Cardiol Clin 26 (2008) 113–125
Heart Failure: Who We Treat Versus Who We Study
Leslie W. Miller, MD
Washington Hospital Center and Georgetown University, 110 Irving Street NW, 1E-7, Washington, DC 20010, USA
The prevalence of patients with the diagnosis
of heart failure (HF) continues to increase, with
recent data suggesting that the current estimate
in the United States should now be over 7 million
patients. This estimate is based on the recent
census confirming a current population of 300
million people in the United States, and an
estimated average prevalence of heart failure in
2.5% of the population [1–4]. There are many
sources of information about the patients with
heart failure, including population surveys [5–
14] and data from patients identified and fol-
lowed from the time of a hospitalization for
HF [15–17], as well as inpatient registries
[18,19]. Many patients have been enrolled in
pharmaceutical and devices trials in HF, but
the patients enrolled are often not reflective of
the patients being managed outside of these trials
in terms of age, gender, race, and comorbidities.
And yet, investigators have extrapolated the
results of these trials to all patients with heart
failure. This article is a comparison of the demo-
graphics and outcomes of the patients with heart
failure that are treated and those that have been
studied.
Age
There are many demographic factors that
influence the prevalence of HF, but age is the
most powerful influence. It is clear that heart
failure is a disease of advancing age, being
relatively uncommon in those below the age of
50 years, but the disease increases progressively
with each subsequent decade [1–4]. It affects as
many as 10% to 15% of people over the age of
E-mail address: leslie.w.miller@medstar.net
0733-8651/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccl.2007.10.005
65 years, and even higher in those over 75 years
(Fig. 1). The average age of patients admitted to
the hospital is 75 years [2–19]. Patients over
65 years make up only 12% of the population,
but account for 38% of hospital discharges and
46% of hospital days [2]. The finding of prepon-
derance of hospitalized patients being elderly is
also reflected in data from the Centers for Disease
Control [2], which showed almost no increase in
the number of patients under the age of 64 years
who were hospitalized with HF over the last
25 years, while the number between 64 and 84
years, and those over the age of 85 years, has
nearly doubled (Fig. 2). The population over 65
years is expected to double in the next 20 years
from an estimated 32 million in the year 2000,
to nearly 70 million by the year 2025 [2,3]. Thus,
heart failure will be a major health problem for
the aging United States population for the next
several decades.
Race and gender
The prevalence of heart failure varies consid-
erably by race and gender [20–26]. Data have
shown that the overall prevalence is essentially
equal between men and women, averaging ap-
proximately 2.4% in males and 2.6% in females
[1–4]. However, this percentage varies between
2.5% and 3.1% in males, being highest in Afri-
can American males, and between 1.6% and
3.5% in females, with the lowest prevalence in
Latino women and highest in African American
women (Table 1). More men seem to have HF
under the age of 55 years, but women are
equally affected thereafter, and by living an aver-
age of 7 years longer, women have an equal
overall prevalence. The percentage of men who
are hospitalized is nearly equal, as shown in
cardiology.theclinics.com
114 MILLER

Total = 7 million
12
10.6
10.1
10
9
8.2
% of Population

6
4.7 4.9

4
2.1
2 1.3
0.7 0.5
0.3 0.1 0.2
0
20-29 30-39 40-49 50-59 60-69 70-79 >80
Age (Years)

Males Females

Fig. 1. Impact of age and gender on the prevalence of heart failure. (Data from Thom T, Haase N, Rosamond W, et al.
Heart disease and stroke statisticsd2006 update: A report from the American Heart Association Statistics Committee
and Stroke Statistics Subcommittee. Circulation. 2006;113:e85-e151.)

the large Acute Decompensated Heart Failure disease prevalence. The mortality also varies
National Registry (ADHERE) database [19,20]. considerably by race and gender, with the high-
The racial mix was predominantly Caucasian, est mortality of 3.5% in African American
but reflective of national race percentages and females.

Fig. 2. Influence of age on the rate of hospitalization for heart failure. (From Centers for Disease Control. Heart failure
fact sheet. Atlanta, GA: Centers for Disease Control and Prevention, 2006. Available at http://www.cdc.gov/dhdsp/
library/pdfs/fs_heart_failure.pdf.)
 HEART FAILURE 115

Table 1
Differing prevalence and incidence of heart failure by race and gender
Population Prevalence New cases Mortality Hosp D/Cs
Total 7M 500,000 57,000 (287K) 1.1 M
Males 2.4 M (2.6%) 22,300 (39%)
Females 2.6 M (2.1%) 34,905 (61%)
NHW males 2.5%
NHW females 1.9%
AA males 3.1%
AA females 3.5%
Latino males 2.7%
Latino females 1.6%
Abbreviations: AA, African American; D/Cs, discharges; M, million; NHW, nonwhite hispanic.
Data from Heart Disease and Stroke Statisticsd2006 Update. A Report from the American Heart Association
Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85–151. Available at: http://circ.
ahajournals.org/cgi/content/full/113/6/e85#TBL9.

