ORIGINAL INVESTIGATION

A Prospective Study of Anemia Status, Hemoglobin

Concentration, and Mortality in an Elderly Cohort
The Cardiovascular Health Study
Neil A. Zakai, MD; Ronit Katz, PhD; Calvin Hirsch, MD; Michael G. Shlipak, MD, MPH;
Paulo H. M. Chaves, MD, PhD; Anne B. Newman, MD, MPH; Mary Cushman, MD, MSc

Background: Anemia is viewed as a negative prognos-
tic factor in the elderly population; its independent im-
pact on survival is unclear.
Methods: Baseline hemoglobin quintiles and anemia,
as defined by the World Health Organization criteria, were
assessed in relation to mortality in the Cardiovascular
Health Study, a prospective cohort study with 11.2 years
of follow-up of 5888 community-dwelling men and
women 65 years or older, enrolled in 1989-1990 or 1992-
1993 in 4 US communities.
Results: A total of 1205 participants were in the lowest
hemoglobin quintile (⬍13.7 g/dL for men; ⬍12.6 g/dL
for women), and 498 (8.5%) were anemic (⬍13 g/dL for
men; ⬍12 g/dL for women). A reverse J-shaped relation-
ship with mortality was observed; age-, sex-, and race-
adjusted hazard ratios (95% confidence interval [CI]) in
the first and fifth quintiles, compared with the fourth quin-
tile, were 1.42 (95% CI, 1.25-1.62) and 1.24 (95% CI,
1.09-1.42). After multivariate adjustment, these hazard
ratios were 1.33 (95% CI, 1.15-1.54) and 1.17 (95% CI,
1.01-1.36). The demographic- and fully-adjusted haz-
ard ratios of anemia for mortality were 1.57 (95% CI, 1.38-
1.78) and 1.38 (95% CI, 1.19-1.54). Adjustment for causes
and consequences of anemia (renal function, inflamma-
tion, or frailty) did not reduce associations.
Conclusions: Lower and higher hemoglobin concen-
trations and anemia by World Health Organization cri-
teria were independently associated with increased mor-
tality. The World Health Organization criteria did not
identify risk as well as a lower hemoglobin value. Addi-
tional study is needed on the clinically valid definition
for and causes of anemia in the elderly and on the in-
creased mortality at the extremes of hemoglobin con-
centrations.
Arch Intern Med. 2005;165:2214-2220

Author Affiliations:
Department of Medicine,
University of Vermont College
of Medicine and Fletcher Allen
Health Care, Burlington
(Drs Zakai and Cushman);
Department of Medicine, Brown
University, Providence, RI
(Dr Zakai); Collaborative
Health Studies Coordinating
Center, University of
Washington, Seattle (Dr Katz);
Departments of Medicine and
Public Health Science, Davis
Medical Center, University of
California, Sacramento
(Dr Hirsch); Department of
Medicine, University of
California, San Francisco
(Dr Shlipak); Johns Hopkins
Center on Aging and Health,
Baltimore, Md (Dr Chaves); and
Department of Epidemiology,
University of Pittsburgh,
Pittsburgh, Pa (Dr Newman).
A
NEMIA IS USUALLY RE-
garded as an abnormal
laboratory value, with its
associated morbidity and
mortality related to under-
lying diseases.1 However, increasing evi-
dence indicates that anemia is common in
the elderly population and adversely af-
fects morbidity and mortality.2-7 The preva-
lence of anemia among elderly individu-
als and its independent impact on survival
remain unclear.
The number of elderly individuals is in-
creasing in America and is projected to reach
50 million by 2050.5,6 Estimates of the preva-
lence of anemia among the elderly popula-
tion vary widely (2.9%-61% of men and
3.3%-41% of women) depending on the
population studied and the definition of ane-
mia that is used.6,7 The World Health Or-
ganization (WHO)4 defines anemia as a he-
moglobin concentration of less than 12 g/dL
for women and less than 13 g/dL for men.
These criteria have physiological corre-
lates in younger individuals, although their
appropriateness for elderly individuals is de-
bated; there is evidence of increased mor-
bidity and mortality across the healthy ref-
erence range of hemoglobin concentration
defined by the WHO.1,5,8,9
See also pages 2187,
2222, 2229, and 2237
Few studies have assessed the associa-
tion of anemia with clinical outcomes in the
elderly population; a meta-analysis6 cited
only 4 articles related to outcomes (1 spe-
cifically to mortality). Several small stud-
ies2,3 evaluated anemia and mortality in el-
derly individuals, adjusting only for age and
sex. In select groups, such as patients with
renal10-12 or cardiac diseases,13,14 human im-
munodeficiency virus,15 and other chronic
diseases,9,16 anemia adversely influences
survival.

