US Pharm. 2006;7:58-68.

Heart failure is a major health problem in the United States. Approximately five million people have heart failure, and 550,000 patients are diagnosed with heart failure each year.1,2 Heart failure is generally characterized as a disease of the elderly; approximately 80% of patients hospitalized with heart failure are older than 65. Thus, the incidence of heart failure is expected to grow as the population ages.2 Heart failure–related hospitalizations increased by approximately 25%, to more than one million, between 1990 and 1999. In 2001, heart failure directly caused 53,000 deaths. Heart failure–related deaths have risen in recent years, which can be attributed to an increase in survival from prior cardiovascular events.

Heart failure is a clinical syndrome in which functional or structural changes occur in the heart, resulting in clinical symptoms such as dyspnea, fatigue, limited exercise tolerance, pulmonary congestion, and peripheral edema.1-3 Many known risk factors, such as coronary artery disease (CAD), diabetes, obesity, hypertension, and family history of cardiomyopathies, are associated with the onset and progression to heart failure (Table 1).4 In addition, valvular heart disease is still a common cause of heart failure. Hypertension precedes heart failure approximately 90% of the time and increases a patient's risk of heart failure threefold.5 CAD is the most common cause of systolic heart failure. Myocardial infarction (MI) accounts for systolic heart failure in nearly 70% of patients. Additional etiologies associated with systolic dysfunction and heart failure include dilated cardiomyopathies and ventricular hypertrophy.2,4




Pathophysiology
Systolic heart failure is associated with impairment of left ventricular contractility that results in inefficient cardiac output, especially during exertion. Heart failure usually begins with some injury or stress on the myocardium that results in a change in the structure of the heart; this is known as cardiac remodeling. Cardiac remodeling precedes the onset of symptoms by months or even years. As dilation changes the ventricle to a more spherical shape, hemodynamic stresses begin to add strain on the walls of the failing ventricle, leading to depressed mechanical function and increased regurgitant flow through the mitral valve.1-3

The neurohormonal system has an active role in the acceleration of cardiac remodeling. Heart failure patients have increased levels of norepinephrine, angiotensin II, aldosterone, endothelin, vasopressin, and cytokines. The activation of the renin-angiotensin-aldosterone system increases peripheral vasoconstriction, resulting in increased afterload and cardiac remodeling. In addition, the activation of the sympathetic nervous system causes tachycardia, leading to increased myocardial oxygen demand. Increased cardiac oxygen demand without changes in supply may cause increased myocardial ischemia and further cardiac remodeling. The neurohormones may exert cardiotoxic effects on the cells, which can further change the architecture and performance of the heart.2

Clinical Presentation
Systolic heart failure is a syndrome diagnosed based on data collected from a thorough patient history, including an evaluation of symptomatology, and physical findings. Most patients present in one of three ways: with decreased exercise tolerance, with fluid retention, or without symptoms.2,6 Dyspnea on exertion and shortness of breath are the cardinal symptoms of heart failure. Upon physical exam, peripheral edema, pulmonary congestion, or both symptoms may be present.2

Classification of heart failure is based on the combination of the American College of Cardiology/American Heart Association's four stages of heart failure ( Table 1), which range from at risk for heart dysfunction (stage A) to refractory heart failure (stage D), and on the New York Heart Association (NYHA) guidelines.2,6 The NYHA classification is the most commonly used method for quantifying the degree of functional limitation imposed by heart failure (Table 2). Overall, the functional classification of heart failure tends to decline over time due to the progression of the cardiac remodeling.2






The single most useful diagnostic test is the comprehensive two-dimensional echocardiogram, which is used along with Doppler flow studies to determine whether there are structural and functional abnormalities in the heart. The transthoracic echocardiogram (TTE) is a noninvasive ultrasound study that produces images of the heart using sound waves. It provides information on estimating left ventricular ejection fraction (LVEF), ventricular dimensions and volumes, wall volumes, heart chamber geometry, and regional wall motion. In patients with systolic heart failure, LVEF is usually less than 40%.2 Other studies used in conjunction with the TTE to assess etiology, severity, and potential drug-related treatment effects in heart failure include baseline chest radiograph, 12-lead electrocardiography, and measures of brain natriuretic peptide, serum electrolytes, and renal function. These studies are important because health care professionals may use them as a baseline for determining whether a patient has experienced a change in clinical status.2,6