Etiology and type of heart failure
It is clear that there are significant differences
in both the etiology and type of heart failure by
race, gender, and age. African Americans typically
have hypertension as the major cause of their HF,
while ischemic heart disease is the primary cause
in Caucasians [1–4]. African Americans present
typically at a younger age than Caucasians, with
more advance heart failure at presentation, have
a 3- to 7-fold higher incidence of hypertension
as the cause of HF, and a 15- to 18-fold higher in-
cidence of end stage renal disease compared with
Caucasians.
Recently it has also become clear that a nearly
equal percentage of patients with heart failure
have preserved systolic function (formerly called
diastolic heart failure) as have reduced systolic
function, in both the United States [27–32] and
Europe [33,34]. The ADHERE database [19]
showed that 46% of patients hospitalized had an
ejection fraction (EF) greater than 40% by echo-
cardiography. There are several differences in the
demographics of those with preserved versus re-
duced systolic function, as noted in Table 2. It is
clear that the prevalence of heart failure with pre-
served systolic function increases significantly with
advancing age, and is much more common in
women and those with a history of hypertension.
The much higher prevalence of heart failure
with preserved systolic function in women was
demonstrated in a study by Vasan and colleagues
[29] conducted from the Framingham database.
These investigators performed an echocardiogram
on a random sample of 74 patients being followed
for heart failure by their criteria. The data showed
that over 50% of men in the random sample had
an EF greater than 41% and nearly 30% had an
EF greater than 50%. In comparison, of the 33
women in this study, 80% had an EF greater
than 41%, and 75% had an EF greater than
50%. In contrast, the incidence of coronary artery
disease is lower in those with preserved EF, com-
pared with those with reduced EF (52.9% versus
63.7%). There are also differences in comorbid-
ities between patients with preserved versus re-
duced systolic function, including the incidence
of atrial fibrillation, which is more common in
those with preserved EF (41% versus 28%)
[27,28,31].
Comorbidities
Patients with HF often have a number of
comorbidities. Several databases have shown
that there is a very high prevalence of diabetes
in patients with heart failure, averaging as much
as 40% [35–39]. While the majority of patients
with diabetes will develop atherosclerosis and cor-
onary artery disease as the cause of their heart
failure, patients with diabetes who do not have
coronary artery disease may have an even higher
mortality than those with coronary artery disease
[7]. Hypertension is the primary cause of HF in
the African American patients, but is also com-
mon in other racial groups and significantly pre-
disposes patients to the development of HF.
Patients with ischemic etiology of their heart fail-
ure often have hyperlipidemia, and an increasing
percentage of HF patients are obese [1–4]. Recent
data have suggested however, that there is a sur-
prising paradox of increased survival in obese
patients with HF [40]. Renal dysfunction is
116 MILLER

Table 2 symptomatic heart failure over this 15-year obser-

Clinical demographics of patients with heart failure and vation period, and a similar 40% survival at
either preserved or reduced ejection fraction 5 years for those with preserved systolic function
Reduced Preserved (Fig. 3), making it worse than most forms of can-
Characteristic EF EF P value cer [51,52]. More recently, in a study of 2,445 pa-
Age 71.7 74.4 !0.001 tients with an average age of 76 years who were
Male sex (%) 65.4 44.3 0.17 hospitalized in Worcester, Massachusetts for HF
BMI 28.6 29.7 0.002 in the year 2000, and followed until 2005, showed
Obesity 35.5 41.4 0.007 that the all cause mortality at one year was 37%,
Serum 1.6  1.0 1.6  1.1 NS and the survival at 5 years was only 21% [53]. The
creatinine survival was lower in those whose first hospitaliza-
Hypertension 48.0 62.7 !0.001 tion for HF was the incident admission in the
CAD 63.7 52.9 !0.001
study.
Diabetes 34.3 33.1 0.61
A Fib 28.5 41.3 !0.001
Abbreviations: A fib, atrial fibrillation; BMI, body Who investigators study
mass index; CAD, coronary artery disease.
Data from Owan TE, Hodge DO, Herges RM, et al. There are significant differences in the out-
Trends in prevalence and outcome of heart failure with comes and demographics of those treated versus
preserved ejection fraction. N Engl J Medicine those studied in clinical trials [54–56]. This is a re-
2006;355(3):251–9. sult of many factors, including the desire to avoid
enrolling patients with comorbidities, such as re-
nal insufficiency and other conditions that might
becoming an increasing problem in patients with
adversely influence the outcome of trials in-
HF [41–48] and is caused by multiple factors, in-
dependent of a treatment effect [57]. Therefore, in-
cluding advancing age and the coexistence of in-
vestigators base nearly all of their current
trinsic renal disease secondary to hypertension
recommendations for the treatment of patients
or diabetes, as well as low perfusion and use of
with heart failure on clinical trials which have
high doses of diuretics [48] and potentially neph-
had a disproportionately small percentage of
rotoxic drugs, such as angiotensin-converting
those with the highest prevalence of the disease.
enzyme (ACE) inhibitors. The development of sig-
nificant renal impairment has been shown to be Survival
a high risk factor for mortality, and has been con-
firmed in studies of both outpatient and hospital- The body of evidence of results in HF trials is
ized cohorts [42,47]. nicely summarized in recently published HF
guidelines [58,59]. The survival of patients with
HF in clinical studies is often much better than
Survival what has been reported in population studies de-
The survival with heart failure over the last scribed above. There is a uniform finding that sur-
decade has been variably reported [49,50], but sev- vival worsens with advancing stage of the disease,
eral reports suggest that the survival has unfortu- but there is a great deal of variability in the defini-
nately declined over the last 15 years. The tion of Stage C HF, as evidence by recently pub-
Framingham database [6] suggested that the aver- lished trials which reported 1-year mortalities
age survival at 5 years, for all patients followed that range from 11% to 35% [60–69], versus
from the time of diagnosis of HF, was 50%. How- 37% to 57% in population studies. There is
ever, Owan and colleagues [27], from the Mayo more uniformity of the data in those with the
Clinic, followed a large number of patients from most advanced or refractory HF Stage D who
Olmstead County, Minnesota over a 15-year pe- have an extremely high mortality, which may be
riod. Their data demonstrated that there had as high as 80% at 1 year [70,71].
been approximately an 8% overall improvement
Age
in survival in those with systolic heart failure be-
tween 1987 and 2001, but in the most recent era Although it has been shown that the preva-
survival was only 40% at 5 years. In contrast, lence of HF rises significantly over the age of 60
there was no improvement in 5-year survival in years, only a few studies have examined patients
patients with preserved systolic function and above this age. Heiat and Krumholz [55]
 HEART FAILURE 117

