception of disease were similar among all subgroups. Few pa- initial status and candidate sex. The outcome vari- tients were undergoing dialysis. able of this model was whether patients were listed as status 1A. Based on the output of this model, we WAITLIST MORTALITY. There were 1,290 women and evaluated the probability that a patient would be 4,286 men who died during a median follow-up of 3.7 placed as status 1A as predicted by the set of cova- years. Women had a statistically significant worse riates in the model. 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. 1) but a better survival than men 2-sample t-test) to understand whether sex was when listed as UNOS status 2 (Fig. 2). There were no associated with greater predicted likelihood of status significant sex differences in survival for patients 1A placement. initially listed as UNOS status 1B. All analyses were performed using SAS version Higher mortality in women than in men initially 9.2 software (SAS Institute, Cary, North Carolina). listed as UNOS status 1A was associated with lower A p value of <0.05 was considered statistically likelihood for undergoing OHT (Fig 3A). Lower mor- significant. tality in women than in men initially listed as UNOS status 2 was associated with higher likelihood for OHT (Fig. 3C). There were no significant sex differ- RESULTS ences in competing outcomes between transplantation and death among patients awaiting OHT as STUDY POPULATION. Baseline characteristics of UNOS status 1B patients (Fig. 3B). Both women and 28,852 adult HF patients (24% women) awaiting OHT men in all UNOS subgroups had the highest mortality are shown in Table 1. This cohort included 6,163 and transplantation rate within the first year after UNOS status 1A (25% women), 9,168 UNOS status 1B listing. There was a plateau in the mortality and (25% women), and 13,521 UNOS status 2 (24% women) transplantation curves around the second and third patients. Most patients were white, with a higher years after listing, except for the mortality curve 349 350 Hsich et al. JACC: HEART FAILURE VOL. 2, NO. 4, 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 1,529) Male (n ¼ 4,634) 49 (36,58) 54 (45,61) UNOS Status 1B Female (n ¼ 2,251) 51 (39,58) Male (n ¼ 6,917) 55 (45,61) UNOS Status 2 Female (n ¼ 3,249) 51 (39,58) Male (n ¼ 10,272) 56 (48,61) Race White 983 (64) 3,334 (72) 1,304 (58) 4,747 (69) 2,524 (67) 8,551 (78) Black 351 (23) 767 (17) 686 (31) 1,417 (21) 820 (22) 1,333 (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, kg/m2 14–19 181 (12) 196 (4) 236 (11) 243 (4) 20–24 561 (37) 1,342 (29) 735 (33) 1,990 (29) 972 (30) 233 (2) 25–29 441 (29) 1,752 (38) 655 (29) 2,564 (37) 993 (31) 4,114 (40) 30–34 213 (14) 986 (21) 441 (20) 1,542 (22) 725 (22) 2,763 (27) 35–40 92 (6) 274 (6) 153 (7) 498 (7) 249 (8) Private 910 (60) 2,791 (60) 1,178 (52) 3825 (55) 1,950 (60) 5,937 (58) Medicare/Medicaid 569 (37) 1,672 (36) 1,025 (46) 2933 (42) 1,260 (39) 4,200 (41) 50 (3) 171 (4) 48 (2) 159 (2) 39 (1) 2,251 (22) 801 (8) Insurance Other 135 (1) Era Jan 1, 2000–Mar 31, 2008 1,102 (72) 3,376 (73) 1,488 (66) 4,622 (67) 2,477 (76) 8,046 (78) Apr 1, 2008–Dec 31, 2010 427 (28) 1258 (27) 763 (34) 2,295 (33) 772 (24) 2226 (22) A 561 (37) 1842 (40) 807 (36) 2,647 (38) 1,244 (38) 4,197 (41) B 234 (15) 651 (14) 325 (14) 931 (14) 398 (12) 1,226 (12) O 666 (44) 1,925 (42) 1,014 (45) 3,035 (44) 1,478 (46) 4,438 (43) AB 68 (5) 216 (5) 105 (5) 304 (4) 129 (4) 823 (54) 1,807 (39) 1,426 (63) 23 (2) 62 (1) ABO blood type 411 (4) Diagnosis Dilated CMP Congenital CAD 3,218 (47) 1,729 (53) 84 (4) 127 (2) 221 (7) 3,484 (34) 328 (3) 487 (22) 3,072 (44) 719 (22) 5,328 (52) 408 (27) 2,288 (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) 2,204 (49) 1,334 (60) 4,624 (68) 1,658 (52) 6,248 (62) Diabetes mellitus 104 (17) 438 (23) 141 (20) 513 (23.) 275 (19) 1101 (23) Dialysis at listing 70 (5) 196 (4) 33 (1) 143 (2) 60 (2) 178 (2) 278 (31) 1,174 (43) 468 (31) 1,740 (37) 550 (31) 2,467 (45) Other Prior cardiac surgery Prior OHT 137 (9.0) Hypertension 425 (32) 1,676 (41) 762 (37) 2,764 (44) Tobacco usage 312 (34) 1,392 (51) 608 (40) Malignancy 118 (8) 171 (4) 227 (10) 41 (3) 127 (3) 58 (3) PVD Prior CVA Antiarrhythmic 270 (5.8) 57 (2.5) 176 (2.5) 163 (5.0) 503 (4.9) 1,151 (39) 4,621 (49) 2,491 (53) 617 (35) 3,034 (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) 1,618 (41) 636 (33) 2,314 (39) 805 (29) 3,157 (35) eGFR, ml/min/1.73 m2 64 (43,83) 66 (47,85) 65 (48,83) 66 (50,82) 67 (49,82) Serum albumin, g/dl 3.4 (2.8,3.6) 3.5 (2.9,3.7) 3.6 (3.2,4.0) 3.6 (3.2,4.0) 3.8 (3.6,4.2) 3.9 (3.6,4.3) 28 (21,34) 66 (51,81) Mean PAP, mm Hg 30 (26,35) 30 (27,37) 30 (24,36) 31 (26,38) 28 (20,32) PCWP, mm Hg 20 (18,25) 20 (19, 27) 20 (15,25) 20 (17,27) 18 (12,22) 19 (13,24) CO, l/min 3.9 (3.0,5.9) 4.6 (3.5,6.9) 