MANAGEMENT OF SYSTOLIC HEART FAILURE
Nonpharmacologic
Controlling the risk factors such as hypertension, diabetes mellitus, dyslipidemias, atherosclerotic vascular diseases, and thyroid disorders may slow the progression of heart failure and cardiac remodeling.2,4,6 Heart failure patients should receive the influenza and pneumococcal vaccines to reduce the risk of comorbidities such as respiratory infections.2 The most significant modifiable risk factor would be high-risk behaviors such as smoking, alcohol, and illicit drug use.2,7

Sodium restriction (?2 grams/day) aids in the reduction of volume overload and may decrease the use of diuretics. Furthermore, daily weighing allows patients to assess volume status, upon which diuretic dosage adjustment may be based. However, no studies have examined the effect of dietary sodium restriction on morbidity or mortality.7,8 Physical activity has been shown to decrease mortality and hospitalizations for stable heart failure patients. Restriction of exercise promotes physical deconditioning, which may contribute to a patient's exercise intolerance. Lastly, compliance with diet and therapeutic medication regimen has a significant role in prevention of acute hospitalizations.2,7

Pharmacologic
Most patients with heart failure are managed with a standard combination three-medication regimen: a loop diuretic, an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), and a beta-adrenergic receptor blocker.1,2 Diuretics are the mainstay for reduction of symptoms of volume overload in heart failure, whereas ACE inhibitors, ARBs, and beta-blockers have been shown to reduce morbidity and mortality.2 Aldosterone antagonists are indicated as adjunctive therapy for patients with symptomatic NYHA class III or IV heart failure or after early acute MI in patients with reduced left ventricular function and clinical evidence of heart failure. If patients continue to be symptomatic, digoxin may be added to the standard medication regimen to reduce symptoms, decrease hospitalizations, and enhance exercise tolerance. Drugs used to treat heart failure are discussed in Table 3. Lifestyle modifications and drug therapies for systolic heart failure are designed to reduce morbidity and mortality, prevent the progression of cardiac remodeling, and improvepatients' quality of life. 2




Diuretics: The mainstay of symptomatic treatment of volume overload in heart failure, diuretics decrease fluid retention that causes pulmonary congestion, peripheral edema, jugular venous distention, and/or increased body weight. Loop diuretics acting in the loop of Henle increase serum sodium excretion by 20% to 25%, enhance free water elimination, and maintain their efficacy in patients with renal impairment.1,2 In contrast, thiazide diuretics reduce sodium excretion by 5% to 10%, enhance free water elimination, and lose their efficacy in patients with chronic kidney disease (creatinine clearance <40 mL/min). Loop diuretics are the preferred agents for heart failure treatment, but thiazides may be used in patients with mild fluid retention and hypertension. Diuretics, as well as ACE inhibitors and beta-blockers, are recommended for use in all patients in stage C heart failure.2 Studies have shown that diuretics improve cardiac function, symptoms, and exercise intolerance in patients with heart failure. However, the long-term effects of diuretics on mortality are unknown.1,2,8

ACE Inhibitors: ACE inhibitors reduce the activity of the renin-angiotensin-aldosterone system by blocking the conversion of angiotensin I to angiotensin II, preventing angiotensin II–induced vasoconstriction. They also inhibit aldosterone release, leading to a decrease in sodium and fluid retention. These combined effects reduce both preload and afterload and slow the progression of cardiac remodeling.1,2 ACE inhibitors may also have additional activity with enhanced kinins and kinin-mediated prostaglandin production.2 Over 30 clinical controlled trials evaluating the efficacy of ACE inhibitors have demonstrated that ACE inhibitors reduce the risk of death and combined risk of death and hospitalizations. All patients with left ventricular systolic heart failure should be given an ACE inhibitor unless it is contraindicated (angioedema, bilateral renal artery stenosis, serum potassium >5.5 mEq/L, pregnancy, symptomatic hypotension, or unstable renal failure). ACE inhibitors should be initiated at low doses and slowly titrated based on tolerability of adverse effects.1,2,8

ARBs: Compared to trials of ACE inhibitors, fewer clinical trials have studied the use of ARBs in patients with heart failure; thus, these agents are reserved for patients with demonstrated intolerance of ACE inhibitors. ARBs selectively block angiotensin II by binding to the angiotensin receptor. ARBs reduce the severity of the kinin adverse reactions, such as cough and angioedema, although angioedema has been reported with these agents. The addition of an ARB to standard therapy including an ACE inhibitor may reduce the size of the left ventricle and the number of hospitalizations, but evidence is insufficient in reduction of mortality.2,8 One study showed that candesartan added to an ACE inhibitor reduced cardiovascular deaths.9 However, another study of valsartan in patients with MIand heart failure demonstrated no benefit from valsartan and an ACE inhibitor given together compared to an ACE inhibitor alone.10 Prescribing a combination of ACE inhibitors, ARBs, and aldosterone antagonists is not recommended due to the risk of hyperkalemia. ARBs remain an alternative to ACE inhibitors in the treatment of heart failure.2