Fig. 3. Survival in patients with heart failure with either reduced (A) or preserved (B) systolic dysfunction over a 15-year
period. Reproduced from Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure
with preserved ejection fraction. N Engl J Medicine 2006;355(3):251–9; with permission.

examined the mean age of patients involved in
heart failure studies and found that it averaged
59 years in the late 1980s, but rose to an average
of 64 years in the late 1990s, largely because of
a few studies specifically targeting older patients,
such as the two evaluation of Losartan in the el-
derly trials [63], and the Heart Outcomes Preven-
tion Evaluation [64]. The latter enrolled over
10,000 patients with an average age of 72 years.
Subsequent trials, such as Candesartan in Heart
Failure Assessment of Reduction in Mortality
and Morbidity [65], had an average age of 66
years, but the very recent African American Heart
Failure (AHFT) trial [60] had an average age of
only 58 years. The ability of older patients to tol-
erate multiple drug regimens, and the doses used
in these trials, is typically much less [72,73].
More studies are needed in the older population
to verify the benefit and tolerability of HF medi-
cations reported in younger patients.
118 MILLER

Race Americans compared with Caucasians [76,77]. At

4 years of follow-up, 50% of the African Ameri-
Similar disparities exist by race, in particular
cans had developed symptomatic heart failure ver-
lower percentages of African Americans and
sus only 25% of the Caucasians (Fig. 4).
Latinos compared with Caucasians included in
Reanalysis of the data by race in the SOLVD
clinical trials [55]. Data show that until the last 2
treatment study [76] found no measurable differ-
to 3 years, there has been a disproportionately low
ence in all cause or cardiovascular mortality by
percentage of nonwhites in heart failure trials,
race, but there was a highly significant reduction
from a low of 13% in the late 1990s, to 27% in
in hospitalization for heart failure in Caucasians
more recent studies, and the AHFT trial [60] con-
versus African Americans (0.54% versus 0.95%,
ducted solely in African Americans. There have
P ¼ .005%). When death or hospitalization for
been very few Latino patients enrolled in any
heart failure were combined, there was also a sig-
heart failure trials to date.
nificantly lower benefit, 9% in African Americans
Does the lack of a broad representation of all
versus 25% in the Caucasian population (P ¼
subgroups with HF in most of the seminal trials
.02).
upon which we have based our recommendations
When beta-blocker trials were examined, Shek-
for therapy have any impact? The answer is, yes.
elle and colleagues [74] found that Caucasians
Based on our understanding of the pathogenesis
have always benefited in the series of beta-blocker
of heart failure, in particular the importance of
trials, including the beta-blocker evaluation of
the neurohormonal system, we have assumed that
survival trial (BEST) [66], the Carvedilol prospec-
observations made in trials in which there were on
tive randomized cumulative survival trial [61], the
average only 10% to 15% African Americans
Metoprolol CR/XL randomized intervention trail
would hold in that population as well. However,
[65], and the United States Carvedilol trial [62],
this assumption has been shown to be quite
but African Americans represented less than
erroneous, as shown in the meta-analysis by
15% of those enrolled. When the benefit of Biso-
Shekelle and colleagues [74]. The reviews of the
prolol was examined retrospectively in the BEST
original studies of left ventricular dysfunction
trial [66], which had 27% African Americans,
(SOLVD) prevention trial [75] for example dem-
there was in fact an adverse affect of the beta
onstrated that there was a very substantial differ-
blocker in the African Americans, compared
ence in the development of heart failure in African

