THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

9. Heart Failure - Robert B. Parker, PharmD, FCCP

9-1. Overview

Introduction

Heart failure is a clinical syndrome resulting from a variety of cardiac disorders that impair the ventricle's ability to fill with or eject blood. When the ventricle is impaired as such, the heart is unable to pump blood at a sufficient rate to meet the metabolic demands of the body, a condition that is described as heart failure.

• Nearly 6 million people in the United States have heart failure; 670,000 new patients are diagnosed each year.

• Heart failure is the only major cardiovascular disease that is increasing in prevalence.

• Approximately 300,000 patients die from heart failure each year. At the time of heart failure diagnosis, the 5-year mortality rate is nearly 50%.

• A large majority of patients are elderly; approximately 10% of individuals over the age of 75 have heart failure.

• Each year, there are more than 1 million hospital discharges for heart failure, and it is the most common hospital discharge diagnosis for Medicare patients. More Medicare dollars are spent for diagnosis and treatment of heart failure than for any other disorder.

• Current estimates indicate that annual expenditures for heart failure exceed $37 million.

Classification

The New York Heart Association Functional Classification for heart failure has been widely used for many years. The classification scheme primarily reflects the severity of heart failure symptoms based on a subjective assessment by the provider. A patient's functional class can change frequently over a short period because of changes in medications, diet, or intercurrent illnesses. The classification scheme, as follows, does not recognize preventive measures, nor does it recognize the progressive nature of heart failure:

• Functional class I includes patients with cardiac disease but without limitations of physical activity. Ordinary physical activity does not cause undue fatigue, dyspnea, or palpitations.

• Functional class II includes patients with cardiac disease that results in slight limitations of physical activity. Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina.

• Functional class III includes patients with cardiac disease that results in marked limitation of physical activity. Although patients are comfortable at rest, less than ordinary activity will lead to symptoms.

• Functional class IV includes patients with cardiac disease that results in an inability to carry on physical activity without discomfort. Symptoms of heart failure are present even at rest. With any physical activity, increased discomfort is experienced.

The most recent guidelines for evaluation and management of heart failure from the American College of Cardiology (ACC) and the American Heart Association (AHA) recommend an additional classification scheme that emphasizes both the evolution and the progression of the disease. That additional classification scheme more objectively identifies patients within the course of the disease and links to treatments that are appropriate for each stage. Patients in stages A and B do not have heart failure but do have risk factors that predispose them to the development of heart failure.

• Stage A includes patients at high risk of developing heart failure because of the presence of conditions that are strongly associated with heart failure. Patients in stage A have no known cardiac abnormalities and no heart failure signs or symptoms. Examples include patients with hypertension, coronary artery disease, and diabetes mellitus.

• Stage B includes patients with structural heart disease that is strongly associated with the development of heart failure but who have never shown signs or symptoms of heart failure. Examples include patients with previous myocardial infarction, left ventricular hypertrophy, or impaired left ventricular systolic function.

• Stage C includes patients who have current or prior symptoms of heart failure associated with underlying structural heart disease. Examples include patients with dyspnea or fatigue attributable to left ventricular systolic dysfunction, as well as asymptomatic patients who are undergoing treatment for prior symptoms of heart failure. Most patients with heart failure are in stage C.

• Stage D includes patients who have advanced structural heart disease, who have marked symptoms of heart failure at rest despite maximal medical therapy, and who require specialized interventions. Patients in stage D include those who frequently are hospitalized for heart failure and cannot be discharged from the hospital safely, those who are in the hospital awaiting heart transplantation, and those who are supported with a mechanical circulatory assist device.

Acute Decompensated Heart Failure

Both the growing number of patients with heart failure and the progressive nature of the syndrome have led to substantial increases in hospitalizations for heart failure. Acute decompensated heart failure (ADHF) is defined as new or worsening signs or symptoms that are usually caused by (1) volume overload (pulmonary congestion, systemic congestion, or both); (2) hypoperfusion (hypotension, renal insufficiency, shock syndrome, or some combination); or (3) both volume overload and hypoperfusion. ADHF frequently requires hospitalization for acute treatment.

Causes of ADHF include medication and dietary noncompliance, atrial fibrillation, myocardial ischemia, uncorrected high blood pressure, recent addition of negative inotropic drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), excessive alcohol or illicit drug use, and progression of heart failure.

To determine the proper approach to therapy, patients are assigned to one of four hemodynamic profiles:

• Warm and dry: Adequate perfusion (i.e., cardiac output) and no signs or symptoms of volume overload

• Warm and wet: Adequate perfusion but signs or symptoms of volume overload

• Cold and dry: Inadequate perfusion and no signs or symptoms of volume overload

• Cold and wet: Inadequate perfusion and signs or symptoms of volume overload

Most patients (about 70%) are assigned to the warm and wet classification.

Clinical Presentation

The primary manifestations of heart failure are (1) dyspnea and fatigue that may limit exercise tolerance and (2) fluid retention that may lead to pulmonary and peripheral edema. Both abnormalities can limit a patient's functional capacity and quality of life, but they do not necessarily occur at the same time. Some patients may have marked exercise intolerance but little evidence of fluid retention, whereas others may have prominent edema with few dyspnea or fatigue symptoms.

Other symptoms may include paroxysmal nocturnal dyspnea, orthopnea, tachypnea, cough, ascites, and nocturia. Other signs include jugular venous distension, hepatojugular reflux, hepatomegaly, bibasilar rales, pleural effusion, tachycardia, pallor, and S3 gallop. Patients with ADHF experience similar symptoms but they may be more severe.

