Chapter 21: Heart Failure

Increased survivorship after acute myocardial infarction (MI) and improved treatment of hypertension, valvular heart disease, and coronary artery disease (CAD) have led to a significant increase in the prevalence of heart failure in the United States. Overall prevalence of any heart failure diagnosis is estimated at 2.6% (2.7% in men; 1.7% in women) and increases with age. Asymptomatic left ventricular systolic dysfunction (LVSD) has been found to be as prevalent as symptomatic LVSD: 1.4% and 1.5%, respectively. In patients with clinical symptoms of heart failure, moderate or severe isolated diastolic dysfunction appears to be as common as systolic dysfunction, and systolic dysfunction appears to increase with the severity of diastolic dysfunction.

As defined by the American Heart Association (AHA) and the American College of Cardiology (ACC), heart failure is “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.”As cardiac output decreases in response to the stresses placed on the myocardium (Table 21-1) activation of the sympathetic nervous and renin-angiotensin-aldosterone system occur. These neurohormonal adaptations help increase blood pressure for tissue perfusion and also increase blood volume to enhance preload, stroke volume, and cardiac output. These compensatory mechanisms, which increase afterload, also lead to further myocardial deterioration and worsening myocardial contractility.

Coronary artery disease and diabetes mellitus are the leading causes of heart failure in the United States. It is estimated that 60–70% of patients having systolic heart failure have CAD as the underlying etiology. CAD is a substantial predictor of developing symptomatic heart failure with LVSD compared to asymptomatic LVSD. Heart failure is twice as common in diabetic patients and is one of the most significant factors for developing heart failure in women. This is likely due to the direct effect of diabetes in developing cardiomyopathy as well as the effects of CAD risk and progression. Poorly controlled hypertension and valvular heart disease also remain major precipitants of heart failure. Often overlooked risk factors in the development of heart failure are smoking, physical inactivity or obesity, and lower socioeconomic status. Tobacco is estimated to cause approximately 17% of heart failure cases in the United States, likely due to the enhanced CAD risk. Lower socioeconomic status may limit access to higher quality health care, resulting in decreased adherence to treatment of modifiable risk factors such as hypertension, diabetes mellitus, and CAD.

The most important component to classifying heart failure is whether left ventricular ejection fraction (LVEF) is preserved or reduced (<50%). A reduced LVEF in heart failure is a powerful predictor of mortality. The American College of Cardiology (ACC)/American Heart Association (AHA) classified heart failure into stages emphasizing the progressive nature of the clinical syndrome. These stages more clearly define appropriate therapy at each level that can reduce morbidity and mortality and delay the onset of clinically evident disease (Table 21-2).

Patients in ACC/AHA stages A and B do not have clinical symptomatic heart failure but are at risk for developing heart failure. Stage A includes those at risk but not manifesting structural heart disease. Early identification and aggressive treatment of modifiable risk factors remain the best prevention for heart failure. Lifestyle modification, pharmacologic therapy, and counseling can improve or correct conditions such as CAD, hypertension, diabetes mellitus, hyperlipidemia, obesity, tobacco abuse, and alcohol or illicit substance abuse. Stage B represents patients who are asymptomatic but have structural heart disease or left ventricular systolic dysfunction. Stage C comprises the majority of patients with heart failure who have past or current symptoms and associated underlying structural heart disease, including left ventricular systolic dysfunction. Stage D includes refractory patients with heart failure who may need advanced and specialized treatment strategies.

The NYHA classification gauges the severity of symptoms for patients with stage C and D heart failure. The NYHA classification is a more subjective assessment that can change frequently, secondary to treatment response, but it is a well-established predictor of mortality.

A high index of suspicion is necessary to diagnose the syndrome of heart failure early in its clinical presentation, because of nonspecific signs and symptoms. Patients are often elderly with comorbidity, symptoms may be mild, and routine clinical assessment lacks specificity. A prompt diagnosis allows for early treatment with therapies proven to delay the progression of heart failure and improve quality of life. Evaluation is directed at confirming the presence of heart failure, determining cause, identifying comorbid illness, establishing severity, and guiding response to therapy. Heart failure is a clinical diagnosis for which no single symptom, examination, or test can establish the presence or absence with certainty.