Fig. 4. Differing likelihood of development of heart failure by race in the SOLVD prevention trial of ACE inhibitors
versus placebo in asymptomatic patients with reduced systolic function. Reproduced from Dries DL, Strong MH, Cooper
RS, et al. Efficacy of angiotensin-converting enzyme inhibition in reducing progression from asymptomatic left ventric-
ular dysfunction to symptomatic heart failure in black and white patients. J Am Coll Cardiol 2002;40(2):311–7; with
permission.
 HEART FAILURE 119

with the Caucasians in the study, that nearly
reached statistical significance. When these four
trials were compared, there was no net benefit of
beta-blockers in African Americans compared
with the average 31% reduction in mortality in
Caucasians.
The trial that had perhaps the greatest impact
of race on outcome was the original vasodilator
heart failure (VHFT-1) trial [78], which was con-
ducted in Veterans Administration Hospitals
with largely Caucasian males of an average age
of 62 years. This trial was the first to show a sur-
vival advantage of the combination of hydralazine
and nitrates, compared with prazosin or placebo
(Fig. 5). When the data from that landmark study
was examined retrospectively, it showed an insig-
nificant difference in mortality in the Caucasian
patients who received hydralazine throughout
the 5-year follow-up, compared with a 47% rela-
tive risk reduction in African Americans (P ¼
.04) [55]. This observation led to the AHFT trail
[60] conducted exclusively among African Ameri-
cans, which examined the benefit of adding hy-
dralazine and nitrates versus placebo to the
standard background combination of an ACE in-
hibitor, digoxin, and diuretics. The study was
stopped prematurely because of a 43% relative
risk reduction at 600 days in favor of the hydral-
azine-nitrate combination (Fig. 6). The findings
have led to research which has demonstated a re-
duction in the production of nitric oxide in Afri-
can Americans, who therefore, not surprisingly,
benefited from the use of the antioxidant and
nitrate donor drug combination [78]. There are
likely polymorphisms of multiple genes which
are important in patients with heart failure, which
provide some scientific basis for the disparities
observed.
Gender
Another very substantial disparity has been the
incredibly low percentage of women who have
participated in cardiovascular trials of any type.
Despite the equal prevalence of HF in women
compared with men, the percentage of women
who have been enrolled in HF trials since 1985 has
averaged only 22% [55]. Many of the early trials
of heart failure, particularly the VHFT trials,
upon which a great deal of our understanding of
the pathogenesis of heart failure are based, in
fact contained almost no women. The percentage
of women in the SOLVD trial [75] that confirmed
the benefit of ACE inhibitors varied from 11% in
the prevention arm to 20% in the treatment arm.
The highest percentage of women in an HF study
was the 40% enrolled in the recent AHFT trial
[60].
Much as we have presumed that all races
would respond uniformly to all heart failure
therapies, this concept has been shown to also
be erroneous by gender. A retrospective review of
over 7,000 patients enrolled in the international
digoxin trial demonstrated that women had
a worse outcome, with a 30% higher death from
any cause in women (P ¼ .014), a 28% higher

Fig. 5. Differing benefit of the combination of hydralazine and fixed dose nitrates on survival by race in the VHFT-1
trial. (From Carson P, Ziesche S, Johnson G, et al. Racial differences in response to therapy for heart failure: Analysis
of the vasodilator-heart failure trials. J Card Fail 1999;5:178–87.)
120
100
95
Survival (%)
90
Hazard ratio=0.57
P=.01
85
0 100 200
Days Since Baseline Visit
Fixed-dose I/H 518 463 407
Placebo 532 466 401
Fig. 6. Survival benefit on survival with the addition of hydralizine and fixed-dose nitrates over standard medical ther-
apy in African Americans with heart failure in the AHFT trial. Reproduced from Taylor AL, Ziesche S, Yancy C, et al.
Combination of Isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351(20):2049–57;
with permission.
incidence of cardiovascular death (P ¼ .035), and
a 38% higher likelihood of developing worsening
heart failure (P ¼ .026) when compared with
men at the same age [79]. The hospitalizations
because of heart failure were also 21% higher
(P ¼ .01) in women, demonstrating a higher over-
all risk in women versus men who received di-
goxin therapy.
Shelleke and colleagues [74] analyzed the out-
come of various treatment trials for HF and com-
pared the outcomes between women versus men.
The results were not uniform. The study showed
that there was a 10% relative worse outcome for
women versus men in all of the ACE inhibitor tri-
als (Fig. 7). The mean risk reduction was 18%
in males versus 8% in females, while the difference
in four recent beta-blocker trials showed only
a 3% net relative difference, with a 34% relative
risk reduction in men versus a 37% in women.
Not all drugs have shown an adverse outcome
in women. Although there was an overall highly
significant reduction in the relative risk of death
with the hydralzine-nitrate therapy in the AHFT
MILLER
Fixed-dose I/H
Placebo
300 400 500 600
359 313 251 13
340 285 232 24
trials compared with placebo, there was a signifi-
cantly greater benefit in females than males (57%
versus 39%) [80].
Comorbidities
One of the other major differences in patients
enrolled in clinical trials, as opposed to those
treated outside of clinical trials, is the prevalence
of comorbidities, such as previous stroke, diabe-
tes, hypertension, and particularly renal dysfunc-
tion. Patients with these conditions are often
excluded from the trials, whereas they represent
a substantial percentage of the patients treated by
a physician. Heiat and colleagues [55] examined
the prevalence of contraindications to enrollment
in heart failure trials over the past 15 years
(Fig. 8), and demonstrated that renal insufficiency
(creatinine greater than 1.6) was listed as a contra-
indication to enrollment in as many as 30% of the
trials between 1995 and 1999. Physicians and
pharmaceutical companies interested in conduct-
ing prospective trials evaluating a new drug or
 HEART FAILURE 121

