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Section 15: management of heart failure in special populations

Journal of Cardiac Failure Vol. 16 No. 6 2010 Section 15: Management of Heart Failure in elderly. The progressive aging of the US population is well establishedand has profound implications for theprevalence of cardiovascular disease-particularly HF. A number of studies have documented the substantial increasein the prevalence of this syndrome as age As Heart failure (HF) is a prevalent condition in women, with most illnesses in the elderly, HF is associated with African Americans, and the elderly of both sexes and any higher rates of morbidity and mortality than in younger pa- race. In the absence of contradictory data, the clinical tients.Among elderly patients hospitalized with HF, me- recommendations based on trial data derived from predom- dian survival is approximately 2.5 years, with 25% of inately younger white male study populations have gener- ally been applied equally to these groups. However, thereare etiologic and pathophysiologic considerations specific Pathophysiology of HF in the Elderly. There are a num- to these groups that warrant attention if care and outcomes ber of well described changes in cardiovascular physiology are to be optimized. Discussion in this section is based pri- which occur with aging. Resting systolic left ventricular marily on available data from subgroup analyses of ran- (LV) function appears to be preserved, but perhaps at the domized HF trials and the results of cohort studies. A substantial amount of the data on drug efficacy comes stolic function has been documented in otherwise normal from studies of patients treated after a recent acute myocar- elderly individuals.Exercise capacity declines with age, most likely from a combination of changes in cardiac and Although a significant number of women and elderly pa- peripheral vascular factors, ventricular-vascular coupling tients with HF have preserved left ventricular ejection frac- and aortic distensibilityWith age, diastolic filling of tion (LVEF) there are few evidence-based data to guide the ventricle becomes more dependent on atrial contraction therapy in this group. Other special populations, ethnic and ventricular volume changes with increasing cardiac groups such as Hispanics, Asians, American Indians, or Pa- output are significantly different than those seen in younger cific Islanders, are important special populations but there Though these diverse cardiovascular changes are inadequate data currently available about HF manage- tend to reduce exercise capacity, their impact on health ment to discuss these groups individually. Asian, particu- and quality of life remains modest in most individuals com- larly Chinese, patients have been reported to have a high pared to the detrimental effects of HF.
incidence of cough with angiotensin converting enzyme The presentation of HF may differ in elderly patients (ACE) inhibitors, although this finding was not confirmed with HF. Although they commonly present with the classic in a larger study of perindopril.Mitochondrial aldehyde symptoms of dyspnea and fatigue, the elderly are more dehydrogenase-2 is responsible for the bioactivation of ni- likely than younger patients to present with atypical symp- troglycerin as well as the clearance of acetaldehydA toms such as poor executive functioning, altered mental sta- polymorphism of this enzyme is present in 30-50% of Asians, and it is associated with decreased efficacy of theanti-anginal effects of nitroglycerin and an inability to clear acetaldehyde resulting in flushing after alcohol ingestion.
Thus, it is possible, though not tested, that the combination 15.1 As with younger patients, it is recommended that of hydralazine and isosorbide dinitrate may not be effective elderly patients, particularly those age O80 years, in a significant number of Asians with HF. No HF treatment be evaluated for HF when presenting with symp- data is currently available in Hispanics, although epidemi- toms of dyspnea and fatigue. (Strength of Evi- ologic factors such as diabetes may be particularly impor- 15.2 Beta blocker and ACE inhibitor therapy is recom- The recommendations that follow are specific for the el- mended as standard therapy in all elderly patients derly, African-Americans, and women with HF and abnor- with HF due to LV systolic dysfunction. (Strength mal systolic function, as there are substantial data of Evidence 5 B) In the absence of contraindica- concerning HF management in these subgroups.
tions, these agents are also recommended in thevery elderly (age O80 years). (Strength of Evi- 15.3 As in all patients, but especially in the elderly, Clinical Characteristics and Prognosis. HF represents careful attention to volume status, the possibil- a significant and growing public health problem for the and the presence of postural hypotension is rec-ommended during therapy with ACE inhibitors, beta blockers and diuretics. (Strength of Evi- Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.cardfail.2010.05.024 Journal of Cardiac Failure Vol. 16 No. 6 June 2010 greater in women than in men.A growing body of evi-dence has demonstrated significant differences in the clini- Beta Blockers. Diminished response to catecholamine cal characteristics and prognosis of HF in women and men.
