Pronostico Pacientes No Oncológicos

CLINICAL RESEARCH STUDY
Systematic Review of Noncancer Presentations with a

Median Survival of 6 Months or Less
Shelley R. Salpeter, MD,a,b Esther J. Luo, MD,c Dawn S. Malter, MD, PhD,d Brad Stuart, MDb
a
Stanford University School of Medicine, Stanford, Calif; bSutter Care at Home, Fairfield, Calif; cKaiser Permanente Santa Clara
Medical Center, Santa Clara, Calif; dSamaritan House Medical Clinic, Redwood City, Calif.
ABSTRACT
PURPOSE: We report on clinical indicators of 6-month mortality in advanced noncancer illnesses and the
effect of treatment on survival.
METHODS: The MEDLINE database was searched comprehensively to find studies evaluating survival for
common advanced noncancer illnesses. We retrieved and evaluated studies that reported a median survival of
1 year and evaluated prognostic factors or effect of treatment on survival. We extracted data on presentations
with median survivals of 6 months for heart failure, chronic obstructive pulmonary disease, dementia, geriatric
failure to thrive, cirrhosis, and end-stage renal failure. Independent risk factors for survival were combined and
included if their combination was associated with a 6-month mortality of 50%.
RESULTS: The search identified 1000 potentially relevant studies, of which 475 were retrieved and
evaluated, and 74 were included. We report the common clinical presentations that are consistently
associated with a 6-month median survival. Even though advanced noncancer syndromes differ clinically,
a universal set of prognostic factors signals progression to terminal disease, including poor performance
status, advanced age, malnutrition, comorbid illness, organ dysfunction, and hospitalization for acute
decompensation. Generally, a 6-month median survival is associated with the presence of 2-4 of these
factors. With few exceptions, these terminal presentations are quite refractory to treatment.
CONCLUSION: This systematic review summarizes prognostic factors common to advanced noncancer
illness. There is little evidence at present that treatment prolongs survival at these terminal stages.
2012 Elsevier Inc. All rights reserved. The American Journal of Medicine (2012) 125,
512.e1-512.e16
KEYWORDS: Prognosis; Survival; Systematic review; Terminal illness
Treatment decisions in advanced illness can be difficult, in

part due to prognostic uncertainty and lack of evidence
concerning efficacy of treatments in far advanced disease. It
would be helpful to identify those prognostic factors that are
associated with a high likelihood of mortality within a
defined period of time despite the use of aggressive
treatments.
This systematic review summarizes the data on clinical
indicators of 6-month mortality in prevalent advanced noncancer illnesses, and the effect of treatment on survival at
Funding: None.
Conflict of Interest: None.
Authorship: All authors had access to the data and a role in writing the
manuscript.
Requests for reprints should be addressed to Shelley R. Salpeter, MD,
700 S. Claremont St, Suite 220, San Mateo, CA 94402.
E-mail address: salpeter@stanford.edu
0002-9343/$ -see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2011.07.028
these terminal stages. A similar study on terminal cancer

presentations is published separately.1
METHODS
The MEDLINE database was searched comprehensively to
identify prospective or retrospective studies in any language
published between 1980 and November 2010 that evaluated
survival or prognostic factors for each of the diseases selected for this review, using the search terms prognosis,
survival, survival analysis, or median survival. Common prognostic factors for each disease were searched for
using terms such as performance status or weight loss.
The search was augmented by scanning references of identified articles and reviews.
Potentially relevant studies were retrieved and evaluated
if they reported a disease presentation with a median survival of 1 year. We identified disease-specific presenta-
512.e2
The American Journal of Medicine, Vol 125, No 5, May 2012
tions that were consistently reported to have median

were reported for the best available care. Once the results
survival estimates of 6 months, with or without treatfor each disease were obtained, we performed an addiments. Prognostic factors evaluated included age, functional literature search to evaluate whether there is any
tional status, laboratory values, severity of disease,
evidence from randomized controlled trials that specific
symptoms, comorbid illness, and hospitalizations for extreatments can prolong survival when given to patients
acerbations. We chose to include
with these terminal presentaclinical presentations that are
tions.
easy to identify and laboratory
CLINICAL SIGNIFICANCE
tests that are readily available.
RESULTS
If a disease presentation was
The common clinical presentations in
We identified approximately 1000
reported to have a median survival
advanced noncancer illnesses that are
potentially relevant articles, and
above and below 6 months, further
consistently associated with a 6-month
evaluated 475 with a median sursubgroup analyses explored poprognosis include poor performance stavival of 1 year. We included 74
tential heterogeneity in the results.
tus,
advanced
age,
malnutrition,
comorstudies from 1999 to 2010 in the
Presentations with median surprognosis analysis, with 60 addibid
illness,
organ
dysfunction,
and
hosvival estimates in the range of 4-7
tional studies on treatment (Figpitalization for acute decompensation.
months were included if the
ure). Fifty-eight (78%) of the
weighted average from all avail In far advanced illness, with few excepprognostic studies were prospecable studies was 6 months. For
tions, there is little evidence that treattive, of which 28 (48%) were valmultivariate analysis, independent
ments can prolong survival.
idation studies of previously asrisk factors for survival were comsessed prognostic factors.
Discussion with patients and families on
bined and included here if their
The specific diseases evaluated
prognosis and goals of care can be
combination is associated with a
here
include heart failure, demen6-month mortality risk of 50%.
guided by the information reviewed
tia,
geriatric
failure-to-thrive synWe attempted to contact investihere.
drome,
hepatic
cirrhosis, chronic
gators to request additional inobstructive
pulmonary
disease,
formation on 6-month mortality
and
end-stage
renal
disease.
This
rates.
list
represents
approximately
70%
of
the
noncancer
diagnoWe extracted and analyzed data from trials published
ses on admission to hospice;2 the results are shown in
between 1980 and 2010 but only include studies pubTable 1 (references in the Appendix, online). The comlished between 1999 and 2010. This allowed us to permonly used scales for assessing performance status, the
form an extensive literature search and systematic review
Karnofsky performance score3 and the Activities of Daily
while providing the most recent data. Survival estimates
- Potentially relevant studies from