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 In this analysis from the Cardiovascular Health Study
(CHS) cohort of community-dwelling elderly individu-
als, we compared the association of hemoglobin concen-
tration and anemia status with subsequent mortality over
11 years. We evaluated whether hemoglobin was an in-
dependent predictor of mortality and investigated pos-
sible causal pathways using exploratory modeling.
METHODS
SUBJECTS
The CHS is a prospective, observational study of risk factors for
and consequences of cardiovascular disease in older community-
dwelling adults.17 In 1989 and 1990, 5201 men and women 65
years or older were recruited from 4 US communities (Forsyth
County, North Carolina; Sacramento County, California; Wash-
ington County, Maryland; and Allegheny County, Pennsylva-
nia). An additional cohort of 687 black men and women were
recruited in 1992 and 1993, giving a total cohort of 5888. Pro-
spective participants and age-eligible household members were
identified by Medicare eligibility lists of the Health Care Financ-
ing Administration. Exclusion criteria included being wheelchair-
bound, receiving treatment for cancer, and being institutional-
ized or unable to give informed consent. Among those screened
for participation, 9.6% were ineligible, and 57.3% of those eli-
gible enrolled.18 Enrollment interviews and physical examina-
tions were conducted with standardized interviews that as-
sessed health history, physical function, physical activity,
noninvasive measures of vascular disease, spirometry, height,
weight, blood pressure, grip strength, and gait speed.17 In-
formed consent was established using methods approved by in-
stitutional review committees at each study site.17
LABORATORY ANALYSIS
Fasting blood tests were performed in the morning at enroll-
ment. Hemoglobin concentration and platelet and white blood
cell counts were measured on automated instruments at local he-
matology laboratories near each field center. Internal and exter-
nal quality-assurance reports were examined, and concurrently
obtained duplicate samples were analyzed for 3% of partici-
pants.19 Fibrinogen, albumin, creatinine, and C-reactive protein
concentrations were measured as described elsewhere.19
DEFINITIONS
Anemia was defined by the WHO criteria as a hemoglobin con-
centration of less than 13 g/dL in men and less than 12 g/dL in
women.4 Because of differences among ethnic groups, ethnic-
ity was assessed and defined by participant self-report from the
following list: white, black, American Indian/Alaskan Native,
Asian/Pacific Islander, and other. Health status was assessed
by self-report, and activity level was assessed by question-
naire.17 Baseline coronary heart disease consisted of myocar-
dial infarction, angina, angioplasty, or coronary bypass sur-
gery prior to enrollment and was confirmed by a committee
using medical record review. Renal insufficiency was defined
as a creatinine concentration of at least 1.5 mg/dL (132.6 µmol/L)
for men and at least 1.3 mg/dL (114.9 µmol/L) for women.20
Frailty was defined as having 3 of the 5 following characteris-
tics: unintentional weight loss of at least 10% of body weight
in the previous year; being in the lowest quintile for grip strength,
timed walk, or physical activity level; and self-reported poor
endurance or energy.21 Presence of inflammation was defined
as any 2 of the following: an albumin concentration in the bot-
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tom tertile or C-reactive protein, white blood cell count, or fi-
brinogen concentration in the top tertile of the distribution. Prior
cancer was determined by questionnaire and defined as can-
cer in the past 5 years. Hypertension was defined as a blood
pressure greater than 140/90 mm Hg or use of antihyperten-
sive medications with a physician’s diagnosis of hypertension.
Chronic obstructive pulmonary disease was defined as self-
reported physician diagnosis of chronic bronchitis, asthma, or
emphysema.
OUTCOMES AND FOLLOW-UP
Participants were contacted biannually; telephone interviews
and clinic examinations were conducted alternately. Periodic
searches of the Health Care Financing Administration Medi-
care utilization files were compiled to identify events missed
