Section 15: Management of Heart Failure in Special Populations

Abstract

Overview Heart failure (HF) is a major problem in women, African Americans, and the elderly of both sexes and any race. The clinical conclusions based on trial data derived from predominately younger white male study populations generally apply equally to these groups. However, there are etiologic or pathophysiologic considerations specific to some of these groups that warrant attention if care is to be optimized. Discussion in this section is based primarily on available data from subgroup analyses of randomized HF trials and the results of cohort studies. A substantial amount of the data on drug efficacy comes from studies of patients treated after a recent acute myocardial infarction (MI). Elderly Patients With HF Clinical Characteristics and Prognosis. HF represents a significant and growing public health problem for the elderly. The progressive aging of the US population is well established1Batchelor W.B. Jollis J.G. Friesinger G.C. The challenge of health care delivery to the elderly patient with cardiovascular disease. Demographic, epidemiologic, fiscal, and health policy implications.Cardiol Clin. 1999; 17 (vii): 1-15Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar and has profound implications for the prevalence of cardiovascular disease—particularly HF. A number of studies have documented the substantial increase in the prevalence of this syndrome as age increases.2Kannel W.B. Belanger A.J. Epidemiology of heart failure.Am Heart J. 1991; 121: 951-957Abstract Full Text PDF PubMed Scopus (737) Google Scholar As with most illnesses in the elderly, HF is associated with higher rates of morbidity and mortality than in younger patients.3Rich M.W. Epidemiology, pathophysiology, and etiology of congestive heart failure in older adults.J Am Geriatr Soc. 1997; 45: 968-974PubMed Google Scholar, 4Alexander M. Grumbach K. Remy L. Rowell R. Massie B.M. Congestive heart failure hospitalizations and survival in California: patterns according to race/ethnicity.Am Heart J. 1999; 137: 919-927Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Pathophysiology of HF in the Elderly. There are a number of well described changes in cardiovascular physiology which occur with aging. Resting systolic left ventricular (LV) function appears to be preserved, but perhaps at the expense of some LV enlargement.5Schulman S.P. Cardiovascular consequences of the aging process.Cardiol Clin. 1999; 17 (viii): 35-49Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar A diminution of diastolic function has been documented in otherwise normal elderly individuals.6Schulman S.P. Lakatta E.G. Fleg J.L. Lakatta L. Becker L.C. Gerstenblith G. Age-related decline in left ventricular filling at rest and exercise.Am J Physiol. 1992; 263: H1932-H1938PubMed Google Scholar Exercise capacity declines with age, most likely from a combination of cardiac and peripheral vascular factors and ventricular-vascular coupling.7Najjar S.S. Schulman S.P. Gerstenblith G. Fleg J.L. Kass D.A. O'Connor F. et al.Age and gender affect ventricular-vascular coupling during aerobic exercise.J Am Coll Cardiol. 2004; 44: 611-617Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Though these diverse cardiovascular changes tend to reduce exercise capacity, their impact on health and quality of life remains modest in most individuals compared to the detrimental effects of HF. Recommendations 15.1As with younger patients, it is recommended that elderly patients, particularly those age ?>>80 years, be evaluated for HF when presenting with symptoms of dyspnea and fatigue. (Strength of Evidence = C)15.2β-blocker and angiotensin-converting enzyme (ACE) inhibitor therapy is recommended as standard therapy in all elderly patients with HF due to LV systolic dysfunction. (Strength of Evidence = B) In the absence of contraindications, these agents are also recommended in the very elderly (age ?>> 80 years). (Strength of Evidence = C)15.3As in all patients, but especially in the elderly, careful attention to volume status, the possibility of symptomatic cerebrovascular disease, and the presence of postural hypotension is recommended during therapy with ACE inhibitors and β-blockers. (Strength of Evidence = C) Background β-Blockers. Diminished response to catecholamine stimulation in elderly individuals has been shown by several investigators8Guarnieri T. Filburn C.R. Zitnik G. Roth G.S. Lakatta E.G. Contractile and biochemical correlates of beta-adrenergic stimulation of the aged heart.Am J Physiol. 