1980 to 2010 of non-cancer
illness with a median survival of
1 year (n = 1000)
Studies excluded:
Insufficient survival data (n = 525)
Studies from 1980 to 2010 providing

non-cancer survival data with a
median survival 1 year (n = 475)
Studies from 1999 to 2010 with

survival data on prognostic factors
for patients with a median survival of
6 months (n = 74)
Figure
Studies evaluated in review:

Median survival > 6 months (n = 323)
Studies with median survival 6
months from 1980 to 1998 (n = 18)
Trials evaluating treatment effect in
advanced disease (n = 60)
Flow chart of studies search.
Salpeter et al
Table 1
Terminal Noncancer Presentations
512.e3
Presentations Associated with a Median Survival of 6 Months or less, with Effect of Treatments on Survival*
Terminal Illness Presentations

Cardiovascular disease
Heart failure
Hospitalization for
moderate to severe
symptomatic heart failure,
NYHA Class III or IV, with
3 or more of the following
presentations:
Geriatric syndromes
Dementia
Advanced dementia with
dependency in all activities
of daily living, bedbound
status, urinary and bowel
incontinence, decreased
ability to communicate
verbally, and admission to
a hospital or skilled
nursing facility, with 1 or
more of the following
presentations:
Geriatric failure to thrive
Age 75 years, serum
albumin 3.5 g/dL and
dependency in 2
activities of daily living,
with admission to an acute
care hospital or skilled
nursing facility and 1 or
presentations:
Survival Benefit of Treatment
Age 70 years
Left ventricular ejection fraction 20%
Serum B-type natriuretic peptide 950 pg/mL
Cardiac troponin I 0.4 ng/mL
C-reactive protein 3.5 mg/L
Fourth hospitalization for heart failure or repeat
hospitalization in 2 months
Dependency of 3 or more activities of daily
living or need for home care after hospital
discharge
Weight loss of 2.3 kg within 2 months or
serum albumin 2.5 g/d
History of cardiogenic shock, ventricular or
supraventricular arrhythmia, cardiac arrest,
cardiopulmonary resuscitation, or mechanical
ventilation
Systolic blood pressure 110
Serum creatinine 2 mg/dL or blood urea
nitrogen 40 mg/dL
Serum sodium 135 mEq/L
Cardiovascular disease (ischemic, peripheral
vascular, or cerebrovascular disease)
Other comorbid illness (diabetes mellitus,
dementia, chronic obstructive pulmonary
disease, cirrhosis, cancer)
Beta-blockers: reduce mortality by 35% in severe

symptomatic heart failure, proportional to
degree of heart rate reduction, with benefit
seen after 3 weeks in those with terminal
presentations. Exclusions: Systolic blood pressure
85 mm Hg, third-degree heart block (unless with
pacemaker)
Angiotensin-converting enzyme inhibitors:
reduce mortality by 20% in severe,
symptomatic heart failure, with benefit seen
after 6 weeks, although no evidence of benefit
for age 75 years or renal failure
Implantable defibrillators and cardiac
resynchronization: no evidence of survival
benefit in terminal disease
Left ventricular assist device: improved survival
in end-stage heart failure for those on
inotropic therapy and not eligible for heart
transplantation, although it is not clear if the
use of beta-blockers could have same survival
benefit as mechanical device. Exclusions:
Comorbid illness or surgical risk
Heart transplantation: no randomized trials, but
eligible patients who receive a transplant live
longer than those who do not.
No consistent survival benefit seen with
angiotensin-receptor blockers, statins,
recombinant human erythropoietin, calcium
channel blockers, digitalis, diuretics and
aldosterone blockers
Inotropic and anti-arrhythmic agents: associated
with increased mortality
Malnutrition (manifested by body mass index

No treatment has been shown to improve
18.5 kg/m2, decreased oral intake, or
survival in advanced dementia
Enteral feeding through nasogastric or
significant weight loss)
gastrostomy tube: no mortality benefit seen
Presence of at least one pressure ulcer
Evidence of at least one comorbid illness
Male sex plus age 90 years
Placement of a nasogastric or gastrostomy
feeding tube, due to inability to eat or history
of aspiration pneumonia
No treatment, including enteral feeding, has

Dependency in all activities of daily living with
been shown to improve survival in geriatric
malnutrition (weight loss 10% of body
failure to thrive
weight or serum albumin 3 g/dL)
Evidence of heart failure
Serum creatinine 3 mg/dL
Evidence of delirium during hospitalization
Significant disability before hospitalization, with
further functional decline posthospitalization
512.e4
Table 1

