Heart Failure in the Elderly: Advances and Challenges

Bodh I Jugdutt

Expert Rev Cardiovasc Ther. 2010;8(5):695-715.

Abstract and Introduction

Abstract

The elderly population (age ≥65 years) is increasing, and with it the prevalence of heart failure and associated morbidity, hospitalizations and costs. Despite advances, clinical trial data on heart failure therapy exclusively for elderly patients are lacking. However, trials of therapy for heart failure with left ventricular systolic dysfunction or low ejection fraction in primarily non-elderly patients showed mortality benefit in elderly patients. By contrast, trials for heart failure with normal left ventricular systolic function or preserved ejection fraction have not shown mortality benefit in elderly or non-elderly patients. Heart failure pharmacotherapy in the elderly is challenging; it needs to be individualized and consider aging-specific changes in physiology, drug metabolism, drug pharmacokinetics and tolerance, comorbidities, polypharmacy and drug–drug interactions that can contribute to adverse effects. More research into the biology of aging and clinical trials in elderly patients may lead to the discovery of new therapies for heart failure in the elderly.

Introduction

Heart failure (HF) is a major healthcare burden in developed countries and a particularly important problem in the elderly (age ≥65 years).^[1] There are at least five reasons for this. First, HF is a progressive disorder, commonly the end-stage in a cardiovascular disease (CVD) continuum (Figure 1) and a common cause of hospitalization in elderly patients. Second, the elderly population is increasing steadily and is particularly prone to HF owing in most part to biological factors and comorbid conditions associated with aging.^[2,3] Third, improved CVD therapies, especially those for myocardial infarction (MI) and hypertension, have increased the number of younger patients (i.e., age <65 years) who survive into old age, thereby increasing the toll of HF-prone elderly patients.^[1,4–6] Fourth, coronary heart disease (CHD) is common in the elderly and a common cause of HF besides hypertension.^[1,7] Fifth, MI is more common in the elderly,^[1] and ST-segment elevation MI (STEMI) is especially serious as it leads to more severe left ventricular (LV) dysfunction, adverse remodeling and HF in elderly than non-elderly patients.^[3,8] HF in the elderly therefore warrants attention and novel treatment strategies. This article focuses on HF in the elderly, therapeutic advances and challenges.

(Enlarge Image)

Figure 1.

Heart failure, aging and the cardiovascular disease continuum. Heart failure can be considered as a progressive disorder in a disease continuum occurring in parallel with aging and leading to disability and ultimate death. Progressive changes during aging and the cardiovascular disease continuum contribute to swell the heart failure burden in the elderly.
AGE: Advanced glycation end product; CV: Cardiovascular; EF: Ejection fraction; HF: Heart failure; LV: Left ventricular; PEF: Preserved ejection fraction.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Next Section

Cite this: Heart Failure in the Elderly: Advances and Challenges - Medscape - May 01, 2010.

Table 1. Major trials of angiotensin-converting enzyme inhibitors in heart failure.
Year	Trial	Patients (n)	Drug	Comparator	Age (years)	Outcome	Ref.
1987	CONSENSUS	253	Enalapril	Placebo	70	27% ↓ mortality; ↓ morbidity	^[40]
1989	Lisinopril	189	Lisinopril	Captopril	60	↑ EF, function and QOL	^[41]
1991	SOLVD (symptomatic)	2569	Enalapril	Placebo	61	16% ↓ mortality; ↓ morbidity	^[42]
1992	SOLVD (asymptomatic)	4228	Enalapril	Placebo	59.1	8% ↓ mortality (NS); ↓ morbidity	^[43]
2000	ATLAS	3164	Lisinopril (high dose)	Lisinopril (low dose)	63.6	↓ mortality; ↓ morbidity with high dose	^[44]
2006	PEP-CHF	850	Perindopril	Placebo	76	Short-term improvement in symptoms, ↓ hospitalization	^[45]

↓: Decrease in; ↑: Increase in; ATLAS: Assessment of Treatment with Lisinopril And Survival trial; CONSENSUS: Cooperative North Scandinavian Enalapril Survival Study; EF: Ejection fraction; HF: Heart failure; NS: Non-significant; PEP-CHF: Perindopril in Elderly People with Chronic Heart Failure; QOL: Quality of life; SOLVD: Studies of Left Ventricular Dysfunction.

