Diagnosis and Management of Decompensated Congestive Heart Failure

    Authors: Santosh G. Menon, MD, and Roger M. Mills Jr., MD, Division of Cardiology, University of Kentucky.

    Peer Reviewer: J. Thomas Heywood, MD, Director, Cardiomyopathy Program and Adult Cardiac Transplant, Loma Linda University Medical Center, Loma Linda, CA.

Editor's Note-Congestive heart failure is one of the top discharge diagnoses from acute hospitals in this country. It also accounts for a large percentage of readmissions to the hospital. In the elderly populations seeing primary care physicians, CHF is a common condition and is associated with significant morbidity and mortality. This issue deals with the major pharmacological and surgical interventions found to be useful in the management of CHF and ranks these interventions in light of recent scientific clinical studies. Although not specifically addressed in this issue, patient compliance with salt and fluid restriction has always been a hallmark of treatment. One modality that has been rediscovered to help reduce the readmission rate to the hospital is daily weights. One U.S. hospital with arguably the lowest readmission rates for CHF employed a simple and inexpensive strategy-it provided easily readable scales for its CHF patients. The patients were carefully instructed to record morning weights and were empowered to take certain actions when the targeted dry weight ranges were exceeded. Readmission rates were dramatically reduced-a happy outcome for patient, physician, and managed care.

Definition of the Problem

Every year nearly 400,000 people in the United States experience the onset of congestive heart failure (CHF).1 Of the 4.7 million people with CHF (1.5% of the total U.S. population), 900,000 will be hospitalized each year for exacerbation of their CHF. The cost of caring for these patients exceeds $6 billion annually. The total expenditure for heart failure treatment (DRG127) is nearly 5% of the total clinical expenditures of Health Care Financing Administration (HCFA).8 In patients older than 65 years, CHF is the most common diagnosis-related group (DRG). It is the fourth leading cause of hospitalizations in U.S. adults.7

Heart failure is a syndrome associated with aging. As the U.S. population ages, both the incidence and prevalence of CHF will increase. The prevalence of CHF in those older than age 75 years is nearly 10%,6 and chronic heart failure is characterized by a markedly reduced life expectancy.2 In the face of these vast numbers, the present number of 2000 heart transplants in the United States per year cannot offer any meaningful effect, no matter how successful it may be for individual patients. Cardiologists deliver only a small fraction of heart failure care; most patients with heart failure see general internists or family physicians for management. The enormous expense, intense regulatory interest, and dire prognosis of CHF have prompted us to review state-of-the-art management of CHF for primary care physicians. First, we will briefly review the pathophysiology. We will then comment on newer diagnostic studies in patients with coronary artery disease. Finally, we will look at new and established pharmacologic strategies for management.

Pathophysiology of Congestive Heart Failure

Congestive heart failure occurs when the heart is unable to generate an adequate forward cardiac output to meet the metabolic needs of the body at normal filling pressures. When the cardiac output is limited due to left ventricular dysfunction, several neurohormonal mechanisms respond in an attempt to restore or maintain blood flow to meet the metabolic demand. This neurohormonal activation of this system is not only compensatory in nature, but also detrimental.

Neuroendocrine activation: During the early stages of CHF, a complex sequence of neurohormonal changes takes place. Activation of peripheral receptors by the hypoperfusion due to the inadequate intravascular volume is characteristic of systolic heart failure. Initially, these compensatory mechanisms include activation of the renin-angiotensin-aldosterone axis, heightened adrenergic drive, and augmented release of vasopressin; these mechanisms help to maintain perfusion to vital organs and increase the reduced intra-arterial volume. The extravascular volume expansion, increased peripheral vascular resistance, and tachycardia produced by the neurohormonal response translates into: a) hemodynamic abnormalities including elevated filling pressures, increased pulmonary artery pressures, and increased pulmonary capillary wedge pressure; and b) remodeling of the heart with hypertrophy, dilatation, compensatory mitral regurgitation, and increased wall tension. As heart failure becomes chronic, these compensatory mechanisms are deleterious in that they cause excessive vasoconstriction, increased afterload, arrhythmias, sodium and fluid retention, and electrolyte abnormalities. Some of these effects are counteracted by release of atrial and ventricular naturetic peptides (ANP and VNP) in response to cardiac distention. The naturetic peptides, however, usually do not restore the situation to normal. Increased sympathetic activity is documented by the elevation of plasma and urine adrenergic norepinephrine (NE) in patients with CHF. Plasma levels in CHF patients at rest are two- to three-fold higher than in normal subjects at rest.9 Twenty-four-hour urinary NE excretion is also markedly elevated in patients with CHF.10 The elevated NE levels result from a combination of increased release of NE from adrenergic nerve endings and the consequent "spillover" into plasma. The increased spillover of NE into the plasma from cardiac tissue is attributable to increased rates of sympathetic nerve firing. The severity of the left ventricular dysfunction correlates directly with the plasma NE level.9 Ventricular tissue NE, conversely, is decreased in patients with CHF and correlates inversely with the plasma norepinephrine level.