A. Symptoms and Signs

The most common manifestations of symptomatic heart failure are dyspnea and fatigue, but many conditions present with these symptoms. Limited exercise tolerance and fluid retention may eventually lead to pulmonary congestion and peripheral edema. Neither of these symptoms necessarily dominates the clinical picture at the same time. The absence of dyspnea on exertion is helpful to rule out the diagnosis of heart failure with a sensitivity of 84%. Other symptoms that are helpful in diagnosing heart failure include orthopnea, paroxysmal nocturnal dyspnea (PND), and peripheral edema. PND has the highest specificity: 84% of any symptom for heart failure. It is important to remember that no single clinical symptom has been shown to be both sensitive and specific. A substantial portion of the population has asymptomatic left ventricular systolic dysfunction, and the history alone is insufficient to make the diagnosis of heart failure. However, a detailed history and review of symptoms remain the best approach in identifying the cause of heart failure and assessing response to therapy.

B. Physical Examination

The clinical examination is helpful to assess the degree of reduced cardiac output, volume overload, and ventricular enlargement. It can also provide clues to noncardiac causes of dyspnea. A third heart sound, S₃ (ventricular filling gallop), on examination is specific for increased left ventricular end-diastolic pressure and decreased left ventricular ejection fraction. It has the best specificity of any exam finding for heart failure: 99%. Thus, a third audible sound along with a displaced cardiac apex are both very predictive and effectively rule in a diagnosis of left ventricular systolic dysfunction. Volume overload from heart failure can present with many signs on examination. The presence of jugular venous distention and a hepatojugular reflex can be present and moderately effective in diagnosing heart failure. Other signs such as pulmonary rales (crackles), a murmur, or peripheral edema have a smaller but helpful effective in diagnosing heart failure.

Other exam findings can assist in determining causes of heart failures or assess other differential diagnosis. Cardiac murmurs may be an indication of primary valvular disease. Asymmetric rales or rhonchi on the pulmonary examination may suggest pneumonia or chronic obstructive pulmonary disease (COPD). Dullness to percussion or auscultation of the lungs could indicate pleural effusion. Examination of the thyroid can exclude thyromegaly or goiter, which could cause abnormal thyroid function precipitating heart failure. Hepatomegaly can indicate passive hepatic congestion.

C. Laboratory Findings

Objective tests can aid in confirmation of heart failure by assessing the differential diagnosis and excluding other possible causes for the signs and symptoms. A complete blood count can rule out anemia as a cause of high-output failure. Electrolyte (including magnesium and calcium) analysis may reveal deficiencies that are commonplace with treatment and can render the patient prone to arrhythmias. Hyponatremia is a poor prognostic sign indicating significant activation of the renin-aldosterone-angiotensin system. Abnormalities on liver tests can indicate hepatic congestion. Thyroid function tests can detect hyper- or hypothyroidism. Fasting lipid profile, fasting glucose, and hemoglobin A_1c level can reveal comorbid conditions that may need to be better controlled. Iron studies can detect iron deficiency or overload. If the patient is malnourished or an alcoholic and presents with high-output failure, thiamine testing is indicated to rule out deficiency related to beriberi. Further testing to determine any other etiologic factors of heart failure should be based on historical findings.

