1940 PART 6 Disorders of the Cardiovascular System

TABLE 257-8 Differential Diagnosis of Heart Failure

SYMPTOM OR SIGN DIFFERENTIAL DIAGNOSIS

Dyspnea Chronic lung disease

Pulmonary arterial hypertension

Neuromuscular disease

Anemia

Iron-deficiency anemia

Edema Venous insufficiency

Nephrotic syndrome

Deep vein thrombosis

Lymphedema

Ascites Hepatic cirrhosis

Portal vein thrombosis

Malignant carcinomatosis

Pleural effusion(s) Chronic infection

Lung cancer

Collagen vascular or rheumatologic disease

Jugular venous distension Constrictive pericarditis

Pericardial effusion

Superior vena cava syndrome

Clinical management of patients with heart failure (HF) varies widely

based on the clinical phenotype at presentation. Those in the earliest

stage of disease with asymptomatic ventricular dysfunction (American

College of Cardiology [ACC]/American Heart Association [AHA]

stage B) may be amenable to treatment with neurohormonal antagonists, including angiotensin-converting inhibitors and β-adrenergic

receptor antagonists, with the goal of facilitating ventricular recovery

and preventing the development of clinical HF (not further discussed).

Those with symptomatic HF (ACC/AHA stage C) comprise a heterogeneous group in whom the approach to therapy is differentiated

largely based on measurement of the left ventricular ejection fraction.

Data from prospective, randomized clinical outcomes trials enrolling

patients with symptomatic chronic HF and reduced ejection fraction

(HFrEF) has provided a rich evidence base that supports the efficacy

of stepped pharmacologic therapy with neurohormonal antagonists,

including renin-angiotensin-aldosterone system (RAAS) antagonists,

neprilysin inhibitors, β-adrenergic receptor antagonists, and mineralocorticoid receptor antagonists, as a complement to device-based

treatment with cardiac resynchronization therapy and implantable

cardioverter-defibrillators. By contrast, treatment of patients with

symptomatic chronic HF and preserved ejection fraction (HFpEF)

has remained heavily symptom-focused owing to the lack of evidence

to support specific pharmacologic therapies to modify disease progression. Even with effective therapy, patients with both HFrEF and

HFpEF are at risk for clinical deterioration, typically as a consequence

of progressive sodium and fluid retention that fuels the development

of congestive symptoms and acute decompensated HF (ADHF). Management of these exacerbations (frequently hospital-based) is heavily

focused on hemodynamic stabilization, decongestion, and institution

of appropriate disease-modifying therapy in the transition back to

chronic ambulatory management. Recurrent episodes of ADHF despite

careful longitudinal follow-up and effective treatment may signal the

onset of an advanced or refractory HF phenotype (ACC/AHA stage

D) in which the risk of mortality from sudden death or end-stage HF

is high, and consideration of salvage therapies including cardiac transplant or mechanical circulatory support may be appropriate prior to

escalation of palliative measures (Chap. 260).

258 Heart Failure:

Management

Akshay S. Desai, Mandeep R. Mehra

magnetic stimulation, on HF morbidity and mortality requires further

study.

DIFFERENTIAL DIAGNOSIS

Many symptoms and signs suggesting HF may be caused by other

conditions (Table 257-8). In a patient with dyspnea, the clinician must

distinguish cardiac from pulmonary causes, although the differentiation may be difficult. For example, orthopnea may be a well-established

symptom in some patients with severe chronic lung disease. Patients

with underlying pulmonary disease may also experience episodic

shortness of breath during sleep that mimics PND. In chronic lung disease, this is usually due to accumulation of tracheobronchial secretions

and is relieved by coughing and expectoration, whereas in cardiac disease, the patient has to sit upright. Wheezing caused by bronchoconstriction may be a prominent symptom when left ventricular failure

supervenes in individuals with reactive airways disease. Patients with

cardiac asthma may be more likely to exhibit diaphoresis and varying

degrees of cyanosis compared to patients with bronchial asthma. Differentiating dyspnea related to HF versus pulmonary disease may be

impossible when the diseases coexist, a situation that is common in

chronically ill older patients with active or prior smoking. Following

effective diuresis, pulmonary function tests may help to determine the

predominant cause of dyspnea. In ambulatory patients with advanced

HF, cardiopulmonary exercise testing can also help to make this distinction. Finally, a very low BNP or NT-proBNP level may be helpful in

excluding HF as the cause of dyspnea in nonobese patients.

Apart from pulmonary disease, HF needs to be distinguished from

conditions in which congestion results from abnormal salt and water

retention but in which cardiac structure and function are normal (e.g.,

renal failure) and from noncardiac causes of pulmonary edema (e.g.,

acute respiratory distress syndrome). Non-HF causes of lower extremity edema such as venous insufficiency, lymphedema, and obesity

should also be considered.

Acknowledgement

Dr. Douglas L. Mann and Dr. Murali Chakinala contributed to this

chapter in the 20th edition, and some material from that chapter has

been retained here.

■ FURTHER READING

Adamo L et al: Reappraising the role of inflammation in heart failure.

Nat Rev Cardiol 17:269, 2020.

Aimo A et al: Imaging, biomarker, and clinical predictors of cardiac

remodeling in heart failure with reduced ejection fraction. JACC

Heart Fail 7:782, 2019.

Boorsma EM et al: Congestion in heart failure: A contemporary look

at physiology, diagnosis and treatment. Nat Rev Cardiol 17:641, 2020.

Dunlay SM et al: Type 2 diabetes mellitus and heart failure: A scientific statement from the American Heart Association and the Heart

Failure Society of America. Circulation 140:e294, 2019.

Lam CSP et al: Classification of heart failure according to ejection

fraction. J Am Coll Cardiol 77:3217, 2021.

Ponikowski P et al: 2016 ESC guidelines for the diagnosis and

treatment of acute and chronic heart failure: The task force for the

diagnosis and treatment of acute and chronic heart failure of the

European Society of Cardiology (ESC) developed with the special

contribution of the Heart Failure Association (HFA) of the ESC. Eur

Heart J 37:2129, 2016.

Verbrugge FH et al: Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol 62:485, 2013.

Yancy CW et al: 2013 ACCF/AHA guideline for the management

of heart failure: A report of the American College of Cardiology

Foundation/American Heart Association Task Force on Practice

Guidelines. J Am Coll Cardiol 62:e147, 2013.

Heart Failure: Management

1941CHAPTER 258

HEART FAILURE WITH PRESERVED

EJECTION FRACTION

■ GENERAL PRINCIPLES

Although clinical trials of renin-angiotensin-aldosterone antagonists,

digoxin, β-adrenergic receptor blockers, and neprilysin inhibitors have

been conducted in patients with HFpEF, none has conclusively demonstrated a mortality reduction. In the absence of specific pharmacologic

therapies proven to improve clinical outcomes, management of patients

with HFpEF is therefore focused on improving symptoms and effort

tolerance through lifestyle modification, control of congestion, stabilization of heart rhythm (particularly in those with atrial fibrillation),

control of blood pressure to guideline-recommended targets, and management of comorbidities that may contribute to disease progression

(including, for example, obesity, obstructive lung disease, obstructive

sleep apnea, diabetes/insulin resistance, anemia, iron deficiency, and

chronic kidney disease).

■ CLINICAL TRIALS IN HFpEF

Attempts to export the benefits of drugs that improve clinical outcomes

in patients with HFrEF, including angiotensin-converting enzyme

(ACE) inhibitors, angiotensin receptor blockers (ARBs), β-adrenergic

receptor blockers, digoxin, and mineralocorticoid receptor antagonists, to those with HFpEF have generally been unsuccessful. The

Candesartan in Heart Failure—Assessment of Mortality and Morbidity

(CHARM) Preserved study showed a statistically significant reduction in HF hospitalizations but no difference in all-cause mortality

in patients with HFpEF who were treated with the ARB candesartan.

Similarly, the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial demonstrated no differences in the composite

of cardiovascular death or HF hospitalization during treatment with

the ARB irbesartan compared with placebo. Apparent early benefits of

the ACE inhibitor perindopril on HF hospitalizations and functional

capacity in the Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study were attenuated over longer-duration follow-up.

The Digitalis Investigation Group (DIG) Ancillary Trial found no

impact of digoxin on all-cause mortality or on all-cause or cardiovascular hospitalization among patients with chronic HF, ejection fraction

(EF) >45%, and sinus rhythm, although a modest reduction in HF hospitalizations was noted. Although no dedicated study of beta blockers

has been conducted in HFpEF, the subgroup of elderly patients with

prior hospitalization and HFpEF enrolled in the Study of the Effects of

Nebivolol Intervention on Outcomes and Rehospitalization in Seniors

with Heart Failure (SENIORS) trial of nebivolol, a vasodilating beta

blocker, did not appear to experience significant reductions in all-cause

or cardiovascular mortality.