In the milieu of elevated circulating catecholamines, Camici and associates confirmed down-regulation of beta-adrenergic receptors in the heart. They showed that the degree of down regulation was proportional to the severity of the heart failure.13 Of the two types of beta-receptors in the heart (beta-1 and beta-2), beta-1 receptor down-regulation is most evident possibly because of the local action of elevated plasma NE levels.

As outlined above, impaired cardiac output leads to the activation of the renin-angiotensin system. The major stimulus for the release of renin from the juxtaglomerular apparatus appears to be stimulation of beta-1 adrenoreceptors by the elevated plasma NE levels. Reduction in renal flow also activates baroreceptors in the kidney, which leads to release of renin. Elevated plasma renin activity (PRA) can be demonstrated in most patients with CHF, leading to elevations in Angiotensin II, a potent vasoconstrictor. Importantly for preventive strategies, both symptomatic and asymptomatic CHF patients show elevated Angiotensin-II levels.13 Angiotensin II increases afterload by its vasoconstrictor action; it also enhances the release of NE and facilitates sodium and water retention.

Arginine vasopressin (AVP) is a pituitary hormone that regulates free water clearance and plasma osmolality. Patients with CHF, especially those who develop CHF after an acute myocardial infarction, have elevated levels of AVP. Levels are higher in more symptomatic patients as compared to levels in asymptomatic patients. In contrast to normal physiology, secretion of AVP is not inhibited by a reduction in osmolality in CHF patients. This altered regulatory physiology may contribute to the inability to excrete free water in advanced heart failure, perhaps accounting for the serum hypo-osmolarity in some patients.

Although neurohormonal activation initially counteracts the effect of a low cardiac output by maintaining perfusion to the vital organs, chronic vasoconstriction and fluid retention has deleterious effects which tend to make the heart failure worse. Several changes take place in the myocardium in patients with CHF, such as apoptosis, which can be initiated by several factors, including: increased cytosolic free calcium levels, hypoxia, and muscle stretch. This process may play a crucial role in the development of CHF. Genetic studies have shown that 20% of dilated cardiomyopathy cases are familial.39 Modern pharmacotherapy of CHF has shifted from dealing with the consequences of neurohormonal activation to blocking these neurohormonal effects with drugs such as angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers, and beta-blockers. Table 1 lists non-ischemic causes of CHF.

Table 1. Non-ischemic Causes of CHF

1. Hypertension

2. Familial Idiopathic

3. Diabetes Mellitus

4. Longstanding Hypothyroidism

5. Pheochromocytoma

6. Chronic Alcohol Abuse

7. Heavy Metals:

· Iron (Hemochromatosis)

· Arsenic

· Lead

· Cobalt

8. Infectious/Post-infectious:

· Viral: Coxsackievirus, Adenovirus

· Bacterial: Tuberculosis

· Rickettsia: Typhus, Q-fever

· Protozoal: Chagas, Malaria

· Post-Streptococcal infection/Rheumatic Fever and valvular disease

· Pulmonary Hypertension and Right Heart Failure secondary to Schistosomiasis

9. Neuromuscular disease:

· Fredriech's Ataxia

· Myasthenia Gravis

· Limb-girdle dystrophy of Erb

· Duchenne muscular dystrophy

10. Toxins:

· Carbon monoxide

· Amphetamines

· Cocaine· Anthracyclines

· Cyclophospamide

· Radiation (can cause valvular lesions, pericardial disease, and severe epicardial coronary artery disease)

11. Miscellaneous acquired:

· Peripartum cardiomyopathy

· Obesity

· Prolonged Tachycardia

· Giant Cell Myocarditis


Work-Up of a Patient with CHF

Before initiating therapy, physicians must recognize that CHF is a non-specific syndrome that requires careful evaluation to: a) confirm that CHF is present; and b) clarify the etiology. Steps in evaluating a patient are outlined below.