3.7 (2.9,4.9) 4.4 (3.4,5.7) 4.0 (3.2,5.1) 4.5 (3.7,5.6) PVO2, ml/kg/min 11 (9,13) 12 (10,14) 307 (20) 686 (15) 57 (3) 137 (2) 18 (1) 69 (1) Inotrope 912 (60) 2594 (56) 1461 (65) 4,396 (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) 1,039 (22) 141 (6) 440 (6) 32 (1) Ventilator 10 (8,12) 11 (9,13) 10 (8,13) 11 (9,13) 118 (1) Continued on the next page Hsich et al. JACC: HEART FAILURE VOL. 2, NO. 4, 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 1,529) Male (n ¼ 4,634) UNOS Status 1B UNOS Status 2 Female (n ¼ 2,251) Male (n ¼ 6,917) Female (n ¼ 3,249) Male (n ¼ 10,272) * * 33 (1) * * * ECMO 71 (5) 100 (2) * * * * IABP 313 (21) 1,029 (22) 55 (2) 173 (3) 20 (1) 96 (1) Values are median (interquartile range) or n (%). *Frequency <10 patients. BMI ¼ body mass index; CAD ¼ coronary artery disease; CMP ¼ cardiomyopathy; CO ¼ cardiac output; CVA ¼ cerebral vascular accident; ECMO ¼ extracorporeal membrane oxygenation; eGFR ¼ estimated glomerular filtration rate; IABP ¼ intra-aortic balloon pump; ICD ¼ implantable cardioverter-defibrillator; LVAD ¼ left ventricular assist device; MCS ¼ mechanical circulatory support; OHT ¼ orthotopic heart transplant; PAP ¼ pulmonary arterial pressure; PVD ¼ peripheral vascular disease; PVO2 ¼ peak oxygen consumption; RVAD ¼ right ventricular assist device; TAH ¼ total artificial heart. among UNOS status 2 patients, which continued to were status 2; and 19% females vs. 15% males were rise with time. inactive status 7; p < 0.0001). 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, there were no significant sex differences UNOS status 1A patients (adjusted HR: 1.20; 95% CI: among the percentages of patients who were UNOS 1.05 to 1.37, p ¼ 0.01 after adjusting for >30 con- status 1A (82% females vs. 81% males were status founding factors including age, ABO blood type, body 1A at end of study, p ¼ 0.87), but fewer women mass index, GFR, IABP, ECMO, defibrillator, type of than men who initially did not have mechanical VAD, and era. In contrast, 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: 0.75, 95% CI: 0.67 to females vs. 42% males; p < 0.0001). 0.84, p < 0.001). No sex differences were noted Among patients initially listed as UNOS status 1B, among UNOS status 1B patients. 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. The males vs. 33% males were status 1A at end of study; only significant interaction we found was between 55% females vs. 51% males were status 1B; 2% fe- sex and presence of coronary artery disease (p value males vs. 2% males were status 2; and 16% females for interaction ¼ 0.03). vs. 15% males were inactive status 7; p < 0.0001). 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, we created a underwent transplantation, 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, using the entire OHT vs. 40% males were status 1A at end of study; 65% cohort in SRTR from 2000 to 2010. We then assessed females vs. 59% males were status 1B; 2% females vs. the likelihood that a patient listed as status 1A would 1% males were status 2; p < 0.0001). Again more men be a woman versus a man. 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 (22.2% females vs. 20.9% or TAH at the time of transplantation (21% females males, p < 0.001). vs. 30% males; p < 0.0001). To further evaluate sex differences in outcome Among patients initially listed as UNOS status 2, among patients initially listed as UNOS status 1A, women were less likely than men to have a higher 1B, or 2, we analyzed changes in status at end of status at the end of the study (12% females vs. 17% study (censored at time of transplantation, death, or males were status 1A at end of study; 22% females last day of study while on waiting list). Among vs. 24% males were status 1B; 44% females vs. 36% patients initially listed as UNOS status 1A, there males were status 2; and 22% females vs. 23% males were slightly fewer women than men remaining at were inactive status 7; p < 0.0001). When the urgent status and more women temporarily inactive cohort was limited to only those who underwent on UNOS waiting list (63% females vs. 67% males transplantation, women were less likely than men to remained status 1A at end of study; 16% females vs. have a higher UNOS status at the end of the study 17% males were status 1B; 2% females vs. 1% males (17% females vs. 26% males were status 1A at end of 351 352 Hsich et al. JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:347–55 Mortality on the Heart Transplant Waiting List risk of death among patients listed initially as UNOS status 1A, and male sex was associated with a higher risk of death among patients listed initially as UNOS status 2. No sex differences were noted among UNOS status 1B patients. Our study adds to the growing concern that the current OHT allocation