by other methods. All deaths were reviewed and classified by a
committee using information from death certificates, autopsy
and coroners’ forms, hospital records, and interviews with phy-
sicians, next of kin, and witnesses.17,22 Deaths were classified
as cardiovascular or noncardiovascular. Complete follow-up was
available through June 2001.
STATISTICAL ANALYSIS
Hemoglobin was analyzed in 2 ways: by dividing the distribu-
tion into sex-specific quintiles (to assess linearity between he-
moglobin and mortality) and by the WHO criteria. Cross-
sectional associations of baseline risk factors with hemoglobin
quintiles and anemia were performed using ␹2 analysis, 2-tailed
t tests, or Wilcoxon rank sum tests as appropriate. Staged Cox
proportional hazards models were used to assess the indepen-
dent association of baseline hemoglobin quintiles or anemia with
subsequent mortality. The first model (A) included no poten-
tial confounders. Model B was adjusted for age, sex, and race
(black vs white plus other). We then considered predictors of
5-year mortality in the CHS cohort, namely, cardiovascular dis-
ease, chronic obstructive pulmonary disease, congestive heart
failure, diabetes mellitus, prevalent stroke or transient ische-
mic attack, hypertension, prior cancer, ankle-arm index of 0.9
or lower, body mass index (calculated as weight in kilograms
divided by the square of height in meters), fair or poor self-
reported health status, physical activity concentration (kilo-
calories expended per week), alcohol use (number of drinks
per week), history of cigarette use, and forced vital capacity (in
liters).17,22 A final model (C) was selected that included all co-
variates that changed the coefficient for hemoglobin in model
B by at least 5%. All-cause mortality, cardiovascular mortality,
and noncardiovascular mortality were examined separately. An-
other exploratory model evaluated the addition of potential
causes and consequences of anemia to model C (renal func-
tion, inflammation status, and frailty). Renal function was ex-
pressed as the reciprocal of creatinine to achieve a normal dis-
tribution. Using an age-, sex-, and race-adjusted model, stratified
models were explored to assess the impact of baseline inflam-
mation, renal insufficiency, and cardiovascular disease on the
association of hemoglobin concentration with mortality.
RESULTS
PREVALENCE OF ANEMIA
Of 5888 participants, 5797 (98.5%) had baseline hemo-
globin concentration determined. The mean (SD) hemo-
globin concentration was 14.0 (1.4) g/dL. Men had a
higher mean hemoglobin concentration than women (14.7
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Table 1. Prevalence of Anemia (Based on World Health
Organization Criteria4) at Baseline by Sex and Race*
All White Black
Participants Participants Participants
Variable (N = 5797) (n = 4923) (n = 874)
All (n = 5797) 498 (8.5%) 344 (7.0%) 154 (17.6%)
Men (n = 2466) 227 (9.2%) 169 (7.9%) 58 (17.6%)
Women (n = 3331) 271 (8.1%) 175 (6.3%) 96 (17.6%)
P value (men vs women) .15 .75 .99
*P⬍.001 for white participants vs black participants.
[1.3] vs 13.5 [1.2] g/dL; P⬍.001) and white individuals
had higher mean values than black individuals (14.1 [1.3]
vs 13.4 [1.4] g/dL; P⬍.001). Black women had the low-
est mean hemoglobin value, 13.0 (1.2) g/dL. There were
1205 participants in the first hemoglobin quintile (⬍13.7
g/dL for men and ⬍12.6 g/dL for women). Based on the
WHO criteria for anemia, 498 participants were anemic
at enrollment (8.5% of the cohort; 41.3% of those in the
first hemoglobin quintile). The prevalence of anemia was
higher in black than white individuals and similar in men
and women (Table 1).
CORRELATES OF
HEMOGLOBIN CONCENTRATION
Participants in the lower hemoglobin quintiles were older,
were more likely to be black, and had a greater preva-
lence of comorbid conditions (Table 2). The strongest
correlates of low hemoglobin concentration were low body
mass index, low activity level, fair or poor self-reported
health, frailty, congestive heart failure, and stroke or tran-
sient ischemic attack. A low hemoglobin concentration
was also associated with higher concentrations of cre-
atinine, C-reactive protein, and fibrinogen, and lower lev-
els of albumin and white blood cell count (Table 2).
ASSOCIATION OF HEMOGLOBIN