History and physical examination: This is a vital part of the evaluation of any patient who presents with CHF.

Exercise intolerance, primarily manifested by subjective dyspnea, is the hallmark of heart failure and is often the first symptom. It is very important to differentiate dyspnea due to CHF from other causes of shortness of breath such as COPD, asthma, etc. Other, more advanced, symptoms of CHF include orthopnea, paroxysmal nocturnal dyspnea, edema (which usually indicates the presence of right heart failure but may also be secondary to medications [e.g., calcium channel blockers]), cough (which may be secondary to CHF or due to side-effects of the medications including ACEI), fatigue and weakness usually due to a low flow state, nocturia, and oliguria caused by the redistribution of blood flow with an increase in the renal blood flow in the supine position. Chest pain, which may indicate obstructive coronary artery disease (CAD), may also occur in the absence of obstructive CAD in patients with pulmonary hypertension, valvular heart disease, or cardiomyopathy. Gastrointestinal complaints including vomiting, malabsorption, protein-losing enteropathy, and hepatic dysfunction usually occur with right heart failure. Neurologic symptoms include faintness and syncope, which may reflect hypotension or arrhythmias.

The physical examination should assess the severity and possibly the cause of the heart failure. Resting tachycardia, elevated jugular venous pressure, an S3 gallop, rales, and peripheral edema suggest severe CHF with total body fluid overload. Other signs of severe compromise often overlooked include cool extremities caused by a low cardiac output and subsequent peripheral vasoconstriction and mild confusion (especially in the elderly). When the heart failure is long-standing and severe, patients may become cachectic. Cardiac cachexia may also be mistaken for malignancy. Protein-losing enteropathy, reduced caloric intake, increased caloric expenditure due to the excessive work of breathing, and markedly increased tumor necrosis factor (TNFa) levels may all play a role in the pathogenesis of cachexia.

Ancillary testing: Table 2 lists a number of useful initial diagnostic tests for patients with CHF. Two-dimensional and Doppler echocardiography provide a tremendous amount of information. Routine echocardiography will demonstrate conditions, such as valvular heart disease or hypertrophic cardiomyopathy (IHSS), which may be the cause of the CHF. Transesophageal echcocardiography (TEE) is usually reserved for those patients in whom an initial transthoracic study was sub-optimal. However, identification of valvular vegetations or intracardiac thrombus can be done with much greater accuracy with TEE. Radionuclide angiography (first-pass and gated equilibrium) allows quantification of ejection fractions (EF) but does not give the wealth of physiologic information available from a carefully performed echocardiogram. Other diagnostic studies that should be done in patients with CHF include: complete blood count (CBC), iron studies, especially in patients who have dilated cardiomyopathy, and a urinalysis to look for the presence of nephrotic syndrome, serum electrolytes, TSH (especially in patients with atrial fibrillation and CHF), and ECG. As indicated below, patients with angina or large areas of ischemic or hibernating myocardium, cardiac catheterization is warranted.19 Right heart catheterization will help in tailoring the management. Right ventricular endomyocardial biopsy can be used to confirm the presence of infiltrative diseases such as amyloid, sarcoid, hemochromatosis, or acute myocarditis, but it is rarely indicated otherwise.19 Twenty-four-hour Holter monitoring can be done to look for arrhythmias or silent myocardial ischemia. To help differentiate a cardiac cause from a pulmonary cause of shortness of breath, a VO2max (O2 consumption) can be done.

