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Heart Failure: Who We Treat Versus Who We Study
Leslie W. Miller, MDWashington 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 millionpatients. 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 [14]. 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 [1517], as well as inpatient registries
[18,19]. Many patients have been enrolled in
pharmaceutical and devices trials in HF, butthe 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 [14]. It affects as
many as 10% to 15% of people over the age of
65 years, and even higher in those over 75 years
(Fig. 1). The average age of patients admitted to
the hospital is 75 years [219]. 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 [2026]. 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
[14]. 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 whoare hospitalized is nearly equal, as shown inE-mail address: leslie.w.miller@medstar.net
0733-8651/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccl.2007.10.005 cardiology.theclinics.com
Cardiol Clin 26 (2008) 113125
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the large Acute Decompensated Heart Failure
National Registry (ADHERE) database [19,20].
The racial mix was predominantly Caucasian,
but reflective of national race percentages and
disease prevalence. The mortality also varies
considerably by race and gender, with the high-
est mortality of 3.5% in African American
females.
0.3 0.2
1.3
4.7
8.2
10.1
4.9
0
2
4
6
8
10
12
0.50.7
2.1
0.1
20-29 30-39 40-49 50-59 60-69 70-79 >80
Age (Years)
Males Females
10.6
Total = 7 million
%o
fPopulatio
n
9
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.)
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.)
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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 [14]. 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 [2732] 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 thedemographics 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 followedfor 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 inthose 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% [3539]. 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 [14]. Recent
data have suggested however, that there is a sur-prising paradox of increased survival in obese
patients with HF [40]. Renal dysfunction is
Table 1
Differing prevalence and incidence of heart failure by race and gender
Population Prevalence New cases Mortality Hosp D/Cs
Total 7 M 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:e85151. Available at: http://circ.
ahajournals.org/cgi/content/full/113/6/e85#TBL9.
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becoming an increasing problem in patients with
HF [4148] and is caused by multiple factors, in-
cluding advancing age and the coexistence of in-
trinsic renal disease secondary to hypertension
or diabetes, as well as low perfusion and use of
high doses of diuretics [48] and potentially neph-
rotoxic drugs, such as angiotensin-convertingenzyme (ACE) inhibitors. The development of sig-
nificant renal impairment has been shown to be
a high risk factor for mortality, and has been con-
firmed in studies of both outpatient and hospital-
ized cohorts [42,47].
Survival
The survival with heart failure over the last
decade has been variably reported [49,50], but sev-
eral reports suggest that the survival has unfortu-nately declined over the last 15 years. The
Framingham database [6] suggested that the aver-
age survival at 5 years, for all patients followed
from the time of diagnosis of HF, was 50%. How-
ever, Owan and colleagues [27], from the Mayo
Clinic, followed a large number of patients from
Olmstead County, Minnesota over a 15-year pe-
riod. Their data demonstrated that there had
been approximately an 8% overall improvement
in survival in those with systolic heart failure be-
tween 1987 and 2001, but in the most recent era
survival was only 40% at 5 years. In contrast,there was no improvement in 5-year survival in
patients with preserved systolic function and
symptomatic heart failure over this 15-year obser-
vation period, and a similar 40% survival at
5 years for those with preserved systolic function
(Fig. 3), making it worse than most forms of can-
cer [51,52]. More recently, in a study of 2,445 pa-
tients with an average age of 76 years who werehospitalized in Worcester, Massachusetts for HF
in the year 2000, and followed until 2005, showed
that the all cause mortality at one year was 37%,
and the survival at 5 years was only 21% [53]. The
survival was lower in those whose first hospitaliza-
tion for HF was the incident admission in the
study.
Who investigators study
There are significant differences in the out-comes and demographics of those treated versus
those studied in clinical trials [5456]. This is a re-
sult of many factors, including the desire to avoid
enrolling patients with comorbidities, such as re-
nal insufficiency and other conditions that might
adversely influence the outcome of trials in-
dependent of a treatment effect [57]. Therefore, in-
vestigators base nearly all of their current
recommendations for the treatment of patients
with heart failure on clinical trials which have
had a disproportionately small percentage of
those with the highest prevalence of the disease.
Survival
The body of evidence of results in HF trials is
nicely summarized in recently published HF
guidelines [58,59]. The survival of patients with
HF in clinical studies is often much better than
what has been reported in population studies de-
scribed above. There is a uniform finding that sur-
vival worsens with advancing stage of the disease,
but there is a great deal of variability in the defini-
tion of Stage C HF, as evidence by recently pub-
lished trials which reported 1-year mortalities
that range from 11% to 35% [6069], versus
37% to 57% in population studies. There is
more uniformity of the data in those with the
most advanced or refractory HF Stage D who
have an extremely high mortality, which may be
as high as 80% at 1 year [70,71].