AND MORTALITY
The median follow-up period was 11.2 years with 53 866
person-years of observation. The overall mortality rate was
43.6 per 1000 person-years. When mortality was exam-
ined by hemoglobin quintiles, a reverse J-shaped relation-
ship was observed (Figure 1). Mortality was highest in
the first quintile (49%), decreasing over the second, third,
and fourth quintiles but increasing in the fifth quintile
(41%). This pattern was also apparent for cardiovascular
and noncardiovascular mortality. Compared with the fourth
quintile, the age-, race-, and sex-adjusted hazard ratios
(HRs) of mortality for hemoglobin in the first, second, third,
and fifth quintiles were 1.42 (95% confidence interval [CI],
1.25-1.62), 1.09 (95% CI, 0.95-1.25), 1.07 (95% CI, 0.93-
1.23), and 1.24 (95% CI, 1.09-1.42), respectively.
In Figure 2, the 11-year death rates for those with
and without anemia based on the WHO criteria were 57%
and 39%, respectively (P⬍.001). Unadjusted mortality
was higher for those with than those without anemia for
both cardiovascular (21% vs 16%; P⬍.001) and noncar-
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diovascular mortality (36% vs 23%; P⬍.001). Based on
the WHO criteria, the age-, race-, and sex-adjusted HR
for mortality was 1.57 (95% CI, 1.38-1.78) for persons
with anemia.
MULTIVARIATE ANALYSIS
Table 3 presents the multivariate analyses relating he-
moglobin to mortality. Hemoglobin quintiles and anemia
status were independently associated with mortality. Com-
pared with the unadjusted analysis (model A), the HR for
the lowest quintiles was modestly attenuated with demo-
graphic adjustment, whereas the highest quintile’s was less
changed (Table 3). In contrast, adjustment for comorbid
conditions had a larger relative effect on the HR for the
fifth quintile than the first and lessened the difference be-
tween the fourth and fifth quintiles.
The effect of multivariate adjustment in the models
for anemia based on the WHO criteria was similar to that
for the lowest hemoglobin quintile. In model C, the as-
sociation of anemia with mortality, with a HR of 1.38,
was slightly greater than associations of other estab-
lished risk factors for mortality in this model, such as
smoking (HR, 1.25; 95% CI, 1.14-1.38) and baseline car-
diovascular disease (HR, 1.19; 95% CI, 1.07-1.33), but
not as strong as for male sex (HR, 2.14; 95% CI, 1.90-
2.42), diabetes (HR, 1.57; 95% CI, 1.41-1.75), conges-
tive heart failure (HR, 1.67; 95% CI, 1.41-1.98), and prior
cancer (HR, 2.18; 95% CI, 1.95-2.44).
We explored the effect of adding covariates to model
C that might be causes or consequences of lower hemo-
globin concentrations. When the reciprocal of creati-
nine, inflammation status, and frailty were added to model
C, the HRs for mortality for the first quintile compared
with the fourth, or for anemia based on the WHO crite-
ria, were similar to the HRs in model C: 1.25 (95% CI,
1.07-1.47) and 1.20 (95% CI, 1.02-1.42). For the fifth
hemoglobin quintile, the HR compared with the fourth
quintile remained elevated at 1.22 (95% CI, 1.04-1.42).
When we added the components of inflammation (C-
reactive protein, white blood cell count, and fibrinogen
and albumin concentrations) as continuous variables to
model C, the HRs for the first hemoglobin quintile com-
pared with the fourth and for anemia were 1.27 (95% CI,
1.09-1.47) and 1.35 (95% CI, 1.15-1.53), respectively.
Table 4 shows the associations of lower hemoglobin
concentration or anemia with cardiovascular and noncar-
diovascular mortality. After adjustment for demographic
factors and in subsequent models, there was a weaker as-
sociation of hemoglobin concentration or anemia with car-
diovascular than noncardiovascular mortality.
There were no significant differences in mortality by he-
moglobin in groups stratified by inflammation status, coro-
nary heart disease, renal insufficiency, or race (P values for
interaction were 0.77, 0.35, 0.09, and 0.3, respectively).
COMMENT
In this elderly cohort, the prevalence of anemia was 7.0%
among white and 17.6% among black individuals. After
11.2 years of follow-up, lower hemoglobin concentra-
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 Table 2. Prevalence of Risk Factors for Mortality by Hemoglobin Quintiles*