Continued

Hepatic disease
Cirrhosis
Decompensated hepatic
cirrhosis and 1 or more of
the following
presentations:
Decompensated hepatic
cirrhosis with
hospitalization for an
acute illness related to
liver disease and 1 or more
of the following
presentations:
Pulmonary disease
Chronic obstructive pulmonary
disease (COPD)
Hospitalization for a severe
COPD exacerbation, with
hypoxemia (pO2 55 mm
Hg), hypercapnia (pCO2
50 mm Hg), and
supplemental oxygen
dependence, with 3 or
presentations:
Child-Pugh score 12
MELD score 21
Child-Pugh score 10
MELD score 18
Child-Pugh score 9 plus dependency in 3
activities of daily living and malnutrition
(significant weight loss, and albumin 2.5
g/dL)
Hospitalization in an intensive care unit related
to severe decompensation of liver disease,
with hypotension requiring the use of
pressors, serum creatinine 1.5 mg/dL, or
evidence of jaundice
Evidence of hepatopulmonary syndrome or
rapidly progressive hepatorenal syndrome
Systematic reviews have found very few

interventions that improve survival in
decompensated cirrhosis
Nonselective beta-blockers for primary or
secondary prevention of variceal bleeding:
improved survival, but no evidence of benefit
for severe decompensated cirrhosis, advanced
age, or severe comorbid illness
Antibiotics for hospitalized patients with upper
gastrointestinal bleeding: improved short-term
survival in pooled trial data, with no evidence
of a long-term survival benefit. Exclusions:
Active infection, nonhepatic terminal illness
Oral antibiotics in advanced cirrhosis: reduced
spontaneous bacterial peritonitis and
improved survival, but no evidence of survival
benefit with active illness, comorbid disease,
active bleed, renal failure, encephalopathy
Vasopressin analogue terlipressin in acute
variceal bleed: reduced hospital mortality, but
treatment not available in the US and
associated with hyponatremia, ischemia and
arrhythmia, without known effect on longterm survival. Exclusions: Vascular disease,
organ dysfunction, or comorbid illness
No survival benefit for treatment of variceal
bleeding with somatostatin or its analogue
octreotide, compared with placebo or terlipressin
Endoscopic procedures (ligation, sclerotherapy):
not shown to improve survival compared with
medical therapy
Portosystemic shunts: increases risk of
encephalopathy, with a variable effect on mortality
Liver transplantation offers the potential for
cure, although no randomized trials have been
performed and the frequency of successful
transplants is too low to have an effect on
survival data.
Age 70 years
Ambulatory oxygen therapy in severe COPD with
Evidence of right-sided heart failure (cor
hypoxia: improved long-term survival for those
pulmonale)
with poor prognosis, although benefit seen
Repeat hospitalization for COPD within 2 months
after 6-12 months so of unclear benefit in
History of intubation and mechanical ventilation
terminal illness. Exclusions: Age 70 years
Karnofsky performance status 60 or
Inhaled beta-agonist or anticholinergic
dependency of 3 or more activities of daily
bronchodilators, or inhaled corticosteroids:
living before the hospitalization
not shown to have significant survival benefit
Need for home care after hospital discharge
For COPD exacerbations, short courses of
Malnutrition (weight loss of 2.3 kg, serum albumin
antibiotics and noninvasive positive pressure
2.5 g/dL or body mass index 18 kg/m2)
ventilation: reduce hospital mortality, but not
studied in terminal illness
Serum creatinine 2 mg/dL
Salpeter et al
Table 1
512.e5
Continued

Renal disease
End-stage renal disease
End-stage renal disease on
dialysis, with age 70
years and 2 or more of the
following presentations:

without the use of dialysis,
with age 70 years and 1 or
presentations:
Karnofsky performance status 50, or

dependency in activities of daily living
Significant comorbid condition such as coronary
artery disease, peripheral vascular disease,
heart failure, cancer
Malnutrition (body mass index 19.5 lg/m2 or
serum albumin 2.2 mg/dL)
Residence in a skilled nursing facility
Admission to an intensive care unit for an acute
illness
Hip fracture with inability to ambulate
Dialysis withheld for those with decreased
performance status and significant
comorbidity
Dialysis withdrawn due to advanced age,
functional dependence and comorbidity
Beta-blockers: reduce mortality by 50% in

patients on dialysis, with and without dilated
cardiomyopathy. Exclusions: NYHA Class IV
heart failure, ventricular arrhythmia, recent
myocardial infarct or stroke, frail elderly with
significant comorbidity
No survival benefit for angiotensin-converting
enzyme inhibitors, angiotensin receptor
blockers, erythropoietin, statins, and
sevelamer.
Erythropoietin use with higher hemoglobin
targets increase total mortality, thrombosis,
and poorly controlled hypertension, compared
with its use with lower hemoglobin targets.
No survival advantage for early initiation of
dialysis compared with late initiation
No survival advantage for the use of dialysis
compared with nondialytic treatment for
elderly patients with poor prognosis
Kidney transplantation: most patients with the
terminal presentations here are not eligible
for renal transplantation. No randomized
trials, but eligible patients who receive a
transplant live longer than those who remain
on dialysis
MELD Model of End-stage Liver Disease; NYHA New York Heart Association.
*References for documentation can be found in the online appendix.
Living scale,4 are provided in Table 2. For this analysis,