Table 2. Recommended Tests forPatients with Suspected CHF

    1. Electrocardiogram~

    2. Complete blood count (CBC)_

    3. Urinalysis±

    4. Serum Creatinine@

    5. Serum Albumin§

    6. T4 and TSH*

    7. Echocardiogram

    8. Right and Left Heart Catheterization (if indicated)

    ~Look for: myocardial ischemia/old myocardial infarction, arrhytmias (atrial fibrillation-look for thyroid disease) left ventricular hypertrophy (consider diastolic dysfunction).

    _ Look for: anemia (reduced oxygen carrying capacity, which may worsen CHF)

    ± Proteinuria-suggestive of nephrotic syndrome

    @ Volume overload may be due to renal failure

    § Hypoalbuminemia may worsen peripheral edema due to excess extravascular volume

    * Hypo- as well as hyperthyroidism may cause orexacerbate CHF

CHF due to Coronary Artery Disease (CAD)

CHF secondary to coronary artery disease: In the United States, probably 40% of all CHF patients have CAD, and patients who develop CHF secondary to coronary artery disease have a significantly worse prognosis when compared to patients who have a non-ischemic cause of their heart failure, despite appropriate medical treatment with vasodilators, beta-blockers, etc.

Ischemia due to inadequate coronary blood flow results in myocellular hypoxia. This hypoxia leads to cellular and biochemical damage to the myocyte. Coronary flow occurs mostly in diastole. When the left ventricular end diastolic pressure (LVEDP) is elevated, the diastolic flow is reduced and further worsens myocardial ischemia. Diastolic dysfunction appears to be the most sensitive to ischemia. Myocardial relaxation can be impaired within 20 seconds of coronary occlusion, making it one the first manifestations of myocardial ischemia.

Myocardial stunning: Myocardial stunning occurs after either a single or multiple brief episodes of coronary insufficiency. There is essentially a downregulation of myocardial function in response to the low blood flow. The stunned myocardium contracts normally when stimulated with inotropes. Also, following lytic therapy, there is a latent period of a few days to a few weeks after which the stunned myocardium will recover function. Over time, stunned myocardium will recover function without any sort of intervention.

Hibernating myocardium: Hibernating myocardium occurs when there is a reduction of coronary perfusion, which leads to persistent left ventricular dysfunction. Studies have shown that ventricular function can be improved by restoring flow. The reduction in myocardial function is thought to be secondary to reduced tissue oxygen delivery. Other features of hibernating myocardium may include remodeling without necrosis, as demonstrated by Smart et al.15

Evaluation for hibernating myocardium: Heart failure patients with coronary artery disease must be evaluated for possible myocardial viability in areas of hypoperfusion. A search for a history of ongoing angina or angina-equivalent (i.e., shortness of breath, dyspnea on exertion) is vital when evaluating a patient with CHF thought to be secondary to coronary artery disease. Patients with severe left ventricular dysfunction (ejection fractions < 20%) may show significant improvement in functional status and ejection fraction after revascularization of hibernating myocardium, either with CABG or balloon angioplasty (PTCA).18

Thallium (201TI) scintigraphy and dobutamine echocardiography (DSE) are widely available and useful for identifying viable myocardium in patients with CHF secondary to coronary artery disease.16-17 However, 23% of dysfunctional segments showing severely reduced 201Tl uptake at four-hour redistribution improve after revascularization. Thus, a four-hour redistribution study may not be adequate to detect hibernating myocardium, but a 24-hour study may be able to detect viable myocardium in those patients who initially had fixed defects at four hours. Both the thallium uptake and dobutamine echo are of comparable sensitivity and specificity for the diagnosis of hibernating myocardium. The "gold standard" for detecting hibernating myocardium is positron emission tomography (PET scan), which is costly and not widely available, due to the expense of the equipment. Technetium -99m sestamibi is of value in measuring ventricular function and detecting ischemia but appears to be of lesser value in assessing myocardial viability.

Treatment of CHF

Once the diagnosis of CHF has been made and the severity of heart failure ascertained, then treatment should be begun immediately. The following discussion will be divided into the medical and surgical managements of CHF.