With regard to mineralocorticoid receptor antagonists, which have

potent antifibrotic effects in HFrEF, the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT)

trial explored the potential benefit of spironolactone compared to

placebo in HFpEF. This trial demonstrated no improvement in the

primary composite endpoint of cardiovascular death, HF hospitalizations, or aborted cardiac arrest but did show a reduction in HF hospitalizations among those allocated to spironolactone. Post hoc analyses

of the study suggested significant regional differences in the baseline

characteristics, event rates, adverse effects, and adherence to spironolactone among patients randomized in Russia and the Republic of

Georgia compared with those randomized in the Americas that raised

concerns about study conduct in Russian and Georgian sites. Apparent

reductions in cardiovascular death and HF hospitalization associated

with spironolactone among the subgroup of patients randomized in the

Americas suggest that these study design issues may have obscured a

signal of spironolactone benefit. These data have supported a weak recommendation for spironolactone in patients with HFpEF who meet the

inclusion criteria for the TOPCAT trial and are at low risk for adverse

effects, including hyperkalemia and worsening renal function, in

the most recent U.S. and European guidelines. However, the results of

the Aldosterone Receptor Blockade in Diastolic Heart Failure (ALDODHF) study in which spironolactone improved echocardiographic

indices of diastolic dysfunction but failed to improve exercise capacity,

symptoms, or quality-of-life (QOL) measures highlight the need for

further study. Ongoing trials, including the registry-based Spironolactone Initiation Registry Randomized Interventional Trial in Heart

Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) (SPIRRIT-HFpEF; clinicaltrials.gov identifier NCT02901184) and the randomized Study to Evaluate the Efficacy and Safety of Finerenone on

Morbidity and Mortality in Participants with Heart Failure and Left

Ventricular Ejection Fraction Greater than or Equal to 40% (FINEARTS-HF, clinicaltrials.gov identifier: NCT04435626) may provide

additional insight in this regard.

In contrast to the rather disappointing results of these studies of

targeted drug therapy, small studies of exercise training in patients

with HFpEF have suggested benefits on functional capacity and QOL,

indicating a possible role for lifestyle interventions to improve cardiorespiratory fitness in this population.

■ NOVEL TARGETS

A novel paradigm for understanding the pathophysiology of HFpEF

has focused on the role of microvascular endothelial inflammation

driven by comorbidities that results in impaired nitric oxide (NO)

signaling and associated increases in myocardial stiffening. This paradigm has emphasized the potential for improving outcomes in HFpEF

by enhancing NO bioavailability and improving downstream protein

kinase G–based signaling. In this regard, a small trial demonstrated

that the phosphodiesterase-5 inhibitor sildenafil improved filling pressures and right ventricular function in a cohort of HFpEF patients with

pulmonary venous hypertension. This finding led to the phase 2 trial,

Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX), in HFpEF patients

(left ventricular EF [LVEF] >50%) with New York Heart Association

(NYHA) functional class II or III symptoms, who received sildenafil at

20 mg three times daily for 3 months, followed by 60 mg three times

daily for another 3 months, compared with a placebo. There was no

improvement in functional capacity, QOL, or other clinical and surrogate parameters in those allocated to sildenafil compared to placebo.

On the premise that nitrates, which are NO donors, might improve

preload, coronary perfusion, endothelial function, and exercise tolerance, the Nitrate’s Effect on Activity Tolerance in Heart Failure with

Preserved Ejection Fraction (NEAT-HFpEF) study was conducted.

Isosorbide mononitrate did not improve QOL or submaximal exercise capacity and decreased overall activity levels in treated patients.

Inorganic nitrate compounds have also been shown to enhance NO

signaling but did not improve functional capacity compared to placebo among patients with HFpEF randomized in the Inorganic Nitrite

Delivery to Improve Exercise Capacity in Heart Failure with Preserved

Ejection Fraction (INDIE-HFpEF) trial.

Neprilysin inhibition is known to increase circulating levels of

various vasoactive peptides, including the natriuretic peptides, which

may facilitate cyclic guanosine 3′,5′-monophosphate based signaling,

enhance myocardial relaxation, and reduce ventricular hypertrophy.

Composite angiotensin receptor-neprilysin inhibition (ARNI) with

sacubitril-valsartan reduced cardiovascular mortality, overall mortality,

and HF hospitalization compared with enalapril among patients with

HFrEF randomized in the PARADIGM-HF trial. The PARAGON-HF

trial randomized 4822 patients with symptomatic HFpEF (LVEF

≥45%), elevated natriuretic peptides, and structural heart disease to

treatment with either sacubitril-valsartan or valsartan with the novel

composite primary endpoint of cardiovascular death and total hospitalizations for HF. Although there was a 13% reduction in the rate of

the primary composite endpoint in those allocated to sacubitril-valsartan,

this result narrowly missed the margin for statistical significance in

the primary statistical analysis (p = .06). Directional benefits in secondary endpoints including QOL, NYHA class, and renal function

favoring sacubitril-valsartan support a possible modest benefit of neprilysin inhibition in this population, particularly among patients with

lower (i.e., mildly reduced or mid-range) EF and women, subgroups

who appeared to derive greater benefit. On the basis of these data,

sacubitril-valsartan has recently been approved in the United States

1942 PART 6 Disorders of the Cardiovascular System

for treatment of symptomatic heart failure across the full spectrum of

ejection fraction, with benefits acknowledged to be greatest in those

with LVEF below normal. Further study may be required to define the

optimal therapeutic role for neprilysin inhibition in HFpEF.

Treatment of diabetic patients with inhibitors of the sodium-glucose

cotransporter-2 (SGLT-2) has been shown to reduce the incidence of

HF, raising the possibility that these agents may be effective in patients

with established HF. Addition of the SGLT-2 inhibitor dapagliflozin

to guideline-directed medical therapy of HFrEF was associated with

reductions in cardiovascular mortality and HF hospitalization among

patients with and without diabetes enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. Ongoing clinical trials of dapagliflozin (Dapagliflozin Evaluation to Improve

the Lives of Patients with Preserved Ejection Fraction Heart Failure

[DELIVER]; clinicaltrials.gov identifier: NCT03619213) and empagliflozin (Empagliflozin Outcome Trial in Patients with Chronic Heart

Failure with Preserved Ejection Fraction [EMPEROR-PRESERVED];

clinicaltrials.gov identifier: NCT03057951) will assess whether these

benefits can be extended to the population of patients with HFpEF,

both with and without diabetes.

■ CLINICAL GUIDING PRINCIPLES

In the absence of evidence-based, targeted medical therapy, treatment

of HFpEF should focus on decongestion, aggressive management of

medical comorbidities, and relief of exacerbating factors. A careful

diagnostic approach is critical, since patients with HF and a normal

or near normal LVEF compose a heterogenous group that includes

patients with infiltrative heart disease (amyloidosis, hemochromatosis, sarcoidosis), storage disease (Fabry’s disease, Gaucher’s disease),

hypertrophic cardiomyopathy, pericardial disease, pulmonary arterial

hypertension, valvular heart disease, and primary right ventricular

failure who may require a different management approach. For those

with true HFpEF, aggressive control of blood pressure to guidelinerecommended targets and relief of volume overload with diuretics are

critical to symptom relief. Excessive decrease in preload with diuretics

and vasodilators may lead to underfilling the ventricle and subsequent

azotemia, hypotension, and syncope. For patients at risk for coronary

heart disease, deliberate evaluation for ischemia and consideration of

coronary revascularization is important. Since clinical outcomes in

HFpEF are worse in the setting of atrial fibrillation, aggressive rate

control, anticoagulation, and early consideration of sinus rhythm restoration are important. Comorbidities such as obesity, obstructive lung

disease, sleep apnea, chronic kidney disease, and anemia/iron deficiency are increasingly recognized as important contributors to diminished functional capacity and QOL in patients with HFpEF and may be

additional targets for therapy. Some investigators have suggested that

the exercise intolerance in HFpEF is a manifestation of chronotropic

insufficiency and that such aberrations could be corrected with use of

rate responsive pacemakers, but this remains an inadequately investigated contention (Fig. 258-1).