1. B-type natriuretic peptide

B-type natriuretic peptide (BNP) and N-terminal pro-BNP levels can be effectively utilized to evaluate patients presenting with dyspnea for heart failure. BNP is a cardiac neurohormone secreted from the ventricles and, to some extent, the atrial myocardium in response to stretching and increased wall tension from volume and pressure overload. Circulating BNP levels are increased in patients with heart failure and have a rapid turnover; thus they vary as volume status changes. Factors to consider when interpreting BNP levels are that they increase with age, are higher in women and African-American individuals, and can be elevated in renal failure. Overall, BNP appears to have better reliability than N-terminal pro-BNP, especially in older populations. Although no BNP threshold indicates the presence or absence of heart failure with 100% certainty, multiple systematic reviews have that shown normal or low BNP or N-terminal BNP levels can effectively rule out a heart failure diagnosis. The average BNP level for diagnosing heart failure in one review was 95 pg/ mL or an N-terminal pro-BNP level of 642 pg/ mL. Elevated BNP levels can assist in diagnosing heart failure, but the effect of this diagnostic tool is small at these cutoffs. As the levels increase, the specificity and likelihood of heart failure increases especially to differentiate between a pulmonary and cardiac cause of dyspnea (Table 21-3).

Recent studies have also shown that high BNP levels (>200 pg/mL) or N-terminal pro-BNP levels (>5180 pg/mL) during acute heart failure are a strong predictor of mortality and cardiovascular admissions events during the following 2–3 months. Some evidence also suggests that a 30–50% reduction in BNP at hospital discharge lead to improved survival and less frequent rehospitalization. Similarly, studies suggest that having improved outpatient BNP targets showed improvements in decompensations, hospitalizations, and mortality.

2. Electrocardiography (ECG)

The ECG helps identify possible causes of heart failure. Signs of ischemic heart disease, acute or previous myocardial infarction, left ventricular hypertrophy, left bundle branch block, or atrial fibrillation can be identified and lead to further cardiac evaluation and treatment options. A left bundle branch block with heart failure is a poor prognostic sign with an increased 1-year mortality rate from any cause, including sudden death. In terms of diagnostic value, a normal ECG (or only minor abnormalities) has a small effect on ruling out systolic heart failure. Similarly, the presence of atrial fibrillation, new T wave changes, or any abnormality has a small effect on the diagnostic probability of heart failure being present.

D. Imaging Studies

1. Chest radiography

The chest radiograph can provide valuable clues in patients presenting with acute dyspnea, especially to identify pulmonary causes such as pneumonia, chronic obstructive pulmonary disease, pneumothorax, or a mass. The presence of venous congestion and interstitial edema is more conclusive and effective in diagnosing heart failure (specificity levels 96% and 97%, respectively). Findings such as cardiomegaly and a pleural effusion are suggestive of heart failure but only slightly increase the likelihood of the diagnosis in dyspneic patients. Likewise, the absence of cardiomegaly or venous congestion only slightly decreases the probability of a diagnosis of heart failure.

2. Cardiac Doppler echocardiography

Echocardiography with Doppler imaging is the most important component in evaluation of suspected heart failure (Table 21-4). It identifies systolic dysfunction through assessment of left ventricular ejection fraction. Diastolic dysfunction can also be determined by assessing for elevated left atrial pressures as well as impaired left ventricular relaxation and decreased compliance.

Echocardiographic findings can also help differentiate among the various causes of heart failure, including ischemic heart disease (wall motion abnormalities), valvular heart disease or various cardiomyopathies such as dilated (idiopathic), hypertrophic, restrictive, or hypertensive cardiomyopathy (left ventricular hypertrophy). Other potential reversible etiologies of heart failure can be evaluated are pericardial disorders such as effusion or tamponade.

The routine reevaluation with echocardiography of clinically stable patients in whom no change in management is contemplated is not recommended. If the echocardiography results are inadequate or the body habitus of the patient makes it impractical, transesophageal echocardiography, radionuclide ventriculography, or cardiac catherization ventriculogram can be performed to assess left ventricular ejection fraction.

3. Cardiac catheterization

Coronary angiography is recommended for patients with new-onset heart failure of uncertain etiology, despite the absence of anginal symptoms or negative findings on exercise stress testing. Coronary angiography should be strongly considered for patients with LVSD and a strong suspicion of ischemic myocardium based on noninvasive testing (echocardiography or nuclear imaging).

As stated, heart failure remains a clinical diagnosis for which no single finding can establish its presence or absence with certainty. Historically, criteria’s such as Framingham and Boston have been developed that utilize history, examination, and chest radiography to better determine a clinical diagnosis of heart failure. Ultimately, using a combination of history, examination, laboratory analysis (including BNP testing), chest radiography, and ECG provide the best information in suspected cases while proceeding to evaluate left ventricular function by echocardiography.