Male Female
CONSENSUS CONSENSUS

SAVE SAVE

SOLVD (Prev) SOLVD (Prev)

SOLVD (Tx) SOLVD (Tx)

SMILE SMILE

TRACE TRACE

Combined Combined

0.4 0.82 1.1 1.9 0.4 0.92 1 1.9

Relative Risk Relative Risk

Fig. 7. Differing effect of ACE inhibitors by gender in clinical heart failure trials. Abbreviations: CONSENSUS, coop-
erative North Scandinavian enalapril survival study; SAVE, survival and ventricular enlargement; SMILE, survivors of
myocardial infarction long-term evaluation; TRACE, trandolapril cardiac evaluation. Reproduced from Shekelle PG,
Rich MW, Morton SC, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management
of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical
trials. J Am College Cardiol 2003;41:1529–38; with permission.

Fig. 8. Prevalence of common comorbidities in heart failure trials that have been contraindications to enrollment in clin-
ical heart failure trials over time. From Heiat A, Gross CP, Krumholz HM. Representation of the elderly, women, and
minorities in heart failure clinical trials. Arch Intern Med 2002;162;1682–8; with permission.
122
intervention are somewhat understandably reluc-
tant to include patients with comorbidities, which
may influence outcome and lead to erroneous con-
clusions about the potential benefit of that
therapy.
Summary
There is a significant disparity between those
treated and those studied with HF, including
a significant lack of clinical trial data in some of
the populations with the highest prevalence of the
disease: females, African Americans, and Latinos,
as well as those with preserved systolic function
and those with common comorbidities. While
retrospective reviews and sub group analysis
may also be somewhat misleading, the results of
many major trials upon which much of today’s
current therapy for HF are based may have shown
different conclusions if balanced populations by
race, gender, or potentially several comorbidities
were included. Therefore, it seems that investiga-
tors cannot extrapolate all of the findings of
clinical trials to patients in the general population.
The important role of polymorphisms in gene
expression and pharmacogenomics will also be
important to a physician’s approach to drug
selection for individual patients in the future.
Future trials of HF therapy will need to include
a more representative sample from those more
reflective of the expanding population with HF.
References
[1] American Heart Association Heart and Stoke
Facts–2006 at AHA Heart Stoke Facts.
[2] Center for Disease Control and Health Statistics.
Available at: http://CDC.org/Heartfailure/faststats/
2006.
[3] Available at: http://UScensus.org.
[4] National Heart, Lung, and Blood Institute. Conges-
tive heart failure data fact sheet. Available at: http://
www.nhlbi.nih.gov/health/public/heart/other/CHF.
htm. Accessed 2006.
[5] Redfield MM. Heart failuredan epidemic of uncer-
tain proportions. N Engl J Med 2002;347(18):
1442–4.
[6] Levy D, Kenchaiah S, Larson MG, et al. Long-term
trends in the incidence of and survival with heart fail-
ure. N Engl J Med 2002;347(18):1397–402.
[7] Ammar KA, Jacobsen SJ, Mahoney DW, et al. Prev-
alence and prognostic significance of heart failure
stages: application of the American College of Car-
diology/American Heart Association heart failure
MILLER
staging criteria in the community. Circulation
2007;115(12):1563–70.
[8] Rodeheffer RJ. The new epidemiology of heart fail-
ure. Curr Cardiol Rep 2003;5(3):181–6.
[9] Roger VL, Weston SA, Redfield MM, et al. Trends
in heart failure incidence and survival in a commu-
nity-based population. JAMA 2004;292(3):344–50.
[10] Wang TJ, Evans JC, Benjamin EJ, et al. Natural his-
tory of asymptomatic left ventricular systolic dys-
function in the community. Circulation 2003;
108(8):977–82.
[11] Senni M, Tribouilloy CM, Rodeheffer RJ, et al.
Congestive heart failure in the community: trends
in incidence and survival in a 10-year period. Arch
Intern Med 1999;159(1):29–34.
[12] Goldberg RJ, Ciampa J, Lessard D, et al. Long-term
survival after heart failure: a contemporary popula-
tion-based perspective. Arch Intern Med 2007;
167(5):490–6.
[13] Goldberg RJ, Spencer FA, Farmer C, et al. Inci-
dence and hospital death rates associated with heart
failure: a community-wide perspective. AM J Med
2005;118(7):728–34.
[14] Cowie MR, Wood DA, Coats AJ, et al. Survival of