ACUTE DECOMPENSATED HEART FAILURE

■ GENERAL PRINCIPLES

ADHF is a heterogeneous clinical syndrome most often resulting in

need for hospitalization due to confluence of interrelated abnormalities

of decreased cardiac performance, renal dysfunction, and alterations in

vascular compliance. Admission with a diagnosis of ADHF is associated with excessive morbidity and mortality, with nearly half of these

patients readmitted for management within 6 months, and a high

short-term (5% in-hospital) and long-term cardiovascular mortality

(20% at 1 year). Importantly, long-term outcomes remain poor, with

Pathology

Hypertrophy

Fibrosis/altered collagen

Infarction/ischemia

Heart Failure with Preserved Ejection Fraction: Pathology and Management

General Therapeutic Principles

• Reduce the congestive state

 – Caution to not reduce preload excessively

• Renin-angiotensin-aldosterone–directed therapy

 – ACEIs and ARBs ineffective (except in “prevention”)

 – Aldosterone antagonists (may be beneficial)

• Digoxin

 – Ineffective (may reduce hospitalizations)

• Beta blockers and calcium channel blockers

 – Ineffective (useful in preventing tachycardia in patients

 with AF)

• Phosphodiesterase-5 inhibitors

 – Sildenafil ineffective

• Novel Therapy

 – ARNIs (may be effective in selected patients)

 – SGLT-2 inhibitors (under investigation)

• Chronotropic insufficiency

 – ? Targeted pacing (unproven)

• Control blood pressure

 – Central aortic blood pressure control may be more relevant

• Maintain atrial contraction and prevent tachycardia

 – Efforts to maintain sinus rhythm in atrial fibrilation may be beneficial

• Treat and prevent myocardial ischemia

 – May mimic HF as an “angina equivalent”

• Detect and treat sleep apnea

 – Common co-morbidity causing systemic hypertension, pulmonary

 hypertension, and right heart dysfunction (adaptive servo-ventilation

 ineffective)

• Lifestyle modification

 – Diet and exercise to promote weight reduction and improve

 functional capacity

Specific Therapy Targets

(beyond general management)

Diabetes

Obesity

Aging

Atherosclerosis

Hypertension

Risk markers

FIGURE 258-1 Pathophysiologic correlations, general therapeutic principles, and results of specific “directed” therapy in heart failure (HF) with preserved ejection

fraction. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; SGLT-2, sodium-glucose

cotransporter-2.

Heart Failure: Management

1943CHAPTER 258

Extreme distress

Pulmonary congestion

Renal failure

Low pulse pressure

Cool extremities

Cardio-renal syndrome

Hepatic congestion

New onset arrhythmia

Valvular heart disease

Inflammatory heart disease

Myocardial ischemia

CNS injury

Drug toxicity

Renal insufficiency

Biomarkers of injury

Acute coronary syndrome, arrhythmia, hypoxia, pulmonary embolism, infection

High-Risk Features

Hypertensive

Heterogeneity of ADHF: Management Principles

Severe Pulmonary Congestion with Hypoxia

Hypoperfusion with End-Organ Dysfunction

Hypotension, Low Cardiac Output, and End-Organ Failure

Acute Decompensation

“Typical”

Acute Decompensation

“Pulmonary edema”

Acute Decompensation

“Low output”

Acute Decompensation

“Cardiogenic shock”

Normotensive

(usually not volume overloaded) (usually volume overloaded)

Hemodynamic monitoring

(suboptimal initial therapeutic response)

Inotropic therapy

(usually catecholamines)

Mechanical circulatory support

(IABP, percutaneous VAD,

ultrafiltration)

Inotropic therapy

(if low blood pressure or

diuretic refractoriness)

Vasodilators

Vasodilators

Vasodilators

Opiates

Diuretics

O2 and noninvasive ventilation

Diuretics

FIGURE 258-2 The distinctive phenotypes of acute decompensated heart failure (ADHF), their presentations, and suggested therapeutic routes. (Unique causes of ADHF,

such as isolated right heart failure and pericardial disease, and rare causes, such as aortic and coronary dissection or ruptured valve structures or sinuses of Valsalva, are

not delineated and are covered elsewhere.) CNS, central nervous system; IABP, intraaortic balloon pump; VAD, ventricular assist device.

a combined incidence of cardiovascular deaths, HF hospitalizations,

myocardial infarction, strokes, or sudden death reaching 50% at

12 months after hospitalization. The management of these patients

remains difficult and principally revolves around volume control and

hemodynamic optimization to maximize end-organ perfusion.

The first principle of management in ADHF is to identify and

address the factors that precipitated decompensation. Important historical factors to consider are nonadherence to medications, dietary

salt indiscretion, and usage of medications (including over-the-counter

preparations) that may exacerbate HF, including nonsteroidal antiinflammatory drugs, thiazolidinediones, tumor necrosis factor inhibitors, selected antidepressants, selected cancer therapies, cold and flu

preparations with cardiac stimulants, and some herbal preparations.

Coronary ischemia frequently drives HF exacerbation in patients with

atherosclerotic cardiovascular disease and should be systematically

investigated (either invasively or noninvasively) in all patients at risk

to identify candidates for revascularization. Atrial and ventricular

arrhythmias are common contributors to HF exacerbation and may

trigger the need for antiarrhythmic drug suppression, cardioversion,

or catheter ablation. Valvular heart disease is increasingly recognized

as a target for therapy in patients with recurrent HF exacerbations and

can be readily identified through echocardiography. Systemic infection

and pulmonary thromboembolism are additional triggers of HF decompensation and should be routinely considered.

Concurrent with the identification of HF precipitants, effective

management of ADHF requires pharmacologic therapy directed at

hemodynamic optimization, including relief of congestion, reduction

in afterload, and maximization of vital organ perfusion. The routine

use of a pulmonary artery catheter is not recommended and should

be restricted to those who present with features typical of low-output

HF or cardiogenic shock who may require vasopressor or mechanical

circulatory support, those who are resistant or refractory to diuretic

therapy, those with combined cardiorenal dysfunction in whom

therapeutic goals are difficult to define at the bedside, and those with

known or suspected pulmonary arterial hypertension in whom vasodilator therapy may be appropriate. Analysis of in-hospital registries

has identified several parameters associated with worse outcomes: a

blood urea nitrogen level >43 mg/dL (to convert to mmol/L, multiply

by 0.357), systolic blood pressure <115 mmHg, a serum creatinine level

>2.75 mg/dL (to convert to μmol/L, multiply by 88.4), and elevated cardiac biomarkers including natriuretic peptides and cardiac troponins.

A useful clinical schema to identify treatment targets for the various

phenotypic presentations and management goals in ADHF is depicted

in Fig. 258-2.

■ VOLUME MANAGEMENT

Intravenous Diuretic Agents Intravenous loop diuretic agents

rapidly and effectively relieve symptoms of congestion and are essential

when oral drug absorption is impaired. When high doses of diuretic

agents are required or when the effect of bolus dosing is suboptimal,

a continuous infusion may be needed to reduce toxicity and maintain

stable serum drug levels. Randomized clinical trials of high- versus

low-dose and bolus versus continuous infusion diuresis have not provided clear justification for the best diuretic strategy in ADHF, and as

such, the use of diuretic regimens remains an art rather than science.

For those refractory to loop diuretic treatment alone, addition of a

thiazide diuretic agent such as chlorothiazide or metolazone to provide

sequential nephron blockade may enhance natriuresis and facilitate

decongestion, but also increases the risk of significant hypokalemia.

1944 PART 6 Disorders of the Cardiovascular System

Change in weight is often used as a surrogate for adequate diuresis, but

this objective measure of volume status may be surprisingly difficult to

interpret, and weight loss during hospitalization does not necessarily

correlate closely with outcomes. Effective decongestion may also be

confirmed by improvement in clinical symptoms as well as the bedside

examination documenting normalization of the jugular venous pressure, clearance of pulmonary rales, suppression of cardiac gallops, and

resolution of peripheral edema, hepatomegaly, and abdominal ascites.

It is generally advisable to continue diuresis until euvolemia has been

achieved, since residual congestion or volume overload is strongly

associated with risk for recurrent decompensation. Predischarge measurement of natriuretic peptide levels, which are highly correlated with

risk for postdischarge mortality and readmission, may also be useful in

assessing the adequacy of therapy and stratifying risk.