Because heart failure is estimated to be present in only ~30% of patients with dyspnea in the primary care setting, clinicians need to consider differential diagnoses for dyspnea such as asthma, COPD, infection, interstitial lung disease, pulmonary embolism, anemia, thyrotoxicosis, carbon monoxide poisoning, arrhythmia, anginal equivalent (CAD), valvular heart disease, cardiac shunt, obstructive sleep apnea, and severe obesity causing hypoventilation syndrome.

Most evidence-based treatment strategies have focused on patients with systolic rather than diastolic heart failure; hence, stage-specific outpatient management of patients with chronic systolic heart failure (left ventricular systolic dysfunction) is the focus of the discussion that follows. Although stages A–D of the ACC/AHA heart failure classification represent progressive cardiac risk and dysfunction, the treatment strategies recommended at earlier stages are applicable to and recommended for later stages (see Table 21-2).

A. Systolic Heart Failure

1. High risk for systolic heart failure (stage A)

Individuals with conditions and behaviors that place them at high risk for heart failure but who do not have structurally abnormal hearts are classified as ACC/AHA stage A and should be treated with therapies that can delay progression of cardiac dysfunction and development of heart failure. Optimizing hypertension treatment based on the current national guidelines, such as the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) and JNC VIII panel members’ recommendations can reduce new-onset heart failure by 50%. Therapies such as diuretics, β-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs) are proven to be more effective than calcium channel blockers and doxazosin in preventing heart failure. The use of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors or statin therapy in CAD patients based on current hyperlipidemia guidelines [the updated Adult Treatment Panel III (ATP III)] can also reduce the incidence of heart failure by 20%.

Evidence-based disease management strategies for diabetes mellitus, atherosclerotic vascular disease, and thyroid disease, as well as patient avoidance of tobacco, alcohol, cocaine, amphetamines, and other illicit drugs that can be cardiotoxic, are also important components of early risk modification for prevention of heart failure. In diabetic patients, both ACEIs and ARBs (specifically losartan and irbesartan) have been shown to reduce new-onset heart failure compared with placebo. In CAD or atherosclerotic vascular disease patients without heart failure, reviews of the EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease) and HOPE (Heart Outcomes Prevention Evaluation) results show a 23% reduction in heart failure with ACEI therapy as well as reduced mortality, MIs, and cardiac arrest.

2. Asymptomatic with cardiac structural abnormalities or remodeling (stage B)

Patients who do not have clinical symptoms of heart failure but who have a structurally abnormal heart, such as a previous MI, evidence of left ventricular remodeling (left ventricular hypertrophy or low ejection fraction), or valvular disease, are at a substantial risk of developing symptomatic heart failure. Prevention of further progression in these at-risk patients is the goal, and appropriate therapies are dependent on the patient’s cardiac condition.

In all patients with a recent or remote history of MI, regardless of ejection fraction, ACEIs and β-blockers are the mainstay of therapy. Both therapies have been demonstrated in randomized control trials to cause a significant reduction in cardiovascular death and symptomatic heart failure. These therapies are vital in post-MI patients, as is evidence-based management of an ST elevation MI and chronic stable angina, to help further achieve reduction in heart failure morbidity and mortality.

In asymptomatic patients who have not had an MI but have a reduced left ventricular ejection fraction (nonischemic cardiomyopathy), clinical trials reported an overall 37% reduction in symptomatic heart failure when treated with ACEI therapy. The SOLVD (Studies of Left Ventricular Dysfunction) trial and a 12-year follow-up study confirmed the long-term benefit of ACEIs regarding the onset of symptomatic heart failure and mortality. A substudy of the SOLVD trial showed how enalapril attenuates progressive increases in left ventricular dilation and hypertrophy, thus inhibiting left ventricular remodeling. Despite a lack of evidence from randomized controlled trials, the ACC/AHA guidelines recommend β-blockers in patients with stage B heart failure, given the significant survival benefit that these agents provide in worsening stages of heart failure. The RACE (Ramipril Cardioprotective Evaluation) trial provided a clue as to why ACEIs are advantageous over β-blockers for nonischemic cardiomyopathy by demonstrating that ramipril is more effective than the β-blocker atenolol in reversing left ventricular hypertrophy in hypertensive patients.