Medical Management of CHF

ACE inhibitors: These are the first-line drugs in patients with CHF. Most, if not all, patients with symptomatic or asymptomatic left ventricular dysfunction should be started on ACE inhibitors unless contraindicated. In clinical trials, ACEI have been shown in patients with symptomatic and asymptomatic CHF to reduce morbidity and mortality, improve quality of life, decrease hospitalizations, and prevent progression to a more severe disease. The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) showed improved survival in patients treated with enalapril for advanced CHF (NYHA Class IV).20 There was no significant reduction in mortality from sudden death. The improvement in mortality of 28% was due to a reduction in the progression of the heart failure. This study was terminated before completion because of the significant benefit of enalapril on survival, and it was felt to be unjustified to continue the study for ethical reasons.

In patients who are asymptomatic (Class I NYHA), enalapril has been shown to reduce hospitalizations for heart failure and shows a trend toward reduced mortality from CHF. Enalapril had no effect on sudden death when compared to placebo.21

When compared to the vasodilator combination of hydralazine-isosorbide dinitrate, enalapril decreased mortality by 11%. The benefit was greatest during the first two years of therapy.22 The benefit during the first two years was thought to be secondary to a reduction in the risk of sudden death in patients treated with enalapril. This was seen mostly in patients who were mildly symptomatic or those who had asymptomatic left ventricular dysfunction (NYHA Class I, II). The hydralazine/isosorbide dinitrate combination resulted in a significantly greater improvement in ejection fraction during the initial 13 weeks.

Ramapril, in the AIRE study, showed a 27% reduction in mortality when compared to placebo in patients with symptomatic heart failure following an acute myocardial infarction.23 The Survival and Ventricular Enlargement (SAVE) trial was a study that tested captopril vs. placebo in patients with LV systolic dysfunction following acute myocardial infarction.24 Those patients who were randomized to captopril experienced a 19% reduction in the risk of death from all causes and a 22% reduction in the risk of hospitalization for heart failure. Trandolapril, in the TRACE study, was found to reduce all-cause mortality by 22% and sudden death by 24%.25

ACEI may be started concomitant with diuretics for volume overload. Patients should not be volume depleted due to over-diuresis (orthostatic hypotension, prerenal azotemia, or metabolic alkalosis). If this occurs, then it would prudent to stop the diuretics for 24-48 hours prior to starting ACEI. Patients should be monitored closely for first-dose hypotension. This is more common in the elderly and those who have a low serum sodium. These patients should be given a smaller starting dose and titrated up slowly. Patients should be followed closely once an ACEI has been initiated. Serum potassium should be checked within one week of initiation; if the level is greater than 5.5 mEq/L, then the ACEI may need to be stopped. Some patients will have an increase in their serum creatinine after being started on ACEI. If the serum creatinine increases by more than 0.5 mg/dL, stopping the ACEI should be considered. Those patients who do not tolerate ACEI should be tried on the combination of hydralazine and isosorbide dinitrate. Changing therapeutic regimens should be seriously considered in patients who develop hyperkalemia or significant elevation in the creatinine. The dose of ACEI should be titrated up over 2-3 weeks, with the goal of reaching the doses used in large-scale clinical trials.26 In patients who become hypovolemic as a result of diuresis, the diuretic dose should be reduced, and, if the ACEI had been stopped, it should be restarted. If a patient fails a rechallenge with ACEI, then other vasodilators should be tried. Patients who develop a cough while on ACEI should be evaluated to see if the cough is due to heart failure before discontinuing the ACEI. In the SOLVD study, 37% of patients on ACEI developed cough,21 but 31% of patients in the placebo group also developed cough. Patients may also develop angioedema from the ACEI, which mandates stoppage of the drug and is an absolute contraindication to further use of ACEI.

Angiotensin II receptor antagonists: Combination therapy of AT1 receptor antagonists and ACEI would, theoretically, lead to a more complete suppression of the renin-angiotensin system. In the ELITE study, Pitt et al compared losartan and captopril in elderly patients with CHF.38 They found that there was a reduction in mortality and that losartan was better tolerated than captopril, in that fewer patients discontinued therapy in the losartan group. There was no difference in the incidence of renal dysfunction. Present guidelines do not recommend AT1 receptor antagonists as first-line therapy for CHF. They should be used as an additional vasodilator in patients already on maximal doses of ACEI. Studies are under way to look at the long-term benefits of this class of drugs.