The Cardiorenal Syndrome The cardiorenal syndrome is being

recognized increasingly as a complication of ADHF. Multiple definitions have been proposed for the cardiorenal syndrome, but at its simplest, it can be thought to reflect the interplay between abnormalities

of heart and kidney function, with deteriorating function of one organ

while therapy is administered to preserve the other. Approximately

30% of patients hospitalized with ADHF exhibit abnormal renal function at baseline, and this is associated with longer hospitalizations and

increased mortality. However, mechanistic studies have been largely

unable to find correlation between deterioration in renal function,

cardiac output, left-sided filling pressures, and reduced renal perfusion;

most patients with cardiorenal syndrome demonstrate a preserved cardiac output. It is hypothesized that in patients with established HF, this

syndrome represents a complex interplay of neurohormonal factors,

potentially exacerbated by “backward failure” resulting from increased

intraabdominal pressure and impairment in return of renal venous

blood flow. Continued use of diuretic therapy may be associated with

a reduction in glomerular filtration rate and a worsening of the cardiorenal syndrome when right-sided filling pressures remain elevated. In

patients in the late stages of disease characterized by profound low cardiac output state, inotropic therapy or mechanical circulatory support

has been shown to preserve or improve renal function in selected individuals in the short term until more definitive therapy such as assisted

circulation or cardiac transplantation is implemented.

Ultrafiltration Ultrafiltration (UF) is an invasive fluid removal

technique that may supplement the need for diuretic therapy. Proposed

benefits of UF include controlled rates of fluid removal, neutral effects

on serum electrolytes, and decreased neurohormonal activity. This

technique has also been referred to as aquapheresis in recognition of

its electrolyte depletion–sparing effects. In an initial study evaluating

UF versus conventional therapy, fluid removal was improved and

subsequent HF hospitalizations and urgent clinic visits were reduced

with UF; however, no improvement in renal function and no subjective differences in dyspnea scores or adverse outcomes were noted. In

the Cardiorenal Rescue Study in Acute Decompensated Heart Failure

(CARRESS-HF) trial, 188 patients with ADHF and worsening renal

failure were randomized to stepped pharmacologic care or UF. The

primary endpoint was a change in serum creatinine and change in

weight (reflecting fluid removal) at 96 h. Although similar weight loss

occurred in both groups (~5.5 kg), there was a rise in serum creatinine

among patients allocated to the UF group. Deaths and hospitalizations

for HF were no different between groups, but there were more adverse

events in the UF group, mainly due to kidney failure, bleeding complications, and intravenous catheter-related complications. This investigation argues against using UF as a primary strategy in patients with

ADHF who are diuretic-responsive. Whether UF is useful as a rescue

strategy in diuretic refractory patients with advanced renal disease

remains an open question, and this strategy continues to be employed

judiciously in such situations.

■ VASOACTIVE THERAPY

Vasodilators including intravenous nitroglycerin, sodium nitroprusside, and nesiritide (a recombinant brain-type natriuretic peptide) are

frequently used in ADHF to lower intracardiac filling pressures and

reduce systemic vascular tone. Rapid reduction in ventricular preload

and afterload with these therapies may be effective in providing symptom relief in patients with pulmonary edema and in restoring endorgan perfusion for those with low cardiac output and high systemic

vascular resistance. Nitroglycerine principally impacts venous tone and

ventricular preload, whereas sodium nitroprusside is a potent arterial

and venous vasodilator with more comprehensive effects on both preload and afterload. While intravenous nitroglycerine is commonly utilized as an adjunct to diuretics for acute management of symptomatic

HF and pulmonary edema, nitroprusside is typically reserved for use

in those with adequate arterial pressure or hemodynamic monitoring

due to the risk for hypotension. The hemodynamic effects of nesiritide

are intermediate between those of nitroglycerine and nitroprusside,

with head-to-head comparisons with nitroglycerine suggesting more

rapid reduction in pulmonary capillary wedge pressure and pulmonary

vascular resistance. Clinical utilization of nesiritide has waned due to

concerns raised regarding heightened risks of renal insufficiency and

mortality identified in early trials. The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF)

study randomizing 7141 patients with ADHF to nesiritide or placebo

did not confirm this risk, but also identified no clear clinical benefit

with regard to subsequent HF admissions, mortality, or symptom relief

(reduction in dyspnea). Renal function did not worsen, but increased

rates of hypotension were noted. A smaller study of low-dose nesiritide

in acute HF (Renal Optimization Strategies Evaluation Acute Heart

Failure Study [ROSE-AHF]) also showed no incremental benefit over

intravenous diuretics for relief of congestion or preservation of renal

function. Despite apparent safety in ADHF, the routine use of nesiritide

is accordingly not recommended.

Other novel vasodilators have been explored for the management

of ADHF. Recombinant human relaxin-2, or serelaxin, is a vasodilatory hormone known to contribute to cardiovascular and renal

adaptations during pregnancy. In the Relaxin in Acute Heart Failure

(RELAX-AHF) trial, 1161 patients hospitalized with ADHF, evidence

of congestion, and systolic pressure >125 mmHg were randomized to

treatment with serelaxin or placebo in addition to standard HF therapy.

Serelaxin improved dyspnea, reduced signs and symptoms of congestion, and was associated with less early worsening of HF. A positive signal of reduced mortality identified in an exploratory analysis prompted

a second study (RELAX-AHF2), which did not confirm an effect on

cardiovascular death or worsening HF. Accordingly, this agent was not

approved for use in clinical practice.

One hypothesis for the failure of vasodilator therapies to improve

clinical outcomes in ADHF despite favorable hemodynamic effects

is related to the acute injury hypothesis; in this model, acute HF is

analogized to presentation with an acute coronary syndrome, with the

initial hours of presentation representing a period of vulnerability to

myocardial damage (reflected in a rise in markers of myocyte injury

such as cardiac troponins) as a consequence of abrupt increases in ventricular wall stress related to acute plasma volume expansion. To test

this hypothesis, the Trial of Ularitide Safety and Efficacy in Acute Heart

Failure (TRUE-AHF) randomly allocated 2157 patients with acute HF

to early treatment with the synthetic natriuretic peptide ularitide (at

a dose sufficient to reduce ventricular wall stress) or placebo. Despite

a very short duration between initial clinical presentation and pharmacologic intervention (<6 h) and early hemodynamic benefits, no

improvement in clinical outcomes was observed in patients allocated

to ularitide at 6 months. Ularitide was associated with a higher rate

of hypotension and worsening serum creatinine. These data undermine the notion that acute myocardial damage related to ventricular

distension associated with HF exacerbation drives subsequent clinical

outcomes and argue against the clinical importance of early vasodilator

therapy in ADHF.

■ INOTROPIC THERAPY

Impairment of myocardial contractility often accompanies ADHF,

and pharmacologic agents that increase intracellular concentration

of cyclic adenosine monophosphate via direct or indirect pathways, such as sympathomimetic amines (dopamine, dobutamine) and

Heart Failure: Management

1945CHAPTER 258

phosphodiesterase-3 inhibitors (milrinone), respectively, serve as positive

inotropic agents. Their activity leads to an increase in cytoplasmic calcium. Inotropic therapy in those with a low-output state augments cardiac output, reduces systemic vascular resistance, improves perfusion,

and relieves congestion acutely. Although systematic head-to-head

comparisons are available to identify a “best” agent, slight variations

in the hemodynamic effects of inotropic drugs may condition selection of the appropriate drug for a given clinical context. Dopamine

exhibits dose-dependent effects on dopaminergic, α-, and β-adrenergic

receptors, with vasodilatory effects predominating at lower doses

(<2 μg/kg per min), β-adrenergic (inotropic) effects at moderate doses,

and α-adrenergic effects (vasoconstriction) at higher doses (typically

>10 μg/kg per min). Low-dose (“renal dose”) dopamine has been

explored as an adjunctive strategy for preservation of renal function

and augmentation of diuresis in acute HF but does not appear to

provide incremental advantage over routine therapy with intravenous

diuretics (ROSE-AHF).

Milrinone is typically associated with a greater reduction in systemic

and pulmonary vascular resistance than dobutamine and, accordingly,

carries a higher risk of systemic hypotension. Moreover, because milrinone has a longer half-life and is renally excreted, it requires dose

adjustments in the setting of kidney dysfunction. Because milrinone

acts downstream from the β1

-adrenergic receptor, it may provide an

advantage in patients receiving beta blockers when admitted to the

hospital.

Long-term inotropic therapy is associated with a heightened risk

of mortality in HF, perhaps due to the increased risk of arrhythmia

and sudden death. Routine, short-term use of milrinone in patients

hospitalized with ADHF in the Outcomes of a Prospective Trial of

Intravenous Milrinone for Exacerbations of Chronic Heart Failure

(OPTIME-CHF) trial was associated with increased risk of atrial

arrhythmias and prolonged hypotension, but no benefit with regard

to subsequent mortality or HF hospitalization. Accordingly, routine

use of inotropic support in ADHF is discouraged, and these agents are

currently indicated principally for short-term use as bridge therapy (to

either left ventricular assist device support or to transplant) in cardiogenic shock or as selectively applied palliation in end-stage HF.