There is no clear outcome evidence for the use of ARBs in asymptomatic patients with reduced left ventricular ejection fraction. ARB therapy is, however, a guideline recommended alternative in ACEI-intolerant patients. VALIANT (VALsartan In Acute myocardial iNfarcTion) was one trial that showed that the ARB valsartan was as effective as but not superior to captopril, an ACEI, in reducing cardiovascular morbidity and mortality in post-MI patients with heart failure or a reduced left ventricular ejection fraction. The combination of both therapies was no better than captopril alone.

3. Symptomatic systolic heart failure (stage C)

Patients with a clinical diagnosis of heart failure have current or prior symptoms of heart failure and structural heart disease with a reduced left ventricular ejection fraction comprise ACC/AHA stage C. This stage encompasses NYHA classes II, III, and IV, excluding patients who develop refractory end-stage heart failure (see Table 21-2). In patients with symptomatic heart failure and left ventricular dysfunction, neurohormonal activation creates deleterious effects on the heart, leading to pulmonary and peripheral edema, persistent increased afterload, pathologic cardiac remodeling, and a progressive decline in cardiac function. The overall goals in this stage are to improve the patient’s symptoms, slow or reverse the deterioration of cardiac functioning, and reduce the patient’s long-term morbidity and mortality.

Accurate assessment of the cause and severity of heart failure; the incorporation of previous stage A and B treatment recommendations; and correction of any cardiovascular, systemic, and behavioral factors (Table 21-5) are important to achieve control in patients with symptomatic heart failure. Moderate dietary sodium restriction (3–4 g daily) with daily weight measurement further enhance volume control and allow for lower and safer doses of diuretic therapies. Exercise training is beneficial and should be encouraged to prevent physical deconditioning, which can contribute to exercise intolerance in patients with heart failure.

Patients with symptomatic heart failure should be routinely managed with a standard therapy of a diuretic, an ACEI (or ARB if intolerant), and a β-blocker (see Table 21-2). The addition of other pharmacologic therapies should be guided by the need for further symptom control versus the desire to enhance survival and long-term prognosis. A stepwise approach to therapy is presented in Table 21-6 and expanded on later.

A. diuretics

Patients with heart failure who present with common congestive symptoms (pulmonary and peripheral edema) are given a diuretic to manage fluid retention and achieve and maintain a euvolemic state. Diuretic therapy is specifically aimed at treating the compensatory volume expansion driven by renal tubular sodium retention and activation of the renin-angiotensin-aldosterone system.

Loop diuretics are the treatment of choice because they increase sodium excretion by 20–25% and substantially enhance free water clearance. Furosemide is most commonly used, but patients may respond better to bumetanide or torsemide because of superior, more predictable absorptions and longer durations of action. To minimize the risk of over- or underdiuresis, the diuretic response should guide the dosage of loop diuretics (Table 21-7), with dose increases until a response is achieved. Frequency of dosing is guided by the time needed to maintain active diuresis and sustained volume and weight control.

Thiazide diuretics also have a role in heart failure, principally as antihypertensive therapy, but they can be used in combination with loop diuretics to provide a potentiated or synergistic diuresis. As a lone treatment, however, they increase sodium excretion by only 5–10% and tend to decrease free water clearance overall.

Symptom improvement with diuretics occurs within hours to days, as compared with weeks to months for other heart failure therapies. For long-term clinical stability, diuretics are not sufficient, and exacerbations can be greatly reduced when they are combined with ACEI and β-blocker therapies.

