Prognosis and Determinants of Survival in Patients Newly Hospitalized for
Heart Failure

A Population-Based Study

Author Information
<http://archinte.ama-assn.org/issues/v162n15/rfull/#aainfo>   Philip Jong,
MD; Erika Vowinckel, MD; Peter P. Liu, MD; Yanyan Gong, MSc; Jack V. Tu, MD,
PhD
Background  The prognosis in unselected community-dwelling patients with
heart failure has not been widely studied.
Objective  To determine the short- and long-term mortality of patients after
first hospitalizations for heart failure and to examine how age, sex, and
comorbidities influence survival.
Methods  We used the Canadian Institute for Health Information database to
construct a retrospective population-based cohort of 38 702 consecutive
patients with first-time admissions for heart failure from April 1994
through March 1997 in Ontario, Canada. Prognostic variables were collected
from hospital discharge abstracts. Vital status at 30 days and 1 year was
determined through linkage with the Ontario Registered Persons Database.
Regression analyses were used to identify the relationships among survival,
age, sex, and comorbidities.
Results  The crude 30-day and 1-year case-fatality rates after first
admissions for heart failure were 11.6% and 33.1%, respectively. Advancing
age, male sex, and the presence of comorbidities as identified by the
Charlson Index were independently associated with poorer survival. The
30-day and 1-year mortality ranged from 2.3% and 7.6%, respectively, in the
youngest subgroup with minimal comorbidity to 23.8% and 60.7%, respectively,
in the oldest comorbidity-laden subgroup. Complex interactions among age and
sex, sex and comorbidities, and age and comorbidities were observed in
models of short- and long-term survival.
Conclusions  The prognosis of unselected community-dwelling patients with
heart failure remains poor, despite advances in treatment, with substantial
variation seen across different subgroups. Although age, sex, and
comorbidities were confirmed to be independent prognostic indicators of
heart failure, their complex interaction with survival should be considered
in future studies.
Arch Intern Med. 2002;162:1689-1694
IOI10610
ALTHOUGH DECREASING mortality rates observed in clinical trials of heart
failure during the past decades suggest improved prognosis in patients with
heart failure (hereafter referred to as heart failure patients) who were
enrolled in those trials, 1
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r1>  it is unclear
whether such improvement is also seen in heart failure patients from the
general population. In particular, the prognosis of unselected
community-dwelling patients who are newly hospitalized for heart failure has
not been well studied. This omission is not surprising, since subjects
enrolled in clinical trials are often unrepresentative of heart failure
patients from the community, who are likely to be older women and to have
significant comorbidities. 2
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r2> , 3
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r3>
To better characterize the prognosis of heart failure patients from the
general population, past epidemiological studies 4
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r4> , 5
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r5>  have used
administrative databases to assemble cohorts of largely unselected heart
failure patients in whom outcomes can be tracked over time on a population
level. However, most studies 6-11
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r6>  have not eliminated
the confounding effect of disease duration when determining the prognosis of
these patients by failing to select only those with newly diagnosed heart
failure. Thus, an accurate description of the outcomes of this population
and the factors that influence their outcomes is needed. In this study, we
conducted a population-based analysis using hospital discharge abstracts to
determine the short- and long-term survival of patients who have been
admitted for the first time for heart failure in Ontario, Canada, a province
with a population of 11 million. We hypothesized that in the era of
contemporary therapy for heart failure, the case-fatality rates due to heart
failure in the community remain high, and that the poor prognosis of this
population bears a complex relationship to age, sex, and comorbidities that
has not been well described.



PATIENTS AND METHODS



DATA SOURCES

The Canadian Institute for Health Information collects and collates data on
all hospital discharges in Canada. 12
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r12>  This database can
be linked to other data sources using encrypted health card numbers to
anonymously track outcomes of individuals over time. The accuracy of the
Canadian Institute for Health Information data has been described
previously. 13 <http://archinte.ama-assn.org/issues/v162n15/rfull/#r13> , 14
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r14>  Using this
database, we constructed a cohort of consecutive patients who were
hospitalized for the first time for heart failure in the province of Ontario
from April 1994 to March 1997. We identified all individuals (N = 75 642)
who were admitted with a most-responsible diagnosis of congestive heart
failure (International Classification of Diseases, Ninth Revision, Clinical
Modification [ICD-9-CM], code 428). We excluded subjects who were younger
than 20 years (n = 273), those without a valid Ontario heath card number (n
= 927), and those who were admitted to chronic care facilities (n = 713). To
minimize referral bias from outside our catchment area, we excluded all
non-Ontario residents (n = 660) and those who transferred from other acute
care facilities (n = 1626). We also excluded subjects for whom heart failure
was coded as a hospital complication (n = 493) to prevent confounding by the
latter coding on survival. To avoid double counting of cases, we excluded
all individuals for whom this was not the first admission for heart failure
(n = 23 268). We also excluded all subjects with previous admissions for
heart failure or who had a diagnosis of heart failure coded during any
hospital admission in the 5 years before this study (n = 8980).
INDICATORS AND OUTCOMES

