INTRODUCTION
The lifetime risk of developing heart failure (HF) is 20% in both men and women; this risk changes with age and time.1,2 The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult has been instrumental in more clearly articulating the early stages of HF, or the preclinical phase of the disease, and the patterns of disease associated with subsequent progression to clinical symptoms (Fig. 6-1).3 Those risk factors include hypertension, diabetes, hyperlipidemia, coronary artery disease, or any of these factors in combination. (Obviously, there are less readily identifiable risks as well, such as inherited forms of cardiomyopathy that will one day be easily recognized through gene profiling, but are currently unclear and therefore unhelpful to a busy clinician.)

When a clinician encounters a patient with symptomatic HF, the task is to apply the guidelines to the individual patient in a rational and logical manner. The therapeutic goals for the patient with HF are to improve quality of life and to improve survival. A number of studies have clearly documented that patients with HF, especially severe HF, value the absence of discomfort and breathlessness as much or more than the actual duration of their lives.4 Improvement in the quality of life may mean different things to different patients and may include the absence of hospitalizations, the ability to go shopping with family, or the capacity to continue gainful employment. It is a useful exercise to ask each patient what aspect of his or her illness is most troubling, and then follow the impact of disease management on this perceived disability. Certainly, an improvement of score on a formalized questionnaire used in HF to assess quality of life is an indication of enhanced function. Likewise, an increasing ability to perform during exercise testing is another way to document that this goal is being achieved. Irrespective of the method used to chart functional capacity, clinicians need to periodically assess whether their patients with HF are maintaining or improving quality of life. This is an important goal of therapy and one in which individual patients can be monitored.

There has been a deserved emphasis on the high mortality rate of patients with HF, and as public health advocates, we want to favorably impact survival.5–7 However, as practicing clinicians, our patients’ care can’t be dictated by our predictions of their demise. To date, there have been very few reliable methods to accurately calculate an individual’s prognosis after HF becomes evident.8 Rather, clinicians must use those treatments that have been shown in well-designed trials to improve survival, and hope that the broad results are applicable to the single patient at hand. This, then, is the art of medicine. Clinicians must forge ahead with the prescription of drugs that have been shown to be life saving in large studies for an individual patient, who may not resemble the study population.9,10 The goal of this chapter is to present a general therapeutic approach to the patient with HF, focusing on the patient with HF related to left ventricular systolic function. Many of the specific therapies discussed are addressed in considerably greater detail in dedicated chapters in this book. Our goal is to present a general therapeutic algorithm for the clinician encountering such a patient (Fig. 6-2).

INITIAL THERAPEUTIC APPROACH TO THE PATIENT WITH HEART FAILURE

Differentiate Systolic from Diastolic Heart Failure
The overwhelming numbers of studies performed in an HF population have been in those patients with dilated left ventricles that are poorly contracting, a syndrome often referred to as systolic dysfunction. Although there is a growing recognition that as many as 30–50% of all hospitalized patients with HF have normal cardiac contractility, or a preserved ejection fraction (EF), there remains a paucity of evidence-based recommendations for this group. (This syndrome has been called a variety of names including diastolic HF, or nondilated HF.) Most reviews stress the importance of excluding significant coronary ischemia as an exacerbating cause of HF symptoms, and all agree that meticulous control of hypertension is critical.11–13 Many of these patients with HF and a normal EF present with atrial arrhythmias, usually atrial fibrillation, and control of heart rate in this situation can be very useful. Obesity, diabetes, arthritis, and renal insufficiency are typical comorbid conditions in this group of patients, so a search for exacerbating drugs used to treat these conditions may be fruitful. Sleep apnea is common, and a screening interview for sleep disturbances is appropriate.14,15