Table 2. Major trials of angiotensin receptor blockers in heart failure.
Year	Trial	Patients (n)	Drug	Comparator	Age (years)	Outcome	Ref.
1997	ELITE	722	Losartan	Captopril	73	Unexpected 46% in mortality (2° end point)	^[46]
1999	RESOLVD	768	Candesartan	Enalapril	63	Early trend in mortality and HF (2° end point)	^[48]
2000	ELITE II	3152	Losartan	Captopril	71.5	Not superior	^[47]
2001	Val-HeFT	5010	Valsartan	ACE-Is	62.5	Not superior; ↓ composite end point	^[49]
2003	CHARM-Overall	7601	Candesartan	ACE-Is	66	Improved 1° outcome (mortality and morbidity)	^[50]
2003	CHARM-Added	2548	Candesartan	ACE-Is	64	Improved 1° outcome (clinical and morbidity)	^[51]
2003	CHARM-Alternative	2028	Candesartan	ACE-Is	66.5	Improved 1° outcome (mortality and morbidity)	^[52]
2003	CHARM-Preserved	3023	Candesartan	ACE-Is	67	Similar 1° outcome (improved 2° outcome)	^[53]
2003	VALIANT (MI + HF)	14,703	Valsartan	Captopril	65	Not superior, ↑ risk adverse events with combination	^[54]
2008	I-PRESERVE	4128	Irbesartan	Placebo	72	Not superior	^[55]

↓: Decrease in; ↑: Increase in; ACE-I: ACE inhibitor; CHARM: Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; ELITE: Evaluation of Losartan In The Elderly; HF: Heart failure; I-PRESERVE: Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction; MI: Myocardial infarction; RESOLVD: Randomized Evaluation of Strategies for Left Ventricular Dysfunction; Val-HeFT: Valsartan Heart Failure Trial; VALIANT: Valsartan In Acute Myocardial Infarction Trial.

Table 3. Major trials of β-blockers in heart failure.
Year	Trial	Patients (n)	Drug	Comparator	Age (years)	Outcome	Ref.
1994	CIBIS-I	641	Bisoprolol	Placebo	60	Not superior mortality; improved function	^[56]
1996	US-Carvedilol	1094	Carvedilol	Placebo	58	↓ mortality; ↓ risk of hospitalization for CV causes	^[57]
1997	ANZ-Carvedilol	415	Carvedilol	Placebo	63	↓ mortality; ↓ risk of hospitalization for CV causes	^[58]
1999	CIBIS-II	2647	Bisoprolol	Placebo	61	↓ mortality in patients with stable HF	^[59]
2000	MERIT-HF	3991	Metoprolol	Placebo	63.8	↓ mortality; ↓ risk of hospitalization for CV causes	^[60]
2001	Cumulative Survival	2889	Carvedilol	Placebo	63	↓ mortality; ↓ risk of hospitalization for CV causes	^[61]
2001	BEST	2708	Bucindolol	Placebo	60	Lower death rate from CV causes; improved LVEF	^[62]
2002	COPERNICUS	2289	Carvedilol	Placebo	NA	↓ less serious adverse events	^[63]
2003	COMET	1511	Carvedilol	Metoprolol	62	↓ mortality	^[64]
2005	SENIORS	2128	Nebivolol	Placebo	76	↓ mortality; ↓ risk of hospitalization for CV causes	^[65]
2006	SENIORS	112	Nebivolol	Placebo	76	↓ ventricular size; improves EF	^[66]
2008	CIBIS-III	1010	Bisoprolol	Enalapril	72.4	Not superior mortality; ↑ worsening of HF with bisoprolol	^[67]

↓: Decrease in; ↑: Increase in; BEST: Beta-blocker Evaluation of Survival Trial; CIBIS: Cardiac Insufficiency Bisoprolol Study; COMET: Carvedilol or Metoprolol European Trial; COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival; CV: Cardiovascular; HF: Heart failure; LVEF: Left ventricular ejection fraction; MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; NA: Not available; SENIORS: Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors With Heart Failure.

Table 4. Major trials of aldosterone antagonists in heart failure.
Year	Trial	Patients (n)	Drug	Comparator	Age (years)	Outcome	Ref.
1999	RALES	1663	Spironalactone	Placebo	65	↓ mortality; ↓ morbidity	^[68]
2000	RALES (substudy)	261	Spironalactone	Placebo	69	↓ mortality and morbidity, benefit highest in patients with high collagen synthesis markers (PIIINP) at baseline	^[69]
2003	EPHESUS (MI + HF)	6632	Eplenerone	Placebo	64	↓ mortality; ↓ morbidity	^[70]
2005	EPHESUS (substudy)	6632	Eplenerone	Placebo	64	↓ all-cause mortality at 30 days	^[71]
2009	Diastolic HF	44	Eplenerone	Control	80	↓ markers of collagen turnover (PIIINP); no clinical benefit	^[72]

↓: Decrease in; EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; HF: Heart failure; MI: Myocardial infarction; PIIINP: Procollagen III N-terminal propeptide; RALES: Randomized Aldactone Evaluation Study for Congestive Heart Failure.