Pathophysiology

Heart failure can result from any disorder (see "Specific Causes of Heart Failure" next) that impairs the heart's systolic function (i.e., pumping ability) or diastolic function (impaired cardiac relaxation). Many patients have manifestations of both abnormalities. In either case, the initiating event in heart failure is a decrease in cardiac output, which results in the activation of a number of compensatory mechanisms that attempt to maintain an adequate cardiac output.

Recent studies suggest that mutations in certain adrenergic receptors (β1 and α2c) and β-receptor signaling pathways may play an important role in the development of heart failure and response to therapy.

The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and aldosterone antagonists on reducing mortality and slowing heart failure progression have resulted in the neurohormonal model of heart failure pathophysiology. The decrease in cardiac output leads to the activation of compensatory systems that release a number of neurohormones, including angiotensin II, norepinephrine, aldosterone, proinflammatory cytokines, and vasopressin. Those neurohormones can increase renal sodium and water retention, vasoconstriction, and tachycardia and can stimulate ventricular hypertrophy and remodeling. Activation of the compensatory systems results in a systemic disorder that is not confined just to the heart, whose progression is largely mediated by these neurohormones.

Specific Causes of Heart Failure

Coronary artery disease is the cause of heart failure in about 65% of patients with left ventricular systolic dysfunction. Other causes include nonischemic cardiomyopathy (e.g., attributable to hypertension, thyroid disease, or valvular disease). Most of those patients have a reduced left ventricular ejection fraction (usually less than 40%).

Approximately 20%-50% of patients with heart failure have preserved (normal) left ventricular systolic function, and their heart failure is secondary to diastolic dysfunction. This type of heart failure is most often observed in elderly patients.

A number of drugs can precipitate or worsen heart failure:

• Drugs with negative inotropic effects include antiarrhythmics (disopyramide, flecainide, propafenone, and others); β-blockers; calcium channel blockers (verapamil and diltiazem); and oral antifungals (itraconazole and terbinafine).

• Cardiotoxic drugs include doxorubicin, daunorubicin, cyclophosphamide, ethanol, amphetamines (cocaine and methamphetamine), trastuzumab, and imatinib.

• Drugs that cause sodium and water retention can precipitate or worsen heart failure and include NSAIDs (which can also attenuate the efficacy and increase the toxicity of diuretics and ACE inhibitors), glucocorticoids, rosiglitazone, and pioglitazone.

Diagnostic Criteria

No single diagnostic test for heart failure exists; rather, the diagnosis is a clinical one based on history, signs and symptoms, and physical examination. A thorough history and physical examination are important for identifying cardiac and noncardiac disorders or behaviors (e.g., diet, adherence to medications) that may cause or hasten the progression of heart failure.

A rapid bedside assay for B-type natriuretic peptide (BNP) often is used in acute care settings (e.g., emergency departments) as an aid in the diagnosis of suspected heart failure. BNP is synthesized and released from the ventricles in response to pressure or volume overload. BNP counteracts increased sympathetic nervous system activity and renin-angiotensin-aldosterone system activity by increasing diuresis, renal sodium excretion, and vasodilation. The degree of elevation of BNP correlates with prognosis. The BNP assay is useful for differentiating between heart failure exacerbations and other causes of dyspnea, such as chronic obstructive pulmonary disease (COPD), asthma, or infection). Patients with dyspnea secondary to heart failure will have elevated plasma BNP concentrations.

The echocardiogram is one of the most useful diagnostic tests in patients with heart failure.

Patients with a left ventricular ejection fraction (LVEF) less than 40% generally are considered to have systolic dysfunction. LVEF can be determined by an echocardiogram, by nuclear imaging scans, or during a cardiac catheterization. Note that, in general, there is a poor correlation between LVEF and symptoms.

Treatment Principles and Goals of Therapy

The goals of therapy include improving the patient's quality of life, reducing symptoms, reducing hospitalizations for heart failure exacerbations, slowing progression of the disease, and improving survival.

ACC-AHA guidelines for heart failure treatment according to stage are shown in

Figure 9-1. In stages A and B, therapy primarily is targeted toward prevention of heart failure development; in stages C and D, however, the focus is targeted toward treatment of patients with symptomatic heart failure.

An algorithm for treatment of patients with ADHF is shown in

Figure 9-2.

9-2. Drug Therapy of Heart Failure

Introduction

The following section on drug therapy focuses on treatment of patients with stage C heart failure (i.e., patients with left ventricular dysfunction with current or prior symptoms). This drug therapy commonly is referred to as outpatient treatment. Patients with stage C heart failure should be routinely managed with a combination of three drugs: a diuretic (if needed to control volume retention), an ACE inhibitor,

[Figure 9-1. American College of Cardiology-American Heart Association Stages of Heart Failure and Recommended Therapy by Stage]

[Figure 9-2. Acute Decompensated Heart Failure]

and a β-blocker. Drug therapies that can be considered in selected patients include angiotensin II receptor blockers (ARBs), digoxin, aldosterone antagonists, and hydralazine-isosorbide dinitrate.

Loop Diuretics

Only patients with signs or symptoms of volume overload will need diuretic therapy. Most heart failure patients require use of the more potent loop diuretics versus thiazide diuretics (

Table 9-1).

Mechanism of action

Loop diuretics reduce the sodium and fluid retention associated with heart failure by inhibiting reabsorption of sodium and chloride in the loop of Henle.

Patient instructions and counseling

• Patients allergic to sulfa-containing medications also may be allergic to loop diuretics.

• Patients should take medication once a day in the morning, or, if taking twice daily, take in the morning and afternoon.

[Table 9-1. Loop Diuretics]

• Loop diuretics can cause frequent urination.

• Patients should weigh themselves daily (preferably in the morning, after urinating). Patients who gain more than 1 pound per day for several consecutive days or 3-5 pounds in a week should contact their health care provider.