Novel inotropic agents that leverage the concept of myofilament

calcium sensitization rather than increasing intracellular calcium

levels have been introduced. Levosimendan is a calcium sensitizer that

provides inotropic activity but also possesses phosphodiesterase-3

inhibition properties that are vasodilatory. Two trials, the second

Randomized Multicenter Evaluation of Intravenous Levosimendan

Efficacy (REVIVE II) and Survival of Patients with Acute Heart Failure

in Need of Intravenous Inotropic Support (SURVIVE), have tested

this agent in ADHF. SURVIVE compared levosimendan with dobutamine, and despite an initial reduction in circulating B-type natriuretic

peptide levels in the levosimendan group compared with patients in

the dobutamine group, this drug did not reduce all-cause mortality at

180 days or affect any secondary clinical outcomes. The second trial

compared levosimendan against traditional noninotropic therapy and

found a modest improvement in symptoms with worsened short-term

mortality and ventricular arrhythmias. Although levosimendan has

been approved for use to support management of HF in several countries worldwide, it is not approved for use in the United States, largely

owing to the lack of compelling data for incremental efficacy in comparison with conventional inotropic drugs or standard HF therapies.

(Table 258-1 depicts typical inotropic, vasodilator, and diuretic

drugs used in ADHF.)

■ OTHER THERAPIES FOR ADHF

Other trials testing unique agents have yielded disappointing results in

the situation of ADHF. Adenosine has been implicated as a mediator

of worsening renal function and diuretic resistance, and accordingly,

treatment with adenosine receptor antagonists was postulated to be

potentially beneficial in relieving symptoms and preserving renal

function in patients with acute HF. Among patients with acute HF

and renal dysfunction enrolled in the Placebo-Controlled Randomized

Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline

for Patients Hospitalized with Acute Decompensated Heart Failure

and Volume Overload to Assess Treatment Effect on Congestion and

Renal Function (PROTECT) trial, no cardiovascular or renal benefit

was observed. Similarly, despite compelling theoretical benefit of vasopressin receptor antagonism in acute HF (based on the central role of

vasopressin in mediating the fluid retention that contributes to worsening HF), no benefit of the oral selective vasopressin-2 antagonist

tolvaptan was seen with regard to mortality or HF-associated morbidity

in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome

Study with Tolvaptan (EVEREST) trial.

■ CLINICAL GUIDING PRINCIPLES

In the absence of data to support specific pharmacologic interventions

in ADHF, management is largely goal-directed and focused on decongestion to relieve symptoms, investigation and suppression of triggers

for recurrent decompensation, and careful transition to longitudinal

HF management. Patients who fail to respond adequately to medical

therapy or who develop hemodynamic instability may benefit from

pulmonary artery catheter placement to guide titration of vasoactive

therapy or inotropic support; in those with hemodynamics suggestive of cardiogenic shock, mechanical assist devices may be required

(Chap.  260). Following stabilization, all patients should receive education regarding HF self-management prior to discharge, including

guidance regarding diet and lifestyle modification, identification of

worsening HF symptoms, and whom to contact in the event of clinical

deterioration. Early postdischarge follow-up of patients following hospitalization for management of worsening HF is associated with lower

rates of hospital readmission. For patients with HFrEF hospitalized

with ADHF, data suggest that institution of appropriate guidelinedirected medical therapy prior to hospital discharge is associated with

higher rates of adherence to appropriate pharmacologic treatment in

longitudinal follow-up and may be associated with improved outcomes

in the early postdischarge interval. Most recently, in the Comparison of

Sacubitril-Valsartan Versus Enalapril on Effect on NT-proBNP in Patients

Stabilized from an Acute Heart Failure Episode (PIONEER-HF) study of

patients with HFrEF stabilized after hospital admission for ADHF, predischarge initiation of sacubitril-valsartan compared with enalapril was

associated with greater reductions in natriuretic peptides as well as lower

rates of composite death and HF readmission at 8 weeks.

HEART FAILURE WITH REDUCED

EJECTION FRACTION

The past 50 years have witnessed great strides in the management of

HFrEF. Treatment of symptomatic HF has evolved from a renocentric (diuretics) and hemodynamic therapy model (digoxin, inotropic

therapy) to an era of disease-modifying therapy with neurohormonal

antagonism. In this regard, RAAS blockers, beta-adrenergic receptor

blockers, and most recently, SGLT2 inhibitors, form the pillars of

pharmacotherapy and facilitate stabilization and even improvement

in cardiac structure and function with consequent reduction in symptoms, improvement in QOL, decreased burden of hospitalizations, and

a decline in mortality from both pump failure and arrhythmic deaths

(Fig. 258-3).

■ NEUROHORMONAL ANTAGONISM

Meta-analyses suggest a 23% reduction in mortality and a 35% reduction in the combined endpoint of mortality and hospitalizations for

HF in patients with symptomatic HFrEF treated with ACE inhibitors

(ACEIs). Addition of β-adrenergic receptor blockers to background

therapy with ACEIs provides a further 35% reduction in mortality.

Although placebo-controlled studies are lacking, a number of noninferiority trials have demonstrated comparable efficacy of ARBs and

ACEIs in patients with HFrEF, making ARBs a suitable alternative for

patients who are intolerant to ACEIs due to cough or angioedema.

Abundant data support the efficacy across the full spectrum of HF

severity (including those with NYHA class III–IV functional capacity),

as well as the safety data of these agents. These observations demonstrate the basis for the tolerability of these agents even in subgroups

at higher risk for adverse effects such as those with mild-moderate

1946 PART 6 Disorders of the Cardiovascular System

TABLE 258-1 Vasoactive Therapy in Acute Decompensated Heart Failure

DRUG CLASS GENERIC DRUG USUAL DOSING SPECIAL CAUTION COMMENTS

Inotropic therapy Use in hypotension, end-organ hypoperfusion, or shock states

Dobutamine 2–20 μg/kg per min Increased myocardial

oxygen demand,

arrhythmia

Short acting, an advantage; variable efficacy in presence of beta blockers

(requires higher doses); clinical tolerance to prolonged infusions; concerns

with hypersensitivity carditis (rare)

Milrinone 0.375–0.75 μg/kg per

min

Hypotension,

arrhythmia

Decrease dose in renal insufficiency; avoid initial bolus; effectiveness

retained in presence of beta blockers

Levosimendan 0.1 μg/kg per min;

range, 0.05–0.2 μg/kg

per min

Hypotension,

arrhythmia

Long acting; should not be used in presence of low blood pressure; similar

effectiveness as dobutamine but effectiveness retained in presence of beta

blockers

Vasodilators Use in presence of pulmonary congestion for rapid relief of dyspnea, in

presence of a preserved blood pressure

Nitroglycerin 10–20 μg/min, increase

up to 200 μg/min

Headache, flushing,

tolerance

Most common vasodilator but often underdosed; effective in higher doses

Nesiritide Bolus 2 μg/kg and

infusion at 0.01 μg/kg

per min

Hypotension Decrease in blood pressure may reduce renal perfusion pressure; bolus may

be avoided since it increases hypotension predilection

Nitroprusside 0.3 μg/kg per min

titrated to 5 μg/kg

per min

Thiocyanate toxicity

in renal insufficiency

(>72 h)

Requires arterial line placement for titration for precise blood pressure

management and prevention of hypotension

Serelaxin N/A (tested at 30 μg/

kg per d)

Baseline blood

pressure should be

>125 mmHg

Not widely commercially available; ineffective in confirmatory trials

Ularitide 15 ng/kg per min (48 h) Baseline blood

pressure >116 mmHg

Excess hypotension and increased serum creatinine

Diuretics First line of therapy in volume overload with congestion; may use bolus or

continuous dosing; initial low dose (1 × home dose) or high dose (2.5 × home

dose) equally effective with higher risk of renal worsening with higher dose

Furosemide 20–240 mg daily Monitor for electrolyte

loss

In severe congestion, use intravenously and consider continuous infusion

(not trial supported)

Torsemide 10–100 mg daily Monitor for electrolyte

loss

High bioavailability, can be given orally; anecdotally more effective in

advanced heart failure states if furosemide less bioavailable (due to gut

congestion)

Bumetanide 0.5–5 mg daily Monitor for electrolyte

loss

Can be used orally; intermediate bioavailability

Adjuvant diuretics

for augmentation

N/A Metolazone,

chlorthalidone,

spironolactone,

acetazolamide

Acetazolamide is useful in presence of alkalosis; metolazone given in 2.5- to

10-mg doses; concomitant use of loop diuretics and thiazides associated

with risk for severe hypokalemia, careful laboratory monitoring advised;

spironolactone is useful in presence of severe hypokalemia and normal

renal function

Abbreviation: N/A, not applicable.