1980; 239: H501-H508PubMed Google Scholar and appears related to diminished number and activity of both β-1 and β-2 receptors.9Xiao R.P. Tomhave E.D. Wang D.J. Ji X. Boluyt M.O. Cheng H. et al.Age-associated reductions in cardiac beta1- and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases.J Clin Invest. 1998; 101: 1273-1282Crossref PubMed Scopus (163) Google Scholar However, the changes in response to the sympathetic nervous system do not mitigate the need for β-receptor antagonism in the elderly. The striking risk in the elderly of major morbidity and early mortality, combined with the substantial benefit derived from β-blockade, strongly supports the use of these agents as tolerated in elderly patients with symptomatic LV systolic dysfunction. Conclusions from randomized placebo controlled trials are limited concerning the efficacy of β-blockade in the elderly. However, a retrospective analysis of a study of metoprolol CR/XL, which enrolled patients up to age 80 and included a substantial subgroup of elderly patients, found a similar degree of morbidity and mortality reduction in patients 69 or older versus those younger than 69.10Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).Lancet. 1999; 353: 2001-2007Abstract Full Text Full Text PDF PubMed Scopus (4261) Google Scholar, 11Hjalmarson A. Goldstein S. Fagerberg B. Wedel H. Waagstein F. Kjekshus J. et al.Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group.JAMA. 2000; 283: 1295-1302Crossref PubMed Scopus (1120) Google Scholar Observational studies of the outcome of elderly patients after myocardial infarction have consistently shown substantial reductions in mortality when β-blockers are prescribed at discharge.12Gottlieb S.S. McCarter R.J. Vogel R.A. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction.N Engl J Med. 1998; 339: 489-497Crossref PubMed Scopus (870) Google Scholar, 13Rochon P.A. Tu J.V. Anderson G.M. Gurwitz J.H. Clark J.P. Lau P. et al.Rate of heart failure and 1-year survival for older people receiving low-dose beta-blocker therapy after myocardial infarction.Lancet. 2000; 356: 639-644Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 14Shlipak M.G. Browner W.S. Noguchi H. Massie B. Frances C.D. McClellan M. Comparison of the effects of angiotensin converting-enzyme inhibitors and beta blockers on survival in elderly patients with reduced left ventricular function after myocardial infarction.Am J Med. 2001; 110: 425-433Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar These studies have included octogenarians. The one randomized trial of β-blockers in an elderly population with HF (mean age 76) demonstrated a reduction of 14% in the combined endpoint of all-cause mortality or primary cardiovascular admission for the group on nebivolol.15Flather M.D. Shibata M.C. Coats A.J. Van Veldhuisen D.J. Parkhomenko A. Borbola J. et al.Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS).Eur Heart J. 2005; 26: 215-225Crossref PubMed Scopus (1185) Google Scholar ACE Inhibitors. No randomized controlled trial has been conducted specifically to investigate the benefit of ACE inhibition in elderly patients. However, convincing evidence of the effectiveness of ACE inhibition in elderly patients is provided by the results of a trial in which the mean age was 70 and the reduction in mortality was 31% at 2 year and 27% at the end of the study for patients treated with ACE inhibition.16Effects of enalapril on mortality in severe congestive heart failure Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.N Engl J Med. 1987; 316: 1429-1435Crossref PubMed Scopus (4677) Google Scholar Observational studies and a meta-analysis of post-MI patients with HF reinforce these findings,17Flather M.D. Yusuf S. Kober L. Pfeffer M. Hall A. Murray G. et al.Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group.Lancet. 2000; 355: 1575-1581Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar, 18Garg R. Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials.JAMA. 1995; 273: 1450-1456Crossref PubMed Scopus (1700) Google Scholar, 19Gambassi G. Lapane K.L. Sgadari A. Carbonin P. Gatsonis C. Lipsitz L.A. et al.Effects of angiotensin-converting enzyme inhibitors and digoxin on health outcomes of very old patients with heart failure. SAGE Study Group. Systematic Assessment of Geriatric drug use via Epidemiology.Arch Intern Med. 2000; 160: 53-60Crossref PubMed Scopus (97) Google Scholar though caution is necessary in extrapolating the results of post-MI studies to chronic HF. Other Medications. In the absence of data to the contrary, other HF medications, including angiotensin-receptor blockers (ARBs), aldosterone antagonists, and the combination of hydralazine/isosorbide dinitrate, should be considered as options for elderly patients with HF, keeping in mind the complications of polypharmacy in a population characterized by multiple comorbidities. HF in Women Clinical Characteristics and Prognosis. HF is common in women, and among the elderly the prevalence of HF is even greater in women than in men.20Kimmelstiel C.D. Konstam M.A. Heart failure in women.Cardiology. 