• Patients should report muscle cramps, dizziness, excessive thirst, weakness, or confusion, as those may be signs of overdiuresis.

• Patients should avoid sun exposure or use sunscreen when taking loop diuretics.

Adverse drug events

• Electrolyte depletion: hypokalemia and hypomagnesemia

• Hypotension

• Renal insufficiency

Drug-drug and drug-disease interactions

• Food decreases the bioavailability of furosemide and bumetanide, which should be taken on an empty stomach. Food does not affect torsemide absorption.

• The absorption of oral furosemide is slowed significantly in patients with ADHF, resulting in decreased diuretic response. Therefore, those individuals usually will require the use of intravenous (IV) furosemide.

• NSAIDs may diminish the medication's diuretic effect.

• Potassium supplementation may not be required in patients also receiving ACE inhibitors, ARBs, or aldosterone antagonists.

Parameters to monitor

• Serum sodium, potassium, magnesium, creatinine, and blood urea nitrogen (BUN)

• Patient weight (a loss of 0.5-1.0 kg daily is desired until the patient achieves the desired dry weight)

• Urine output

• Blood pressure

• Jugular venous distension

• Improvement in heart failure symptoms (dyspnea and peripheral edema)

Kinetics

Bioavailability of torsemide is not affected by food and is less variable than that of furosemide.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme inhibitors (ACEIs) are recommended for all patients with current or prior symptoms of heart failure and reduced LVEF, unless contraindicated (

Table 9-2). Clinical trials in more than 7,000 patients consistently demonstrate that ACEIs alleviate symptoms, improve clinical status and quality of life, and improve mortality.

Mechanism of action

• ACEIs interfere with the renin-angiotensin system by inhibiting angiotensin-converting enzyme, which is responsible for the conversion of angiotensin I to the potent vasoconstrictor angiotensin II. That inhibition results in a decrease in plasma angiotensin II and aldosterone concentrations, thus reducing the adverse effects of those neurohormones. Inhibition of angiotensin-converting enzyme also prevents the breakdown of the endogenous vasodilator bradykinin.

• ACEIs improve heart failure symptoms and reduce hospitalizations for heart failure.

• ACEIs reduce mortality by 20%-30% and slow the progression of heart failure.

Patient instructions and counseling

• Patients who are pregnant or breast-feeding should not take ACEIs. If patients become pregnant while taking an ACEI, they should contact their physician immediately.

• Captopril should be taken on an empty stomach, either 1 hour before or 2 hours after meals.

[Table 9-2. Angiotensin-Converting Enzyme Inhibitors]

• Salt substitutes that contain potassium should be used cautiously.

• Patients should call their physician immediately if they experience swelling of the face, eyes, lips, tongue, arms, or legs or if they have difficulty breathing or swallowing.

• ACEIs may cause cough.

Adverse drug events

• Hypotension

• Dizziness

• Renal insufficiency

• Cough

• Angioedema

• Hyperkalemia

• Rash

• Taste disturbances

Drug-drug and drug-disease interactions

• NSAIDs can increase the risk of renal insufficiency and attenuate the beneficial effects of ACEIs.

• Potassium supplements or potassium-sparing diuretics should be used with caution.

• Cyclosporine and tacrolimus may increase the risk of nephrotoxicity and hyperkalemia.

• Diuretics increase the risk of hypotension.

Parameters to monitor

• Blood pressure

• Renal function (i.e., serum BUN and creatinine)

• Serum potassium

• Heart failure symptoms

• Dose (initiate therapy at low doses; if lower doses are tolerated well, follow with gradual increases)

Other

ACEIs are pregnancy category C during the first trimester and pregnancy category D during the second and third trimesters. ACEIs can cause fetal and neonatal morbidity and death when administered to pregnant women.

Angiotensin Receptor Blockers

ACEIs remain the drugs of choice for inhibiting the renin-angiotensin-aldosterone system in patients with chronic heart failure. Recent clinical trials confirm the efficacy and safety of candesartan and valsartan in the treatment of heart failure. Whether other ARBs are equally effective in the treatment of heart failure is unknown. Current guidelines recommend candesartan or valsartan for patients that are intolerant to ACEIs—both of those agents are approved for use in patients with heart failure. Intolerance to ACEIs is most often due to cough or angioedema, although caution is advised when using ARBs in patients that have angioedema secondary to an ACEI. Note that ARBs are just as likely as ACEIs to cause impaired renal function, hyperkalemia, or hypotension (

Table 9-3).

Mechanism of action

• ARBs interfere with the renin-angiotensin system by blocking the angiotensin-1 receptor, thereby attenuating the detrimental effects of this hormone.

• Unlike ACEIs, ARBs do not affect the kinin system and thus are not associated with cough.

• ARBs reduce hospitalizations and improve survival.

Patient instructions and counseling

• Patients who are pregnant or breast-feeding should not take ARBs. If a patient becomes pregnant while taking an ARB, she should contact her physician immediately.

• Use salt substitutes that contain potassium cautiously.

• Dizziness or light-headedness may occur, especially in patients taking diuretics.

Adverse drug events

• Hypotension

• Dizziness

• Renal insufficiency

• Hyperkalemia

Drug-drug and drug-disease interactions

• Potassium supplements or potassium-sparing diuretics should be used with caution.

• Diuretics increase the risk of hypotension.

[Table 9-3. Angiotensin Receptor Blockers]

Parameters to monitor

• Blood pressure

• Renal function (i.e., serum BUN and creatinine)

• Serum potassium

• Heart failure symptoms

• Dose (initiate therapy at low doses; if lower doses are tolerated well, follow with gradual increases)

Other

• ARBs are pregnancy category C during the first trimester and pregnancy category D during the second and third trimesters. ARBs can cause fetal and neonatal morbidity and death when administered to pregnant women.

