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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 followed 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 demographics 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

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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 preponderance 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 considerably by race and gender [20–26]. Data have shown that the overall prevalence is essentially equal between men and women, averaging approximately 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 African 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 average of 7 years longer, women have an equal overall prevalence. The percentage of men who are hospitalized is nearly equal, as shown in

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Total = 7 million 12

10.6

10.1

% of Population

10

9 8.2

8 6

4.9

4.7

4 2.1 2 0.3 0

0.1

20-29

0.2

0.7

30-39

1.3

0.5

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 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 highest mortality of 3.5% in African American 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.)

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Table 1 Differing prevalence and incidence of heart failure by race and gender Population

Prevalence

New cases

Mortality

Hosp D/Cs

Total Males Females NHW males NHW females AA males AA females Latino males Latino females

7M 2.4 M (2.6%) 2.6 M (2.1%) 2.5% 1.9% 3.1% 3.5% 2.7% 1.6%

500,000

57,000 (287K) 22,300 (39%) 34,905 (61%)

1.1 M

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 incidence 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 echocardiography. There are several differences in the demographics of those with preserved versus reduced systolic function, as noted in Table 2. It is clear that the prevalence of heart failure with preserved 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, compared with those with reduced EF (52.9% versus 63.7%). There are also differences in comorbidities between patients with preserved versus reduced 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 coronary 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 common in other racial groups and significantly predisposes patients to the development of HF. Patients with ischemic etiology of their heart failure often have hyperlipidemia, and an increasing percentage of HF patients are obese [1–4]. Recent data have suggested however, that there is a surprising paradox of increased survival in obese patients with HF [40]. Renal dysfunction is

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Table 2 Clinical demographics of patients with heart failure and either preserved or reduced ejection fraction Characteristic Age Male sex (%) BMI Obesity Serum creatinine Hypertension CAD Diabetes A Fib

Reduced EF

Preserved EF

P value

71.7 65.4 28.6 35.5 1.6  1.0

74.4 44.3 29.7 41.4 1.6  1.1

!0.001 0.17 0.002 0.007 NS

48.0 63.7 34.3 28.5

62.7 52.9 33.1 41.3

!0.001 !0.001 0.61 !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):251–9.

becoming an increasing problem in patients with HF [41–48] and is caused by multiple factors, including advancing age and the coexistence of intrinsic renal disease secondary to hypertension or diabetes, as well as low perfusion and use of high doses of diuretics [48] and potentially nephrotoxic drugs, such as angiotensin-converting enzyme (ACE) inhibitors. The development of significant renal impairment has been shown to be a high risk factor for mortality, and has been confirmed in studies of both outpatient and hospitalized cohorts [42,47]. Survival The survival with heart failure over the last decade has been variably reported [49,50], but several reports suggest that the survival has unfortunately declined over the last 15 years. The Framingham database [6] suggested that the average survival at 5 years, for all patients followed from the time of diagnosis of HF, was 50%. However, Owan and colleagues [27], from the Mayo Clinic, followed a large number of patients from Olmstead County, Minnesota over a 15-year period. Their data demonstrated that there had been approximately an 8% overall improvement in survival in those with systolic heart failure between 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 observation period, and a similar 40% survival at 5 years for those with preserved systolic function (Fig. 3), making it worse than most forms of cancer [51,52]. More recently, in a study of 2,445 patients with an average age of 76 years who were hospitalized 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 hospitalization for HF was the incident admission in the study.

Who investigators study There are significant differences in the outcomes and demographics of those treated versus those studied in clinical trials [54–56]. This is a result of many factors, including the desire to avoid enrolling patients with comorbidities, such as renal insufficiency and other conditions that might adversely influence the outcome of trials independent of a treatment effect [57]. Therefore, investigators 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 described above. There is a uniform finding that survival worsens with advancing stage of the disease, but there is a great deal of variability in the definition of Stage C HF, as evidence by recently published trials which reported 1-year mortalities that range from 11% to 35% [60–69], 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 prevalence of HF rises significantly over the age of 60 years, only a few studies have examined patients above this age. Heiat and Krumholz [55]

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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 elderly trials [63], and the Heart Outcomes Prevention 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 tolerate 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 medications reported in younger patients.

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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 2 to 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] conducted 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 pathogenesis of 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 demonstrated that there was a very substantial difference in the development of heart failure in African