We used the ICD-9-CM codes recorded on the discharge abstracts of all
hospitalizations, including and within 5 years before the index admission,
to identify the presence of any comorbid condition. The abstract provided up
to 15 fields for secondary or other diagnoses to record comorbid conditions.
Comorbidities were abstracted using the adaptation of the Charlson Index for
administrative databases by Deyo et al. 15
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r15>  The Charlson Index
is a composite score of comorbidity measures commonly used for case-mix
adjustments in studies assessing longitudinal health outcomes. 16
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r16>  We linked our
cohort to the Ontario Registered Persons Database to determine the vital
status of each patient at 30 days and 1 year after the index admission. The
annual emigration rate from Ontario is less than 0.01%. 17
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r17>  Additional deaths
were also captured by searching for subsequent hospital admissions from the
Canadian Institute for Health Information data that coded for in-hospital
deaths.
STATISTICAL ANALYSIS

We calculated the crude 30-day and 1-year case-fatality rates and tabulated
the crude case-fatality rates stratified by age, sex, and the Charlson
comorbidity score. We used Cochran-Mantel-Haenszel statistics 18
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r18>  to test for sex
differences in the case-fatality rates while controlling for the confounding
effect of age. We tested the age-specific case-fatality rates for trend
using the Mantel extension test 19
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r19>  to control for the
confounding effect of sex. We used the chi2 statistic to test the
relationship between case-fatality rates and the Charlson score.
To determine the independent effects of age, sex, and comorbidities on
prognosis, we constructed multivariable logistic regression models for the
30-day and 1-year mortality. All comorbidities with a prevalence of at least
1% in our cohort were considered for inclusion in our models. A univariate
logistic regression model was first performed for each covariate. Only
covariates that had a significance level of P<.20 were entered into the
multivariable logistic models. A backwards elimination procedure (cutoff,
P>.10) was then used to arrive at a final regression model for each outcome.
Because the logit risk for death increased nonlinearly with age, a 4-level
age group was used in the model regression. We tested model calibration by
means of the Hosmer-Lemeshow 20
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r20>  chi2 test, and
assessed model discrimination by means of the c statistic. 21
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r21>  Significance of
each covariate in the final models was tested using the Wald chi2 statistic.
We examined the interdependence among age, sex, and comorbidities on
survival by adding a first-order interaction term among age group, sex, and
the Charlson score in a pairwise fashion to the models. Significance of
interactions was tested using the likelihood ratio tests 22
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r22>  for comparing
different logistic models. All analyses were conducted using SAS software,
Version 8.0 (SAS Institute Inc, Cary, NC).



RESULTS



POPULATION DEMOGRAPHICS

A total of 38 702 patients were hospitalized for heart failure for the first
time in Ontario during the 3-year period. More than half (51.1%) of the
cohort were women. Most patients (84.6%) were 65 years or older, and 57.9%
were 75 years or older.
CRUDE CASE-FATALITY RATES

The crude 30-day and 1-year case-fatality rates after first-time admissions
for heart failure were 11.6% and 33.1%, respectively ( Table 1
<http://archinte.ama-assn.org/issues/v162n15/fig_tab/ioi10610_t1.html> ). In
men, these rates were 11.4% and 34.0%, respectively; in women, 11.8% and
32.3%, respectively. After adjustment for age, men showed a higher 30-day
mortality rate than women (odds ratio [OR], 1.09; chi2 = 10.3; P = .001).
This difference persisted at 1 year after discharge (OR, 1.16; chi2 = 101.9;
P<.001).
As expected, case-fatality rates roses sharply with increasing age. The
30-day case-fatality rate increased from 4.5% in those younger than 50 years
to 15.1% in those 75 years or older. The effect of age on the case-fatality
rate at 1 year was even more dramatic. The 1-year case-fatality rate was
13.5% in those younger than 50 years, which increased to 40.1% in those 75
years or older. Controlling for the confounding effect of sex did not
diminish the powerful effect of age on 30-day (chi2 = 580.9; P<.001) or
1-year (chi2 = 1278.0; P<.001) mortality.
The 30-day and 1-year case-fatality rates were strongly correlated to the
Charlson score (chi2 = 350.4 and chi2 = 1042.0, respectively; P<.001 for
both) ( Table 2
<http://archinte.ama-assn.org/issues/v162n15/fig_tab/ioi10610_t2.html> ).
Among patients with no major comorbidity (Charlson score of 0) except for
heart failure, the 30-day and 1-year mortality rates were 9.3% and 26.8%,
respectively; these rates increased to 18.8% and 50.6% among those with
comorbidity scores of 3 or more.
Table 3
<http://archinte.ama-assn.org/issues/v162n15/fig_tab/ioi10610_t3.html>
describes the 30-day and 1-year case-fatality rates observed in our cohort
stratified by age, sex, and the Charlson score. The 30-day and 1-year
mortality rates ranged from 2.3% and 7.6%, respectively, in the lowest-risk
group to 23.8% and 60.7%, respectively, in the highest-risk group. The
lowest-risk group consisted of patients younger than 50 years with minimal
comorbidity except for heart failure. The highest-risk group included men 75
years or older with significant comorbidities.
INDEPENDENT EFFECTS OF AGE, SEX, AND COMORBIDITIES