β-Blockers

Because of their negative inotropic effects, β-blockers once were considered to be contraindicated in patients with heart failure. However, by inhibiting the deleterious effects of long-term activation of the sympathetic nervous system in heart failure, β-blockers repeatedly have been shown to provide hemodynamic, symptomatic, and survival benefits. Metoprolol succinate (extended-release metoprolol), bisoprolol, and carvedilol all have been shown to be effective, and one of those three agents should be used for the treatment of heart failure (

Table 9-4).

Mechanism of action

• Blockade of β-receptors antagonizes the increase in sympathetic nervous system activity that is one of the important mechanisms responsible for the progression of heart failure. Bisoprolol and metoprolol succinate are β1-selective agents, whereas carvedilol blocks β1-, β2-, and α1-receptors. Whether those differences in pharmacologic actions have any important effects on outcomes for patients with heart failure remains uncertain.

[Table 9-4. β-Blockers]

• Treatment with β-blockers reduces symptoms, improves clinical status, and decreases the risk of death and hospitalization.

• One of the three β-blockers that have been shown to reduce mortality (bisoprolol, carvedilol, and extended-release metoprolol succinate) should be used in all stable patients with current or prior heart failure symptoms and reduced LVEF, unless contraindicated.

• In general, β-blockers should be used in combination with ACEIs and diuretics.

Patient instructions and counseling

• β-blockers may cause fluid retention or worsening of heart failure upon initiation of therapy or after an increase in dose. Patients should report any cases of body or leg swelling or increased shortness of breath. Patients should weigh themselves daily; if they gain more than 1 pound per day for several consecutive days or 3-5 pounds in a week, they should contact their health care provider.

• Fatigue or weakness may occur in the first few weeks of treatment but usually will resolve spontaneously.

• Patients should report any cases of dizziness, lightheadedness, or blurred vision, which may be caused by the patient's blood pressure being too low or from bradycardia or heart block.

• Patients should take carvedilol with food.

• It is important not to miss doses or stop taking these medications abruptly.

• In patients with diabetes, β-blockers may cause an increase in blood sugar, possibly masking the signs of hypoglycemia (except for sweating).

Adverse drug events

A list of adverse events most commonly observed in heart failure patients receiving β-blockers follows. For other adverse effects of β-blockers, see the chapters on hypertension and ischemic heart disease.

• Fluid retention and worsening heart failure

• Fatigue

• Bradycardia and heart block

• Hypotension

• Abrupt withdrawal can lead to hypertension, tachycardia, or myocardial ischemia

Drug-drug and drug-disease interactions

• Amiodarone and calcium channel blockers (verapamil and diltiazem) can increase the risk of bradycardia, heart block, and hypotension.

• Quinidine, fluoxetine, paroxetine, and other inhibitors of cytochrome P4502D6 inhibit hepatic metabolism of metoprolol and carvedilol and may result in increased plasma concentrations and enhanced effects.

• Concomitant use of ophthalmic β-blockers may increase the risk of bradycardia, heart block, and hypotension.

• β-blockers may cause bronchoconstriction in patients with asthma or COPD.

• Do not use β-blockers in patients with symptomatic bradycardia or heart block unless a pacemaker is present.

• β-blockers may worsen blood glucose control in diabetics and mask the signs of hypoglycemia.

Parameters to monitor

• Blood pressure and heart rate

• Heart failure symptoms

• Weight (daily)

Kinetics

• Bisoprolol is eliminated about 50% by the kidneys, so dosage adjustment may be required in patients with renal insufficiency.

• Both metoprolol and carvedilol are metabolized by the liver.

Other

• Patients must be stable (i.e., minimal evidence of fluid overload or volume retention) before β-blocker treatment is initiated.

• Treatment should be initiated with low doses and titrated slowly upward until the target dose is reached. Doses usually are increased no more frequently than every 2 weeks, with close monitoring of symptoms required during the titration period.

• Fluid accumulation during dose titration usually can be managed by adjusting diuretic doses.

• Staggering the schedule of other heart failure medications that lower blood pressure (e.g., ACEIs and diuretics) may help reduce the risk of hypotension.

• A recent study comparing the effects of carvedilol with immediate-release metoprolol (metoprolol tartrate) in patients with heart failure found that survival is improved in patients receiving carvedilol. Whether carvedilol is superior to extended-release metoprolol (metoprolol succinate) is unknown. However, these results strongly suggest that only β-blockers proven to improve survival (carvedilol, metoprolol succinate, and bisoprolol) should be used in patients with heart failure.

Aldosterone Antagonists

Elevated plasma aldosterone plays an important detrimental role in the pathophysiology and progression of heart failure. Although short-term treatment with ACEIs or ARBs lowers circulating aldosterone concentrations, that suppression is not sustained with long-term therapy. In low doses, the aldosterone antagonists spironolactone and eplerenone reduce the risk of death and hospitalization in patients with moderate to severe heart failure. Current guidelines recommend the addition of aldosterone antagonists in patients with moderately severe to severe symptoms of heart failure and reduced LVEF that can be monitored closely for renal function and serum potassium (

Table 9-5).

Mechanism of action

Antagonism of aldosterone results in reduced renal potassium excretion.

Patient instructions and counseling

• Potassium-containing salt substitutes should be avoided.

• Patients should call their physician immediately if they experience muscle weakness or cramps; numbness or tingling in hands, feet, or lips; or slow or irregular heartbeat.

• Spironolactone may cause swollen or painful breasts in men.