stimulation in elderly individuals has been shown by sev- Early results from the Framingham Heart Study pointed to eral inand appears related to diminished num- a difference in prognosis between men and women with HF, ber and activity of both beta1 and beta2 receptors.
with men having worse survival than women.Subse- However, the changes in response to the sympathetic ner- quent findings from some HF databases have confirmed vous system do not mitigate the need for beta receptor an- this observation in both a broad population of patients tagonism in the elderly. The striking risk in the elderly of with HF and those at a very advanced stage.These major morbidity and early mortality, combined with the studies have suggested that women’s survival advantage is substantial benefit derived from beta blockade, strongly etiology-dependent, with better outcomes noted when the supports the use of these agents as tolerated in elderly pa- primary cause is non-ischemic. Hypertension and diabetes tients with symptomatic LV systolic dysfunction.
carry with them significantly greater risk of subsequent Conclusions from randomized placebo-controlled trials HF in women compared to For women with coro- are limited concerning the efficacy of beta blockade in the el- nary artery disease but no symptoms of HF, diabetes con- derly. However, a retrospective analysis of a study of meto- fers particular risk for the subsequent development of prolol CR/XL, which enrolled patients up to age 80 and HFDiabetes and coronary disease are also associated included a substantial subgroup of elderly patients, found with excess mortality in women with HF and systolic dys- a similar degree of morbidity and mortality reduction in pa- tients 69 or older versus those younger than Observa-tional studies of the outcome of elderly patients after MI have Sex and Cardiovascular Pathophysiology. A number of consistently shown substantial reductions in mortality when experimental studies point to fundamental, sex-related dif- beta blockers are prescribed at discharge.These studies ferences in the nature and extent of myocardial hypertrophy have included octogenarians. The one randomized trial of and adaptation, which might account for the survival advan- beta blockers in an elderly population with HF (mean age tage for females.Early studies of spontaneously hyper- 76) demonstrated a reduction of 14% in the combined end- tensive rats suggested that the adverse influence of point of all-cause mortality or primary cardiovascular admis- hypertrophy on cardiac function was greater in male than in female A number of animal studies suggest sex-related differences in myocardial remodeling in response ACE Inhibitors. No randomized controlled trial has been conducted specifically to investigate the benefit ofACE inhibition in elderly patients. However, convincing ev- Treatment Response. Recognition of the pathophysio- idence of the effectiveness of ACE inhibition in elderly pa- logic and clinical differences between men and women tients is provided by the results of a trial in which the mean with HF has raised concern that treatment response might age was 70 and the reduction in mortality was 31% at 2 differ as well. Results of individual controlled clinical tri- year and 27% at the end of the study for patients with LV als, even of standard therapeutic agents for HF from sys- dysfunction following MI treated with ACE inhibition.
tolic dysfunction, generally are inconclusive, because of Observational studies and a meta-analysis of post-MI pa- the small number of women enrolled. Data from pooled tients with HF reinforce these though caution analyses are equally sparse. Recommendations are made is necessary in extrapolating the results of post-MI studies in the context of this limited database.
Other Medications. In the absence of data to the con- trary, other HF medications, including angiotensin receptor 15.4 Beta blocker therapy is recommended for women blockers (ARBs), aldosterone antagonists, and the combi- nation of hydralazine/isosorbide dinitrate, should be con-  symptomatic LV systolic dysfunction (Strength sidered as options for elderly patients with HF, keeping in mind the complications of polypharmacy in a population  asymptomatic LV systolic dysfunction (Strength characterized by multiple comorbidities. In particular, older age is an independent risk factor for hyperkalemia when in-hibitors of the renin-angiotensin aldosterone system Women are underrepresented in HF clinical trials, as they are in clinical studies of other cardiovascular disease However, a review of the experience of women in severalof the large-scale prospective mortality trials of beta block- Clinical Characteristics and Prognosis. HF is common ade in patients with symptomatic LV dysfunction does sug- in women, and among the elderly the prevalence of HF is gest that women and men benefit to a similar Similarly, a pooling of the mortality results from several Evidence for Other Medical Therapy in Women other large trials showed strong evidence of a similar ben-eficial effect in women and menGiven the absence of Although digoxin therapy has been demonstrated to de- contrary data, the most prudent course is to recommend the crease HF hospitalizationit has not been demonstrated routine use of beta blockade for HF in both women and to improve survival. In a retrospective analysis of the Dig- italis Investigation Group (DIG) trial, digoxin was associ-ated with an increased risk of death from any cause among women, but not men, with HF and reducedLVEF.However, that analysis did not account for serum 15.5 ACE inhibitor therapy is recommended as stan- potassium concentration and serum digoxin concentration dard therapy in all women with symptomatic or differences. Another analysis of the same trial reported no asymptomatic LV systolic dysfunction. (Strength excess mortality in either women or men with digoxin at se- rum concentrations between 0.5 and 0.9 This re- port demonstrated that digoxin levels are higher inwomen compared to men at any given dose presumably As with beta blockers, the available data on ACE inhibi- due to decreased lean body mass and renal function. Anal- tion suggest comparable effects in women and men with ysis of the Studies of Left Ventricular Dysfunction HF. A meta-analysis of large-scale HF and post-MI ran- (SOLVD) trials also did not demonstrate an increase in domized trials demonstrated evidence of a mortality benefit of ACE inhibition in women. A more convincing effect was Although sex-specific data is not available from prospec- seen on the composite end point of death, reinfarction, or tive trials on the benefits of aldosterone antagonists for admission for HF. Comparable findings related to sex women with LV systolic dysfunction and symptoms of were also noted in the meta-analysis of mostly small- HF, adequate numbers of women were included in the large scale, short-term studies of ACE inhibition, which found randomized, controlled trials of these agents and subgroup similar favorable point estimates for reduction in mortality analyses were shown to demonstrate benefit in women.
