Download 1 - JACC: Heart Failure

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. E-mail:
clinically indicated, so it remains unknown whether
[email protected].
Hsich et al.
JACC: HEART FAILURE VOL. 2, NO. 4, 2014
AUGUST 2014:347–55
Mortality on the Heart Transplant Waiting List
REFERENCES
1. Scientific Registry of Transplant Recipients:
Heart: Candidates: Gender 2000–2009 Heart
Waiting List. Available at: http://srtr.transplant.hrsa.
gov/annual_reports/2010/iHR_Candidates_gender.
htm?o¼5&g¼1&c=1. Accessed on June 19, 2014.
2. Weidner G, Zahn D, Mendell NR, et al. Patients’
sex and emotional support as predictors of death
and clinical deterioration in the waiting for a new
heart study: results from the 1-year follow-up.
Prog Transplant 2011;21:106–14.
3. OPTN Policy 3.7. Available at: http://optn.
transplant.hrsa.gov/PoliciesandBylaws2/policies/
pdfs/policy_9.pdf. Accessed June 19, 2014.
4. Aaronson KD, Schwartz JS, Chen TM, Wong KL,
Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival
in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660–7.
5. Brophy
JM,
Dagenais
GR,
McSherry
F,
Williford W, Yusuf S. A multivariate model for predicting mortality in patients with heart failure and
systolic dysfunction. Am J Med 2004;116:300–4.
6. Levy WC, Mozaffarian D, Linker DT, et al. The
Seattle heart failure model: prediction of survival
in heart failure. Circulation 2006;113:1424–33.
7. He J, Ogden LG, Bazzano LA, Vupputuri S,
Loria C, Whelton PK. Risk factors for congestive
heart failure in US men and women: NHANES I
epidemiologic follow-up study. Arch Intern Med
2001;161:996–1002.
8. Lee DS, Gona P, Vasan RS, et al. Relation of
disease pathogenesis and risk factors to heart
failure with preserved or reduced ejection fraction: insights from the Framingham heart study of
the national heart, lung, and blood institute.
Circulation 2009;119:3070–7.
9. Pina IL, Kokkinos P, Kao A, et al. Baseline differences in the HF-ACTION trial by sex. Am Heart J
2009;158:S16–23.
10. Cappola TP, Harsch MR, Jessup M, et al. Predictors of remodeling in the CRT era: influence of
mitral regurgitation, BNP, and gender. J Card Fail
2006;12:182–8.
11. Douglas PS, Katz SE, Weinberg EO, Chen MH,
Bishop SP, Lorell BH. Hypertrophic remodeling:
gender differences in the early response to left
ventricular pressure overload. J Am Coll Cardiol
1998;32:1118–25.
13. Ghali JK, Lindenfeld J. Sex differences in
response to chronic heart failure therapies. Expert
Rev Cardiovasc Ther 2008;6:555–65.
14. Ghanbari H, Dalloul G, Hasan R, et al. Effectiveness of implantable cardioverter-defibrillators
for the primary prevention of sudden cardiac
death in women with advanced heart failure: a
meta-analysis of randomized controlled trials.
Arch Intern Med 2009;169:1500–6.
15. Hsich EM, Pina IL. Heart failure in women:
a need for prospective data. J Am Coll Cardiol
2009;54:491–8.
16. Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensin-converting enzyme inhibitors
and beta-blockers in the management of left
ventricular systolic dysfunction according to race,
gender, and diabetic status: a meta-analysis of
major clinical trials. J Am Coll Cardiol 2003;41:
1529–38.
17. Jessup M, Pina IL. Is it important to examine
gender differences in the epidemiology and
outcome of severe heart failure? J Thorac Cardiovasc Surg 2004;127:1247–52.
18. Levy D, Kenchaiah S, Larson MG, et al.
Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002;
347:1397–402.
19. Roger VL, Weston SA, Redfield MM, et al.
Trends in heart failure incidence and survival in a
community-based population. JAMA 2004;292:
344–50.
20. Leppke S, Leighton T, Zaun D, et al. Scientific
Registry of Transplant Recipients: collecting,
analyzing, and reporting data on transplantation in
the United States. Transplantations Reviews 2013;
27:50–6.
21. Fine JP, Gray RJ. A proportional hazards model
for the subdistribution of a competing risk. J Am
Stat Assoc 1999;94:496–509.
22. Rogers JG. Defining and refining heart failure
risk stratification to optimize patient selection for
cardiac transplantation. Circ Heart Fail 2013;6:
2–3.
23. Colvin-Adams M, Valapour M, Hertz M, et al.
Lung and heart allocation in the United States. Am
J Transplant 2012;12:3213–34.
12. Piro M, Della Bona R, Abbate A, Biasucci LM,
Crea F. Sex-related differences in myocardial
24. Uriel N, Jorde UP, Woo Pak S, et al. Impact of
long term left ventricular assist device therapy on
donor allocation in cardiac transplantation. J Heart
remodeling. J Am Coll Cardiol 2010;55:1057–65.
Lung Transplant 2013;32:188–95.
25. Scientific Registry of Transplant Recipients.
Heart waiting list by gender 2000–2009. Available
at:
http://www.srtr.org/annual_reports/
2010/survival_rates.htm. Accessed June 19, 2014.
26. Singh TP, Almond CS, Taylor DO, Milliren CE,
Graham DA. Racial and ethnic differences in waitlist outcomes in patients listed for heart transplantation in the United States. Circulation 2012;
125:3022–30.
27. Dardas T, Mokadam NA, Pagani F, Aaronson K,
Levy WC. Transplant registrants with implanted
left ventricular assist devices have insufficient risk
to justify elective organ procurement and transplantation network status 1A time. J Am Coll
Cardiol 2012;60:36–43.
28. Wever-Pinzon O, Drakos SG, Kfoury AG,
et al. Morbidity and mortality in heart transplant candidates supported with mechanical
circulatory support: is reappraisal of the current
United Network for Organ Sharing thoracic organ allocation policy justified? Circulation 2013;
127:452–62.
29. Lietz KL, Miller LW. Improved survival of patients with end-stage heart failure listed for heart
transplantation: analysis of organ procurement
and transplantation network/U.S. United Network
of Organ Sharing data, 1990 to 2005. J Am Coll
Cardiol 2007;50:1282–90.
30. Dardas TF, Cowger J, Koelling TM,
Aaronson KD, Pagani FD. The effectiveness of
United Network of Organ Sharing status 2 transplantation in the modern era. J Heart Lung
Transplant 2011;30:1169–74.
31. Mehra MR, Kobashigawa J, Starling R, et al.
Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation
guidelines for the care of cardiac transplant candidates–2006. J Heart Lung Transplant 2006;25:
1024–42.
32. Elmariah S, Goldberg LR, Allen MT, Kao A.
Effects of gender on peak oxygen consumption
and the timing of cardiac transplantation. J Am
Coll Cardiol 2006;47:2237–42.
33. Hsich E, Chadalavada S, Krishnaswamy G, et al.
Long-term prognostic value of peak oxygen consumption in women versus men with heart failure
and severely impaired left ventricular systolic
function. Am J Cardiol 2007;100:291–5.
KEY WORDS heart failure, mortality, sex,
transplantation
355