we define terminal as a presentation with a median survival of 6 months.
Cardiovascular Disease
Heart Failure. Advanced heart failure, classified as New
York Heart Association (NYHA) Class III and IV, is associated with severe limitation of activity, symptoms with
minimal exertion or at rest, and a median survival of approximately 3 years.5-7 For those hospitalized with NYHA
Class III and IV heart failure, median survival is 6 months
when 3 or more of the following are present: age 70 years;
left ventricular ejection fraction 20%; serum B-type natriuretic peptide 950 pg/mL; cardiac troponin I 0.4 ng/
mL; C-reactive protein 3.5 mg/L; fourth hospitalization
for heart failure or repeat hospitalization within 2 months;
decreased functional status; malnutrition; history of a critical clinical event; systolic blood pressure 110 mm Hg;
renal insufficiency; vascular disease; or other comorbid illness (Appendix Table 1).
The treatment that has been consistently shown to
have the greatest survival benefit in patients with severe
symptomatic heart failure is the use of beta-adrenergic
blockers, which reduce short-term and long-term mortal-
ity by approximately 35% when given to patients with the

terminal presentations listed here (Appendix Table 1).
In addition, angiotensin-converting enzyme inhibitors
have been shown to reduce mortality in severe heart
failure by approximately 20%, although no survival benefit has been seen for those with advanced age or renal
failure.
No consistent mortality benefit in far advanced disease
has been seen with angiotensin receptor blockers, statins,
recombinant human erythropoietin, calcium channel blockers, digitalis, diuretics, or aldosterone blockers, while inotropic therapy and anti-arrhythmic agents other than betablockers have been shown to increase mortality (Appendix
Table 1). Implantable defibrillators and cardiac resynchronization therapy have not been consistently studied in
NYHA Class IV heart failure patients or those with
severe comorbid illness. The use of a left ventricular
assist device was shown in one trial to improve survival
in patients with refractory heart failure who were unable
to undergo heart transplantation. Heart transplantation
appears to improve survival for those who are eligible
and receive one. Multidisciplinary disease management
interventions have not been studied in end-stage heart
failure patients.
512.e6
Table 2

The Karnofsky Performance Status Scale3 and the Activities of Daily Living Scale4
Karnofsky Score3
Level of Functional Capacity
100
90
80
70
60
50
40
30
20
10
0
Normal, no complaints, no evidence of disease

Able to carry on normal activity, minor signs or symptoms of disease
Normal activity with effort, some signs or symptoms of disease
Cares for self, unable to carry on normal activity or to do active work
Requires occasional assistance, but is able to care for most needs
Requires considerable assistance and frequent medical care
Disabled, requires special care and assistance
Severely disabled, hospitalization is indicated although death is not imminent
Hospitalization is necessary, very sick, active supportive treatment necessary
Moribund, fatal processes progressing rapidly
Dead
Basic activities of daily living4
Independence
1. Bathing
2. Dressing
3. Toileting
Receives either no assistance or assistance in bathing only one part of body

Gets clothes and dresses without any assistance except for tying shoes
Goes to toilet room, uses toilet, and returns without any assistance (may use cane or walker
for support and may use bedpan or urinal at night
Moves in and out of bed and chair without assistance (may use cane or walker)
Controls bowel and bladder completely by self, without occasional accidents
Feeds self without assistance, except for help with cutting meat or buttering bread
4. Transferring
5. Continence
6. Feeding
Geriatric Syndromes
Dementia. Advanced dementia, which is characterized by
dependency in all activities of daily living, bedbound status
most of the time, decreased ability to communicate verbally,
and urinary and bowel incontinence, carries a median survival of 1-2 years.8 For those with advanced dementia who
have been hospitalized for an acute illness or admitted to a
skilled nursing facility, median survival is 6 months when
associated with one or more of the following: malnutrition;
at least 1 pressure ulcer; evidence of comorbid illness; male
sex plus age 90 years; or the presence of a nasogastric or
gastrostomy feeding tube (Appendix Table 1).
Survival for patients with advanced end-stage dementia
has not changed significantly over the past 20 years.9,10
There is no treatment that has been shown to improve
survival in advanced dementia patients (Appendix Table 1).
The use of enteral feeding has not been associated with an
improvement in mortality, nutritional status, pressure ulcers, or aspiration pneumonia, compared with orally fed
patients, after adjustment for severity of illness.
Geriatric Failure to Thrive. Geriatric failure to thrive is
characterized by progressive frailty, malnutrition, and functional decline associated with the advanced aging process
and carries a median survival of a few years.11,12 Median
survival is 6 months when patients over the age of 75
years with dependency in 2 activities of daily living and
serum albumin 3.5 g/dL are admitted to an acute care
hospital or skilled nursing facility and have one or more of
the following presentations: malnutrition, heart failure, serum creatinine 3 mg/dL, delirium during hospitalization,
or significant disability before hospitalization with further