1995; 86: 304-309Crossref PubMed Scopus (52) Google Scholar A growing body of evidence has demonstrated significant differences in the clinical characteristics and prognosis of HF in women and men. Early results from the Framingham Heart Study pointed to a difference in prognosis between men and women with HF, with men having worse survival than women.21McKee P.A. Castelli W.P. McNamara P.M. Kannel W.B. The natural history of congestive heart failure: the Framingham study.N Engl J Med. 1971; 285: 1441-1446Crossref PubMed Scopus (2483) Google Scholar, 22Adams Jr., K.F. Dunlap S.H. Sueta C.A. Clarke S.W. Patterson J.H. Blauwet M.B. et al.Relation between gender, etiology and survival in patients with symptomatic heart failure.J Am Coll Cardiol. 1996; 28: 1781-1788Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 23Adams Jr., K.F. Sueta C.A. Gheorghiade M. O'Connor C.M. Schwartz T.A. Koch G.G. et al.Gender differences in survival in advanced heart failure. Insights from the FIRST study.Circulation. 1999; 99: 1816-1821Crossref PubMed Google Scholar Subsequent findings from some HF databases have confirmed this observation in both a broad population of patients with HF and those at a very advanced stage.24American Heart Association.2001 heart and stroke statistical update. American Heart Association, Dallas2000Google Scholar, 25Gillum R.F. Heart failure in the United States 1970–1985.Am Heart J. 1987; 113: 1043-1045Abstract Full Text PDF PubMed Scopus (86) Google Scholar, 26Bourassa M.G. Gurne O. Bangdiwala S.I. Ghali J.K. Young J.B. Rousseau M. et al.Natural history and patterns of current practice in heart failure. The Studies of Left Ventricular Dysfunction (SOLVD) Investigators.J Am Coll Cardiol. 1993; 22: 14A-19AAbstract Full Text PDF PubMed Scopus (334) Google Scholar, 27Afzal A. Ananthasubramaniam K. Sharma N. al-Malki Q. Ali A.S. Jacobsen G. et al.Racial differences in patients with heart failure.Clin Cardiol. 1999; 22: 791-794Crossref PubMed Scopus (56) Google Scholar These studies have suggested that women's survival advantage is etiology-dependent, with better outcomes noted when the primary cause is non-ischemic. Gender and Cardiovascular Pathophysiology. A number of experimental studies point to fundamental, gender-related differences in the nature and extent of myocardial hypertrophy and adaptation, which might account for the survival advantage for females.28Buttrick P. Scheuer J. Sex-associated differences in left ventricular function in aortic stenosis of the elderly.Circulation. 1992; 86: 1336-1338Crossref PubMed Scopus (25) Google Scholar, 29Schaible T.F. Malhotra A. Ciambrone G. Scheuer J. The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats.Circ Res. 1984; 54: 38-49Crossref PubMed Scopus (154) Google Scholar Early studies of spontaneously hypertensive rats suggested that the adverse influence of hypertrophy on cardiac function was greater in male than in female rats.30Pfeffer J.M. Pfeffer M.A. Fletcher P. Fishbein M.C. Braunwald E. Favorable effects of therapy on cardiac performance in spontaneously hypertensive rats.Am J Physiol. 1982; 242: H776-H784PubMed Google Scholar A number of animal studies suggest gender-related differences in myocardial remodeling in response to a pressure load and after MI.30Pfeffer J.M. Pfeffer M.A. Fletcher P. Fishbein M.C. Braunwald E. Favorable effects of therapy on cardiac performance in spontaneously hypertensive rats.Am J Physiol. 1982; 242: H776-H784PubMed Google Scholar, 31Weinberg E.O. Thienelt C.D. Katz S.E. Bartunek J. Tajima M. Rohrbach S. et al.Gender differences in molecular remodeling in pressure overload hypertrophy.J Am Coll Cardiol. 1999; 34: 264-273Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 32van Eickels M. Grohe C. Cleutjens J.P. Janssen B.J. Wellens H.J. Doevendans P.A. 17beta-estradiol attenuates the development of pressure-overload hypertrophy.Circulation. 2001; 104: 1419-1423Crossref PubMed Scopus (244) Google Scholar, 33Cavasin M.A. Sankey S.S. Yu A.L. Menon S. Yang X.P. Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction.Am J Physiol Heart Circ Physiol. 2003; 284: H1560-H1569PubMed Google Scholar, 34Tamura T. Said S. Gerdes A.M. Gender-related differences in myocyte remodeling in progression to heart failure.Hypertension. 