B. ACE inhibitors

ACEIs are prescribed to all patients with symptomatic heart failure unless contraindicated and have proven benefit in alleviating heart failure symptoms, reducing hospitalization, and improving survival. Current ACC/AHA guidelines recommend that all patients with left ventricular systolic dysfunction be started on low-dose ACEI therapy to avoid side effects and raised to a maintenance or target dose (see Table 21-7). There is, however, some uncertainty regarding target doses achieved in clinical trials, and whether these are more beneficial than lower doses. For ACEIs as a class, there does not appear to be any difference in agents in terms of effectiveness at improving heart failure outcomes.

C. β-blockers

In patients with NYHA class II or III heart failure, the β-blockers bisoprolol, metoprolol succinate (sustained release), and carvedilol have been shown to improve mortality and event-free survival. These benefits are in addition to ACEI therapy and support the use of β-blockers as part of standard therapy in these patients. A similar survival benefit has been shown for patients with stable NYHA class IV heart failure.

β-blocker therapy should be initiated near the onset of a diagnosis of left ventricular systolic dysfunction and mild heart failure symptoms, given the added benefit on survival and disease progression. Titrating ACEI therapy to a target dose should not preclude the initiation of β-blocker therapy. Starting doses should be very low, given their effectiveness (see Table 21-7) but doubled at regular intervals, every 2–3 weeks as tolerated, toward target doses to achieve heart rate reductions. Individual studies indicate that there might be a dose-dependent outcome improvement, but recent meta-analysis concluded that the magnitude of heart rate reduction (5 bpm reductions) was associated with an 18% reduction in the risk of death whereas the β-blocker dose was not.

Traditionally the negative inotropic effects of β-blockers were considered harmful in heart failure, but this impact is outweighed by the beneficial effect of inhibiting sympathetic nervous system activation. Current evidence suggests that these beneficial effects may not necessarily be equivalent among proven β-blockers. The COMET (Carvedilol or Metoprolol European Trial) findings showed that carvedilol (an α₁-, β₁-, and β₂-receptor inhibitor) is more effective than twice-daily dosed immediate-release metoprolol tartrate (a highly specific β₁-receptor inhibitor) in reducing heart failure mortality (40% vs 34%, respectively). Previous trials had investigated metoprolol succinate (sustained-release, once-daily dosing), but the COMET trial showed a mortality reduction even with metoprolol tartrate, a very cost-effective alternative. A recent systematic review and meta-analysis suggests, however, that the benefits may be a class effect with no superior agent over others.

Because β-blockers may cause a 4–10-week increase in symptoms before improvement is noted, therapy should be initiated when patients have no or minimal evidence of fluid retention. Relative contraindications include bradycardia, hypotension, hypoperfusion, severe peripheral vascular disease, a P-R interval of >0.24 seconds, second- or third-degree atrioventricular block, severe COPD, or a history of asthma. Race or gender differences in efficacy of β-blocker therapy have not been noted.

D. angiotensin ii receptor blockers

Certain ARBs (see Table 21-7) have been shown in clinical trials to be nearly as effective as, but not consistently as and not superior to, ACEIs as first-line therapy for symptomatic heart failure. The use of ARBs is recommended in ACEI-intolerant patients but not preferentially over ACEIs given the volume of evidence validating ACEIs. Despite unclear evidence, the ACC/AHA guidelines recommend that ARB therapy be considered in addition to ACEI and standard therapy for patients who have persistent symptoms of heart failure. A recent systematic review that analyzed the benefit of ARBs in heart failure found no mortality or morbidity benefit when compared to placebo or ACEI and no benefit to combination with an ACEI.

E. aldosterone antagonists

For selected patients with moderately severe to severe symptoms who are difficult to control (NYHA class III with decompensations or class IV), additional treatment options include the aldosterone antagonists spironolactone and eplerenone (see Table 21-7) to improve mortality and reduce hospitalizations. A recent trial also proved the same outcome benefit of eplerenone in milder symptomatic heart failure, NYHA class II, and reduced ejection fraction of 35%.