Diuretics: Patients with symptoms and signs of significant fluid overload such as dyspnea on exertion (and, in severe cases, at rest), paroxysmal nocturnal dyspnea, and orthopnea with physical signs such as pulmonary rales, an S3, jugular venous distension, and pulmonary edema on chest x-ray should receive diuretics immediately. Those with only mild signs and symptoms of CHF can be managed with thiazide diuretics, which have a less acute diuretic effect when compared to furosemide. Hydrochlorthiazide (HCTZ) should be given initially at a dose of 25-50 mg/d. If patients continue to have significant fluid overload despite 50 mg HCTZ, they should be switched to a loop diuretic such as furosemide. Furosemide should be started at a dose of about 20-40 mg daily, with a lower dose in elderly adults. Initial outpatient dosing of HCTZ should be once a day, and, if the patient does not have a significant response with improvement in symptoms, the dose should be doubled instead of adding a second dose.

When patients have signs and symptoms of marked fluid overload, they should be given intravenous furosemide. There is no standard dose of IV furosemide; it should be titrated to the volume status of the patient. Maximum dose of IV furosemide should be 240 mg/d; above this, a second diuretic should be added. Continuous infusion of furosemide at a dose of 4-16 mg/h after a loading dose can achieve greater diuresis in patients with severe CHF when compared to intermittent intravenous dosing.18

Diuretics can deplete serum potassium and occasionally magnesium. This effect is usually counteracted when patients are on ACEI, which tends to increase the serum potassium. Serum potassium should be checked every three days or so after initiation of therapy until the level stabilizes. A low serum potassium can aggravate ventricular arrhythmias. Serum potassium is not a very accurate indicator of total body potassium; therefore, patients with serum potassium less than 4.0 mEq/L should be given supplements or put on a potassium-sparing agent.19 A rise in serum BUN disproportional to the creatinine usually indicates intravascular depletion and can be corrected by reducing the dose of the diuretic. In patients who are or become diuretic-resistant, a combination of diuretics can be tried (e.g., metolazone with a loop diuretic such as furosemide).

Diuretics have not shown to improve survival in CHF patients. They are ideally reserved for patients who are clinically volume overloaded. Side effects of these drugs include elevation of the renin, aldosterone, and angiotensin-II levels, gout, hyperglycemia, and dyslipidemias.

Digoxin: Cardiac glycosides are a group of drugs used for heart failure for nearly 200 years. Digoxin has been shown to improve symptoms in most patients with heart failure. Patients with mild or moderate CHF who are taken off of digoxin tended have a deterioration in exercise capacity and a reduction in the ejection fraction, when compared to similar patients who were left on the drug.27 In the DIG trial (Digitalis Investigation Group), the investigators found that digoxin did not reduce mortality, but the drug did produce a reduction in hospitalizations and a trend toward a decrease in the risk of death attributed to worsening heart failure.28 Digoxin, if not contraindicated, should be considered for all patients with CHF and atrial fibrillation and most, if not all, in normal sinus rhythm. Loading doses of digoxin are not needed. If renal function is normal, a dose of 0.25 mg po daily can be started. In those patients who have renal insufficiency or in the elderly, a lower dose of 0.125 mg daily can be used. Patients should be monitored closely for symptoms of toxicity (e.g., nausea and vomiting). In symptomatic patients, digoxin should be started along with ACEI and diuretics. It is unclear if digoxin is beneficial in asymptomatic patients, since no benefit has been shown toward survival. Levels of digoxin need not be checked regularly unless there is deterioration of heart failure symptoms, worsened renal function, suspicion of toxicity, or a new medication has been added that may alter the bioavailability.