Adverse drug events

• Hyperkalemia

• Gynecomastia (only with spironolactone)

• Irregular menses

[Table 9-5. Aldosterone Antagonists]

Drug-drug and drug-disease interactions

• ACEIs, ARBs, and NSAIDs increase the risk of hyperkalemia.

• Spironolactone can increase digoxin plasma concentrations.

• Potassium supplements increase the risk of hyperkalemia. Supplements should not be used if serum potassium exceeds 3.5 mEq/L.

• Elderly patients and patients with diabetes are at an increased risk of hyperkalemia.

• Erythromycin, clarithromycin, verapamil, ketoconazole, fluconazole, itraconazole, and other inhibitors of cytochrome P450 3A4 inhibit hepatic metabolism of eplerenone and may result in increased plasma concentrations and enhanced effects.

Parameters to monitor

• Serum creatinine should be less than 2.5 mg/dL in men or less than 2.0 mg/dL in women before therapy is initiated.

• Serum potassium should be less than 5.0 mEq/L before therapy is initiated. Potassium should be evaluated three days after therapy is started, again one week after therapy is started, and at least monthly for the first three months of therapy.

Digoxin

Unlike ACEIs or β-blockers, digoxin does not improve mortality but does appear to produce symptomatic benefits (

Table 9-6).

Mechanism of action

• Digoxin inhibits the Na+-K+-ATPase pump, which results in an increase in intracellular calcium that, in turn, causes a positive inotropic effect.

• Recent evidence indicates that digoxin reduces sympathetic outflow from the central nervous system, thus blunting the excessive sympathetic activation that occurs in heart failure. Those effects occur at low plasma concentrations, where little positive inotropic effect is seen.

[Table 9-6. Digoxin]

Patient instructions and counseling

Patients should report any of the following to their health care provider:

• Dizziness, lightheadedness, or fatigue

• Changes in vision (blurred or yellow vision)

• Irregular heartbeat

• Loss of appetite

• Nausea, vomiting, or diarrhea

Adverse drug events

Major adverse effects involve three systems:

• Cardiovascular (cardiac arrhythmias, bradycardia, and heart block)

• Gastrointestinal (anorexia, abdominal pain, nausea, and vomiting)

• Neurological (visual disturbances, disorientation, confusion, and fatigue)

Toxicity typically is associated with serum digoxin concentrations >2 ng/mL but may occur at lower levels in elderly patients and in patients with hypokalemia or hypomagnesemia.

Drug-drug and drug-disease interactions

The following drugs increase serum digoxin concentrations:

• Quinidine, verapamil, and amiodarone (the dose of digoxin should be decreased by 50% if these medications are added)

• Propafenone

• Flecainide

• Macrolide antibiotics (erythromycin and clarithromycin)

• Itraconazole and ketoconazole

• Spironolactone

• Cyclosporine

Drugs that decrease serum digoxin concentrations include:

• Antacids

• Cholestyramine and colestipol

• Kaolin-pectin

• Metoclopramide

Diuretics increase the risk of digoxin toxicity in the presence of hypokalemia or hypomagnesemia.

Digoxin clearance is reduced in patients with renal insufficiency (see section on kinetics).

Parameters to monitor

• Digoxin serum concentration

• There is little relationship between serum digoxin concentration and therapeutic effects in heart failure.

• Current guidelines suggest a target range of 0.5-1.0 ng/mL.

• Heart rate

• Serum potassium and magnesium

• Renal function (serum BUN and creatinine)

• Heart failure symptoms

Kinetics

See

Table 9-7 for information about the pharmacokinetics of digoxin. Note the following:

• Approximately 60%-80% of the dose is eliminated unchanged in the kidney; therefore, dosage adjustment is required in patients with renal insufficiency.

• Lower doses (0.125 mg daily or every other day) should be used in the elderly or in patients with a low lean body mass.

• No loading dose is needed in the treatment of heart failure.

• Because of the long distribution phase after either oral or intravenous digoxin administration, blood samples for determination of serum digoxin concentrations should be collected at least 6 and preferably 12 hours or more after the last dose.

[Table 9-7. Digoxin Pharmacokinetics]

Hydralazine-Isosorbide Dinitrate

Hydralazine and isosorbide dinitrate initially were combined because of complementary hemodynamic actions. An early clinical trial reported reduced mortality with this combination when compared with placebo. A comparison with an ACEI, however, showed that the ACEI was superior to hydralazine-isosorbide dinitrate. Adverse effects with the combination are common (primarily headache, dizziness, and gastrointestinal complaints), and those effects lead many patients to discontinue therapy. Current guidelines indicate that hydralazine-isosorbide dinitrate can be considered as a therapeutic option in patients who cannot be given an ACEI or an ARB because of drug intolerance, hypotension, or renal insufficiency.

A recent clinical trial found that the hydralazine-isosorbide dinitrate combination, when added to standard background therapy (ACEIs or ARBs, β-blockers, diuretics, digoxin), reduced mortality in African Americans with heart failure by 40% compared with placebo. Whether those benefits are specific to African Americans is unclear. The current heart failure treatment guidelines indicate that the addition of hydralazine-isosorbide dinitrate is a reasonable therapy in patients with reduced LVEF and persistent heart failure symptoms despite therapy with ACEIs and β-blockers.

A fixed-dose combination product is now available (BiDil).

9-3. Drug Therapy for Acute Decompensated Heart Failure

Introduction

Patients with ADHF usually are admitted to the hospital for aggressive treatment with IV diuretics, vasodilators (see

Table 9-8), or positive inotropic drugs (see

Table 9-9). When such patients have hypotension in addition to low cardiac output, they are said to have cardiogenic shock. In those severe cases, therapy may be guided by invasive hemodynamic monitoring. Treatment goals include reducing volume overload and improving cardiac output. The approach to treatment is dictated by the patient's hemodynamic profile.