Hemoglobin Quintiles

1 2 3 4 5 P Value
Baseline Characteristic (n = 1205) (n = 1131) (n = 1183) (n = 1095) (n = 1183) for Trend
Age, mean (SD), y 74.1 (6.2) 73.1 (5.8) 72.5 (5.3) 72.2 (5.0) 72.0 (5.2) ⬍.001
Black race 310 (26) 218 (19) 147 (12) 106 (10) 93 (8) ⬍.001
Cardiovascular disease 252 (21) 233 (21) 222 (19) 182 (17) 243 (20) .21
Chronic obstructive pulmonary disease 141 (12) 149 (14) 141 (12) 140 (13) 168 (15) .17
Renal insufficiency 248 (21) 120 (11) 98 (8) 82 (8) 96 (8) ⬍.001
Congestive heart failure 95 (8) 53 (5) 42 (4) 30 (3) 43 (4) ⬍.001
Diabetes mellitus 194 (16) 176 (16) 175 (15) 156 (14) 236 (20) .05
Frailty 114 (11) 72 (7) 69 (7) 46 (5) 49 (5) ⬍.001
Stroke or transient ischemic attack 103 (9) 75 (7) 54 (5) 42 (4) 64 (5) ⬍.001
Hypertension 704 (58) 634 (56) 675 (57) 650 (59) 726 (61) .04
Inflammation 547 (45) 450 (40) 422 (36) 407 (37) 433 (37) ⬍.001
Prebaseline cancer 185 (15) 151 (13) 179 (15) 128 (12) 180 (15) .22
Ankle-arm index ⱕ0.9 179 (15) 154 (14) 136 (12) 125 (12) 157 (13) .06
Body mass index,† mean (SD) 26.1 (4.9) 26.6 (4.7) 26.7 (4.6) 26.8 (4.4) 27.3 (4.8) ⬍.001
Self-reported health status fair or poor 398 (34) 288 (26) 257 (22) 231 (21) 288 (24) ⬍.001
Activity level, median (IQR), kcal/ wk 810 (1689) 1105 (1853) 1130 (2093) 1080 (1924) 1080 (2025) .002
Alcohol use, mean (SD), drinks/wk 1.7 (4.6) 2.1 (5.8) 2.7 (6.8) 2.9 (7.1) 3.0 (7.2) ⬍.001
History of cigarette use 585 (49) 578 (51) 644 (55) 585 (53) 712 (60) ⬍.001
Forced vital capacity, mean (SD), L 2.83 (0.88) 2.94 (0.89) 2.92 (0.85) 2.97 (0.85) 2.96 (0.89) .002
Albumin, mean (SD), mg/dL 3.88 (0.29) 3.95 (0.28) 4.01 (0.27) 4.03 (0.28) 4.10 (0.28) ⬍.001
C-reactive protein, median (IQR), mg/L 2.10 (3.52) 1.83 (2.44) 1.91 (2.35) 1.82 (2.28) 1.94 (2.21) ⬍.001
Creatinine, mean (SD), mg/dL 1.19 (0.67) 1.05 (0.29) 1.01 (0.27) 1.02 (0.27) 1.04 (0.28) ⬍.001
Fibrinogen, mean (SD), mg/dL 335 (77) 323 (68) 320 (63) 322 (65) 319 (61) ⬍.001
White blood cell count, mean (SD), ⫻103/µL 6.1 (2.9) 6.1 (1.9) 6.2 (1.8) 6.4 (1.6) 6.7 (2.0) ⬍.001

Abbreviation: IQR, interquartile range.