Identify Correctable Causes of the Cardiac Dysfunction
If the patient has HF in the setting of a dilated left ventricle and has a low left ventricular EF as determined by an echocardiogram, nuclear ventriculography, or angiography, then the next phase is to pursue, by means of a complete history and physical examination and a few simple diagnostic tests, a search for reversible or correctable causes of the low systolic function. In the United States, the most common cause of dilated cardiomyopathy is chronic ischemia related to coronary artery It is important to exclude the role of coronary obstruction.16–22 A complete list of potentially artery disease as the cause of left ventricular dyscorrectable etiologies is beyond this chapter, but function. It is estimated that coronary artery dismay include illicit drug use or alcohol abuse, ease is the cause of HF in up to two-thirds of thyroid disorders, or uncontrolled hypertension. patients with left ventricular systolic dysfunction.23

It has been demonstrated that coronary revascularization improves symptoms and survival in patients with HF and angina, although patients with markedly impaired ventricular function were not included in these studies.24 As many as one-third of patients with nonischemic cardiomyopathy may complain of chest pain suggestive of angina, and in these patients noninvasive imaging may demonstrate perfusion defects and segmental wall motion abnormalities. Therefore, it is reasonable to proceed directly to coronary angiography in young patients with HF, angina, and left ventricular systolic dysfunction. It is debated whether or not routine coronary angiography is warranted in all patients, who present with HF and left ventricular dysfunction in the absence of chest pain, because coronary revascularization has not been clearly demonstrated to improve survival in patients without angina.25 Nonetheless, there are data to suggest that revascularization might improve ventricular function. Therefore, it is a reasonable strategy to exclude coronary artery disease in all patients with newly diagnosed HF and left ventricular systolic dysfunction even in the absence of chest pain.

Recognize and Treat Elevated Cardiac Filling Pressures
The next task when encountering the patient with left ventricular systolic function is to assess the clinical status of the patient. The clinical examination should focus on assessing the volume status of the patient, specifically, the degree of elevation of cardiac filling pressures. Most of the “congestion” that characterizes the HF syndrome is directly related to elevations of left-sided cardiac filling pressure, and provides the largest target for symptomatic improvement. Although the presence of peripheral edema, pulmonary rales, and evidence of pulmonary venous hypertension on chest x-ray are highly specific for elevated cardiac filling pressures, the sensitivity of these signs is low.26 The clinical examination finding with the highest sensitivity and specificity for elevated left-sided filling pressures is elevation of the jugular venous pressure.

For example, Drazner and colleagues examined the relationship of right- and left-sided filling pressures in 1000 patients with advanced cardiomyopathy, who underwent right heart catheterization.27 They demonstrated that a right atrial pressure greater than 10 mm Hg correlated with a pulmonary-capillary wedge pressure greater than 22 mm Hg in the large majority (~80%) of patients. The assessment of the jugular venous pressure is a critical skill for the management of patients with HF and can identify the presence of elevated intracardiac filling pressures in the absence of evidence of edema, rales upon auscultation of the lungs, or evidence of pulmonary venous hypertension on chestx-ray. A “square-wave” systolic blood pressure response to the Valsalva maneuver is also a useful clinical tool to detect elevated left ventricular end-diastolic pressure in patients with dilated cardiomyopathy.28–30

When volume overload is identified, the clinician needs to focus attention on a strategy to relieve congestion. Diuretics produce symptomatic benefits more rapidly than any other drug used for HF; they can relieve peripheral or pulmonary edema with hours or days.31 Diuretics are the only drugs used in the outpatient management of HF that can adequately control fluid retention. Nevertheless, they should never be the sole treatment for patients with Stage C HF, even if the patient becomes asymptomatic after the initiation of a diuresis. Using the skills outlined above, a clinician needs to determine whether a patient has signs or symptoms of fluid retention, and then begin a maintenance diuretic regimen. Although some patients with dilated cardiomyopathy, who have been stabilized on a standard regimen of neurohormonal antagonists may be effectively managed without diuretics, the large majority of patients will need a regular dose of diuretic, usually daily. Diuretic dosage may need to be adjusted as time and other circumstances change. Periodic physical examinations coupled with home weight monitoring and laboratory testing should be done to avoid azotemia or electrolyte imbalances. A key reason for follow-up office visits of the HF patient is to assess the need for diuretic dose adjustment.