functional decline posthospitalization (Appendix Table 1).
Survival associated with geriatric failure-to-thrive syndromes has not improved over the past 20 years.13-15 A
review of the literature did not find any treatment that was
associated with an improvement in survival. As with advanced dementia, enteral feeding has not been shown to
improve nutritional status or survival (Appendix Table 1).
Hepatic Disease
Cirrhosis. Decompensated hepatic cirrhosis is characterized by the presence of ascites, variceal bleeding, encephalopathy, or jaundice, and has a median survival of 2
years.16,17 The 2 main prognostic survival models for decompensated cirrhosis are the Child-Pugh score and the
Model of End-stage Liver Disease (MELD) score.18,19 The
Child-Pugh scoring system (Table 3) uses serum bilirubin,
albumin, prolongation of prothrombin time, and the degree
of ascites and encephalopathy. The MELD scale is a logarithmic scoring system that incorporates serum bilirubin,
international normalized ratio, and creatinine, and can be
estimated using an online calculator.19-22
For decompensated cirrhosis, median survival is 6
months when the Child-Pugh score is 12 or the MELD
score is 21 (Appendix Table 1). After a hospitalization for
an acute illness related to decompensated cirrhosis, median
survival is 6 months when associated with a Child-Pugh
score of 10, a MELD score 18, a Child-Pugh score 9
plus dependency in 3 activities of daily living and malnutrition, hepatopulmonary syndrome, rapidly progressive
hepatorenal syndrome, or hospitalization in an intensive
Salpeter et al
Table 3
512.e7
Child-Pugh Scoring System for Cirrhosis18

Points Scored for Increasing Abnormality
Factor
Units
Serum bilirubin
Serum albumin
Prothrombin time
mg/dL
g/dL
Seconds prolonged
International normalized ratio
2.0
3.5
0-4
1.7
None
None
2.0-3.0
3.0-3.5
4-6
1.7-2.3
Slight
Minimal
3.0
3.0
6
2.3
Moderate
Advanced
Ascites
Encephalopathy
Class A: score 5-6.
Class B: score 7-9.
Class C: score 10-15.
care unit with hypotension requiring pressors, serum creatinine 1.5 mg/dL, or jaundice.
Systematic reviews have found very few interventions
that improve survival for end-stage liver disease (Appendix
Table 1). Improvements in survival have been seen with
nonselective beta-adrenergic blockers for the primary and
secondary prevention of variceal bleeds, and with antibiotic
prophylaxis to prevent rebleeding from varices and to decrease bacterial infections. Variable results have been seen
with vasopressin and somatostatin analogues, endoscopic
therapies, and portosystemic shunts. Liver transplantation
offers the potential for cure, although no randomized trials
have been performed and the frequency of successful transplants is too low to have an effect on survival data.
Pulmonary Disease
Chronic Obstructive Pulmonary Disease. Severe chronic
obstructive pulmonary disease (COPD), characterized by
significant airflow obstruction, dyspnea at rest, hypoxemia,
hypercapnia, and supplemental oxygen dependence, has a
median survival of 2-4 years.23-25 For those with severe
COPD hospitalized for an exacerbation, median survival is
6 months when associated with 3 or more of the following: age 70 years, right-sided heart failure, decreased
functional status, need for home care after hospital discharge, malnutrition, serum creatinine 2 mg/dL, repeat
hospitalization for COPD within 2 months, or history of
intubation and mechanical ventilation (Appendix Table 1).
Continuous ambulatory oxygen therapy in patients with
severe symptomatic airflow obstruction and hypoxia has
been shown to improve survival, with a survival benefit seen
after 6-12 months (Appendix Table 1). Those who had the
poorest prognosis, with decreased performance status, rightsided heart failure, or significant hypoxia and hypercapnia,
had the most pronounced survival benefit. Inhaled bronchodilators and corticosteroids have not consistently been
shown to prolong survival. For acute exacerbations of
COPD, short courses of antibiotics and noninvasive positive
pressure ventilation have both been shown to reduce hospital mortality, but their effect on long-term survival is not
clear.
Renal Disease
End-stage Renal Disease. Frail elderly patients with endstage renal disease (serum creatinine 8 mg/dL or glomerular filtration rate 9 mL/min) and significant comorbidities have median survivals of 1-2 years, with and without
the use of dialysis.26-31 For those on dialysis, median survival is 6 months when associated with age 70 years and
2 or more of the following: poor performance status, significant comorbid condition, malnutrition, residence in a
skilled nursing facility, admission to an intensive care unit
for an acute illness, or hip fracture with inability to ambulate
(Appendix Table 1). For those with end-stage renal disease
who do not undergo dialysis, median survival is 6 months
when associated with age 70 years, decreased performance status, and significant comorbid illness. For patients
on chronic dialysis who stop treatment, median survival is
significantly less than 6 months after withdrawal.
The only treatment that has been shown to significantly
improve survival in dialysis patients is the use of betaadrenergic blockers for dilated cardiomyopathy, which reduces all-cause mortality by 50% compared with placebo
(Appendix Table 1). Treatments without proven survival
benefit include angiotensin-converting enzyme inhibitors,
angiotensin receptor blockers, recombinant human erythropoietin, statins, and sevelamer. No survival advantage has
been seen for the initiation of dialysis early in the course of
end-stage renal disease compared with initiation later in the
disease course. Most patients with the presentations listed
here are ineligible for renal transplantation.
For patients with poor prognosis for long-term survival,
such as those with advanced age, decreased functional status, malnutrition, and comorbidities, there is no evidence
that the initiation of dialysis prolongs survival when compared with nondialytic management (Appendix Table 1).
One trial compared the use of dialysis with nondialytic
treatment in elderly patients with a glomerular filtration
rate of 5-7 mL/min, and found that nondialytic treatment
improved 1-year survival and reduced hospitalizations,
compared with dialysis. This survival advantage of nondialytic treatment could be due to the increased risk for
512.e8
complication and death that occurs within the first several
months of dialysis.32
DISCUSSION
In this systematic review, we report the common clinical
presentations that are consistently associated with a
6-month median survival. Although advanced noncancer
syndromes differ clinically, certain common prognostic indicators signal terminal disease, including poor performance status, advanced age, malnutrition, comorbid illness,
increasing organ dysfunction, and hospitalization for acute
decompensation. A 6-month median survival is generally
associated with the presence of 2-4 of these factors. Our
review of studies from 1980 to 1998 found similar results,
indicating that survival for these end-stage illnesses has not
changed significantly in the past 30 years. With few exceptions, these terminal presentations are quite refractory to
treatment.
Predicting the progression from advanced chronic noncancer illness to the terminal phase is more challenging than
with cancer because of the greater prognostic uncertainty
inherent in noncancer diseases.33,34 Most advanced cancers
are characterized by a progressive trajectory toward death,
and have a median survival of about 1 year.33-36 Patients in
the advanced, preterminal phases of noncancer disease typically experience unpredictable exacerbations with intercurrent periods of stability, and median survivals of 2-3
years.5-8,11,12,16,17,23-31 A median survival of 6 months
was chosen for this review in part because the Medicare
hospice eligibility criteria define terminal illness as life
expectancy of 6 months or less, assuming the disease runs
its normal course.37
General guidelines were developed in the 1990s by the
National Hospice Organization to help determine prognosis
in selected noncancer diseases.38 This review could serve to
update and extend those guidelines, and adds new knowledge about prognosis and treatment in common end-stage
noncancer diseases. Much prognostic uncertainty remains.
Despite this challenge, prognostication is important in latestage chronic illness to help clarify goals of care and guide
treatment decisions.39
Despite the inexorable progression and therapeutic resistance of chronic illness in its late stage, current practice may
often be biased toward treatment. Over one quarter of all US
health care costs are accrued in the last year of life, with
40% of that cost occurring in the last month of life, mostly
for hospital care.40 Patients with noncancer disease, for
example, heart failure, tend to undergo more aggressive
treatment than do those with cancer, and to be referred less
often to hospice and palliative care.41 Treatment intensity
and costs in the last 6 months of life vary widely across the
US and overtreatment is common in high-utilizing areas,
without evidence that more treatment constitutes better
care.42
This systematic review has several limitations. This is a
qualitative analysis of prospective and retrospective studies