patients with a new diagnosis of heart failure: a pop-
ulation based study. Heart 2000;83(5):505–10.
[15] Jong P, Vowinckel E, Liu PP, et al. Prognosis
and determinants of survival in patients newly
hospitalized for heart failure: a population-
based study. Arch intern Med 2006;220;162(15):
1689–94.
[16] Shahar E, Lee S, Kim J, et al. Hospitalized heart fail-
ure: rates and long-term mortality. J Card Fail 2004;
109(5):374–9.
[17] Cowie MR, Fox KF, Wood DA, et al. Hospitaliza-
tion of patients with heart failure: a population-
based study. Eur Heart J 2002;23(11):877–85.
[18] Pulignano G, Del Sindaco D, Tavazzi L, et al. for the
IN-CHF Investigators. Clinical features and out-
comes of elderly outpatients with heart failure fol-
lowed up in hospital cardiology units: data from
a large nationwide cardiology database (IN-CHF
Registry). Am Heart J 2002;143(1):45–55.
[19] Fonarow GC, Gregg C, Heywood J, et al. ADHERE
Scientific Advisory Committee and Investigators
Temporal trends in clinical characteristics, treat-
ments, and outcomes for heart failure hospitaliza-
tions, 2002 to 2004: findings from Acute
Decompensated Heart Failure National Registry
(ADHERE). Am Heart J 2007;153(6):1021–8.
[20] ADHERE. Insights from the ADHERE Registry Re-
port 3.31.2006. Available at: http://www.adhereregistry.
com. Accessed 2006.
[21] Adams KF, Sueta CA, Gheorghiade M, et al. Gen-
der differences in survival in advanced heart failure:
insights from the FIRST study. Circulation 1999;99:
1816–21.
[22] Gold LD, Krumholz HM. Gender differences in
treatment of heart failure and acute myocardial
 HEART FAILURE
infarction: a question of quality or epidemiology?
Cardiol Rev 2006;14(4):180–6.
[23] Hoppe BL, Hermann DD. Sex differences in the
causes and natural history of heart failure. Curr Car- [37]
diol Rep 2003;5(3):193–9.
[24] Yancy CW. Heart failure in African Americans. Am
J Cardiol 2005;96(7B):3i–12i.
[25] Dries DL, Strong MH, Cooper RS, et al. Efficacy of [38]
angiotensin-converting enzyme inhibition in reduc-
ing progression from asymptomatic left ventricular
dysfunction to symptomatic heart failure in black
and white patients. J Am Coll Cardiol 2002;40(2): [39]
311–7.
[26] Yancy CW. Heart failure therapy in special popula-
tions: the same or different? Rev Cardiovasc Med [40]
2004;1(Suppl 5):S28–35.
[27] Owan TE, Hodge DO, Herges RM, et al. Trends in
prevalence and outcome of heart failure with pre-
served ejection fraction. N Engl J Med 2006; [41]
355(3):251–9.
[28] Bursi F, Weston SA, Redfield MM, et al. Systolic
and diastolic heart failure in the community.
JAMA 2006;296(18):2209–16. [42]
[29] Vasan RS, Larson MG, Benjamin EJ, et al. Conges-
tive heart failure in subjects with normal versus re-
duced left ventricular ejection fraction: prevalence [43]
and mortality in a population-based cohort. J Am
Coll Cardiol 1999;33(7):1948–55.
[30] Yancy CW, Lopatin M, Stevenson LW, et al, for the
ADHERE Scientific Advisory Committee and In- [44]
vestigators. Clinical presentation, management,
and in-hospital outcomes of patients admitted with
acute decompensated heart failure with preserved
systolic function: a report from the Acute Decom-
pensated Heart Failure National Registry [45]
(ADHERE) database. J Am Coll Cardiol 2006;
47(1):76–84.
[31] Owan TE, Redfield MM. Epidemiology of diastolic
heart failure. Prog Cardiovasc Dis 2005;47(5): [46]
320–32.
[32] Redfield MM, Jacobsen SJ, Burnett JC Jr, et al.
Burden of systolic and diastolic ventricular dys-
function in the community: appreciating the scope
of the heart failure epidemic. JAMA 2003;289(2): [47]
194–202.
[33] Lenzen MJ, Scholte op Reimer WJ, Boersma E, et al.
Differences between patients with a preserved and
a depressed left ventricular function: a report from
the Euro J Heart Failure 2004;25(14):1214–20.
[34] Thomas MD, Fox KF, Coats AJ, et al. The epidemi- [48]
ological enigma of heart failure with preserved sys-
tolic function. Eur J Heart Fail 2004;6(2):125–36.
[35] From AM, Leibson CL, Bursi F, et al. Diabetes in [49]
heart failure: prevalence and impact on outcome in
the population. Am J Med 2006;119(7):591–9.
[36] Greenberg BH, Abraham WT, Albert NM, et al. In- [50]
fluence of diabetes on characteristics and outcomes
in patients hospitalized with heart failure: a report
from the Organized Program to Initiate Lifesaving