Initiate Therapy with Neurohormonal Antagonists
All patients with a low EF (in the absence of aortic outflow obstruction) should be initiated and maintained on both an angiotensin-converting enzyme (ACE) inhibitor and a b-blocker.3 For historical reasons, clinicians commonly start an ACE inhibitor first and add a b-blocker as a second agent, but recent data suggest that starting a b-blocker as initial therapy has some advantages.32 Clinicians need to keep in focus that their ultimate task is to maintain patients on both drugs at the highest tolerated dosages. Thus, it is reasonable to start both drugs at very low doses and then uptitrate each drug alternately until target doses are reached or patients become intolerant. If hypotension or azotemia develops, reducing diuretics or staggering the dosing time of the drugs may alleviate symptoms.

Clinicians, in their eagerness, may simultaneously start a patient with newly diagnosed dilated cardiomyopathy and HF on diuretics, ACE inhibitors and b-blockers, all within a 12-hour period. The result is often hypotension, azotemia, or both, and the clinician may wrongly conclude that the patient is intolerant of these life-saving drugs. Once a patient is euvolemic, there is no specific time course that necessitates rushing to get a patient on both drugs. A slow steady approach over several weeks is usually more successful. Many times this can be done without an office visit, but rather through a nurse-administered titration protocol supervised by phone calls.

Unfortunately, not all persons tolerate treatment with an ACE inhibitor. With a 2–10% incidence of a dry cough, potential exacerbation of underlying renal dysfunction and a rare incidence of angioedema, ACE inhibitors have appreciable side effects. In an effort to antagonize the reninangiotensin system without the side effects of ACE inhibition, direct angiotensin receptor blockers (ARBs) were developed. ARBs bind to angiotensin II receptors, attenuating the diverse effects of this hormone. Now proven effective in treatment of HF, ARBs provide an attractive option in those intolerant of ACE inhibitor therapy.

Determine Need for Implantable Cardiac Defibrillators
The management of patients with systolic HF includes the evaluation for additional nonpharmacologic therapies that have been demonstrated to improve survival. The indications for implantable cardiac defibrillators (ICDs) in the systolic HF population continue to evolve. In patients with cardiac arrest due to ventricular tachycardia (VT) or ventricular fibrillation (VF), or hemodynamically significant sustained VT, an ICD is indicated. The ACC/AHA/NASPE guidelines consider the placement of an ICD a Class IIa indication in patients with ischemic cardiomyopathy with an EF less than 30%, who are at least 1 month post-myocardial infraction or 3 months postcoronary artery revascularization.33 This recommendation is supported by the results of MADIT II.34 The release of the results from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) trial suggests that all patients with New York Heart Association (NYHA) Class II HF and an EF less than 35% experience a mortality benefit from an ICD compared to treatment with standard medical therapy, including routine use of b-blockers, or the combination of a b-blocker and amiodarone, in addition to ACE inhibitor therapy. Clinicians encountering patients with HF must, therefore, consider the evaluation for an ICD in conjunction with standard pharmacotherapy. The interpretation and clinical implications of SCD-HeFT will continue to evolve as the data are interpreted by regulatory agencies and additional cost-effectiveness analyses are performed. Strictly interpreted, the data clearly demonstrated that in all patients with symptomatic HF and an EF less than 35%, regardless of etiology, placement of an ICD reduces mortality approximately 23% (hazard ratio 0.77; 95% confidence interval 0.62–0.96; P = 0.007).

Patient and Family Education
Fundamental to our algorithm is the initiation of patient (and family) education.35 There are some key principals to cover with the patient, including, the potential seriousness of the diagnosis; recommendations about diet, that is, whether the patient needs to restrict fluid or sodium; recommendations about exercise; develop a routine for the patient to self-monitor his or her volume status at home, usually done by daily weights; counsel about alcohol and/or nicotine use; an action plan for the patient, who may develop increasing symptoms; and finally, discuss end-of-life wishes. Although these instructions do take time initially, they will serve both the office staff and the patient well in the future. Moreover, there are an increasing number of electronic educational sites available on the Internet that will reinforce the instructions and teaching done in the office.