SI conversion factors: To convert creatinine to micromoles per liter, multiply by 88.4; to convert fibrinogen to micromoles per liter, multiply by 0.0294.
*All values are given as number (percentage) unless otherwise indicated. Hemoglobin quintiles were defined in a sex-specific manner and rounded to the
nearest tenth. Values in women were ⱕ12.6, 12.7 to 13.2, 13.3 to 13.8, 13.9 to 14.4, and ⬎14.4 g/dL, respectively. In men, these were ⱕ13.7, 13.8 to 14.4,
14.5 to 15.0, 15.1 to 15.6, and ⬎15.6 g/dL.
†Calculated as weight in kilograms divided by the square of height in meters.

60 1.0
Total Mortality No Anemia
Noncardiovascular Mortality Anemia
50 Cardiovascular Mortality 0.9

40 0.8
Cumulative Survival
Percent

30 0.7

20 0.6

10 0.5

0 0.4
1 2 3 4 5
Hemoglobin Quintiles
0.3

0 2 4 6 8 10 12
Figure 1. Unadjusted mortality over 11.2 years by hemoglobin quintiles (P
Time to Death, y
values for trend across quintiles are ⬍.001, ⬍.001, and .002, respectively).

Figure 2. Kaplan-Meier curve of survival over 11.2 years by anemia status

tions were associated with increased mortality risk, in-
dependent of many potentially confounding factors. The
magnitude of this association was similar whether the low-
est quintile of hemoglobin or the WHO criteria for ane-
mia were used; however, the number of participants was
much larger when considering the lowest quintile of he-
moglobin concentration. The attributable risk for mor-
tality was 3.3% for anemia based on the WHO criteria
and 6.5% based on the lowest hemoglobin quintile. As-
(based on World Health Organization criteria) (P⬍.001).
sociations were present between hemoglobin and all-
cause and noncardiovascular mortality but not cardio-
vascular mortality. No differences existed in the
associations between low hemoglobin and mortality based
on the presence of coronary disease, inflammation, re-
nal impairment, or race. Furthermore, before and after

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 Table 3. Multivariate-Adjusted Hazard Ratio (HR) for Mortality by Hemoglobin Quintiles
and Anemia Based on the World Health Organization (WHO)4 Criteria

Anemia as
HR (95% Confidence Interval) in Hemoglobin Quintiles Defined by WHO
Quintile
(No. of subjects)* 1 (1205) 2 (1131) 3 (1183) 4 (1095) 5 (1183) (498)
Person-years at risk 10 207 10 507 11 344 10 732 11 075 3803
No. of deaths 590 452 436 384 488 284
Model†
A 1.70 (1.49-1.93) 1.22 (1.07-1.40) 1.08 (0.94-1.24) 1.00 1.25 (1.10-1.43) 1.95 (1.72-2.21)
B 1.42 (1.25-1.62) 1.09 (0.95-1.25) 1.07 (0.93-1.23) 1.00 1.24 (1.09-1.42) 1.57 (1.38-1.78)
C 1.33 (1.15-1.54) 1.15 (0.99-1.33) 1.03 (0.89-1.20) 1.00 1.17 (1.01-1.36) 1.38 (1.19-1.59)

*See Table 2 for quintile definitions.

†Models contained the following baseline variables: A, hemoglobin; B, model A ⫹ adjustment for age, sex, and race; C, model B ⫹ adjustment for baseline
cardiovascular disease, congestive heart failure, diabetes mellitus, prebaseline cancer, ankle-arm index, self-reported health status (fair or poor), history of
cigarette use, and forced vital capacity.

Table 4. Hazard Ratios (HRs) of Cardiovascular and Noncardiovascular Mortality by Hemoglobin Concentration

First vs Fourth Quintile HR (95% CI) Anemia as Defined by WHO Criteria,4 HR (95% CI)
Death Type
(No. of Cases) Age, Sex, and Race Adjusted Fully Adjusted* Age, Sex, and Race Adjusted Fully Adjusted*
All cause (2350) 1.42 (1.25-1.62) 1.33 (1.15-1.54) 1.57 (1.38-1.78) 1.38 (1.19-1.59)
Cardiovascular (966) 1.23 (1.00-1.50) 1.17 (0.94-1.46) 1.39 (1.13-1.71) 1.20 (0.96-1.51)
Noncardiovascular (1384) 1.58 (1.33-1.87) 1.48 (1.23-1.79) 1.70 (1.44-1.99) 1.53 (1.28-1.84)

Abbreviations: CI, confidence interval; WHO, World Health Organization.