123
Treatment in Hospitalized Patients with Heart Fail-
ure (OPTIMIZE-HF). Am Heart J 2007;154(2):
277e1–8.
Fonarow GC, Horwich TB, Eshaghian S. Hemoglo-
bin A1c and mortality: an unexpected relationship in
patients with advanced heart failure. Am Heart J
2006;152(1):7–12.
Smooke S, Horwich TB, Fonarow GC. Insulin-
treated diabetes is associated with a marked increase
in mortality in patients with advanced heart failure.
Am Heart J 2005;149(1):168–74.
Masoudi FA, Inzucchi SE. Diabetes mellitus and
heart failure: epidemiology, mechanisms, and phar-
macotherapy. Am J Cardiol 2007;99(4A):113B–32B.
Artham SM, Lavie CJ, Milani RV, et al. The obesity
paradox and discrepancy between peak oxygen con-
sumption and heart failure prognosisdit’s all in the
fat. Congest Heart Fail 2007;13(3):177–80.
Krumholz HM, Chen YT, Vaccarino V, et al. Corre-
lates and impact on outcomes of worsening renal
function in patients O 65 years of age with heart fail-
ure. Am J Cardiol 2000;85(9):1110–3.
Patel J, Heywood JT. Management of the cardiore-
nal syndrome in heart failure. Curr Cardiol Rep
2006;8(3):211–6.
Gottlieb SS, Abraham W, Butler J, et al. The prog-
nostic importance of different definitions of worsen-
ing renal functions in congestive heart failure. J Card
Fail 2002;8(3):136–41.
Butler J, Forman DE, Abraham WT, et al. Relation-
ship between heart failure treatment and develop-
ment of worsening renal function among
hospitalized patients. Am Heart J 2004;147(2):
331–8.
Smith GL, Vaccarino V, Kosiborod M, et al. Wors-
ening renal function: what is a clinically meaningful
change in creatinine during hospitalization with
heart failure? J Card Fail 2003;9(1):13–25.
Smith GL, Shlipak MG, Havranek EP, et al. Serum
urea nitrogen, creatinine, and estimators of renal
function: mortality in older patients with cardiovas-
cular disease. Arch Intern Med 2006;166(10):
1134–42.
Fonarow GC, Adams KF Jr, Abraham WT, et al,
ADHERE Scientific Advisory Committee, Study
Group, and Investigators. Risk stratification for
in-hospital mortality in acutely decompensated
heart failure: classification and regression tree anal-
ysis. JAMA 2005;293(5):572–80.
Levy WC, Mozaffarian D, Linker DT, et al. The
Seattle heart failure model: prediction of survival
in heart failure. Circulation 2006;113(11):1424–33.
Cleland JG, Gennell I, Khound A, et al. Is the prog-
nosis of heart failure improving? Eur J Heart Fail
1999;1(3):229–41.
Hellermann JP, Goraya TY, Jacobsen SJ, et al. Inci-
dence of heart failure after myocardial infarction: is
it changing over time? Am J Epidemiol 2003;157(12):
1101–7.
124
[51] Stewart S, MacIntyre K, Hole DJ, et al. More ‘‘ma-
lignant’’ than cancer? Five-year survival following
a first admission for heart failure. Eur J Heart Fail
2001;3(3):315–22.
[52] National Cancer Institute. Cancer mortality
maps & graphs Available at: http//www3.cancer.
gov/atlasplus/charts.html. Accessed July 14, 2007.
[53] Poole-Wilson PA. Left ventricular dysfunction
among elderly patients in general practice. Evidence
based medicine is not yet possible in these patients.
BMJ 1999;318(7196):1483–4.
[54] Gross CP, Mallory R, Heiat A, et al. Reporting the
recruitment process in clinical trials: who are these
patients and how did they get there? Ann Intern
Med 2002;137(1):10–6.
[55] Heiat A, Gross CP, Krumholz HM. Representation
of the elderly, women, and minorities in heart failure
clinical trials. Arch Intern Med 2002;162:1682–8.
[56] Britton A, McKee M, Black N, et al. Threats to the
applicability of randomized trails: exclusions and se-
lective participation. J Health Serv Res Policy 1999;
4:112–21.
[57] Coca SG, Krumholz HM, Garg AX, et al. Under
representation of renal disease in randomized con-
trolled trials of cardiovascular disease. JAMA
2006;296(11):1377–84.
[58] Swedberg K, Cleland J, Dargie H, et al. Guidelines
for the diagnosis and treatment of chronic heart fail-
ure: executive summary (update 2005) European
Society of Cardiology. Eur Heart J 2005;26(11):
1115–40.
[59] Hunt SA, Baker DW, Chin MH, et al, for the Amer-
ican College of Cardiology/American Heart Associ-
ation. ACC/AHA guidelines for the evaluation and
management of chronic heart failure in the adult: ex-
ecutive summary. J Am Coll Cardiol 2001;38(7):
2101–13.
[60] Taylor AL, Ziesche S, Yancy C, et al, African-Amer-