Placebo

ACE inhibitor/ARB

β-Blockers

(carvedilol, metoprolol

succinate, bisoprolol)

Mineralocorticoid

receptor antagonist

Higher

Lower

ARNI

(instead of ACEi/ARB)

Vericiguat

Omecamtiv mecarbil

SGLT2 i

Endothelin antagonists

Xamoterol

(mixed β-agonist/antagonist)

Moxonidine

(imidazoline receptor agonist)

Oral inotropes

(vesnarinone, flosequinan)

• Erythropoietin for anemia

• Warfarin/low-dose

rivaroxaban to prevent

 thromboembolism (absent

 high risk features)

• SSRI for depression

• Statins for HF

• Adaptive Servo-Ventilation for

 central sleep apnea (increased

 mortality)

Potentially Effective

Ineffective Adjuncts

• N-3 PUFA

• Iron Supplementation

Special Populations

• Hydralazine/Isosorbide

• Ivabradine

Risk of mortality

FIGURE 258-3 Progressive decline in mortality with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) or angiotensin receptorneprilysin inhibitors (ARNIs), beta blockers, mineralocorticoid receptor antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and balanced vasodilators

(*selected populations such as African Americans); addition of selected therapies (ivabradine, vericiguat) may further reduce heart failure (HF) hospitalization but does not

substantially impact mortality; further stack-on neurohormonal therapy is ineffective or results in worse outcome; management of comorbidity (e.g., iron deficiency, sleep

apnea) is of unproven efficacy. HFrEF, heart failure with reduced ejection fraction; PUFA, polyunsaturated fatty acid; SSRI, selective serotonin reuptake inhibitor.

Heart Failure: Management

1947CHAPTER 258

chronic kidney disease. In diabetes mellitus and chronic obstructive

lung disease, these agents have been established as foundational therapy for HFrEF as directed by consensus guidelines. Both agents are

generally recommended for all patients with HFrEF, independent of

symptom burden, and should be titrated to the doses proven to provide

clinical benefit or to the maximally tolerated dose. The inability to

tolerate initiation or dose titration of neurohumoral antagonists due to

hypotension, worsening HF, or progressive renal insufficiency is a poor

prognostic marker and may be a cardinal manifestation of transition to

an advanced HF phenotype.

Class Effect and Sequence of Administration ACEIs and

ARBs exert their beneficial effects in HFrEF as a class; however, the

beneficial effects of beta blockers are thought to be limited to specific

drugs. Beta blockers with intrinsic sympathomimetic activity (xamoterol) and other agents, including bucindolol, have not demonstrated

a survival benefit. On the basis of the available data, beta blocker use

in HFrEF should ideally be restricted to carvedilol, bisoprolol, and

metoprolol succinate—agents tested and proven to improve survival in

clinical trials. Whether beta blockers or ACEIs should be started first

was answered by the Cardiac Insufficiency Bisoprolol Study (CIBIS)

III, in which outcomes did not vary based on the sequence of drug

initiation. Thus, it matters little which agent is initiated first; what does

matter is that optimally titrated doses of both ACEIs and beta blockers

be established in a timely manner.

Dose and Outcome In general, the benefits of neurohumoral

antagonists in HFrEF are closely related to the dose achieved, girding

the rationale for aggressive titration to target doses as defined by clinical trials. Prospective trials of high- versus low-dose ACEIs (ATLAS),

ARBs (HEAAL), and beta blockers (MOCHA) consistently favor the

higher dose, with lower rates of death and HF hospitalization seen

in the higher-dose group. Clinical experience suggests that, in the

absence of symptoms to suggest hypotension (fatigue and dizziness),

pharmacotherapy may be uptitrated every 2 weeks in stable ambulatory patients as tolerated. Notably, data from large registries in the

United  States and Europe suggest that guideline-directed medical

therapy for patients with HFrEF is frequently underutilized and underdosed, leaving considerable room for quality improvement.

■ MINERALOCORTICOID RECEPTOR ANTAGONISTS

Addition of mineralocorticoid receptor antagonists to treatment with

ACEI/ARBs and beta blockers in patients with symptomatic HFrEF

(NYHA class II–IV) is associated with further reductions in morbidity

and mortality. Elevated aldosterone levels in HFrEF promote sodium

retention, electrolyte imbalance, and endothelial dysfunction and may

directly contribute to myocardial fibrosis. Hyperkalemia and worsening renal function are concerns, especially in patients with underlying

chronic kidney disease, and renal function and serum potassium levels

must be closely monitored. Spironolactone is the most commonly

utilized agent in this class based on efficacy demonstrated in the Randomized Aldactone Evaluation Study (RALES) in patients with HFrEF

and NYHA class III–IV symptoms. Eplerenone (studied principally in

patients with milder NYHA class II symptoms and those with HF or

left ventricular dysfunction complication myocardial infarction) lacks

the antiandrogen effects of spironolactone and may be a suitable alternative for patients who experience sexual side effects (gynecomastia,

erectile dysfunction, diminished libido).

■ RAAS THERAPY AND NEUROHORMONAL

“ESCAPE”

Since angiotensin II can be generated by non-ACE pathways, levels of

angiotensin II may recover to pretreatment levels during long-term

ACEI therapy. This phenomenon of neurohormonal “escape” has

fueled interest in dual blockade of the RAAS using ACEI and ARBs

in combination. In both the Valsartan Heart Failure Trial (Val-HeFT)

and the Candesartan in Heart Failure Assessment of Reduction in

Mortality and Morbidity (CHARM-Added) trial, addition of an ARB

to an ACEI and other HF therapy was associated with a lower risk of

HF hospitalizations. Since neither trial mandated an evidence-based

dose of an ACEI, however, it remained unclear whether combination

therapy was clearly superior to a strategy of maximizing a single agent

through dose titration. Subsequent data from the Valsartan in Acute

Myocardial Infarction (VALIANT) trial suggested that the addition of

the ARB valsartan to an evidence-based dose of the ACEI captopril in

patients with HF complicating myocardial infarction was associated

with an increase in adverse events without any added benefit compared

with monotherapy for either group. The findings of the VALIANT trial

are buttressed by more recent data from the Aliskiren Trial to Minimize

Outcomes in Patients with Heart Failure (ATMOSPHERE), which randomly allocated 7016 patients with HFrEF to treatment with enalapril

(targeted dose 10 mg twice daily as recommended by guidelines), the

plasma renin inhibitor aliskiren, or the combination on top of standard

HF therapy. In that study, combination treatment with aliskiren and

enalapril was associated with higher rates of hyperkalemia, hypotension, and worsening renal function, but no incremental benefit with

regard to HF hospitalization or cardiovascular mortality. Together,

these data argue for a ceiling of benefit of angiotensin inhibition in

HFrEF, beyond which further inhibition brings more adverse effects

without additional efficacy. Guidelines discourage the combination of

an ACEI, ARB, and spironolactone in HFrEF due to the risks of hyperkalemia and renal dysfunction, and for most patients, treatment with

either an ACEI or ARB and spironolactone is appropriate.

■ ALTERNATIVE VASODILATORS

The combination of hydralazine and nitrates has been demonstrated

to improve survival in HFrEF. Hydralazine reduces systemic vascular

resistance and induces arterial vasodilatation by affecting intracellular calcium kinetics; nitrates are transformed in smooth muscle cells

into NO, which stimulates cyclic guanosine monophosphate production and consequent arterial-venous vasodilation. This combination

improves survival but to a lesser extent than ACEIs. However, in

individuals with HFrEF unable to tolerate RAAS-based therapy for

reasons such as renal insufficiency or hyperkalemia, this combination

is preferred as a disease-modifying approach. A trial conducted in

self-identified African Americans, the African-American Heart Failure Trial (A-HeFT), studied a fixed dose of isosorbide dinitrate with

hydralazine in patients with advanced symptoms of HFrEF who were

receiving standard background therapy including an ACEI and beta

blocker. The study demonstrated improvements in survival and hospital admission for HF in the treatment group. Adherence to this regimen

is limited by the thrice-daily dosing schedule.