1999; 33: 676-680Crossref PubMed Scopus (100) Google Scholar, 35Carroll J.D. Carroll E.P. Feldman T. Ward D.M. Lang R.M. McGaughey D. et al.Sex-associated differences in left ventricular function in aortic stenosis of the elderly.Circulation. 1992; 86: 1099-1107Crossref PubMed Scopus (384) Google Scholar Treatment Response. Recognition of the pathophysiologic and clinical differences between men and women with HF has raised concern that treatment response might differ as well. Results of individual controlled clinical trials, even of standard therapeutic agents for HF from systolic dysfunction, generally are inconclusive, because of the small number of women enrolled. Data from pooled analyses are equally sparse. Recommendations are made in the context of this limited database. Recommendation 15.4β-blocker therapy is recommended for women with HF from:•symptomatic LV systolic dysfunction (Strength of Evidence = B)•asymptomatic LV systolic dysfunction (Strength of Evidence = C) Background Women are underrepresented in HF clinical trials, as they are in clinical studies of other cardiovascular diseases.36Lindenfeld J. Krause-Steinrauf H. Salerno J. Where are all the women with heart failure?.J Am Coll Cardiol. 1997; 30: 1417-1419Abstract Full Text PDF PubMed Scopus (96) Google Scholar However, a recent review of the experience of women in several of the large-scale prospective mortality trials of β-blockade in patients with symptomatic LV dysfunction does suggest that women and men benefit to a similar degree.37Ghali J.K. Pina I.L. Gottlieb S.S. Deedwania P.C. Wikstrand J.C. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF).Circulation. 2002; 105: 1585-1591Crossref PubMed Scopus (186) Google Scholar Similarly, a pooling of the mortality results from several other large trials showed strong evidence of a similar beneficial effect in women and men.37Ghali J.K. Pina I.L. Gottlieb S.S. Deedwania P.C. Wikstrand J.C. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF).Circulation. 2002; 105: 1585-1591Crossref PubMed Scopus (186) Google Scholar, 38Dunlap S.H. Sueta C.A. Tomasko L. Adams Jr., K.F. Association of body mass, gender and race with heart failure primarily due to hypertension.J Am Coll Cardiol. 1999; 34: 1602-1608Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Given the absence of contrary data, the most prudent course is to recommend the routine use of β-blockade for HF in both women and men. Recommendation 15.5ACE inhibitor therapy is recommended as standard therapy in all women with symptomatic or asymptomatic LV systolic dysfunction. (Strength of Evidence = B) Background As with β-blockers, the available data on ACE inhibition suggest comparable effects in women and men with HF. A meta-analysis of large-scale HF and post-MI randomized trials demonstrated evidence of a mortality benefit of ACE inhibition in women. A more convincing effect was seen on the composite end point of death, reinfarction, or admission for HF. Comparable findings related to gender were also noted in the meta-analysis of mostly small-scale, short-term studies of ACE inhibition, which found similar favorable point estimates for reduction in mortality and for mortality plus hospitalization in women.17Flather M.D. Yusuf S. Kober L. Pfeffer M. Hall A. Murray G. et al.Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group.Lancet. 2000; 355: 1575-1581Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar Other Medications. In the absence of data to the contrary, other HF medications, including ARBs, aldosterone antagonists, and the combination of hydralazine/isosorbide dinitrate, should be considered as options for women with HF. HF in African Americans Clinical Characteristics and Prognosis. Cardiovascular disease is a major health issue for African Americans.24American Heart Association.2001 heart and stroke statistical update. American Heart Association, Dallas2000Google Scholar, 25Gillum R.F. Heart failure in the United States 1970–1985.Am Heart J. 1987; 113: 1043-1045Abstract Full Text PDF PubMed Scopus (86) Google Scholar Traditionally, concern has focused on hypertension and stroke as key components of the burden of cardiovascular disease in this population. However, HF represents a major source of cardiovascular morbidity and mortality for African Americans. Epidemiologic data suggests that they are at greater risk for HF than Caucasians, with approximately 3% of all African-American adults affected. A number of clinical studies have documented substantial differences between the baseline clinical characteristics of African Americans and Caucasians with HF.26Bourassa M.G. Gurne O. Bangdiwala S.I. Ghali J.K. Young J.B. Rousseau M. et al.Natural history and patterns of current practice in heart failure. The Studies of Left Ventricular Dysfunction (SOLVD) Investigators.J Am Coll Cardiol. 