ican Heart Failure Trial Investigators. Combination
of isosorbide dinitrate and hydralazine in blacks with
heart failure. N Engl J Med 2004;351(20):2049–57.
[61] Packer M, Fowler MB, Roecker EB, et al, for the
Carvedilol Prospective Randomized Cumulative Sur-
vival (COPERNICUS) Study Group. Effect of carve-
dilol on the morbidity of patients with severe chronic
heart failure. Circulation 2002;106(17):2194–9.
[62] Packer M, Bristow MR, Cohn JN. The effect of Car-
vedilol on morbidity and mortality in patients with
chronic heart failure. N Engl J Med 1996;334:1340–55.
[63] Pitt B. Evaluation of Losartan in the Elderly
(ELITE) Trial: clinical implications. Eur Heart J
1997;18(8):1197–9.
[64] Yusuf S, Sleight P, Pogue J, et al. Effects of an angio-
tensin-converting enzyme inhibitor, ramaplril, on
cardiovascular events in high-risk patients. The
Heart Outcomes Prevention Evaluation (HOPE)
Study. N Engl J Med 2000;342:145–53.
[65] Young JB, Dunlap ME, Pfeffer MA, et al. Cande-
sartan in Heart failure Assessment of Reduction in
MILLER
Mortality and Morbidity (CHARM) in patients
with chronic heart failure and left ventricular sys-
tolic dysfunction. Circulation 2004;110(17):
2618–26.
[66] The Beta-Blocker Evaluation of Survival Trial
(BEST) Investigators. A trial of the beta-blocker
Bucidilol in patients with advanced chronic heart
failure. N Engl J Med 2001;344:1659–67.
[67] Konstam MA, Gheorghiade M, Burnett JC Jr. Effi-
cacy of Vasopressin Antagonism in Heart Failure
Outcome Study With Tolvaptan (EVEREST) in pa-
tients hospitalized for worsening heart failure.
JAMA 2007;297(12):1319–31.
[68] Celand JG, Daubert JC, Erdmann E. Cardiac
Resynchronization-Heart Failure (CARE-HF)
Study. The effect of cardiac resynchronization on
morbidity and mortality in heart failure. N Engl
J Med 2005;352(15):1539–49.
[69] Bardy GH, Lee KL, Mark DB. Sudden Cardiac
death in Heart Failure Trail (SCD-HeFt) Amiodar-
one or an implantable cardioverter-defibrillator for
congestive heart failure. N Engl J Med 2005;
352(3):225–37.
[70] Rose EA, Gelijns AC, Moskowitz AJ, et al. Ran-
domized Evaluation of Mechanical Assistance for
the Treatment of Congestive Heart Failure (RE-
MATCH) Study Group. N Engl J Med 2001;
345(20):1435–43.
[71] Rogers J, Kormos RL, Griffith BA, et al. Random-
ized trial of pulsatile ventricular assist device versus
medical therapy in patients who are inotrope depen-
dent, the INTREPID Trial. J Am Coll Cardiol 2007;
50:741–7.
[72] Masoudi FA, Baillie CA, Wang Y. The complexity
and cost of drug regimens of older patients hospital-
ized with heart failure in the United States, 1998–
2001. Arch Intern Med 2005;165(18):2069–76.
[73] Ko DT, Tu JV, Masoudi F. Quality of care and out-
comes of older patients with heart failure hospital-
ized in the United States and Canada. Arch Intern
Med 2005;165(21):2486–92.
[74] Shekelle PG, Rich MW, Morton SC, et al. Efficacy
of angiotensin-converting enzyme inhibitors and
beta-blockers in the management of left ventricular
systolic dysfunction according to race, gender, and
diabetic status; a meta-analysis of major clinical
trials. J Am Coll Cardiol 2003;41:1529–38.
[75] Effect of enalapril on survival in patients with re-
duced left ventricular ejection fractions and conges-
tive heart failure. The SOLVD investigators. N Engl
J Med 1991;325:293–302.
[76] Exner DV, Dries DL, Domanski MJ, et al. Lesser re-
sponse to angiotensin-converting enzyme inhibitor
therapy in black as compared to white patients
with left ventricular dysfunction. N Engl J Med
2001;344:1351–7.
[77] Cohn JN, Archibald DG, Ziesche S, et al. Effect of
vasodilator therapy on mortality in chronic congres-
tive heart failure: results of a Veterans
 HEART FAILURE 125

Administration Coorperative Study (V-HFT). N
Engl J Med 1986;314:1547–52.
[78] Cohn JN, Loscalzo J, Franciosa JA. Nitric oxide’s
role in heart failure: pathophysiology and treatment.
J Card Fail 2003;9(5):S197–8.
[79] Adams KF Jr, Patterson JH, Gattis WA, et al. Rela-
tionship of serum digoxin concentration to mortality
and morbidity in women in the digitalis investigation
group trial: a retrospective analysis. J Am Coll
Cardiol 2005;46(3):497–504.
[80] Taylor AL, Lindenfeld J, Ziesche S, et al, A-HeFT
Investigators. Outcomes by gender in the African-
American heart failure trial. J Am Coll Cardiol
2006;48(11):2263–7.