■ NOVEL NEUROHORMONAL ANTAGONISTS

Despite an abundance of animal and clinical data demonstrating deleterious effects of activated neurohormonal pathways beyond the RAAS

and sympathetic nervous system, targeting such pathways with incremental blockade has been largely unsuccessful. As an example, the endothelin antagonist bosentan is associated with worsening HF in HFrEF

despite demonstrating benefits in right-sided HF due to pulmonary

arterial hypertension. Similarly, the centrally acting sympatholytic agent

moxonidine worsens outcomes in left HF. The combined drug omapatrilat hybridizes an ACEI with a neutral endopeptidase (neprilysin)

inhibitor, and this agent was tested in the Omapatrilat Versus Enalapril

Randomized Trial of Utility in Reducing Events (OVERTURE) trial.

This drug did not favorably influence the primary outcome measure of

the combined risk of death or hospitalization for HF requiring intravenous treatment compared with enalapril alone, and notably, the risk of

angioedema was increased in patients assigned to omapatrilat.

The risk of angioedema with composite ACE/neprilysin inhibition

appears to be related to excessive blockade of bradykinin breakdown

by this combination. Blockade of angiotensin at the receptor level with

an ARB leaves intact the ACE pathway for bradykinin breakdown and

is associated with lower angioedema risk. Recently, a composite ARNI,

sacubitril-valsartan (formerly LCZ696), was developed and applied to

the treatment of patients with HFrEF. In the PARADIGM-HF trial,

8399 patients with HFrEF treated with guideline-directed medical

therapy were randomly allocated to treatment with either enalapril or

sacubitril-valsartan after a run-in period designed to ensure tolerability

1948 PART 6 Disorders of the Cardiovascular System

TABLE 258-2 Guideline-Directed Pharmacologic Therapy and Target Doses in Heart Failure with Reduced Ejection Fraction

DRUG CLASS GENERIC DRUG

MEAN DAILY DOSE IN

CLINICAL TRIALS (mg) INITIATION (mg) TARGET DOSE (mg)

Angiotensin-Converting Enzyme Inhibitors

Lisinopril 4.5–33 2.5–5 qd 20–35 qd

Enalapril 17 2.5 bid 10–20 bid

Captopril 123 6.25 tid 50 tid

Trandolapril N/A 0.5–1 qd 4 qd

Angiotensin Receptor Blockers

Losartan 129 50 qd 150 qd

Valsartan 254 40 bid 160 bid

Candesartan 24 4–8 qd 32 qd

Aldosterone Antagonists

Eplerenone 42.6 25 qd 50 qd

Spironolactone 26 12.5–25 qd 25–50 qd

Beta Blockers

Metoprolol succinate CR/XL 159 12.5–25 qd 200 qd

Carvedilol 37 3.125 bid 25–50 bid

Bisoprolol 8.6 1.25 qd 10 qd

Arteriovenous Vasodilators

Hydralazine isosorbide dinitrate 270/136 37.5/20 tid 75/40 tid

Fixed-dose hydralazine/isosorbide

dinitrate

143/76 37.5/20 qid 75/40 qid

Angiotensin Receptor-Neprilysin Inhibitor

Sacubitril-valsartan 375 100 bid 200 bid

Novel Therapies (Under Investigation)

Vericiguat (sGC stimulator) 9.2 2.5 qd 10 qd

Dapagliflozin, Empagliflozin

(SGLT-2 inhibitors)

10 10 qd 10 qd

Omecamtiv mecarbil (myosin

activator)

Not reported 25 bid Up to 50 mg bid (based on

plasma concentrations)

Abbreviations: sGC, soluble guanylyl cyclase; SGLT-2, sodium-glucose cotransporter-2.

of both drugs at target doses. Compared to those assigned to enalapril,

patients assigned to sacubitril-valsartan experienced a dramatic 20%

reduction in the composite primary endpoint of cardiovascular death

or HF hospitalization and a 16% reduction in all-cause mortality, as well

as clinically important improvements in QOL measures. Sacubitrilvalsartan was well tolerated and associated with lower rates of hyperkalemia and worsening renal function, but greater rates of symptomatic hypotension, than enalapril. Guidelines now advocate a switch to

ARNI for patients with symptomatic HFrEF who tolerate ACEIs and

ARBs, and emerging data suggest that up-front utilization of ARNI in

patients with de novo HF naïve to ACEIs/ARBs may also be appropriate for those with adequate blood pressure to tolerate it. Given ongoing

concern for angioedema, use of ARNI is contraindicated in patients

with prior history of angioedema, and those being transitioned from

ACEIs should receive ARNI only after a 36-hour gap to limit the risk of

overlap. Table 258-2 lists the common neurohormonal and vasodilator

regimens for HFrEF.

■ HEART RATE MODIFICATION

Distinct from β-adrenergic receptor blockers, ivabradine, an inhibitor

of the If

 current in the sinoatrial node, selectively reduces heart rate

without affecting cardiac contractility or vascular tone. The Systolic

Heart Failure Treatment with Ivabradine Compared with Placebo Trial

(SHIFT) was conducted in patients with NYHA class II or III HFrEF, prior

HF hospitalization, sinus rhythm, and heart rate >70 beats/min. Ivabradine reduced the combined endpoint of cardiovascular-related death

and HF hospitalization in proportion to the degree of heart rate reduction, which supports the notion that heart rate may be a therapeutic

target in patients with HFrEF in sinus rhythm. Importantly, despite

a protocol requirement for patients to be treated with a maximally

tolerated dose of a beta blocker prior to study entry, 10% of patients

randomized were not treated with a beta blocker, and 75% were

treated at subtarget doses. Accordingly, it remains unclear whether

this agent would have been effective in patients receiving robust,

guideline-recommended therapy for HF; however, these data do support the potential value of ivabradine as an adjunct or alternative in

those who are intolerant to initiation or dose titration of beta blockers.

Clinical guidelines have been adapted to encourage consideration of

ivabradine in patients with HFrEF who remain symptomatic after

treatment with guideline-based ACEi/ARB/ARNI, beta blockers, and

mineralocorticoid receptor antagonists; are in sinus rhythm; and have

a residual heart rate >70 beats/min.

■ SGLT-2 INHIBITION

Inhibitors of SGLT-2 have been shown to reduce cardiovascular events

and mortality among patients with type 2 diabetes mellitus at high

cardiovascular risk or with established atherosclerotic cardiovascular

disease. A particular signal of benefit has been seen with regard to the

incidence of HF hospitalization, which was reduced by 35% in comparison to placebo in the Empagliflozin Cardiovascular Outcome Event

Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOMES)

study. Because the cardiovascular benefits of SGLT-2 inhibition appear

to be unrelated to the degree of reduction in hemoglobin A1c, it has been

postulated that the HF benefits of this therapy might be extended to

patients without diabetes mellitus. Recently, the Dapagliflozin in Heart

Failure (DAPA-HF) study randomized 4744 patients with symptomatic

HFrEF treated with guideline-directed medical therapy (including a beta

blocker, ACEI/ARB/ARNI, and spironolactone in >70% of patients) to

Heart Failure: Management

1949CHAPTER 258

treatment with either the SGLT-2 inhibitor dapagliflozin (dosage 10 mg

daily) or placebo over a median duration of follow-up of 18.2 months.

Patients allocated to dapagliflozin experienced a highly significant 26%

reduction in the primary composite endpoint of worsening HF or death

from cardiovascular causes, an effect that was consistent in both patients

with (42%) and without diabetes mellitus at baseline. These results have

been reinforced by the results of the EMPEROR-Reduced trial, in which

3730 patients with symptomatic HF and ejection fraction of 40% or less

were randomized to treatment with empagliflozin (dosage 10 mg once

daily) or placebo in addition to recommended therapy. Over median 16

month follow up, patients allocated to empagliflozin experienced a 25%

reduction in the primary composite endpoint of cardiovascular death

or hospitalization for HF, an effect that was again consistent regardless

of the presence or absence of diabetes mellitus. Together, these studies

have driven consensus guidelines to consider use of SGLT2 inhibitors as

foundational therapy for HF alongside ARNI, beta-blockers, and mineralocorticoid receptor antagonists.

