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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: [email protected]

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.)

114 MILLER
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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.

115HEART FAILURE
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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.

116 MILLER


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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.

118 MILLER


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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.)

119HEART FAILURE


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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.

120 MILLER


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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.

121HEART FAILURE


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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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