Beta-Adrenergic Receptor Blockers: Three types of beta-blockers have been shown to reduce mortality: sustained-release metoprolol and bisoprolol, which selectively block beta-1 receptors, and carvedilol, which blocks alpha-1, beta-1, and beta-2 receptors.1,2,8 In comparison, a study showed that short-acting metoprolol had less of an effect compared to carvedilol, but the dose of metoprolol used was lower than the recommended target dose.11 In addition to standard therapy, beta-blockers have shown a combined reduction in death and hospitalization for heart failure. Beta-blockers inhibit adverse effects from the sympathetic nervous system, outweighing the negative inotropic effects.2 Overall, beta-blockers should be initiated at very low doses, titrated slowly at a minimum of two-week intervals, and not abruptly withdrawn, due to the risk of worsening heart failure and acute decompensation.1,2

Aldosterone Antagonists: Aldosterone antagonists block the aldosterone receptor in the distal tubule of the nephron, resulting in potassium retention, sodium excretion, and mild diuresis. Aldosterone antagonists are recommended in patients with moderately severe or severe heart failure and recent decompensation or in those with left ventricular dysfunction soon after an MI.2 When low-dose spironolactone was added to an ACE inhibitor in patients with NYHA class III and IV heart failure, patients experienced a 30% reduction in all-cause mortality.12 Another study showed that eplerenone led to a reduction in mortality in patients with LVEF less than 40% within 14 days of MI, although there are no data on the use of eplerenone in the treatment of heart failure related to causes other than MI.13 The most prominent limiting factor of aldosterone antagonists is potentially life-threatening hyperkalemia.2,14 Hyperkalemia increases progressively when serum creatinine exceeds 1.6 mg/dL, even though studies have examined aldosterone antagonists in patients with entry-level serum creatinine of 2.0 to 2.5 mg/dL. In addition, aldosterone antagonists should be avoided in patients with serum potassium greater than 5.0 mEq per liter.2

Digoxin: Digoxin is a cardiac glycoside that works to increase contractility of the heart by inhibiting the sodium-potassium adenosine triphosphatase (ATPase) pump, thus increasing intracellular calcium. Digoxin is recommended for symptomatic control in patients with mild to moderate heart failure NYHA class II or III.2 In a post hoc analysis, digoxin serum concentrations between 0.5 to 0.9 ng/mL decreased hospitalizations; however, concentrations greater than 1 ng/mL were associated with a trend toward increased mortality compared to placebo.15 While studies have not shown that digoxin reduces mortality, this agent can improve symptoms and exercise intolerance, reduce hospitalizations, and improve overall quality of life.2,8,16

Vasodilator Combination: The recommendation of hydralazine and isosorbide dinitrate (ISDN) in combination is reserved for patients who have demonstrated inability to tolerate an ACE inhibitor or ARB. However, in a recent trial involving a cohort of African-American patients with symptomatic NYHA III or IV heart failure, the addition of hydralazine and ISDN combination to standard therapy (i.e., ACE inhibitor, diuretic, and beta-blocker) led to a 43% improvement in survival and a 33% reduction in the risk of the first hospitalization versus placebo.17 In theory, the hydralazine and ISDN combination may enhance the nitric oxide bioavailability.2 The combination ISDN and hydralazine (BiDil) is FDA approved only for African-Americans as adjunctive therapy to standard heart failure therapy.18 Hydralazine is an arteriole vasodilator, which acts to decrease afterload, while ISDN is a venous vasodilator, which acts to decrease preload. This combination of vasodilators is not preferred over ACE inhibitors or ARBs, since it may have intolerable adverse effects such as headache or dizziness and compliance issues such as missed doses, but it may be used as an adjunctive therapy for the African-American population.2

Alternative Medicines: Hawthorn leaves with flowers, also known as Crataegus extract, have been advocated for mild heart failure (NYHA II). Through in vitro studies, hawthorn leaves have demonstrated positive inotropic effects, vasodilating properties, and increased coronary blood flow. Studies have shown improvement on subjective symptoms in patients with mild heart failure. Due to the digitalis-like effects, patients taking both Crataegus extract and digitalis should be closely monitored. Adverse side effects reported were gastrointestinal symptoms, palpitations, chest pain, and vertigo.19,20