system needs to be refined (22–24). Over the last decade, there has been no significant change in the number of OHTs in the United States annually despite a high waitlist mortality (25). To minimize death on the waiting list, the current transplantation allocation system was based primarily on severity of illness. However, 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), 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 (24,27,28), and status 1A upon listing for heart transplantation. Censored for heart trans- transplantation of stable UNOS status 2 HF patients plantation. UNOS ¼ United Network for Organ Sharing. (29). Our study adds to this literature suggesting that a sex-specific disparity exists in waitlist survival. Few studies have evaluated sex differences in study; 30% females vs. 34% males were status 1B; mortality while patients await OHT (2,30). One small 53% females vs. 40% males were status 2; p < European study noted women had a higher mortality 0.0001) and less likely to have VAD or TAH at the rate than men awaiting OHT, which remained after time of transplantation (7% females vs. 15% males; adjusting for age, HF survival score, serum creatinine p <0.0001). level, inpatient status, cardiac index, low vocational level, smoking, and low emotional support at the DISCUSSION time of transplantation listing (HR: 2.3; 95% CI: 1.04 to 5.12; p ¼ 0.04) (2). A larger study in the United In a large, national transplantation registry, we found States using UNOS data analyzed 14,153 OHT candi- sex differences in mortality while patients awaited dates listed from 2003 to 2008 to determine effec- OHT. After we adjusted for possible confounding tiveness of transplanting UNOS status 2 patients. variables, female sex was associated with a higher Patients were stratified by UNOS status, and based on univariate logistic regression models, 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, whereas the opposite was true for UNOS status 2 patients. 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). Our study found similar sex differences in mortality while patients awaited OHT as UNOS status 1A and 2 patients, even after multivariate analysis accounting for >30 possible confounders. 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. For Listed As UNOS Status 2 patients initially listed as UNOS status 1A, more Kaplan-Meier survival curves for women and men initially listed as UNOS women than men died on the waiting list. Based on status 2 upon listing for heart transplantation. Censored for heart trans- the characteristics available that identified UNOS plantation. UNOS ¼ United Network for Organ Sharing. status 1A patients, we found women and men to have a similar profile at time of listing (22.2% Hsich et al. JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:347–55 Mortality on the Heart Transplant Waiting List predicted vs. 21.8% actual females and 20.9% predicted vs. 21.2% actual males were UNOS status 1A at time of listing). Therefore, the higher mortality rate in women than in men was less likely due to sex differences in severity of illness at time of listing. 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. The data remain limited, 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. Objective evidence to support this is limited in the SRTR database as there was a high rate of missing important variables like hemodynamics, and data were only available at discrete time points (time of listing, time of transplantation, and change in status), preventing capture of any change in variable that affects prognosis but not UNOS status. We also did not have information as to why fewer women received mechanical circulatory support, which might have been due to fewer women than men being eligible for devices or fewer women than men who consented to devices. However, 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- and post-FDA approval of HeartMate II. As for UNOS status 2 patients, 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). We and others have shown that women tend to live longer than men with the same peak oxygen consumption value (32,33). Therefore, 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 those in men. Unfortunately, this hypothesis cannot be explored because data for peak oxygen con- F I G U R E 3 Competing Outcomes for Women and Men on Heart Transplant Waiting List sumption were missing from approximately 50% of Sex-specific competing outcomes are shown for patients listed initially for patients in the SRTR database, even in the cohort heart transplantation as UNOS status 1A (A), UNOS status 1B (B), and UNOS listed as UNOS status 2. However, it is supported by status 2 (C). UNOS ¼ United Network for Organ Sharing. 