that provides an overview of common terminal presentations to help guide clinicians; future validation studies will
be useful. This review pertains only to overall survival, and
does not provide information on intermediate outcomes
such as disease progression or quality of life. By definition,
50% of the patients with a median survival of 6 months will
live longer than 6 months, and it is rarely possible to predict
who will live and who will die within that time.
Another limitation of the review is that the terminal
presentations included do not comprise an exhaustive list.
Other terminal presentations could be associated with different combinations of the prognostic factors listed here,
more qualitative factors such as cognitive decline, other
disease-specific markers, or other serious comorbidities.
General guidelines for assessing prognosis in advanced illness also could be used.38 For example, there is some
evidence that a rapid decrease in functional or nutritional
status could indicate that death is approaching, but that has
been hard to quantify.33 In addition, some chronic noncancer illnesses, such as stroke or amyotrophic lateral sclerosis,
have not been evaluated here.
We found little evidence of a survival benefit from treatment in these terminal stages, but this is due in part to the
fact that elderly patients and those with marked organ failure or comorbid illness are almost invariably excluded from
clinical trials. Future trials are needed to evaluate treatment
regimens in this population.
In summary, the onset of a 6-month median survival in
chronic noncancer illness is characterized by a common set
of clinical indicators, as well as indicators of advanced
organ failure. There is little evidence that aggressive disease-modifying treatments for patients this ill actually prolong survival.
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512.e10
APPENDIX
Appendix Table 1
Presentations associated with a median survival of 6 months or less, with references for documentation.
Terminal illness presentations

Cardiovascular disease
Heart failure
Hospitalization for moderate to
severe symptomatic heart
failure, NYHA Class III or IV,
with 3 or more of the following
presentations:
Geriatric syndromes
Dementia
Advanced dementia with
dependency in all activities of
daily living, bedbound status,
urinary and bowel
incontinence, decreased ability
to communicate verbally, and
admission to a hospital or
skilled nursing facility, with 1
or more of the following
presentations:
Survival benefit of treatment
Age 70 years1-8
Left ventricular ejection
fraction 20%2,21,36,37
Serum B-type natriuretic peptide 950
pg/ml5,38
Cardiac troponin I 0.4 ng/ml38
C-reactive protein 3.5 mg/L38
Fourth hospitalization for heart failure or
repeat hospitalization in 2 months8,37
Dependency of 3 or more activities of
daily living or need for home care
after hospital discharge37,39
Weight loss of 2.3 kg within 2 months
or serum albumin 2.5 g/d37
History of cardiogenic shock, ventricular
or supraventricular arrhythmia, cardiac
arrest, cardiopulmonary resuscitation,
or mechanical ventilation5-8,37
Systolic blood pressure 1101,3,4
Serum creatinine 2 mg/dl or blood
urea nitrogen 40 mg/dL1-5,8
Serum sodium 135 mEq/L1,3-5
Cardiovascular disease (ischemic,
peripheral vascular, or cerebrovascular
disease)1,3,4,40
Other comorbid illness (diabetes
mellitus, dementia, chronic obstructive
pulmonary disease, cirrhosis)1-3
Beta-blockers: reduce mortality by 35% in severe