*Adjusted for age, sex, race, baseline cardiovascular disease, congestive heart failure, diabetes mellitus, prebaseline cancer, ankle-arm index, self-reported
health status (fair or poor), history of cigarette smoking, and forced vital capacity.

multivariate adjustment, higher hemoglobin concentra-
tions were associated with increased mortality.
Anemia is common among elderly individuals, and its
prevalence in this cohort, based on the WHO criteria, adds
to previous findings.5-7,23 The CHS as a community-
dwelling cohort may underestimate the prevalence of ane-
mia in the elderly population because up to 40% of in-
dividuals in long-term care facilities may be anemic.24 Little
previous available data exist on hemoglobin concentra-
tions or the prevalence of anemia among elderly black
individuals. In a recent report from the Third National
Health and Nutrition Examination Survey,7 27.8% of non-
Hispanic black participants had anemia as defined by the
WHO criteria. This was nearly 3 times higher than for
white participants.
Our findings agree with other studies relating ane-
mia to mortality. In one study of 3957 elderly patients
treated at an ambulatory care clinic, a physician diagno-
sis code of anemia was associated with an adjusted HR
of 1.44 (95% CI, 1.16-1.79) for 1-year mortality.23 Izaks
et al3 investigated subjects 85 years and older in the Neth-
erlands. In age- and sex-adjusted models, the 10-year HR
for mortality with anemia using the WHO criteria was
1.84 (95% CI,1.49-2.27), although extensive adjust-
ment for other risk factors was not done. In a 5-year study2
of 618 residents of Olmstead County, Minnesota, the age-
and sex-adjusted HR for mortality with anemia (⬍12 g/dL
for men and ⬍11 g/dL for women) was 1.8 (95% CI, 1.6-
2.0). In studies of specific patient populations, includ-
ing patients with cardiac13,14 and renal10,25,26 disease, the
risk of death related to anemia was similar to that re-
ported herein. In sum, the data suggest that anemia it-
self, regardless of the patient group studied, is a marker
for mortality. These studies are diverse; limitations in-
cluded reliance on physician diagnosis codes for ane-
mia, small sample size, or low generalizability resulting
from inclusion of specific patient populations.
The Atherosclerosis Risk in Communities (ARIC)
study investigators27 showed findings similar to ours in
middle-aged individuals, such as weaker associations of
anemia with cardiovascular than noncardiovascular
mortality. They observed an adjusted HR of 1.65 (95%
CI, 1.30-2.10) for all-cause mortality and an adjusted
HR of 1.41 (95% CI, 1.01-1.95) for cardiovascular mor-
tality in those with anemia. A larger association of ane-
mia with noncardiovascular mortality might be the re-
sult of a greater propensity for inflammatory conditions
(such as cancer or infections) to cause anemia than sub-
clinical cardiovascular disease; however, this would be
speculation because we do not know the cause of ane-
mia in either cohort.
An intriguing finding in our study was the elevated
mortality among those in the highest hemoglobin quin-
tile, even after extensive adjustment for other factors. Al-
though the 95% CI approached 1, this result suggests that
a hemoglobin concentration at the upper range of nor-
mal (⬎15.6 g/dL for men and ⬎14.4 g/dL for women)
may confer an increased risk of mortality. It remains un-
clear whether the impact of hemoglobin on mortality op-
erates through the same or different causal pathways at
higher vs lower values. Participants with higher hemo-
globin concentrations appeared to be healthier at base-