and for mortality plus hospitalization in women.
15.7 The combination of hydralazine/isosorbide dini- trate is recommended as standard therapy for 15.6 ARBs are recommended for administration to African American women with moderate to severe symptomatic and asymptomatic women with an HF symptoms who are on background neurohor- LVEF #40% who are intolerant to ACE inhibi- monal inhibition. (Strength of Evidence 5 B) tors for reasons other than hyperkalemia or renalinsufficiency. (Strength of Evidence 5 A) The A-HeFT (African-American Heart Failure Trial) confirmed the benefit of hydralazine/isosorbide dinitrate Investigators in both the Valsartan Heart Failure Trial in black HF patientImportantly, 40% of the A-HeFT (Val-Heft) and the Candesartan in Heart Failure Assessment cohort were women. An analysis of outcomes by gender of Reduction in Mortality and Morbidity (CHARM) trials in A-HeFT showed that fixed-dose combined hydralazine/ have analyzed the benefits of valsartan and candesartan, re- isosorbide dinitrate improved HF outcomes in both men spectively, in women with HF and systolic dysfunction. In and women. There were no gender differences between Val-HeFT significant reductions in both morbidity and mor- men and women in the benefit of hydralazine/isosorbide di- tality and HF hospitalizations were reported for women and nitrate on the primary composite score, time to first HF hos- were the same as benefits reported in In CHARM there was a significant reduction in all-cause mortalityand HF hospitalization that was the same as in men.Sub-group analysis of the Valsartan in Acute Myocardial Infarc-tion Trial (VALIANT) study also showed no difference in the effects of ARB vs. ACE inhibitor in men and womenstatus post MI complicated by HF, LV dysfunction or Clinical Characteristics and Prognosis. Cardiovascular Thus the recommendations for ARBs in women disease is a major health issue for African Americans.
have a level of evidence similar to those for men. Cough Traditionally, concern has focused on hypertension and due to ACE inhibitors is more than twice as common in stroke as key components of the burden of cardiovascular women compared to men and thus substitution of ARBs disease in this population. However, HF represents a major for ACE inhibitors is also likely to be more common in source of cardiovascular morbidity and mortality for Afri- can Americans. Epidemiologic data suggests that they are Journal of Cardiac Failure Vol. 16 No. 6 June 2010 at greater risk for HF than Caucasians, with approximately 15.10 ARBs are recommended as substitute therapy 3% of all African-American adults affected.
for HF in African Americans intolerant of ACE A number of clinical studies have documented substan- tial differences between the baseline clinical characteristicsof African Americans and Caucasians with HF.Age of onset is significantly younger in blacks than in whites,and HF is less likely to be due to ischemic heart disease.