Table 5. Digoxin, vasodilators and trials of other therapies in heart failure.
Year	Trial	Patients (n)	Drug	Comparator	Age (years)	Outcome	Ref.
1993	RADIANCE	178	Digoxin	Placebo	60	Worsening of HF with digoxin withdrawal	^[73]
1997	DIGITALIS	6800	Digoxin	Placebo	63.4	↓ hospitalization and worsening HF	^[74]
1986	Val-HeFT I	642	Hydralazine/ISDN	Placebo	59	↓ mortality	^[75]
1991	Val-HeFT II	804	Hydralazine/ISDN	Enalapril	57	↓ mortality with enalapril	^[76]
1999	Val-HeFT I/II subanalysis	1449	Hydralazine/ISDN	Placebo	58.8	Hydralazine/ISDN ↓ mortality in black persons	^[77]
2004	A-HeFT	1050	Hydralazine/ISDN	Placebo	56.8	↓ mortality in black persons (African–American)	^[78]
2000	NSGET	127	Nesiritide	Placebo	59	Improves hemodynamics in decompensated HF	^[79]
2002	VMAC	498	Nesiritide	NG/placebo	61	Improves hemodynamics; ↓ symptoms	^[80]
2005	PROACTION	237	Nesiritide	Placebo	66	↓ hospitalization	^[81]
2005	Nesiritide pooled	862	Nesiritide	Placebo	59–66	↑ mortality in acute decompensated HF	^[33]
2001	AGE crosslink breaker	93	ALT-711	Placebo	67	Improve total arterial compliance	^[36]
2002	OVERTURE	5770	Omapatrilat	Enalapril	63.5	↓ mortality; ↓ morbidity; NS 1° clinical events	^[32]
2005	REACH-1	370	Bosentan	Placebo	65	Not superior; non-inferior	^[34]
2008	Bosentan	90	Bosentan	Placebo	70	No benefit; ↑ adverse events	^[35]
2008	OPT-CHF	405	Oxypurinol	Placebo	65	No clinical improvements	^[31]

↓: Decrease in; ↑: Increase in; AGE: Advanced glycation end product; A-HeFT: African–American Heart Failure Trial; DIGITALIS: Digitalis (Digoxin) Investigation Group; HF: Heart failure; ISDN: Isosorbide dinitrate; NG: Nitroglycerin; NS: Non-significant; NSGET: Nesiritide Study Group Efficacy Trial; OPT-CHF: Oxypurinol Therapy for Congestive Heart Failure; OVERTURE: Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events; PROACTION: Prospective Randomized Outcomes Study of Acutely Decompensated Congestive Heart Failure Treated Initially in Outpatients with Natrecor; RADIANCE: Randomized Assessment of Digoxin on Inhibitors of Angiotensin-Converting Enzyme; REACH-1: Research on Endothelin Antagonism in Chronic Heart Failure-1; Val-HeFT: Valsartan Heart Failure Trial; VMAC: Vasodilation in the Management of Acute Congestive Heart Failure.

Table 6. Approved implantable ventricular assist devices.
Device type	Company (location)	Application
Intracorporeal
HeartMate®	Thoratec Corp. (CA, USA)	Bridge to recovery; bridge to transplant; destination therapy
Novacor	WorldHeart Corp. (CA, USA)	Bridge to recovery; bridge to transplant; destination therapy
Axial flow pumps	Generic medical devices	Bridge to transplant; destination therapy
DeBakey	MicroMed Technology, Inc. (TX, USA)	Bridge to transplant
Extracorporeal
Abiomed	Abiomed, Inc. (MA, USA)	Bridge to recovery; bridge to bridge; bridge to transplant
Thoratec BiVAD	Thoratec Corp. (CA, USA)	Bridge to transplant
TandemHeart	CardiacAssist, Inc. (PA, USA)	Triage (bridge to next decision)
Centrifugal pump	Medtronic, Inc. (MN, USA)	Bridge to recovery; destination therapy
ECMO	Generic medical devices	Bridge to recovery; bridge to bridge
Impella	Abiomed, Inc. (MA, USA)	Bridge to next decision
CardioWest™ TAH	SynCardia, Inc. (AZ, USA)	Bridge to transplant

BiVAD: Biventricular assist device; EMCO: Extracorporeal membrane oxygenation; TAH: Total artificial heart.