Beta-Blockers: Due to the excessive neurohormonal activation in CHF, there is uncoupling of the Beta receptors (B1 and B2) in the heart with a 60-70% reduction in B1 receptor density in patients with idiopathic dilated cardiomyopathy (IDC). In patients with post-infarction cardiomyopathy, the down-regulation of the B1 receptors is not as severe. The changes in the adrenergic activity are seen mostly in the heart and kidney and minimally in the lungs or skeletal muscle. This excessive neurohormonal activation can have deleterious effects on the heart including myocyte necrosis, ischemia, and lowering the arrhythmia threshold.29 Recent studies have shown that beta-blockers are beneficial both in terms of survival and improvement in symptoms. Beta-adrenergic blockers blunt the effects of excessive neurohormonal activation on the heart and cause an up-regulation of the B1 receptors. Beta-blockers have several beneficial effects in patients with IDC, including improved ventricular diastolic function, reduction in sudden death, reduction in heart rate, and reduction in afterload by its actions on renin.

Metoprolol was evaluated in the Metoprolol in Dilated Cardiomyopathy trial (MDC).31 In this study, patients with IDC who were already on digitalis, diuretics, and an ACEI were randomized to receive metoprolol. Metoprolol was found to reduce the need for cardiac transplantation listing by 34%, but it had no effect on the primary end point-survival. Hospital readmissions for heart failure or arrhythmias were significantly lower in the metoprolol-treated group. There was also a significant increase in the ejection fraction and exercise tolerance in patients randomized to metoprolol.

The Cardiac Insufficiency Bisoprolol Study (CIBIS) evaluated the effect of the beta-blocker bisoprolol on mortality in patients with chronic heart failure.32 The study found that bisoprolol improved survival in patients with IDC, when compared to placebo. There was no difference in sudden death or the incidence of ventricular tachycardia or fibrillation.

Carvedilol is a nonselective beta-adrenoreceptor antagonist with peripheral vasodilatory activity due to its -adrenergic blocking activity. It also has an additional antioxidant activity, which may be beneficial in coronary ischemia syndromes. In the Multi-center Oral Carvedilol Heart Failure Assessment trial (MOCHA), low-dose (6.25 mg twice daily), medium-dose (12.5 twice daily), and high-dose (25 mg twice daily) carvedilol therapy was given to patients with moderate heart failure.33 Carvedilol had no effects on the primary end point, submaximal exercise. The U.S. Carvedilol Heart Failure StudyGroup (US-CHF) evaluated the effects of carvedilol in patients with CHF in four various protocols.34 Analyses of the data from this study found a 65% overall reduction mortality in the carvedilol group when compared to placebo. This led to the early termination of the study. Carvedilol, in other studies, has been reported to improve LV ejection fraction and LV end-diastolic and end-systolic dimensions, but it did not show any clear-cut improvement in symptoms of CHF.

In CHF patients who are decompensated, addition of beta-blockers may initially worsen their symptoms. Carvedilol was recently approved for the treatment of chronic heart failure, but the drug should be started when the heart failure is compensated. Standard CHF medications, including ACEI, diuretics, and digoxin should be maximized prior to initiating beta-blockers, and the lowest dose should be started (e.g., carvedilol 3.125 mg twice daily with meals). The initial dose of the drug should be given under supervision and blood pressure checked every 15 minutes for two hours. The drug can be up-titrated every two weeks, as tolerated. There may be an initial worsening of symptoms, followed by long-term improvement. Beta-adrenergic blockers should be combined with ACEI in all patients with left ventricular systolic dysfunction. If a patient decompensates while being up-titrated, then the dose of the beta-blocker can be reduced or stopped. Metoprolol should be initiated at very low doses (i.e., 6.25 mg twice daily) and titrated up over several weeks. The patient should be seen by the physician every time the drug dose is increased. Beta-blockers should be used cautiously, if at all, in patients with reactive airway disease, insulin-dependant diabetes mellitus, or peripheral vascular disease.

Positive Inotropic Agents: Oral inotropic agents, overall, have been disappointing. Enoximone, a phospodiesterase inhibitor, in the Enoximone Multicenter Trial (EMT), was found to increase mortality in patients with moderate-to-severe congestive heart failure. The drug had no effect on symptoms or exercise capacity. Milrinone, another phospho-diesterase inhibitor, in the PROMISE trial (Prospective Randomized Milrinone Survival Evaluation) was found to increase all-cause mortality by 28% and increased cardiovascular mortality by 34%.35 This effect was greater in patients with Class IV CHF. Pimobendan, a positive inotropic agent, was also evaluated and found to increase mortality by 1.8 times when compared to placebo. Vesnarinone, a quinolone derivative, was also found to increase mortality significantly at a dose of 120 mg/d (high-dose), and this led to premature termination of the study. Ibopamine, a dopaminergic agonist, reduced plasma norepinephrine levels, and decreased renin activity; it was also found to increase mortality.