Age
Although it has been shown that the preva-
lence of HF rises significantly over the age of 60years, only a few studies have examined patients
above this age. Heiat and Krumholz [55]
Table 2
Clinical demographics of patients with heart failure and
either preserved or reduced ejection fraction
Characteristic
Reduced
EF
Preserved
EF P value
Age 71.7 74.4 !0.001
Male sex (%) 65.4 44.3 0.17
BMI 28.6 29.7 0.002
Obesity 35.5 41.4 0.007
Serum
creatinine
1.6 1.0 1.6 1.1 NS
Hypertension 48.0 62.7 !0.001
CAD 63.7 52.9 !0.001
Diabetes 34.3 33.1 0.61
A Fib 28.5 41.3 !0.001
Abbreviations: A fib, atrial fibrillation; BMI, body
mass index; CAD, coronary artery disease.
Data 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):2519.
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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 over10,000 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 populationto verify the benefit and tolerability of HF medi-
cations reported in younger patients.
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):2519; with permission.
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Race
Similar disparities exist by race, in particular
lower percentages of African Americans and
Latinos compared with Caucasians included in
clinical trials [55]. Data show that until the last 2to 3 years, there has been a disproportionately low
percentage of nonwhites in heart failure trials,
from a low of 13% in the late 1990s, to 27% in
more recent studies, and the AHFT trial [60] con-
ducted solely in African Americans. There have
been very few Latino patients enrolled in any
heart failure trials to date.
Does the lack of a broad representation of all
subgroups with HF in most of the seminal trials
upon which we have based our recommendations
for therapy have any impact? The answer is, yes.
Based on our understanding of the pathogenesisof heart failure, in particular the importance of
the neurohormonal system, we have assumed that
observations made in trials in which there were on
average only 10% to 15% African Americans
would hold in that population as well. However,
this assumption has been shown to be quite
erroneous, as shown in the meta-analysis by
Shekelle and colleagues [74]. The reviews of the
original studies of left ventricular dysfunction
(SOLVD) prevention trial [75] for example dem-
onstrated that there was a very substantial differ-ence in the development of heart failure in African
Americans compared with Caucasians [76,77]. At
4 years of follow-up, 50% of the African Ameri-
cans had developed symptomatic heart failure ver-
sus only 25% of the Caucasians (Fig. 4).
Reanalysis of the data by race in the SOLVD
treatment study [76] found no measurable differ-ence in all cause or cardiovascular mortality by
race, but there was a highly significant reduction
in hospitalization for heart failure in Caucasians
versus African Americans (0.54% versus 0.95%,
P .005%). When death or hospitalization for
heart failure were combined, there was also a sig-
nificantly lower benefit, 9% in African Americans
versus 25% in the Caucasian population (P
.02).
When beta-blocker trials were examined, Shek-
elle and colleagues [74] found that Caucasianshave always benefited in the series of beta-blocker
trials, including the beta-blocker evaluation of
survival trial (BEST) [66], the Carvedilol prospec-
tive randomized cumulative survival trial [61], the
Metoprolol CR/XL randomized intervention trail
[65], and the United States Carvedilol trial [62],
but African Americans represented less than
15% of those enrolled. When the benefit of Biso-
prolol was examined retrospectively in the BEST
trial [66], which had 27% African Americans,
there was in fact an adverse affect of the beta
blocker in the African Americans, compared
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):3117; with
permission.
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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 Caucasianpatients who received hydralazine throughout
the 5-year follow-up, compared with a 47% rela-
tive risk reduction in African Americans (P
.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 findingshave 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 ofthe 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 ofover 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 .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;5:17887.)
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incidence of cardiovascular death (P .035), and
a 38% higher likelihood of developing worsening
heart failure (P .026) when compared with
men at the same age [79]. The hospitalizations
because of heart failure were also 21% higher
(P .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 highlysignificant reduction in the relative risk of death
with the hydralzine-nitrate therapy in the AHFT
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 prevalenceof 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 andpharmaceutical companies interested in conduct-
ing prospective trials evaluating a new drug or
Days Since Baseline Visit
Fixed-dose I/H 518
Placebo 532
463
466
407
401
359
340
313
285
251
232
13
24
0 100 200 300 400 500 600
85
90
95
100
Survival(%)
P=.01
Fixed-dose I/H
Placebo
Hazard ratio=0.57
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):204957;
with permission.
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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;16828; with permission.
SOLVD (Prev)
CONSENSUS
SAVE
SOLVD (Tx)
SMILE
TRACE
Relative Risk
0.4 0.82 1.1 1.9
CONSENSUS
SAVE
SOLVD (Tx)
SMILE
TRACE
Combined
Relative Risk
0.4 0.92 1 1.9
FemaleMale
Combined
SOLVD (Prev)
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;41:152938; with permission.
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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 todays
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 physicians 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.
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