Another alternative medicine that has been used in the treatment of heart failure is coenyzme Q10, a fat-soluble vitamin. Some studies demonstrated that coenzyme Q10 led to improvement in the frequency of hospitalizations, dyspnea, and edema.21 However, a randomized, double-blinded, placebo-controlled trial demonstrated no difference between coenyzme Q10 and placebo in LVEF, exercise tolerance, or peak oxygen consumption in heart failure patients.22 Documented adverse effects of coenzyme Q10 were gastrointestinal discomfort, hypoglycemia, and hypotension.21 Clinical controlled trials of Crataegus extract and coenyzme Q10 are under way to evaluate the efficacy and safety in the treatment of heart failure.20,21

HARMFUL MEDICATIONS IN HEART FAILURE

Several classes of medication can exacerbate heart failure and should be avoided. Antiarrhythmic agents, except amiodarone or dofetilide, may cause a cardiodepressant and proarrhythmic effect on the heart, leading to acute decompensation.1,2 First-generation calcium channel blockers have been associated with increased cardiovascular events and worsening of heart failure. The newer, long-acting calcium channel blockers amlodipine and felodipine appear to be safe, but no studies have demonstrated a statistically significant reduction in mortality. 2,8,23 The thiazolidinediones have been associated with weight gain and fluid retention, possibly leading to heart failure or precipitating an acute heart failure exacerbation. However, edema is more likely to occur when thiazolidinediones are used in combination with insulin therapy.24,25 Thus, thiazolidinediones are not recommended in patients with diabetes mellitus and NYHA class III or IV heart failure.25-27 NSAIDs cause sodium retention and peripheral vasoconstriction, precipitating an acute heart failure exacerbation. In addition, they decrease the efficacy and enhance the risk of toxicity from ACE inhibitors and diuretics. There is a possibility of a drug interaction when aspirin is used in combination with ACE inhibitors, but it remains controversial and requires further study.2

PHARMACIST'S ROLE

An understanding of the benefits of drug therapy in heart failure can lead to optimal pharmaceutical care. Pharmacists can help patients identify and alleviate high-risk behaviors such as smoking, alcohol consumption, and illicit and harmful OTC drug use. Additionally, pharmacists need to monitor patients for disease state progression, including signs and symptoms of heart failure, and encourage patients to chart their weight.

Encouraging patients to adhere to dietary restrictions, exercise guidelines, and medication regimens for heart failure should be a pharmacist's priority. Nonadherence to therapeutic medications has been associated with an increase in mortality and may be related to adverse side effects of medications. Pharmacists should monitor and encourage patients to be compliant with their medications to reduce mortality. By monitoring and educating patients and other health care professionals about drug-related adverse effects, pharmacists may help increase medication compliance. Furthermore, pharmacists need to be aware of alternatives to medications such as ACE inhibitors and discuss with other health care providers the benefits in mortality associated with them in order to provide optimal pharmaceutical care and reduce the risk of mortality.

Patients and health care providers may not be aware of the association between common medications and exacerbations of heart failure. Since some common OTC medications, including NSAIDs, are contraindicated in patients with heart failure, educating the patient about why he or she should not take these medications is another vital role for pharmacists. Pharmacists need to monitor patients for and consult with health care providers and patients about detrimental drug-drug and drug-disease interactions that can result in hospitalization.

References
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18. BiDil [package insert]. Lexington, MA: Nitromed Inc.; August 2005.
19. De Smet PA. Herbal remedies. N Engl J Med. 2002;347:2045-2056.
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21. Bonadkar RA, Guarneri E. Coenzyme Q10. Am Fam Physician. 2005;72:1065-1070.
22. Khatta M, Alexander BS, Krichten CM, et al. The effect of coenyzme Q10 in patients with congestive heart failure. Ann Intern Med. 2000;132:636-640.
23. De Vries RJM, Van Veldhuisen DJ, Dunselman PHJM. Efficacy and safety of calcium channel blockers in heart failure: focus on recent trials with second-generation dihydropyridines. Am Heart J. 2000;139:185-194.
24. Delea TE, Edelsberg JS, Hagiwara M, et al. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes. Diabetes Care. 2003;26:2983-2989.
25. Hollenberg NK. Considerations for management of fluid dynamic issues associated with thiazolidinediones. Am J Med. 2003;115:111S-115S.
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