The addition of aldosterone antagonist therapy can cause life-threatening hyperkalemia in patients with heart failure, who are often already at risk because of reduced left ventricular function and associated renal insufficiency. Current guidelines recommend careful monitoring to ensure that creatinine is <2.5 mg/dL in men or <2.0 mg/dL in women and that potassium is maintained below 5.0 mEq/L (levels >5.5 mEq/L should trigger discontinuation or dose reduction). Higher doses of aldosterone antagonists and ACEI therapy should also raise concern for possible hyperkalemia, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX2) inhibitors, and potassium supplements should be avoided if possible. If the clinical situation does not allow for proper monitoring, the risk of hyperkalemia may outweigh the benefit of aldosterone antagonist therapy.

F. digoxin

Digoxin therapy is indicated only to reduce hospitalizations in patients with uncontrolled symptomatic heart failure or as a ventricular rate control agent if a patient has a known arrhythmia. The DIG (Digitalis Investigation Group) trial proved the benefit of digoxin added to diuretic and ACEI therapy in improving heart failure symptom control and decreasing the rate of hospitalization by 6%, but there was no overall mortality benefit. Subsequent retrospective subgroup analysis of the trial discovered some survival improvement at a serum digoxin concentration of 0.5–0.8 ng/mL in men. A similar but nonsignificant survival trend was also noted in women. Because survival is clearly worse when the serum digoxin concentration is >1.2 ng/mL, patients are best managed within the range noted to avoid potential adverse outcomes given the narrow risk/benefit ratio. Digoxin should be used cautiously in elderly patients, who may have impaired renal function that adversely affects drug levels.

G. hydralazine and nitrates

The combination of hydralazine and isosorbide dinitrate (H-I) is a reasonable treatment in patients, particularly African Americans, who have persistent heart failure symptoms with standard therapy. In V-HeFT I (Vasodilator Heart-Failure Trial), the mortality of African-American patients receiving H-I combination therapy was reduced, but mortality of white patients did not differ from that of the placebo group. In V-HeFT II, a reduction in mortality with the H-I combination was seen only in white patients who had been receiving enalapril therapy. No effect on hospitalization was found in either trial.

The A-HeFT (African-American Heart Failure Trial) findings further supported the benefit of a fixed dose H-I combination (see Table 21-7) by showing a reduction in mortality and heart failure hospitalization rates as well as improved quality-of-life scores in patients with moderate to severe heart failure (NYHA class III or IV) who self-identified as African-American. The H-I combination was in addition to standard therapies that included ACEIs or ARBs, β-blockers, and spironolactone.

H. anticoagulation

It is well established that patients with heart failure are at an increased risk of thrombosis from blood stasis in dilated hypokinetic cardiac chambers and peripheral blood vessels. Despite this known risk, the yearly incidence of thromboembolic events in patients with stable heart failure is between 1% and 3%, even in those with lower left ventricular ejection fractions and evidence of intracardiac thrombi. Such low rates limit the detectable benefit of warfarin therapy, and retrospective data analysis of warfarin with heart failure show conflicting results, especially given the major risk of bleeding. Warfarin therapy is indicated only in heart failure patients with a history of a thromboembolic event or those with paroxysmal or chronic atrial fibrillation or flutter. Likewise, the benefit of antiplatelet therapies, such as aspirin, has not been clearly proved, and these therapies could possibly be detrimental because of their known interaction with ACEIs. Aspirin can decrease ACEI effectiveness and potentially increase hospitalizations due to heart failure decompensation.

I. adverse therapies

Therapies that adversely affect the clinical status of patients with symptomatic heart failure should be avoided. Other than for control of hypertension, calcium channel blockers offer no morbidity or mortality benefit in heart failure. Nondihydropyridine calcium channel blockers (eg, diltiazem and verapamil) and older, short-acting dihydropyridines (eg, nicardipine and nisoldipine) can worsen symptoms of heart failure, especially in patients with moderate to severe heart failure. The newer long-acting dihydropyridine calcium channel blockers amlodipine and felodipine are safe but do not have a role in heart failure treatment and improving outcomes. NSAIDs can also exacerbate heart failure through peripheral vasoconstriction and by interfering with the renal effects of diuretics and the unloading effects of ACEIs. Most antiarrhythmic drugs (except amiodarone and dofetilide) have an adverse impact on heart failure and survival because of their negative inotropic activity and proarrhythmic effects. Phosphodiesterase inhibitors (cilostazol, sildenafil, vardenafil, and tadalafil) can cause hypotension and are potentially hazardous in patients with heart failure. Thiazolidinediones and metformin, both used in treatment of diabetes, can be detrimental in patients with heart failure because they increase the risk of excessive fluid retention and lactic acidosis, respectively.