ACE Inhibition. Long-standing clinical experience sug- Incident HF before 50 years of age is substantially more gests that African Americans with hypertension respond common among blacks than among whites. Hypertension, less well than Caucasians to ACE inhibitors.Concern obesity, and systolic dysfunction that are present before has persisted that differences in the effectiveness of block- a person is 35 years of age are important antecedents.
ade of the RAAS in HF might be present between the 2 Analysis of outcome data from the SOLVD trials has races as well. Recently, retrospective subgroup analysis of shown higher mortality and morbidity rates in blacks com- data from 2 randomized clinical trials has added support pared to whites with HF.Whether these differences reflect to the concept that the response of blacks and whites with differences in baseline characteristics, delivery of care or HF and LV systolic dysfunction to ACE inhibition may dif- socioeconomic factors has not been resolved. Other studies fer. A reanalysis of the SOLVD Prevention and Treatment point to problems with access to care and unfavorable clin- trials investigated the influence of race on the response to ical characteristics independent of HF as factors increasing enalUnadjusted analysis in the matched-cohort indi- the risk of African Americans for worse outcome cated that enalapril reduced the risk of hospitalization for Aggressive, early treatment of hypertension has been pro- HF in white patients by 44%, whereas no significant benefit posed as a major strategy for the prevention of HF in this ra- was seen in black patients. Adjusted analysis confirmed cial group. Persistent hypertension is not uncommon in a beneficial effect on hospitalization risk for Caucasians, African-American patients with HF and systolic dysfunction.
but not for African Americans. At 1 year, enalapril therapywas associated with a significant reduction in both systolicblood pressure and diastolic blood pressure in Caucasian Treatment Response. Although a number of clinical patients, whereas no significant reduction was observed in characteristics have been shown to differ significantly be- tween African Americans and other races afflicted with It must be remembered that this study was a post-hoc HF, the implications of these differences for therapy remain subgroup analyses of randomized studies that were not stratified based on race. The SOLVD data raise the possibil-ity that treatment response to ACE inhibition may vary be- tween the races. However, they do not provide sufficient 15.8 Beta blockers are recommended as part of stan- data to support a strategy other than routine use of ACE in- dard therapy for African Americans with HF hibitors in African Americans with HF.
Clinical studies have also shown that the risk of angioedema is  symptomatic LV systolic dysfunction (Strength greater in African American patients compared to Ca Angiotensin-Receptor Blockade. The use of ARBs in African Americans with HF has not been well characterizedin clinical trials. It would thus be reasonable in this popu- lation to follow the general recommendations for the useof ARBs (see Section 7).
Although 1 trial with bucindolol did not find a beneficial effect of beta blockade in African Americans with HF, subgroup analysis of data from the US Carvedilol Trialssuggests that the beneficial effect of beta blockers on out- 15.11 A combination of hydralazine and isosorbide comes in African Americans with HF from systolic dys- dinitrate is recommended as part of standard therapy in addition to beta blockers and ACE- populOther studies demonstrate similar find- inhibitors for African Americans with LV sys- ings.The totality of the data supports substantial benefit from these agents, regardless of race.
 New York Heart Association (NYHA) class III  NYHA class II HF (Strength of Evidence 5 B) 15.9 ACE inhibitors are recommended as part of stan- dard therapy for African-American patients with HF from symptomatic or asymptomatic LV sys- A strong recommendation now exists for the addition of tolic dysfunction. (Strength of Evidence 5 C) hydralazine to the standard medical regimen for African 7. Alexander M, Grumbach K, Remy L, Rowell R, Massie BM. Conges- Americans with HF. Data from the Vasodilator-Heart Fail- tive heart failure hospitalizations and survival in California: patternsaccording to race/ethnicity. Am Heart J 1999;137:919 ure Trial (VHeFT) I and II suggested that a racial difference 8. Rich MW. Epidemiology, pathophysiology, and etiology of conges- in treatment response existed between white and black pa- tive heart failure in older adults. J Am Geriatr Soc 1997;45: tients with symptomatic LV dysfunction treated with hydralazine-isosorbide dinitrate versus placebo or enalapril, 9. Huynh BC, Rovner A, Rich MW. Long-term survival in elderly pa- respectively.The A-HeFT enrolled 1050 self-identified tients hospitalized for heart failure: 14-year follow-up from a prospec-tive randomized trial. Arch Intern Med 2006;166:1892 black patients who had NYHA class III or IV HF with di- 10. Schulman SP. Cardiovascular consequences of the aging process. Car- lated ventricles and systolic dysfunction.In this placebo- controlled, blinded, and randomized trial, subjects were 11. Schulman SP, Lakatta EG, Fleg JL, Lakatta L, Becker LC, randomly assigned to receive a fixed combination of isosor- Gerstenblith G. Age-related decline in left ventricular filling at rest bide dinitrate plus hydralazine or placebo in addition to and exercise. Am J Physiol 1992;263:H1932e8.
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