Assessment of Response to Therapy
It is important to assess a patient in a routine manner at each visit to accurately determine their symptomatic status. Patients with HF often begin to decrease their attempts at physical activity, usually subconsciously, so that over time their subjective complaints may diminish despite progressive cardiac deterioration. Ask about one or two items that a patient must do on a regular basis, such as making a bed or showering and dressing without stopping, as a routine at each visit. Always ask about social outings or visits with family members, as patients with severe HF or profound fatigue will stop undertaking even pleasurable encounters but may not volunteer this information. Think about incorporating some simple assessment of submaximal exercise into an office visit periodically. This may involve watching the patient walk in place, a measured walk in a hall, or a more formal treadmill test.36 The amount of information gained, including the possibility of noting marked increases in blood pressure, failure of heart rate to augment, or the aggravation of arrhythmias can often justify the time and expense of the test. There are also some standardized questionnaires that assess quality of life in patients with HF that can be self-administered in the office and maintained in the office file.37,38 Additional information that must be acquired and documented at each visit includes any emergency room visits or hospitalizations the patient may have experienced. A review must be made of each medication the patient is taking, including over-the-counter medications that could be exacerbating the HF syndrome. Certain arthritis or pain formulations are common culprits, as are some drugs used for diabetic management.39–41 Other important historical information includes the possibility of dizziness, syncope, chest pain, or severe sleep disturbances; all of these symptoms may be amenable to treatment or may require intervention.

APPROACH TO THE PATIENT WITH CONTINUED SYMPTOMS

Identify Unrecognized Elevation of Cardiac Filling Pressures
In the patient with continued symptoms, the clinician should continue to assess for evidence of persistent elevation of cardiac filling pressures. These patients often have continued elevation of cardiac filling pressures that is unrecognized. They may benefit from more aggressive diuretic doses, including the combination of a loop agent and a distal agent, although sometimes this approach is limited by cardiorenal limitation, defined by worsening renal function limiting the aggressiveness of diuresis. In these patients, it may be useful to define the underlying hemodynamic profile with a right heart catheterization and using this information to tailor therapy to the individual patient.42,43 Although not recommended for the routine management of patients with HF, in the refractory patient this approach may reveal a combination of elevated intracardiac filling pressures coupled with elevated systemic vascular resistance, and the judicious use of an intravenous vasodilator coupled with diuretic therapy may be necessary to achieve compensation and transition the patient to a more stable outpatient medical regimen that can sustain the improvements beyond the index hospitalization.44

Consider Additional Neurohormonal Antagonists
The clinician might also consider additional pharmacological agents in the patient with persistent HF symptoms despite treatment with adequate doses of a b-blocker and ACE inhibitor. The use of digoxin is a Class I indication for the treatment of symptoms of HF in conjunction with the use of diuretics, an ACE inhibitor, and a b-blocker.3 There is only one randomized and placebo-controlled clinical trial that evaluated the effect of digoxin therapy on mortality in patients with HF. The Digitalis Investigation Group (DIG) trial randomized 6800 persons with symptomatic HF on ACE inhibitor and diuretic therapy to treatment with digoxin or placebo.45 Although failing to reach its primary end point, a decrease in all-cause mortality, randomization to digoxin conveyed a significant decrease in risk of death or hospitalization due to worsening HF. Digoxin was well-tolerated and associated with few adverse side effects in this trial. Digoxin dosing should be adjusted for renal dysfunction and concomitant therapy with medications known to increase serum digoxin levels.