1993; 22: 14A-19AAbstract Full Text PDF PubMed Scopus (334) Google Scholar, 27Afzal A. Ananthasubramaniam K. Sharma N. al-Malki Q. Ali A.S. Jacobsen G. et al.Racial differences in patients with heart failure.Clin Cardiol. 1999; 22: 791-794Crossref PubMed Scopus (56) Google Scholar, 38Dunlap S.H. Sueta C.A. Tomasko L. Adams Jr., K.F. Association of body mass, gender and race with heart failure primarily due to hypertension.J Am Coll Cardiol. 1999; 34: 1602-1608Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Age of onset is significantly younger in blacks than in whites, and HF is less likely to be due to ischemic heart disease. Hypertension remains a major etiologic factor for HF in African Americans. Analysis of outcome data from the Studies of Left Ventricular Dysfunction (SOLVD) trials has shown higher mortality and morbidity rates in blacks compared to whites with HF.39Dries D.L. Exner D.V. Gersh B.J. Cooper H.A. Carson P.E. Domanski M.J. Racial differences in the outcome of left ventricular dysfunction.N Engl J Med. 1999; 340: 609-616Crossref PubMed Scopus (298) Google Scholar Whether these differences reflect differences in baseline characteristics, delivery of care or socioeconomic factors has not been resolved. Other studies point to problems with access to care and unfavorable clinical characteristics independent of HF as factors increasing the risk of African Americans for poor outcomes.40Alexander M. Grumbach K. Selby J. Brown A.F. Washington E. Hospitalization for congestive heart failure. Explaining racial differences.JAMA. 1995; 274: 1037-1042Crossref PubMed Scopus (105) Google Scholar, 41Ghali J.K. Kadakia S. Cooper R. Ferlinz J. Precipitating factors leading to decompensation of heart failure. Traits among urban blacks.Arch Intern Med. 1988; 148: 2013-2016Crossref PubMed Google Scholar, 42Ofili E.O. Mayberry R. Alema-Mensah E. Saleem S. Hamirani K. Jones C. et al.Gender differences and practice implications of risk factors for frequent hospitalization for heart failure in an urban center serving predominantly African-American patients.Am J Cardiol. 1999; 83: 1350-1355Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Aggressive, early treatment of hypertension has been proposed as a major strategy for the prevention of HF in this racial group. Persistent hypertension is not uncommon in African-American patients with HF and systolic dysfunction. Treatment Response. Although a number of clinical characteristics have been shown to differ significantly between African Americans and other races afflicted with HF, the implications of these differences for therapy remain to be determined. Recommendation 15.6β-blockers are recommended as part of standard therapy for African Americans with HF due to:•symptomatic LV systolic dysfunction (Strength of Evidence = B)•asymptomatic LV systolic dysfunction (Strength of Evidence = C) Background Although 1 trial with bucindolol did not find a beneficial effect of β-blockade in African Americans with HF,43A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure.N Engl J Med. 2001; 344: 1659-1667Crossref PubMed Scopus (936) Google Scholar subgroup analysis of data from the US Carvedilol Trials suggests that the beneficial effect of β-blockers on outcomes in African Americans with HF from systolic dysfunction is similar to the effects in the larger population.44Yancy C.W. Fowler M.B. Colucci W.S. Gilbert E.M. Bristow M.R. Cohn J.N. et al.Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure.N Engl J Med. 2001; 344: 1358-1365Crossref PubMed Scopus (236) Google Scholar Other studies demonstrate similar findings.12Gottlieb S.S. McCarter R.J. Vogel R.A. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction.N Engl J Med. 1998; 339: 489-497Crossref PubMed Scopus (870) Google Scholar, 45Goldstein S. Deedwania P. Gottlieb S. Wikstrand J. Metoprolol CR/XL in black patients with heart failure (from the Metoprolol CR/XL randomized intervention trial in chronic heart failure).Am J Cardiol. 2003; 92: 478-480Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 46Shekelle P.G. Rich M.W. Morton S.C. Atkinson C.S. Tu W. Maglione M. 