Warm and Dry

• No specific therapy is needed.

Warm and Wet

• The goal is to reduce volume overload and minimize congestive symptoms.

[Table 9-8. Vasodilators]

[Table 9-9. Inotropes]

• IV loop diuretics often are used. For patients who are unresponsive to loop diuretics, the addition of supplemental thiazide diuretics (e.g., metolazone) may be helpful.

• The addition of IV vasodilators (nitroglycerin, nitroprusside, and nesiritide) also can reduce symptoms.

• Inotropic therapy usually is not necessary.

Cold and Dry

• Patients may be clinically stable and often do not present with acute symptoms.

• Rule out volume depletion from overdiuresis as the cause of decreased cardiac output.

• Gradual introduction of β-blockers may be helpful.

Cold and Wet

• Improve cardiac output first (i.e., before removing excess volume).

• Cardiac output can be increased by IV vasodilators or inotropes, or both.

• The relative roles of vasodilators and inotropes in this patient population are controversial.

9-4. Nondrug Therapy

Nondrug therapies include the following:

• Ultrafiltration

• Intra-aortic balloon pump

• Left ventricular assist devices

• Biventricular pacing

• Implantable cardioverter-defibrillator

• Cardiac transplantation

9-5. Key Points

• Heart failure is a clinical syndrome caused by the heart's inability to pump sufficient blood to meet the body's needs.

• Although heart failure has many causes, the most common are coronary artery disease and hypertension.

• Several compensatory mechanisms are activated to help maintain adequate cardiac output; activation of those systems is responsible for heart failure symptoms and contributes to disease progression. Medications that improve patient outcomes antagonize those compensatory mechanisms.

• Drugs that can precipitate or worsen heart failure should be avoided (e.g., NSAIDs, verapamil, and diltiazem).

• All patients with stage C (symptomatic) heart failure should be treated with diuretics, ACEIs, and β-blockers.

• The goal of treatment with diuretics is to eliminate signs of fluid retention, thus minimizing symptoms.

• ACEIs are an integral part of heart failure pharmacotherapy. They improve survival and slow disease progression. ARBs are the preferred alternative for patients who are intolerant to ACEIs.

• β-blockers are recommended for all patients with systolic dysfunction and mild to moderate symptoms. β-blockers improve survival, decrease hospitalizations, and slow disease progression. Bisoprolol, carvedilol, and extended-release metoprolol succinate are agents with proven benefits. They should be started at low doses with slow upward titration to the target dose.

• Digoxin does not improve survival in patients with heart failure but does provide symptomatic benefits. The goal plasma concentration is 0.5-1.0 ng/mL.

• Spironolactone and eplerenone improve survival in patients with moderate to severe heart failure.

• Patients with ADHF often require hospitalization and aggressive therapy with IV diuretics, vasodilators, and positive inotropic drugs.

9-6. Questions

1.

Which of the following combinations represents optimal pharmacotherapy of chronic heart failure?

A. Furosemide, clonidine, hydrochlorothiazide, and propranolol

B. Furosemide, lisinopril, and carvedilol

C. Carvedilol, verapamil, amlodipine, and nesiritide

D. Cardizem, hydrochlorothiazide, digoxin, and sotalol

E. Dobutamine, amiodarone, furosemide, and nitroglycerin

 

2.

Which of the following mechanisms most likely contributes to the benefits of β-blockers in the treatment of heart failure?

A. Stimulation of β2-receptors

B. Increased heart rate and decreased blood pressure

C. Stimulation of β1-receptors

D. Blockade of increased sympathetic nervous system activity

E. Blockade of angiotensin II receptors

 

3.

Appropriate monitoring parameters for enalapril therapy in the treatment of heart failure include

I. serum creatinine.

II. serum potassium.

III. hemoglobin A1c.

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II, and III

 

4.

Patients taking eplerenone for heart failure should avoid taking

A. NSAIDs.

B. ACEIs.

C. β-blockers.

D. Demadex.

E. calcium supplements.

 

5.

All of the following are adverse effects of digoxin except

A. nausea.

B. anorexia.

C. confusion.

D. arrhythmias.

E. acute renal failure.

 

6.

Heart failure may be exacerbated by which of the following medications?

I. Naproxen

II. Glipizide

III. Crestor

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II, and III

 

7.

Cough is an adverse effect associated with which of the following medications?

A. Ramipril

B. Valsartan

C. Carvedilol

D. Torsemide

E. Eplerenone

 

8.

Which of the following ACEIs has the shortest duration of action?

A. Ramipril

B. Captopril

C. Lisinopril

D. Monopril

E. Fosinopril

 

9.

Which of the following adverse effects of lisinopril can be avoided by switching to candesartan?

I. Hypotension

II. Renal insufficiency

III. Hyperkalemia

IV. Cough

A. I, II, and III

B. I and III only

C. II and III only

D. III only

E. IV only

 

10.

A significant interaction can occur if digoxin is administered with

A. Biaxin.

B. fosinopril.

C. glyburide.

D. Lipitor.

E. warfarin.

 

11.

All of the following medications can cause bradycardia except

A. carvedilol.

B. amiodarone.

C. digoxin.

D. verapamil.

E. dobutamine.

 

12.

Which of the following is contraindicated in patients with a history of lisinopril-induced angioedema?

A. Captopril

B. Torsemide

C. Spironolactone

D. Milrinone

E. Carvedilol

 

13.

Nesiritide would be indicated in

A. patients with asymptomatic left ventricular dysfunction.

B. patients with acute decompensated heart failure not responsive to IV diuretics.

C. patients with stage B heart failure.

D. patients with type 2 diabetes.

E. patients intolerant to digoxin.

 

14.