J. implantable devices

Nearly one-third of all heart failure deaths occur as a result of sudden cardiac death. The ACC/AHA recommendations include the use of implantable cardioverter-defibrillators (ICDs) for secondary prevention of sudden cardiac death in patients with symptomatic heart failure; a reduced left ventricular ejection fraction; and a history of cardiac arrest, ventricular fibrillation, or hemodynamically destabilizing ventricular tachycardia. ICDs are recommended for patients with NYHA class II or III heart failure, a left ventricular ejection fraction of <35%, and a reasonable 1-year survival with no recent MI (within 40 days).

As heart failure progresses, ventricular dyssynchrony can also occur. This is defined by a QRS duration of >0.12 ms in patients with a low left ventricular ejection fraction (usually <35%) and NYHA class III or IV heart failure. Clinical trials have shown that cardiac resynchronization therapy with biventricular pacing can improve quality of life, functional class, exercise capacity, exercise distance, left ventricular ejection fraction, and survival in these patients. Patients who meet criteria for cardiac resynchronization therapy and an ICD should receive a combined device, unless contraindicated.

4. Refractory end-stage heart failure (stage D)

Despite optimal medical therapy, some patients deteriorate or do not improve and experience symptoms at rest (NYHA class IV). These patients can have rapid recurrence of symptoms, leading to frequent hospitalizations and a significant or permanent reduction in their activities of daily living. Before classifying patients as being refractory or having end-stage heart failure, providers should verify an accurate diagnosis, identify and treat contributing conditions that could be hindering improvement, and maximize medical therapy.

Control of fluid retention to improve symptoms is paramount in this stage, and referral to a program with expertise in refractory heart failure or referral for cardiac transplantation should be considered. Other specialized treatment strategies, such as mechanical circulatory support, continuous intravenous positive inotropic therapy, and other surgical management can be considered, but there is limited evidence in terms of morbidity and mortality to support the value of these therapies. Careful discussion of the prognosis and options for end-of-life care should also be initiated with patients and their families. In this scenario, patients with ICDs should receive information about the option to inactivate defibrillation.

B. Diastolic Heart Failure

Clinically, diastolic heart failure is as prevalent as LVSD, and the presentation of diastolic heart failure is indistinguishable from LVSD. Nearly 40–50% of patients with symptomatic heart failure experience diastolic failure. Patients with diastolic heart failure are more likely to be women, older, and have hypertension, atrial fibrillation, and left ventricular hypertrophy, but no history of CAD. Diastolic heart failure remains a diagnosis of exclusion in which a thorough differential of heart failure needs to be considered. Compared to systolic heart failure, the treatment of diastolic heart failure lacks validated evidence-based therapies. Management focuses on controlling systolic and diastolic blood pressure, ventricular rate, volume status, and reducing myocardial ischemia, because these entities are known to exert effects on ventricular relaxation. Diuretics are used to control symptoms of pulmonary congestion and peripheral edema, but care must be taken to avoid overdiuresis, which can cause decreased volume status and preload, manifesting as worsening heart failure.

Despite favorable trends in survival and advances in treatment of heart failure and associated comorbidities, prognosis is poor, thus indicating the importance of appropriate diagnosis and treatment. Following diagnosis, survival is 90% at 1 month but declines to 78% at 1 year and only 58% at 5 years. Mortality increases in patients both with and without symptomatic heart failure as systolic function declines. There is also no difference in survival between diastolic and systolic heart failure.