symptomatic heart failure, proportional to
degree of heart rate reduction, with benefit
seen after 3 weeks in those with terminal
presentations9-19
Exclusions: Systolic blood pressure 85, thirddegree heart block (unless with pacemaker)
Angiotensin-converting enzyme inhibitors:
reduce mortality by 20% in severe,
symptomatic heart failure, with benefit seen
after 6 weeks, although no evidence of benefit
for age 75 years or renal failure20
Implantable defibrillators and cardiac
resynchronization: no evidence of survival
benefit in terminal disease
Left ventricular assist device: improved survival
in end-stage heart failure for those on
inotropic therapy and not eligible for heart
transplantation, although it is not clear if the
use of beta-blockers could have same survival
benefit as mechanical device 21,22
Exclusions: Comorbid illness or surgical risk
Heart transplantation: no randomized trials, but
eligible patients who receive a transplant live
longer than those who do not.23
No consistent survival benefit seen with
angiotensin-receptor blockers, statins,
recombinant human erythropoietin, calcium
channel blockers, digitalis, diuretics and
aldosterone blockers24-34
Inotropic and antiarrhythmic agents: associated
with increased mortality35
Malnutrition (manifested by body mass

index 18.5 kg/m2, decreased oral
intake, or significant weight loss)41-47
Presence of at least one pressure ulcer,
or one comorbid illness46,47
Evidence of at least one comorbid
illness46,47
Male gender plus age 90 years43,47
Placement of a nasogastric or
gastrostomy feeding tube, due to
inability to eat or history of aspiration
pneumonia50-53
No treatment has been shown to improve

survival in advanced dementia
Enteral feeding through nasogastric or
gastrostomy tube: no mortality benefit48,49
Salpeter et al
Appendix Table 1
512.e11
Continued

Geriatric failure to thrive
Age 75 years, serum
albumin 3.5 g/dL and
dependency in 2 activities of
daily living, with admission to
an acute care hospital or
skilled nursing facility and 1 or
presentations:
Hepatic disease
Cirrhosis
Decompensated hepatic cirrhosis
and 1 or more of the following
presentations:

Dependency in all activities of daily
living with malnutrition (weight
loss 10% of body weight or serum
albumin 3 g/dL)39,54-56
Evidence of heart failure39
Serum creatinine 3 mg/dL39
Evidence of delirium during
hospitalization57
Significant disability prior to
hospitalization, with further functional
decline post-hospitalization58
No treatment, including enteral feeding, has

been shown to improve survival in geriatric
failure to thrive49
Child-Pugh score 1259-64
Systematic reviews have found very few

interventions that improve survival in
decompensated cirrhosis65,66
Nonselective beta-blockers for primary or
secondary prevention of variceal bleeding:
improved survival, but no evidence of benefit
for severe decompensated cirrhosis, advanced
age, or severe comorbid illness67
Antibiotics for hospitalized patients with upper
gastrointestinal bleeding: improved short-term
survival in pooled trial data, with no evidence
of a long-term survival benefit68
Exclusions: Active infection, nonhepatic terminal
illness
Oral antibiotics in advanced cirrhosis: reduced
spontaneous bacterial peritonitis and
improved survival, but no evidence of survival
benefit with active illness, comorbid disease,
active bleed, renal failure, encephalopathy69
Vasopressin analog terlipressin in acute variceal
bleed: reduced hospital mortality, but
treatment not available in the US and
associated with hyponatremia, ischemia and
arrhythmia, without known effect on longterm survival70,71
Exclusions: vascular disease, organ dysfunction
or comorbid illness
No survival benefit for treatment of variceal
bleeding with somatostatin or its analog
octreotide, compared with placebo or
terlipressin70,72-74
Endoscopic procedures (ligation, sclerotherapy):
not shown to improve survival compared with
medical therapy70,73-80
Portosystemic shunts: increases risk of
encephalopathy, with a variable effect on
mortality81-85
Liver transplantation offers the potential for
cure, although no randomized trials have been
performed and the frequency of successful
transplants is too low to have an effect on
survival data.86
MELD score 2162,87-89
Decompensated hepatic cirrhosis

with hospitalization for an
acute illness related to liver
disease and 1 or more of the
following presentations:
Child-Pugh score 1059-61,63,64,90,91
MELD score 183,59,63,64,89,92-95
Child-Pugh score 9 plus dependency

in 3 activities of daily living and
malnutrition (significant weight loss, and
albumin 2.5 g/dL)37
Hospitalization in an intensive care unit

related to severe decompensation of liver
disease, with hypotension requiring the
use of pressors, serum creatinine 1.5
mg/dL, or evidence of jaundice93,96
Evidence of hepatopulmonary syndrome