All of the following are true about the use of furosemide in heart failure except

A. the drug reduces mortality and slows heart failure progression.

B. hypokalemia is a common adverse effect.

C. response can be evaluated by monitoring patient weight.

D. oral absorption is slowed in patients with acute decompensated heart failure.

E. furosemide's bioavailability is reduced by food.

 

15.

Which of the following is an important consideration when using β-blockers for treating heart failure?

A. They are effective only in post-myocardial infarction patients.

B. All β-blockers are equally effective for the treatment of heart failure.

C. Therapy should be initiated at the target dose.

D. Patients with fluid overload are the optimal candidates for initiating therapy.

E. Therapy should be initiated at low doses and titrated upward slowly.

 

16.

The dose of which of the following medications should be reduced in patients with renal insufficiency?

A. Metoprolol

B. Carvedilol

C. Digoxin

D. Nitroglycerin

E. Dobutamine

 

17.

Which of the following is true regarding digoxin therapy in patients with chronic heart failure?

A. Digoxin reduces mortality.

B. Concomitant amiodarone therapy decreases digoxin plasma concentrations.

C. Digoxin is contraindicated in patients with heart failure and atrial fibrillation.

D. The target digoxin plasma concentration is 0.5-1.0 ng/mL.

E. Concomitant glyburide therapy increases digoxin plasma concentrations.

 

18.

Which of the following β-blockers also blocks α1-receptors and is effective for treating heart failure?

A. Metoprolol

B. Carvedilol

C. Bisoprolol

D. Propranolol

E. Atenolol

 

19.

Patients with heart failure who experience fluid retention after β-blocker initiation should have

A. the β-blocker dose increased.

B. the digoxin dose increased.

C. the β-blocker discontinued.

D. the ACEI discontinued.

E. their diuretic dose adjusted.

 

20.

Which of the following is correct regarding the treatment of ADHF?

A. Nesiritide is the agent of choice in patients with ADHF and hypotension.

B. Milrinone is preferred over dobutamine in patients receiving concomitant β-blocker therapy.

C. Absorption of oral loop diuretics is increased.

D. Dobutamine and milrinone improve survival.

E. Verapamil reduces volume overload and improves cardiac output.

 

Use Patient Profile 1 to answer questions 21 and 22.

 

Patient Name

William Johnson

Age

64

Sex

Male

Allergies

NKA

Height

5'11"

Weight

185 lbs

DIAGNOSIS

Myocardial infarction 2008

 

Hypertension

 

Heart failure

 

Hyperlipidemia

LABORATORY AND DIAGNOSTIC TESTS

 

Echocardiogram in 12/08 showed LVEF 30%

 

Blood pressure on 4/1/09: 145/90 mm Hg

 

Heart rate on 4/1/09: 88 bpm

 

Lipid profile on 4/1/09:

Total cholesterol, 160 mg/dL

LDL cholesterol, 95 mg/dL

HDL cholesterol, 50 mg/dL

Triglycerides, 100 mg/dL

Serum potassium, 2.0 mEq/L

MEDICATION RECORD

Date

Rx #

Physician

Drug/Strength

Quantity

Sig

Refills

4/1

1000

Smith

Lanoxin 0.125 mg

90

1 tab qd

2

4/1

1001

Smith

Lasix 40 mg

60

1 tab q am

3

4/1

1002

Smith

KCl 20 mEq

90

1 tab q am

1

4/1

1003

Smith

Zocor 40 mg

90

1 tab qhs

3

4/1

1004

Smith

EC aspirin 325 mg

90

1 tab q am

2

4/1

1005

Smith

Plavix 75 mg

90

1 tab q am

3

21.

Which of the following medications should be added to Mr. Johnson's regimen?

A. Lisinopril and carvedilol

B. Valsartan and prazosin

C. Torsemide and amlodipine

D. Verapamil and amiodarone

E. Clonidine and hydrochlorothiazide

 

22.

Mr. Johnson's serum potassium level of 2.0 mEq/L (normal 4.0-5.0 mEq/L) could

A. increase the risk of Lanoxin toxicity.

B. be treated by increasing the dose of Lasix.

C. be considered a side effect of therapy with EC aspirin.

D. be caused by an interaction between Zocor and Lanoxin.

E. increase the risk of bleeding from Plavix.

 
 

Patient Name

Ellen Smith

Age

71

Sex

Female

Allergies

NKA

Height

5'4"

Weight

150 lbs

DIAGNOSIS

Heart failure exacerbation with 20-lb weight gain over last 3-4 weeks

 

Hypertension

 

Osteoarthritis

LABORATORY AND DIAGNOSTIC TESTS

 

Echocardiogram in 2/09 showed LVEF 25%

 

Blood pressure on 4/1/09: 130/85 mm Hg

 

Heart rate on 4/1/09: 80 bpm

 

Serum digoxin concentration on 4/1/09: 0.8 ng/mL

MEDICATION RECORD

Date

Rx #

Physician

Drug/Strength

Quantity

Sig

Refills

2/1

100

Jones

Lanoxin 0.125 mg

90

1 tab qd

2

3/1

101

Jones

Furosemide 80 mg

60

1 tab q am

3

1/4

102

Jones

Zestril 20 mg

90

1 tab q am

1

1/4

103

Jones

Toprol-XL 50 mg

90

1 tab qd

3

3/1

104

Nelson

Naproxen 500 mg

90

1 tab bid

3

         

with food

 

Use Hospital Inpatient Profile 2 to answer questions 23 and 24.

23.

According to her profile, the recent worsening of Mrs. Smith's heart failure most likely is related to

A. Zestril.

B. naproxen.

C. subtherapeutic serum digoxin concentration.

D. furosemide.

E. drug interaction between Zestril and furosemide.

 

24.