Box 1. Common myocardial and other diseases causing heart failure.
Coronary artery disease:
STEMI; infarct scar; progressive LV remodeling Regional and global LV systolic dysfunction Reperfusion injury/damage and LV remodeling
Hypertension:
LV hypertrophy, fibrosis or diastolic dysfunction Preserved global LV ejection fraction
Cardiomyopathies:
Familial/genetic Non-familial/non-genetic (e.g., myocarditis) Hypertrophic, dilated or restrictive Arrhythmogenic right ventricular dysplasia Non-classified
Cardiotoxins/drugs:
Alcohol, medication, cocaine Trace elements (mercury, cobalt or arsenic) Cytotoxic agents, chemotherapies or anthracyclines β-blockers, calcium antagonists or antiarrhythmics
Endocrine:
Diabetes mellitus or the metabolic syndrome Hypo/hyperthyroidism Adrenal insufficiency or Cushing's syndrome Pheochromocytoma or excessive growth hormone
Nutritional:
Obesity or cachexia Deficiency of thiamine, selenium or carnitine
Infiltrative:
Sarcoidosis, amyloidosis or hemochromotosis Connective tissue disease
Infection:
HIV infection or Chagas' disease
Other:
Peripartum cardiomyopathy Cardio-renal or end-stage renal failure Valvular heart disease Pulmonary hypertension or liver disease
LV: Left ventricular; STEMI: ST-elevation myocardial infarction.

Box 2. Some biological changes that contribute to heart failure during aging.
Dysregulation of repair mechanisms Mitochondrial dysfunction with increased reactive oxygen species production and oxidative stress Increased fibrosis and advanced glycation end-product cross-linking Increased ventricular–arterial stiffening Left ventricular diastolic dysfunction

Box 3. Physiological changes and pathophysiologic hallmarks during aging.
Increase in systolic blood pressure and pulse pressure, LV mass, incidence of CHD and atrial fibrillation. Decrease in early diastolic filling rate, maximal heart rate, maximum cardiac output, maximal aerobic capacity, exercise-induced augmentation in ejection fraction, reflex response in heart rate, β-adrenergic and endothelial-mediated vasodilation. Cellular, enzymatic and molecular changes in arterial vessel wall leading to arterial remodeling and increased stiffness. Decreased endothelial NO production and increased endothelial apoptosis and superoxide production, with preserved response to non-endothelial-derived substances such as nitrates and nitroprusside. Altered ECM in myocardium, with increased collagen, collagen fibril diameter, collagen cross-linking, collagen type I/III ratio and fibronectin; decreased elastin content; and altered balance between MMPs and TIMPs leading to increased ECM production and contributing to the development of atrial fibrillation. Increased collagen, elastin and calcification leading to conduction abnormalities and valvular calcification. Increase in ventricular collagen and ECM, contributing to cell loss, myocyte hypertrophy and altered myocardial calcium handling, which results in prolonged contraction and relaxation. Increase in fibrinogen, coagulation factors, platelet activity, PAI-1 and prothrombotic cytokines that contribute to ACS and potentiate the development of atherosclerosis. Altered autonomic nervous system function with decreased β-adrenergic, α-adrenergic and dopaminergic functions, resulting in decreased baroreceptor response to stressors and increased sensitivity to parasympathetic stimulation. Decreased ability to increase cardiac output in response to stress, decreased ability to respond to myocardial injury and decreased reserve capacity, thereby lowering thresholds for symptoms.
ACS: Acute coronary syndrome; CHD: Coronary heart disease; ECM: Extracellular collagen matrix; LV: Left ventricular; MMP: Matrix metalloproteinase; NO: Nitric oxide; PAI-1: Plasminogen activator inhibitor-1; TIMP: Tissue inhibitor of metalloproteinase.

Box 4. Current and novel cardiac support approaches for heart failure.
Heart transplantation Total artificial heart Myocardial revascularization: CABG Mitral valve repair or replacement Left ventricular reconstruction Ventricular assist devices: LVAD: first- and new-generation devices RVAD: first-generation devices Passive cardiac restraint devices Cardiac regeneration approaches Myocardial tissue engineering
CABG: Coronary artery bypass surgery; LVAD: Left ventricular assist device; RVAD: Right ventricular assist device.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....

Heart Failure in the Elderly: Advances and Challenges

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Sidebar

Sidebar

Key Issues

Figure 1.

Figure 1.

Comments

Email This

Feedback