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Americans compared with Caucasians [76,77]. At 4 years of follow-up, 50% of the African Americans had developed symptomatic heart failure versus only 25% of the Caucasians (Fig. 4). Reanalysis of the data by race in the SOLVD treatment study [76] found no measurable difference 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 ¼ .005%). When death or hospitalization for heart failure were combined, there was also a significantly lower benefit, 9% in African Americans versus 25% in the Caucasian population (P ¼ .02). When beta-blocker trials were examined, Shekelle and colleagues [74] found that Caucasians have always benefited in the series of beta-blocker trials, including the beta-blocker evaluation of survival trial (BEST) [66], the Carvedilol prospective 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 Bisoprolol 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 ventricular dysfunction to symptomatic heart failure in black and white patients. J Am Coll Cardiol 2002;40(2):311–7; 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 conducted in Veterans Administration Hospitals with largely Caucasian males of an average age of 62 years. This trial was the first to show a survival 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 insignificant difference in mortality in the Caucasian patients who received hydralazine throughout the 5-year follow-up, compared with a 47% relative risk reduction in African Americans (P ¼ .04) [55]. This observation led to the AHFT trail [60] conducted exclusively among African Americans, which examined the benefit of adding hydralazine and nitrates versus placebo to the standard background combination of an ACE inhibitor, digoxin, and diuretics. The study was stopped prematurely because of a 43% relative risk reduction at 600 days in favor of the hydralazine-nitrate combination (Fig. 6). The findings have led to research which has demonstated a reduction in the production of nitric oxide in African Americans, who therefore, not surprisingly, benefited from the use of the antioxidant and

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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.)

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100

Fixed-dose I/H

Survival (%)

95

90

Placebo

Hazard ratio=0.57 P=.01 85 0

Fixed-dose I/H 518 Placebo

532

100

200

400

500

600

463

Days Since Baseline Visit 407 359 313

300

251

13

466

401

232

24

340

285

Fig. 6. Survival benefit on survival with the addition of hydralizine and fixed-dose nitrates over standard medical therapy 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 overall risk in women versus men who received digoxin therapy. Shelleke and colleagues [74] analyzed the outcome of various treatment trials for HF and compared 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 trials (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

trials compared with placebo, there was a significantly 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, diabetes, hypertension, and particularly renal dysfunction. 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 contraindication to enrollment in as many as 30% of the trials between 1995 and 1999. Physicians and pharmaceutical companies interested in conducting prospective trials evaluating a new drug or

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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

Relative Risk

1.9

0.4

0.92

1

1.9

Relative Risk

Fig. 7. Differing effect of ACE inhibitors by gender in clinical heart failure trials. Abbreviations: CONSENSUS, cooperative 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 clinical 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.

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intervention are somewhat understandably reluctant to include patients with comorbidities, which may influence outcome and lead to erroneous conclusions about the potential benefit of that therapy.

[8] [9]

[10]

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 investigators 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. Congestive 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 uncertain 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 failure. N Engl J Med 2002;347(18):1397–402. [7] Ammar KA, Jacobsen SJ, Mahoney DW, et al. Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

staging criteria in the community. Circulation 2007;115(12):1563–70. Rodeheffer RJ. The new epidemiology of heart failure. Curr Cardiol Rep 2003;5(3):181–6. Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA 2004;292(3):344–50. Wang TJ, Evans JC, Benjamin EJ, et al. Natural history of asymptomatic left ventricular systolic dysfunction in the community. Circulation 2003; 108(8):977–82. 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. Goldberg RJ, Ciampa J, Lessard D, et al. Long-term survival after heart failure: a contemporary population-based perspective. Arch Intern Med 2007; 167(5):490–6. Goldberg RJ, Spencer FA, Farmer C, et al. Incidence and hospital death rates associated with heart failure: a community-wide perspective. AM J Med 2005;118(7):728–34. Cowie MR, Wood DA, Coats AJ, et al. Survival of patients with a new diagnosis of heart failure: a population based study. Heart 2000;83(5):505–10. Jong P, Vowinckel E, Liu PP, et al. Prognosis and determinants of survival in patients newly hospitalized for heart failure: a populationbased study. Arch intern Med 2006;220;162(15): 1689–94. Shahar E, Lee S, Kim J, et al. Hospitalized heart failure: rates and long-term mortality. J Card Fail 2004; 109(5):374–9. Cowie MR, Fox KF, Wood DA, et al. Hospitalization of patients with heart failure: a populationbased study. Eur Heart J 2002;23(11):877–85. Pulignano G, Del Sindaco D, Tavazzi L, et al. for the IN-CHF Investigators. Clinical features and outcomes of elderly outpatients with heart failure followed up in hospital cardiology units: data from a large nationwide cardiology database (IN-CHF Registry). Am Heart J 2002;143(1):45–55. Fonarow GC, Gregg C, Heywood J, et al. ADHERE Scientific Advisory Committee and Investigators Temporal trends in clinical characteristics, treatments, and outcomes for heart failure hospitalizations, 2002 to 2004: findings from Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2007;153(6):1021–8. ADHERE. Insights from the ADHERE Registry Report 3.31.2006. Available at: http://www.adhereregistry. com. Accessed 2006. Adams KF, Sueta CA, Gheorghiade M, et al. Gender differences in survival in advanced heart failure: insights from the FIRST study. Circulation 1999;99: 1816–21. Gold LD, Krumholz HM. Gender differences in treatment of heart failure and acute myocardial

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[23]