Toprol-XL is an agent that

A. is contraindicated in heart failure.

B. blocks β1-, β2-, and α1-receptors.

C. blocks only β1-receptors.

D. should not be used in combination with Zestril.

E. increases the serum digoxin concentration.

 

9-7. Answers

1.

B. Furosemide, lisinopril (an ACEI), and carvedilol (a β-blocker) in combination should be used routinely in patients with heart failure.

 

2.

D. Activation of the sympathetic nervous system plays an important role in the initiation and progression of heart failure. The benefits of β-blockers are thought to be due to the blockade of the sympathetic nervous system's increased activity.

 

3.

C. Enalapril, as well as other ACEIs, can cause renal insufficiency and an increase in serum potassium. Thus, serum creatinine and potassium should be monitored.

 

4.

A. Use of eplerenone is associated with renal potassium retention. Concomitant use of NSAIDs significantly increases the risk of hyperkalemia.

 

5.

E. Nausea, anorexia, confusion, and arrhythmias all are common signs and symptoms of digoxin toxicity. Digoxin does not affect renal function.

 

6.

A. Naproxen, an NSAID, can worsen heart failure (1) by increasing renal sodium and water retention and (2) by attenuating the efficacy and enhancing the toxicity of ACEIs and diuretics. Neither glipizide nor Crestor affects heart failure.

 

7.

A. Cough is frequently encountered as an adverse effect of ACEIs.

 

8.

B. Captopril must be given three times daily in patients with heart failure. The other agents can be given once daily.

 

9.

E. The angiotensin receptor blocker candesartan is just as likely to cause hypotension, hyperkalemia, and renal insufficiency as is lisinopril (or any other ACEI). Candesartan is an alternative agent for patients intolerant to ACEIs because of cough.

 

10.

A. The macrolide antibiotic Biaxin (clarithromycin) is associated with a 50%-100% increase in serum digoxin concentrations.

 

11.

E. Dobutamine is a β-receptor agonist and is associated with an increase in heart rate. The other choices listed as possible answers all slow heart rate through various mechanisms.

 

12.

A. Lisinopril is an ACEI, and angioedema is a known adverse effect of all agents in that class. Thus, captopril, which also is an ACEI, should not be used in this situation.

 

13.

B. Nesiritide is indicated for use only in patients with severe or decompensated heart failure. It must be given intravenously.

 

14.

A. Although furosemide plays an important role in patients with heart failure by interfering with sodium and water retention, it provides only symptomatic benefits. Furosemide and other diuretics do not improve survival or affect heart failure progression.

 

15.

E. When used to treat heart failure, β-blocker therapy should be started at low doses and gradually titrated upward to the target dose that was shown in clinical trials to improve survival. Starting at the target dose or initiating treatment in patients with fluid overload increases the risk of worsening heart failure. Only carvedilol, bisoprolol, and metoprolol succinate extended-release are proven to be effective in heart failure.

 

16.

C. Only digoxin is eliminated by the kidneys.

 

17.

D. Current guidelines suggest a target digoxin plasma concentration of 0.5-1.0 ng/mL. Digoxin does not improve survival in patients with heart failure—it only improves symptoms. Amiodarone increases digoxin plasma concentrations; glyburide does not affect digoxin concentrations. Digoxin is useful in the management of patients with heart failure who also have atrial fibrillation.

 

18.

B. Only carvedilol blocks α1-receptors and has been shown to be effective in patients with heart failure.

 

19.

E. Some patients with heart failure may experience increases in fluid retention after initiation of β-blocker therapy. Fluid retention typically is managed best by adjusting the diuretic dose and closely monitoring the patient's weight.

 

20.

B. The positive inotropic effects of milrinone are not mediated through the β-receptor; therefore, its effects are not diminished by concomitant β-blocker therapy. Nesiritide is associated with an increased risk of hypotension. No inotropic agents are shown to improve survival. Absorption of oral loop diuretics is decreased in ADHF. Verapamil has negative inotropic effects and would worsen volume overload.

 

21.

A. An ACEI and β-blocker are indicated in this patient with heart failure to improve survival and slow disease progression.

 

22.

A. Hypokalemia increases the risk of digoxin toxicity.

 

23.

B. The addition of the NSAID naproxen approximately 3-4 weeks before admission likely is the cause of this episode of ADHF. NSAIDs can increase sodium and water retention and negate the effects of diuretics and ACEIs.

 

24.

C. Toprol-XL (metoprolol succinate) is a cardioselective β-blocker. It blocks only the β1-receptor at usual therapeutic doses.

 

9-8. References

Adams KF, Lindenfeld J, Arnold JMO, et al. Evaluation and management of patients with acute decompensated heart failure. J Card Fail. 2006; 12:e86-103.

Brater DC. Pharmacology of diuretics. Am J Med Sci. 2000;319:38-50.

Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-75.

Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525-33.

Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet. 1999;353:2001-7.

Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Int Med. 2009;169:141-9.

Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to update the 2001 guidelines for the evaluation and management of heart failure). Circulation. 2005;112:e154-235.

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Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996; 334:1349-55.

Parker RB, Rodgers JE, Cavallari LH. Heart failure. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:173-216.

Petersen JW, Felker GM. Inotropes in the management of acute heart failure. Crit Care Med. 2008; 36:S106-11.

Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet. 2003;362:759-66.

Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-21.

Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-17.

Poole-Wilson PA, Swedberg K, Cleland JGF, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): Randomised controlled trial. Lancet. 2003;362:7-13.

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Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-57.

Wong J, Patel RA, Kowey PR. The clinical use of angiotensin-converting enzyme inhibitors. Prog Cardiovasc Dis. 2004;47:116-30.