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. so that as variables for an individual change, the level Sex differences in survival while awaiting OHT is of risk is adjusted. The lung allocation system is the a concern, and despite not identifying the cause, best example, whereby regression models are used to a solution to reduce mortality must be found. We balance differences and assign a weight score that propose changing a “rule-based” heart transplant is used to rank patients. 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, mechanical ventilation, pulmo- vival. We also propose making the process dynamic nary artery pressures, 6-min walk distance, and model includes variables like oxygen 353 354 Hsich et al. JACC: HEART FAILURE VOL. 2, NO. 4, 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. Nonetheless, the low percent of “possible errors” would not be expected to alter the data significantly. It is also important to mention that the database is not inclusive of all objective data. In our multivariate analysis some important variables were not utilized such as natriuretic peptides, panel of reactive antibody and cardiac index. The lack of these variables, which were not available, limits the analysis not only for our study but also for future studies that may help in changing the allocation system. However, for the purpose of this study, 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. Thus, the po- Awaiting OHT tential for this incomplete data to alter the qualitaThe risk of being female while initially listed as UNOS status 1A, 1B, and 2 are shown as unadjusted and multivariate adjusted data. CI ¼ confidence interval; HR ¼ hazard ratio; OHT ¼ orthotopic heart transplantation; other abbreviations as in Figure 1. tive findings of the study should be minimal but does prevent further understanding of sex differences in waitlist survival. Another important limitation is the fact that baseline data entered may not be standardized. For instance, peak VO 2 (ml/kg/min) is underlying lung disease. Prognostic risk factors can calculated using an individual’s weight, 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. To create a similar strategy differences in body composition. Furthermore, if lean for OHT, more research will be needed to further body mass is used to calculate peak VO2 , there is no define the variables associated with mortality and to requirement as to how to calculate it (i.e., estimated determine whether there are possible interactions vs. measured). Hemodynamics and serum laboratory with other variables. We would also propose chang- values should be provided at the time of listing, but ing the system to a dynamic process where variables which values are entered if more than 1 is obtained is, can be updated daily to change an individual’s again, determined by the individual center. Finally, risk score. This not only will provide a better alloca- despite the fact that the SRTR database is the best tion system for the patients, but it will also improve database available with which to study patients our current registry. A system that depends on awaiting transplantation, it captures only informa- entering essential variables will be properly updated tion at given time points such as time of listing, time with information and likely have a lower rate of of transplantation, and time of status change. missing data. Therefore, variables that affect prognosis but do not STUDY LIMITATIONS. Our study has several impor- tant limitations. The validity of the data is dependent on accuracy upon data entry. To minimize human error, SRTR data are assessed by edit checks, valida- change the status of the patient are not routinely updated. CONCLUSIONS tion of data at time of entry, and internal verification when there are outliers. Despite these attempts, In a large, national registry, we found sex differences there are still likely database errors. For instance, in survival among patients awaiting OHT even after among ambulatory stable UNOS status 2 candidates rigorous multivariable risk adjustment. The cause are patients on mechanical ventilation (women ¼ remains unknown but should raise concern as the 0.6%, men ¼ 0.7%), inotropes therapy (women ¼ 5.5%, men ¼ 6.1%), use of LVADs (women ¼ 1.2%, current UNOS transplant criteria does not account for this disparity. men ¼ 1.5%), and use of IABPs (women ¼ 0.6%, men ¼ 0.9%). These appear to be errors as the level REPRINT REQUESTS AND CORRESPONDENCE: Dr. of medical support does not match the severity Eileen M. Hsich, Kaufman Center for Heart Failure, of illness defined by UNOS status. However, indi- Heart and Vascular Institute, Cleveland Clinic, J3-4, vidual centers may list at a lower UNOS status than 9500 Euclid Avenue, Cleveland, Ohio 44195. 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