Multivariate modeling confirmed the strong independent effect of age on
mortality after the first hospitalization for heart failure ( Table 4
<http://archinte.ama-assn.org/issues/v162n15/fig_tab/ioi10610_t4.html> ). We
found a stepwise increase in the risk for death with advancing age. Patients
in the highest-age bracket had ORs for death of 3.55 at 30 days and 4.24 at
1 year (P<.001 for both) compared with those in the lowest-age bracket. In
contrast, sex exerted an independent effect on long but not short-term
survival. Compared with men, women had a significantly higher survival at 1
year (OR, 0.84; P<.001) but not at 30 days. Furthermore, most comorbid
conditions identified by the Charlson Index were found to be significant
independent predictors of 30-day and 1-year mortality. These included
malignancy (ORs, 2.32 and 2.89 [for 30-day and 1-year mortality,
respectively]; P<.001 for both), renal disease (OR, 1.97 and 2.35; P<.001
for both), dementia (ORs, 1.77 and 1.85; P<.001 for both), cerebrovascular
disease (ORs, 1.57 and 1.60; P<.001 for both), rheumatologic disease (ORs,
1.32 and 1.47; P = .04 and P<.001), peripheral vascular disease (ORs, 1.17
and 1.42; P = .03 and P<.001), and previous myocardial infarction (ORs, 1.16
and 1.12; P<.001 for both). The presence of chronic pulmonary disease and
diabetes mellitus with chronic complications were significant predictors of
mortality at 1 year (ORs, 1.13 and 1.52; P<.001 for both) but not at 30
days. The Hosmer-Lemeshow tests showed no lack of fit for our 30-day and
1-year models (chi28 = 10.68 and chi27 = 6.30; P = .22 and P = .51). The c
statistics were 0.64 and 0.65, respectively, on par with other models 23
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r23>  that incorporated
the Deyo adaptation of the Charlson Index in predicting survival in the
population with heart failure.
INTERACTIONS AMONG AGE, SEX, AND COMORBIDITIES

The effect of sex on survival after first hospitalizations for heart failure
differed across age groups ( Table 5
<http://archinte.ama-assn.org/issues/v162n15/fig_tab/ioi10610_t5.html> ). We
found an interaction between age group and sex that approached statistical
significance in the model that predicted 30-day mortality (chi23 = 6.64; P =
.08) and became statistically significant in the model that predicted 1-year
mortality (chi23 = 8.39; P = .04). In particular, among patients 75 years or
older, the gender gaps in the ORs for death at 30 days and 1 year were only
10.8% and 40.3%, respectively, of the gaps observed among the group younger
than 50 years. Likewise, the cumulative effect of comorbidity on survival
after first-time admissions for heart failure differed between the sexes. We
found significant interactions between the Charlson score and sex in models
that predicted 30-day and 1-year mortality (chi21 = 30.34 and chi21 =
149.87, respectively; P<.001 for both). The direction of the interaction in
both models suggested that the sex gaps in mortality diminished with
increasing comorbidities. Any survival advantage possessed by women was lost
when the Charlson score was greater than 2 in our 30-day model and greater
than 3 in our 1-year model. Significant interactions were also seen between
age group and the Charlson score when predicting 30-day and 1-year mortality
after first hospitalizations for heart failure (chi23 = 140.61 and chi23 =
416.69, respectively; P<.001 for both). The gap in mortality rates owing to
differences per unit of the Charlson score was lower among patients 75 years
or older than among those in the next 2 younger age brackets. In all cases,
addition of these significant interactions improved the discriminative
powers of our models (c statistic increases, 0.003-0.013) in predicting
mortality.