Intravenous inotropic agents including dobutamine and milrinone are useful in patients with chronic heart failure that is refractory to therapy. Current practice is to initiate intravenous inotropes on admission for most patients with decompensated CHF. Benefits of these medications include increase in diuresis and increased tolerance for higher doses of ACEI and beta-blockers. Long-term, low dose dobutamine or milrinone infusion via a central venous catheter may help improve the patient's symptoms.40 Continuous intravenous therapy is most useful in patients who are difficult to wean off of inotropes. Milrinone, with its vasodilating activity is useful in patients with pulmonary hypertension and CHF. The advantage of milrinone over dobutamine is that rarely does a patient develop tolerance to the drug. Intermittent outpatient or inpatient therapy with IV inotropes for 24-48 hours may also improve symptoms in patients with refractory CHF who are admitted repeatedly for exacerbations.

Calcium Channel Blockers (CCBs): In theory, CCBs have the ability to reduce afterload and have anti-ischemic effects. In clinical trials, however, both diltiazem and nifedipine exacerbated CHF and possibly increased mortality in post-infarction patients with pulmonary edema or ejection fraction less than 40%.36,37 In the PRAISE trial, amlodipine, a longer-acting dihydropyridine CCB had a survival benefit in patients with CHF. In patients with heart failure secondary to coronary artery disease, amlodipine produced neither benefit nor detriment. Mortality trials are under way to test the hypothesis that amlodipine reduces mortality in patients with idiopathic dilated cardiomyopathy. The MACH-1 trial with mibefradil, a nonvoltage regulator T-channel calcium antagonist, is currently evaluating the use of this drug in heart failure patients.30

On the basis of currently available evidence, amlodipine is the only CCB that might have a role in therapy of patients with CHF. The drug may be used as an adjunctive measure in addition to standard therapy to help control hypertension or otherwise intractable ischemia.

Anticoagulation: Routine anti-coagulation is not recommended for heart failure.26 Patients who have a history of systemic embolism, pulmonary embolism, atrial fibrillation, or a mobile left-ventricular thrombi should be placed on warfarin. The prothrombin time should be 1.2-1.8 times each laboratory control (INR of 2.0-3.0).

Summary of Medical Management of CHF

Patients with CHF who are either symptomatic or asymptomatic should be started on an ACE inhibitor. Diuretics should be added if there are signs and symptoms of fluid overload. Digoxin, is most likely also beneficial in terms of improving symptoms. Angiotensin II receptor antagonists may have a role in patients who are not tolerant of ACEI due to a class-specific side-effect or in addition to ACEI. Anticoagulation with warfarin should be limited to patients with atrial fibrillation with CHF, those with documented left ventricular or left atrial clot, and those with a history of embolic stroke. Antiarrhythmics, especially amiodarone, may be beneficial in patients with a history of sudden death, syncope secondary to an arrhythmia, and documented ventricular tachycardia, but its role as prophylaxis in CHF patients remains unclear.

Newer Agents: Toborinone, an analogue of vesnarinone for parenteral use, has potent positive inotropic effects and may have a role in short-term in-patient management of CHF.

Surgical Management of CHF

In several trials, patients with moderate-to-severe LV dysfunction, angina, and multivessel disease enjoyed better survival after CABG.41 "Stunned" or "hibernating" viable myocardium will regain function with successful revascularization.

The role of percutaneous transluminal coronary angioplasty (PTCA) in heart failure management remains unclear, but almost certainly PTCA will be employed in more patients as stent technology and anti-platelet drugs improve.

Other surgical procedures that remain experimental include ventricular volume reduction surgery with repair of the mitral valve (the "Batista" procedure), dynamic cardiomyoplasty, TMR, and chronic ventricular assist devices (VADs). A number of trials are being conducted to evaluate the safety and efficacy of these procedures.


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