or rapidly progressive hepatorenal
syndrome94,97,98
512.e12
Appendix Table 1

Continued
Pulmonary disease
Chronic obstructive pulmonary disease (COPD)
Hospitalization for a severe COPD
Age 70 years99-101
exacerbation, with hypoxemia
Evidence of right-sided heart failure (cor
(pO2 55 mm Hg),
pulmonale)37
hypercapnea (pCO2 50 mm
Repeat hospitalization for COPD within 2
Hg), and supplemental oxygen
months37,105
dependence, with 3 or more of
History of intubation and mechanical
the following presentations:
ventilation100,101,106,107
Karnofsky performance status 60 or
dependency of 3 or more activities of
daily living prior to the
hospitalization37,101,105
Need for home care after hospital
discharge37
Malnutrition (weight loss of 2.3 kg,
serum albumin 2.5 g/dL or body mass
index 18 kg/m2)37,106
Serum creatinine 2 mg/dl101,107
Renal disease
Karnofsky performance status 50, or
End-stage renal disease on
dependency in activities of daily
dialysis, with age 70 years
living108-117
and 2 or more of the following
presentations:
Significant comorbid condition such as
coronary artery disease, peripheral
vascular disease, heart failure, cancer108115,117,131-136
Malnutrition (body mass index 19.5

lg/m2 or serum albumin 2.2 mg/dL)108117,132,135
Residence in a skilled nursing facility116

Admission to an intensive care unit for
an acute illness131,134
Hip fracture with inability to ambulate133
End-stage renal disease without
the use of dialysis, with 1 or
presentations:
Dialysis withheld for those with age 70

years, decreased performance status, and
significant comorbidity111,115,137,138
Dialysis withdrawn due to advanced age,
functional dependence and
comorbidity139,140
Ambulatory oxygen therapy in severe COPD with

hypoxia: improved long-term survival for those
with poor prognosis, although benefit seen
after 6-12 months so of unclear benefit in
terminal illness102
Exclusions: Age 70 years
Inhaled beta-agonist or anticholinergic
bronchodilators, or inhaled corticosteroids:
not shown to have significant survival
benefit103
For COPD exacerbations, short courses of
antibiotics and noninvasive positive pressure
ventilation: reduce hospital mortality, but not
studied in terminal illness104
Beta-blockers: reduce mortality by 50% in

patients on dialysis, with and without dilated
cardiomyopathy16,118-120
Exclusions: NYHA Class IV heart failure,
ventricular arrhythmia, recent myocardial
infarct or stroke, frail elderly with significant
comorbidity
No survival benefit for angiotensin converting
enzyme inhibitors, angiotensin receptor
blockers, erythropoietin, statins, and
sevelamer. Erythropoietin use with higher
hemoglobin targets increase total mortality,
thrombosis and poorly controlled
hypertension, compared with its use with
lower hemoglobin targets.121-126
No survival advantage for early initiation of
dialysis compared with late initiation127
No survival advantage for the use of dialysis
compared with non-dialytic treatment for
elderly patients with poor prognosis128
Kidney transplantation: most patients with the
terminal presentations here are not eligible
for renal transplantation129 No randomized
trials, but eligible patients who receive a
transplant live longer than those who remain
on dialysis130
Salpeter et al
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CLINICAL RESEARCH STUDY

Systematic Review of Noncancer Presentations with a

Treatment decisions in advanced illness can be difficult, in

these terminal stages. A similar study on terminal cancer

The American Journal of Medicine, Vol 125, No 5, May 2012

tions that were consistently reported to have median

- Potentially relevant studies from

Studies from 1980 to 2010 providing

Studies from 1999 to 2010 with

Studies evaluated in review:

Flow chart of studies search.

Terminal Noncancer Presentations

Terminal Illness Presentations

Survival Benefit of Treatment

Beta-blockers: reduce mortality by 35% in severe

Malnutrition (manifested by body mass index

No treatment, including enteral feeding, has

The American Journal of Medicine, Vol 125, No 5, May 2012

Terminal Illness Presentations

Survival Benefit of Treatment

Systematic reviews have found very few

Terminal Noncancer Presentations

Terminal Illness Presentations

End-stage renal disease

Survival Benefit of Treatment

Karnofsky performance status 50, or

Beta-blockers: reduce mortality by 50% in

Living scale,4 are provided in Table 2. For this analysis,

ity by approximately 35% when given to patients with the

The American Journal of Medicine, Vol 125, No 5, May 2012

Level of Functional Capacity

Normal, no complaints, no evidence of disease

Basic activities of daily living4

Receives either no assistance or assistance in bathing only one part of body

or significant disability before hospitalization with further

Terminal Noncancer Presentations

Child-Pugh Scoring System for Cirrhosis18

The American Journal of Medicine, Vol 125, No 5, May 2012

Terminal Noncancer Presentations

9. Hanrahan P, Luchins DJ. Feasible criteria for enrolling end-stage

spective randomized multicenter controlled study. Am J Kidney Dis.

The American Journal of Medicine, Vol 125, No 5, May 2012

Terminal illness presentations

Survival benefit of treatment

Beta-blockers: reduce mortality by 35% in severe

Malnutrition (manifested by body mass

No treatment has been shown to improve

Terminal Noncancer Presentations

Terminal illness presentations

Survival benefit of treatment

No treatment, including enteral feeding, has

Child-Pugh score 1259-64

Systematic reviews have found very few

MELD score 2162,87-89

Decompensated hepatic cirrhosis

Child-Pugh score 1059-61,63,64,90,91

MELD score 183,59,63,64,89,92-95

Child-Pugh score 9 plus dependency

Hospitalization in an intensive care unit

Evidence of hepatopulmonary syndrome

The American Journal of Medicine, Vol 125, No 5, May 2012

Terminal illness presentations

Survival benefit of treatment

Malnutrition (body mass index 19.5