The use of an aldosterone antagonist should be considered in patients with recent or current symptoms of HF despite the use of digoxin, diuretics, an ACE inhibitor and a b-blocker. The Randomized Aldactone Evaluation Study (RALES) randomized 1663 persons with NYHA Class III–IV symptoms to treatment with spironolactone or placebo.46 At baseline, the majority of participants were receiving diuretics, an ACE inhibitor, and digoxin. Spironolactone conferred a significant reduction in the risk of death as well as a reduction in the risk for hospitalization from cardiovascular causes. Favorable side effect and safety profiles were also established as hyperkalemia, renal dysfunction, and hypotension were no different between the spironolactone and placebo groups. Gynecomastia and breast pain were significantly more common in the treatment group, likely due to the steroid activity of spironolactone. Although a single study, the Randomized Aldactone Evaluation Study (RALES) trial established spironolactone as a potent therapeutic agent in advanced HF. The main criticism of this study is the relatively low use of b-blocker therapy in the enrolled subjects. Nonetheless, the current ACC/AHA guidelines recommend use of spironolactone in persons with a history of NYHA Class IIII or IV symptoms, normal renal function, and normal serum potassium levels.3

Assess Need for Cardiac Resynchronization Therapy
Data continue to accumulate from randomized controlled clinical trials demonstrating that cardiac resynchronization therapy (CRT) may reduce symptoms, improve functional capacity, and possible improve mortality in select patients with systolic HF.47,48 Currently, the surface electrocardiogram is used as an indicator to identify patients who may benefit from CRT; patients with a prolonged QRS interval, especially if greater than 140 milliseconds, appear to benefit from CRT. Increasingly, however, there are data to suggest that the surface electrocardiogram lacks sensitivity in identifying patients who have significant mechanical contraction dyssynchrony.49 The key challenge is to use these techniques to improve our ability to identify patients with the greatest likelihood to benefit from CRT. It is appropriate to consider CRT in patients with refractory symptoms of HF and evidence of either interventricular or intraventricular dyssynchrony.

Evaluate Contribution of Related Comorbidities to Symptoms
In the HF patient with continued symptoms, the clinician should also consider other potential etiologies. Is there evidence of new or exacerbated ischemia that accounts for the patient’s symptoms? Perhaps a reevaluation for coronary artery disease should be considered. Is the patient’s fatigue and nocturnal restlessness a manifestation of sleep apnea rather than worsening HF with orthopnea? Sleep apnea, both obstructive and central, is common in patients with HF and can be treated.50,51 Depression is not uncommon in patients with HF and may contribute to increased mortality.52–54 Highly efficacious therapy is available to treat depression and should be utilized in these patients.

THE PATIENT WITH REFRACTORY HEART FAILURE
Despite great advances in our management strategies for HF, there will always be patients who do not respond to our best efforts or our most efficacious drugs. As our therapeutic approaches improve, the population of patients with advanced cardiomyopathy is increasing. Cardiac transplantation is an option for only a very select few of this group.55 The results of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study have revealed that in patients who are not candidates for cardiac transplantation, permanent ventricular assist devices (VAD) may improve survival and quality of life.56–59 These devices may become technologically improved in the future and may provide a solution for a larger and more meaningful group of patients. Most importantly, a repeat discussion about end-of-life decisions and wishes must be undertaken. Although home inotropic therapy may increase mortality, it may improve quality of life. Recent studies have demonstrated that in many patients with Stage D/refractory HF quality of life is more desired than length of life. Hospice is an appropriate alternative for many patients, as compared to an endless cycle of increasingly longer hospital admissions.60

SUMMARY
The clinician evaluating the patient with HF must differentiate systolic from diastolic HF. Diastolic HF is treated with diuretics and pharmacotherapy aimed at controlling heart rate and blood pressure. Randomized clinical trials are lacking in this population. For the patient with systolic HF, reversible causes of systolic dysfunction should be considered. A left heart catheterization to exclude coronary artery disease should be considered. The clinician must then focus upon treatment aimed at improving symptoms and improving survival. Symptom relief depends upon the recognition of elevated cardiac filling pressures and judicious use of diuretic therapy to reduce elevated cardiac filling pressures. Next, pharmacotherapy with an ACE inhibitor and b-blocker therapy is initiated. Frequent follow-up is critical to assess response to therapy as neurohormonal antagonists are uptitrated. Patient education is of paramount importance in achieving and maintaining clinical stability. The clinician must consider a variety of cardiac and noncardiac conditions in the patient with persistent symptoms.

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