COMMENT



Our study has documented the high short- and long-term mortality rates after
first-time admissions for heart failure in unselected patients from a large
population-based sample in Ontario. We also demonstrated a substantial
variation in the case-fatality rates across different patient subgroups.
Only young subjects with minimal comorbidity had the low mortality rates
that were typically seen in contemporary clinical trials of heart failure. 1
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r1>  For most
community-dwelling subjects with heart failure who were more likely to be
older women with significant comorbidities, their prognosis remained poor.
The large disparity between case-fatality rates observed in our study and
those reported in clinical trials is due to selection bias of the
populations enrolled in these trials. Contemporary clinical trials of heart
failure have largely been conducted in white, male populations with mean
ages of about 60 years and a minimal number of comorbidities. 1
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r1>  Although it is
unclear what percentage of patients with heart failure encountered in
clinical practice would not qualify for participation in these trials,
studies evaluating the effect of screening on trial enrollment suggest that
typically 35% to 85% of those undergoing screening were excluded from
participation. 24 <http://archinte.ama-assn.org/issues/v162n15/rfull/#r24>
Therefore, a serious concern is raised that the evidence-based practice that
currently exists for heart failure may only be appropriate for the limited
segment of the population with heart failure included in the trials.
Our ability to track the outcomes of anonymous subjects in a large community
using unique identifiers may improve on another study 4
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r4>  that used only
probabilistic matching to link subjects between databases, because there is
no guarantee in the latter approach that an individual from the first
database corresponds to the same individual from a different database.
Furthermore, because Canada uses a single-payer healthcare system, our
database provides uniform information covering an entire geographic area
across a broad population inclusive of all socioeconomic strata that is not
readily available in the United States. By selecting only subjects with
newly diagnosed heart failure, we minimized the confounding effects of
disease duration on survival. Prevalence (as opposed to incidence) studies
6-11 <http://archinte.ama-assn.org/issues/v162n15/rfull/#r6>  that reported
on survival after heart failure are prone to bias 25
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r25>  because they may
miss early fatal cases with survival not long enough to be counted.
We were aware of only 5 large-scale studies 4
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r4> , 5
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r5> , 26-28
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r26>  that provided
longitudinal health data from heart failure patients on a community level in
a contemporary setting. The Scottish Heart Failure Study 4
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r4>  used probabilistic
linkages to track the outcomes of 66 547 patients admitted to the hospital
for the first time with heart failure from 1986 to 1995 in Scotland. The
crude 1-year case-fatality rate in that study was 44.5% (44.0% in men and
44.9% in women). Moreover, our study and theirs showed that chronic
comorbidities independently increased the mortality rates of patients with
newly diagnosed heart failure. The Framingham Heart Study 26
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r26>  followed up 652
subjects undergoing screening from 1948 through 1988 and in whom new-onset
heart failure developed. The 1-year mortality rates were 43% in men and 36%
in women. As in the Scottish Heart Failure Study, the rates in the
Framingham Heart Study were higher than in our own, perhaps owing to
progress made in heart failure therapy since the early 1990s and to
differences in the underlying population. Unlike our study, new cases of
heart failure in the Framingham Heart Study were captured by interval
examinations performed every 2 years rather than by hospital discharge
abstracts.
In contrast, our approach is similar to a that of Swedish study 5
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r5>  in which 2461
patients from 1980 to 1987 were followed up after their first
hospitalizations for heart failure. The 1-year mortality rate was just above
20%. The lower mortality rate in that study compared with our own might be
related to the younger age composition of the population with heart failure
in Sweden. About half of the subjects in that study were aged 61 to 65
years, whereas more than half of our cohort were 75 years or older. The
Rochester Epidemiology Project 28
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r28>  described the
prognosis of 107 and 141 patients who presented with new-onset heart failure
in 1981 and 1991, respectively. The 1-year mortality rate was 28% in the
first cohort and 23% in the second. The same group of investigators also
followed up 216 patients from Olmstead County, Minnesota, who had a first
diagnosis of heart failure in 1991. 27
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r27>  They found a
1-year case-fatality rate of 24%. Because comorbidities were not
systematically listed in either of these studies, it was unclear whether the
lower observed mortality rates compared with our own were related to a lower
prevalence of comorbidities in their cohorts of heart failure patients.
Although a number of studies 5
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r5> , 11
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r11> , 27
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r27> , 28
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r28>  have identified
prognostic indicators in unselected community-dwelling heart failure
patients, few studies 4
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r4> , 26
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r26>  have addressed how
these indicators interact with each other in determining mortality. This
omission is understandable because interactions between predictors in
prognostic models are often difficult to quantify and interpret clinically.
We demonstrated that such interactions could be readily quantifiable and
that their inclusion might elucidate meaningful understanding of the
competing risks among age, sex, and comorbidity in influencing survival in
the population with heart failure. The Framingham Heart Study has long
recognized that the mortality rate due to heart failure in men but not in
women increased at more than a simple exponential rate with advancing age.
26 <http://archinte.ama-assn.org/issues/v162n15/rfull/#r26>  MacIntyre et al
4 <http://archinte.ama-assn.org/issues/v162n15/rfull/#r4>  reported a
significant age-sex interaction in their Scottish cohort of heart failure
patients for the 30-day case-fatality rate, although the interaction did not
persist at 1 year. An age-sex interaction was evident in our population and
we found meaningful interactions between sex and comorbidity and between age
and comorbidity. Barring statistical variations, these interactions
qualitatively raise, although do not prove, the hypothesis that a common
mechanism of competing risks may determine heart failure survival, ie, that
the presence of one risk diminishes the gap in survival created by the
presence or the absence of a second risk. The improvement in the performance
of our models by the addition of these interaction terms implies a complex
interdependence among age, sex, and comorbidity that should not be ignored
in any future prognostic modeling of mortality due to heart failure.
There are several limitations to our study. We tracked only subjects who
were hospitalized for the first time for heart failure. Thus, we omitted
individuals with newly diagnosed heart failure who had not been admitted for
any reason in the 5 years before our study. This omission is unlikely to
alter the outcome of our study, because about 80% of the new heart failure
patients are presented through hospital admissions, 29
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r29>  and because
community surveys 30
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r30>  have shown that
the remaining heart failure patients would have been hospitalized at least
once within the first 2 years of identification. Also, the use of ICD-9-CM
codes might result in an undernumeration of heart failure cases, 31
<http://archinte.ama-assn.org/issues/v162n15/rfull/#r31>  although this
problem is less important in Canada than in the United States. We also did
not apply standardized diagnostic criteria through random chart reviews to
confirm the diagnosis of heart failure in this study cohort. At the time of
our study, we could not distinguish heart failure patients with normal vs
reduced ejection fractions or classify the cause of the heart failure. In
particular, undercoding of hypertension in discharge abstracts forbade
estimation of the true prevalence of hypertension, a common cause of heart
failure, in our population. We could not take into account differences
between subpopulations of heart failure patients in use of drugs that would
influence their survival. Some demographic variables, such as ethnicity and
socioeconomic status, were missing in our database and could not be adjusted
for. Although undercoding of comorbid conditions in our cohort was certainly
possible, serious comorbid conditions were unlikely to be missed.