[24] [25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

infarction: a question of quality or epidemiology? Cardiol Rev 2006;14(4):180–6. Hoppe BL, Hermann DD. Sex differences in the causes and natural history of heart failure. Curr Cardiol Rep 2003;5(3):193–9. Yancy CW. Heart failure in African Americans. Am J Cardiol 2005;96(7B):3i–12i. Dries DL, Strong MH, Cooper RS, et al. Efficacy of angiotensin-converting enzyme inhibition in reducing progression from asymptomatic left ventricular dysfunction to symptomatic heart failure in black and white patients. J Am Coll Cardiol 2002;40(2): 311–7. Yancy CW. Heart failure therapy in special populations: the same or different? Rev Cardiovasc Med 2004;1(Suppl 5):S28–35. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355(3):251–9. Bursi F, Weston SA, Redfield MM, et al. Systolic and diastolic heart failure in the community. JAMA 2006;296(18):2209–16. Vasan RS, Larson MG, Benjamin EJ, et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999;33(7):1948–55. Yancy CW, Lopatin M, Stevenson LW, et al, for the ADHERE Scientific Advisory Committee and Investigators. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) database. J Am Coll Cardiol 2006; 47(1):76–84. Owan TE, Redfield MM. Epidemiology of diastolic heart failure. Prog Cardiovasc Dis 2005;47(5): 320–32. Redfield MM, Jacobsen SJ, Burnett JC Jr, et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 2003;289(2): 194–202. 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. Thomas MD, Fox KF, Coats AJ, et al. The epidemiological enigma of heart failure with preserved systolic function. Eur J Heart Fail 2004;6(2):125–36. From AM, Leibson CL, Bursi F, et al. Diabetes in heart failure: prevalence and impact on outcome in the population. Am J Med 2006;119(7):591–9. Greenberg BH, Abraham WT, Albert NM, et al. Influence of diabetes on characteristics and outcomes in patients hospitalized with heart failure: a report from the Organized Program to Initiate Lifesaving

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

123 Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart J 2007;154(2): 277e1–8. Fonarow GC, Horwich TB, Eshaghian S. Hemoglobin 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. Insulintreated 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 pharmacotherapy. Am J Cardiol 2007;99(4A):113B–32B. Artham SM, Lavie CJ, Milani RV, et al. The obesity paradox and discrepancy between peak oxygen consumption 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. Correlates and impact on outcomes of worsening renal function in patients O 65 years of age with heart failure. Am J Cardiol 2000;85(9):1110–3. Patel J, Heywood JT. Management of the cardiorenal syndrome in heart failure. Curr Cardiol Rep 2006;8(3):211–6. Gottlieb SS, Abraham W, Butler J, et al. The prognostic importance of different definitions of worsening renal functions in congestive heart failure. J Card Fail 2002;8(3):136–41. Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 2004;147(2): 331–8. Smith GL, Vaccarino V, Kosiborod M, et al. Worsening 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 cardiovascular 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 analysis. 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 prognosis of heart failure improving? Eur J Heart Fail 1999;1(3):229–41. Hellermann JP, Goraya TY, Jacobsen SJ, et al. Incidence of heart failure after myocardial infarction: is it changing over time? Am J Epidemiol 2003;157(12): 1101–7.

124

MILLER

[51] Stewart S, MacIntyre K, Hole DJ, et al. More ‘‘malignant’’ 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 selective 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 controlled 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 failure: 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 American College of Cardiology/American Heart Association. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. J Am Coll Cardiol 2001;38(7): 2101–13. [60] Taylor AL, Ziesche S, Yancy C, et al, African-American 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 Survival (COPERNICUS) Study Group. Effect of carvedilol 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 Carvedilol 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 angiotensin-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. Candesartan in Heart failure Assessment of Reduction in

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

Mortality and Morbidity (CHARM) in patients with chronic heart failure and left ventricular systolic dysfunction. Circulation 2004;110(17): 2618–26. 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. Konstam MA, Gheorghiade M, Burnett JC Jr. Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) in patients hospitalized for worsening heart failure. JAMA 2007;297(12):1319–31. 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. Bardy GH, Lee KL, Mark DB. Sudden Cardiac death in Heart Failure Trail (SCD-HeFt) Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352(3):225–37. Rose EA, Gelijns AC, Moskowitz AJ, et al. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. N Engl J Med 2001; 345(20):1435–43. Rogers J, Kormos RL, Griffith BA, et al. Randomized trial of pulsatile ventricular assist device versus medical therapy in patients who are inotrope dependent, the INTREPID Trial. J Am Coll Cardiol 2007; 50:741–7. Masoudi FA, Baillie CA, Wang Y. The complexity and cost of drug regimens of older patients hospitalized with heart failure in the United States, 1998– 2001. Arch Intern Med 2005;165(18):2069–76. Ko DT, Tu JV, Masoudi F. Quality of care and outcomes of older patients with heart failure hospitalized in the United States and Canada. Arch Intern Med 2005;165(21):2486–92. 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. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD investigators. N Engl J Med 1991;325:293–302. Exner DV, Dries DL, Domanski MJ, et al. Lesser response 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. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congrestive heart failure: results of a Veterans

HEART FAILURE

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. Relationship of serum digoxin concentration to mortality

125

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 AfricanAmerican heart failure trial. J Am Coll Cardiol 2006;48(11):2263–7.