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 line compared with those in the lowest hemoglobin quin-
tile; they had lower concentrations of inflammation
markers and creatinine and lower prevalences of con-
gestive heart failure and frailty. Although they smoked
more, they were not more likely to have lung disease. Simi-
lar findings have been reported in elderly women9 and
patients with renal disease10,28; hypotheses suggest that
higher hemoglobin concentrations lead to increased blood
viscosity, blood pressure, and dialysis-access thrombo-
sis.4 Many studies3,11-13 have not shown a reverse J-
shaped relationship between hemoglobin concentra-
tion and mortality, and reported increased mortality only
with lower hemoglobin concentrations. Additional study
of this phenomenon is needed.
Along with our observational findings and those of
other studies, current data suggest a hypothesis that low
hemoglobin concentrations are causally related to ad-
verse outcomes. Underlying diseases may induce ane-
mia through increased inflammation suppressing eryth-
ropoiesis,14,29 a low hemoglobin concentration as a marker
for heart or renal failure,29 or malnutrition.29 In the pres-
ent study, a lower hemoglobin concentration was a risk
factor for mortality independent of these factors that might
modify the effect of anemia and independent of factors
that might be involved in the causal pathways between
anemia and mortality (eg, inflammation or renal func-
tion). Accumulating evidence suggests that a low hemo-
globin concentration adversely affects the cardiovascu-
lar system30-32 and that correction of anemia in renal
patients may reduce mortality by up to 20% and reverse
mild left ventricular dilation.33,34
The major limitations of this study are that it was an ob-
servational study of a community-dwelling population; par-
ticipants may not represent a cross-section of the elderly
population. Furthermore, observational studies cannot de-
termine causality. It could be argued that transient ane-
mia from gastrointestinal losses would not confer as great
a risk of mortality as a persistently low hemoglobin con-
centration. We do not have information on the etiology of
anemia (vitamin B12, folate, ferritin concentrations, and red
blood cell indices) and cannot speculate on the magni-
tude of this effect. The fact that anemia independently pre-
dicted mortality over a long period and the linearity of the
Kaplan-Meier survival curve (Figure 2) suggest that it may
contribute to long-term adverse physiologic changes rather
than serve as a proxy for another, unmeasured condition.
Because this was a study assessing cardiovascular risk, some
confounding variables, such as malignancy, may not have
been adequately assessed.
In conclusion, a lower hemoglobin concentration was
independently associated with mortality in this elderly
cohort. The bottom hemoglobin quintile defined a larger
group at risk than anemia status based on the WHO cri-
teria. Future areas of investigation should determine the
optimal hemoglobin value that defines an abnormal con-
centration in elderly individuals, study the causes of low
hemoglobin concentrations in elderly individuals and how
these relate differentially to outcomes, evaluate the causes
of increased mortality in individuals with low and high
hemoglobin concentrations, and assess whether treat-
ment of low hemoglobin in the general population re-
duces mortality.
(REPRINTED) ARCH INTERN MED/ VOL 165, OCT 24, 2005
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Accepted for Publication: April 19, 2005.
Correspondence: Mary Cushman, MD, MSc, University
of Vermont, 208 S Park Dr, Suite 2, Colchester, VT 05446
(mary.cushman@uvm.edu).
Group Members: A full list of participating Cardiovas-
cular Health Study investigators and institutions can be
found at http://www.chs-nhlbi.org.
Financial Disclosure: Dr Cushman has received re-
search funding in the form of a subcontract with the Uni-
versity of Alabama funded by Amgen; the project is not
related to this manuscript.
Funding/Support: This research was supported by con-
tracts N01-HC-85079 through N01-HC-85086, N01-HC-
35129, and N01 HC-15103 from the National Heart, Lung,
and Blood Institute, Bethesda, Md.
Role of the Sponsor: The sponsor was involved in the
design and conduct of the study and approval of the manu-
script.
Additional Information: Dr Cushman had full access to
all the data in the study and takes responsibility for the in-
tegrity of the data and the accuracy of the data analysis.
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its abstract submissions of controversies of interest to a
broad spectrum of internists. In the “Controversies in
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ments in favor of a particular point of view and the other
presents a counterpoint or arguments against that point
of view. The example published in this issue of the AR-
CHIVES pairs an article presenting the arguments in fa-
vor of thrombolytic therapy for pulmonary embolism as-
sociated with right heart dysfunction with an article
opposing such therapy.
Potential authors are invited to submit a 250-word
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the position taken regarding this controversy (eg, “pro”
or “con”), and a brief summary of arguments support-
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