CONCLUSIONS



Our study highlights the high case-fatality rates in unselected
community-dwelling patients after first-time hospitalizations for heart
failure. Furthermore, the complex relationships among age, sex, and
comorbidity and their relationship to survival are likely more involved than
previously described and demand validation in other heart failure
populations. Despite recent advances in medical treatment, we found
persistent high mortality rates in our contemporary cohort of heart failure
patients. This finding should be a sobering note to the medical community
that much more remains to be done to improve the outcomes of this seriously
ill population than is currently believed.



Author/Article Information


From the Heart & Stroke/Richard Lewar Centre of Excellence and the Toronto
General Hospital, University Health Network (Drs Jong, Vowinckel, and Liu),
and the Departments of Medicine, Public Health Sciences, and Health
Administration (Ms Gong and Dr Tu), University of Toronto; the Institute for
Clinical Evaluative Sciences (Ms Gong and Dr Tu), and the Division of
General Internal Medicine and the Clinical Epidemiology and Health Care
Research Program, Sunnybrook and Women's College Health Sciences Centre (Ms
Gong and Dr Tu), Toronto, Ontario.

Corresponding author and reprints: Jack V. Tu, MD, PhD, Institute for
Clinical Evaluative Sciences, G-106, 2075 Bayview Ave, Toronto, Ontario,
Canada M4N 3M5 (e-mail: [log in to unmask] <mailto:[log in to unmask]> ).
Accepted for publication April 8, 2002.
This study was supported by a Canadian Institute for Health Research
Fellowship (Ottawa, Ontario) (Dr Jong), a Heart & Stroke Studentship Award
(Dr Vowinckel), a Canada Research Chair in Health Services Research (Dr Tu),
and an operating grant from the Canadian Institute of Health Research and
the Heart & Stroke Foundation, Toronto, Ontario.




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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.