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: 1529-1538Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar The totality of the data supports substantial benefit from these agents, regardless of race. Recommendations 15.7ACE inhibitors are recommended as part of standard therapy for African-American patients with HF from symptomatic or asymptomatic LV systolic dysfunction. (Strength of Evidence = C)15.8ARBs are recommended as substitute therapy for HF in African Americans intolerant of ACE inhibitors. (Strength of Evidence = B) Background ACE Inhibition. Long-standing clinical experience suggests that African Americans with hypertension respond less well than Caucasians to ACE inhibitors.47Saunders E. Hypertension in minorities: blacks.Am J Hypertens. 1995; 8: 115s-119sCrossref PubMed Scopus (43) Google Scholar Concern has persisted that differences in the effectiveness of blockade of the renin-angiotensin system in HF might be present between the 2 races as well. Recently, retrospective subgroup analysis of data from 2 randomized clinical trials has added support to the concept that the response of blacks and whites with HF and LV systolic dysfunction to ACE inhibition may differ. A reanalysis of the SOLVD Prevention and Treatment trials investigated the influence of race on the response to enalapril.48Exner D.V. Dries D.L. Domanski M.J. Cohn J.N. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction.N Engl J Med. 2001; 344: 1351-1357Crossref PubMed Scopus (460) Google Scholar Unadjusted analysis in the matched-cohort indicated that enalapril reduced the risk of hospitalization for HF in white patients by 44%, whereas no significant benefit was seen in black patients. Adjusted analysis confirmed a beneficial effect on hospitalization risk for Caucasians, but not for African Americans. At 1 year, enalapril therapy was associated with a significant reduction in both systolic blood pressure and diastolic blood pressure in Caucasian patients, whereas no significant reduction was observed in African-American patients. It must be remembered that this study was a post-hoc subgroup analyses of randomized studies that were not stratified based on race. The SOLVD data raise the possibility that treatment response to ACE inhibition may vary between the races. However, they do not provide sufficient data to support a strategy other than routine use of ACE inhibitors in African Americans with HF. Angiotensin-Receptor Blockade. The use of ARBs in African Americans with HF has not been well characterized in clinical trials. It would thus be reasonable in this population to follow the general recommendations for the use of ARBs (see Section 7). Recommendation 15.9A combination of hydralazine and isosorbide dinitrate is recommended as part of standard therapy in addition to β-blockers and ACE-inhibitors for African Americans with LV systolic dysfunction and:•New York Heart Association class III or IV HF (Strength of Evidence = A)•New York Heart Association class II HF (Strength of Evidence = B) Background A strong recommendation now exists for the addition of the fixed combination of isosorbide dinitrate and hydralazine to the standard medical regimen for African Americans with HF. Data from the Vasodilator-Heart Failure Trial (VHeFT) I and II suggested that a racial difference in treatment response existed between white and black patients with symptomatic LV dysfunction treated with hydralazine-isosorbide dinitrate versus placebo.49Carson P. Ziesche S. Johnson G. Cohn J.N. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group.J Card Fail. 1999; 5: 178-187Abstract Full Text PDF PubMed Scopus (397) Google Scholar The African-American Heart Failure Trial (A-HeFT) enrolled 1050 black patients who had New York Heart Association class III or IV HF with dilated ventricles and systolic dysfunction.50Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino Jr., R. Ferdinand K. et al.Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.N Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1288) Google Scholar In this placebo-controlled, blinded, and randomized trial, subjects were randomly assigned to receive a fixed combination of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for HF. The primary end point was a composite score made up of weighted values for death from any cause, a first hospitalization for HF, and change in the quality of life. The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given the fixed combination of isosorbide dinitrate plus hydralazine. The mean primary composite score was significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group, as were its individual components: 43% reduction in the rate of death from any cause, 33% relative reduction in the rate of first hospitalization for HF, and an improvement in the quality of life.