■ SOLUBLE GUANYLYL CYCLASE STIMULATION

Soluble guanylyl cyclase (sGC) is a key enzyme of the NO signaling pathway that catalyzes synthesis of cyclic guanosine monophosphate (GMP),

producing vasodilation. Vericiguat is a novel oral sGC stimulator that

enhances cyclic GMP and NO signaling by directly stimulating sGC and

sensitizing sGC to endogenous NO. The Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA)

randomly assigned 5050 patients with chronic HF, NYHA class II–IV

symptoms, LVEF <45%, elevated natriuretic peptide levels, and evidence of worsening HF (requiring recent hospitalization or intravenous

diuretic therapy) despite guideline-directed medical therapy to treatment

with vericiguat (target dose 10 mg) or matching placebo over a median

follow-up of 11 months. The primary study results were notable for a

modest 10% relative risk reduction in the primary composite outcome

of cardiovascular death or HF hospitalization among those assigned to

vericiguat, an effect driven principally by effects on HF hospitalization,

rather than cardiovascular death. As vericiguat was generally well tolerated with a low rate of serious adverse events, these data suggest a potential role for sGC stimulation as an adjunct to guideline-directed medical

therapy in the high-risk group of HFrEF patients with recent congestive

exacerbations requiring treatment, although these data await further

review by regulatory agencies and guidelines committees.

■ MYOSIN ACTIVATION

A novel approach to augmentation of cardiac output is to prolong ventricular systole without increasing myocardial contractility. As a selective myosin activator, omecamtiv mecarbil prolongs the ejection period

and increases fractional shortening without altering the force of contraction as a consequence. This agent, distinct from inotropic agents,

is not associated with an increase in myocardial oxygen demand.

Importantly, the drug is available for oral, rather than intravenous,

administration, enabling chronic use in the ambulatory setting. In the

COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase

Contractility in Heart Failure) trial of 448 patients with chronic HF

and left ventricular systolic dysfunction, treatment with omecamtiv

mecarbil for 20 weeks was associated with significant improvements

in cardiac function and indices of left ventricular remodeling, as well

as reductions in natriuretic peptide levels. Notably, the safety profile

was comparable to placebo, with no increase in cardiac adverse events

despite a modest increase in cardiac troponins in patients allocated

to omecamtiv mecarbil. These promising preliminary data fueled a

larger clinical outcomes trial (GALACTIC-HF, in which 8256 patients

with symptomatic chronic heart failure and ejection fraction of 35% or

less were randomized to treatment with omecamtiv mecarbil (dosage

25-50 mg twice daily based on plasma levels) or placebo in addition to

standard HF therapy. Over median follow up of 21.8 months, patients

allocated to omecamtiv mecarbil experienced a 14% reduction in the

primary composite endpoint of death from cardiovascular causes or

first heart failure event (hospitalization or urgent visit for heart failure),

an outcome driven principally by reduction in heart failure events (no

measureable effect on CV death alone). A possible signal of greater

benefit in patients with features of advanced HF (lower EF, higher

natriuretic peptide levels, more severe symptoms) combined with a

favorable safety and tolerability profile suggests a possible role for this

agent in patients with late-stage disease, though additional study is

needed.

■ DIGOXIN

Digitalis glycosides exert a mild inotropic effect, attenuate carotid

sinus baroreceptor activity, and are sympatho-inhibitory. These effects

decrease serum norepinephrine levels, plasma renin levels, and possibly aldosterone levels. The Digitalis Investigation Group (DIG) trial

demonstrated a reduction in HF hospitalizations in the treatment

group (patients with HF and sinus rhythm) but no reduction in mortality or improvement in QOL. Importantly, treatment with digoxin

resulted in a higher mortality rate and hospitalizations in women

than men. It should be noted that low doses of digoxin are sufficient

to achieve any potentially beneficial outcomes, and higher doses

breach the therapeutic safety index. Although digoxin levels should be

checked to minimize toxicity and although dose reductions are indicated for higher levels, no adjustment is made for low levels. Generally,

digoxin is now relegated as late-line therapy for patients who remain

profoundly symptomatic despite optimal neurohormonal blockade and

adequate volume control.

■ ORAL DIURETICS

Neurohormonal activation results in avid salt and water retention.

Diuretic therapy is typically required in patients with symptomatic HF

to remedy congestive symptoms as a prelude to initiation and titration

of neurohormonal therapy. Because of their potent effect on renal

sodium excretion, loop diuretic agents are the preferred agents, with

thiazide diuretics reserved for use in combination with loop diuretics

for those with refractory volume overload. Frequent dose adjustments

of loop diuretics may be necessary during longitudinal follow-up of

patients with HF because of variable oral absorption and fluctuations in renal function. Patients who fail to respond to furosemide at

high doses may benefit from transition to torsemide or bumetanide,

which have greater oral bioavailability. Importantly, clinical trial data

confirming efficacy are limited, and no data suggest that these agents

improve survival. Since loop diuretics do enhance neurohumoral

activation, dosing should be minimized as possible to maximize the

balance of risk and benefit.

■ CALCIUM CHANNEL ANTAGONISTS

Amlodipine and felodipine, second-generation calcium channel–

blocking agents, safely and effectively reduce blood pressure in HFrEF

but do not affect morbidity, mortality, or QOL. The first-generation agents,

including verapamil and diltiazem, may exert negative inotropic effects

and destabilize previously asymptomatic patients. Accordingly, their

use should be discouraged in patients with HFrEF.

■ ANTI-INFLAMMATORY THERAPY

Targeting inflammatory cytokines such as tumor necrosis factor α

(TNF-α) for the management of HF by using anticytokine agents such

as infliximab and etanercept has been unsuccessful and associated

with worsening HF. Use of intravenous immunoglobulin therapy in

nonischemic etiology of HF has not been shown to result in beneficial outcomes. Nonspecific immunomodulation has been tested in

the Advanced Chronic Heart Failure Clinical Assessment of Immune

Modulation Therapy (ACCLAIM-HF) trial where ex vivo exposure

of a blood sample from systolic HF patients to controlled oxidative

stress was hypothesized to initiate apoptosis of leukocytes soon after

intramuscular gluteal injection of the treated sample. The physiologic

response to apoptotic cells results in a reduction in inflammatory

cytokine production and upregulation of anti-inflammatory cytokines.

This promising hypothesis was not proven, although certain subgroups (those with no history of previous myocardial infarction and

those with mild HF) showed signals in favor of immunomodulation.

Most recently, in the Canakinumab Anti-inflammatory Thrombosis

Outcomes Study (CANTOS), treatment of post–myocardial infarction patients with elevated high-sensitivity C-reactive protein using a

1950 PART 6 Disorders of the Cardiovascular System

monoclonal antibody targeted at interleukin 1β was associated with a

dose-dependent reduction in hospitalization for HF and HF-associated

mortality. Whether this approach might have relevance for patients

with established HF remains unclear.

■ HMG-CoA REDUCTASE INHIBITORS (STATINS)

Potent lipid-altering and pleiotropic effects of statins reduce major

cardiovascular events and improve survival in non-HF populations.

Once HF is well established, this therapy may not be as beneficial and

theoretically could even be detrimental by depleting ubiquinone in the

electron transport chain. Two trials, Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) and Gruppo Italiano per lo

Studio della Sopravvivenza nell’Insufficienza Cardiac (GISSI-HF), have

tested low-dose rosuvastatin in patients with HFrEF and demonstrated

no improvement in aggregate clinical outcomes. If statins are required

to treat progressive atherosclerotic vascular disease or significant

dyslipidemia in the background setting of HF, then they should be

employed. However, no rationale appears to exist for routine statin

therapy in nonischemic HF.

■ ANTICOAGULATION AND ANTIPLATELET

THERAPY

HFrEF is accompanied by a hypercoagulable state and therefore a high

risk of thromboembolic events, including stroke, pulmonary embolism,

and peripheral arterial embolism. Although the value of long-term oral

anticoagulation is established in certain groups, including patients with

atrial fibrillation, the data are insufficient to support the use of warfarin

in patients in normal sinus rhythm without a history of thromboembolic events or echocardiographic evidence of left ventricular thrombus. In the large Warfarin versus Aspirin in Reduced Cardiac Ejection

Fraction (WARCEF) trial, full-dose aspirin or international normalized

ratio–controlled warfarin was tested with follow-up for 6 years. Among

patients with reduced LVEF in sinus rhythm, there was no significant

overall difference in the primary outcome between treatment with

warfarin and treatment with aspirin. A reduced risk of ischemic stroke

with warfarin was offset by an increased risk of major hemorrhage. A

recent trial of the direct oral anticoagulant rivaroxaban at low dose

(2.5 mg daily) for patients with ischemic heart disease, HFrEF, and

sinus rhythm also indicated no reduction in stroke or ischemic events

compared with placebo. Aspirin blunts ACEI-mediated prostaglandin

synthesis, but the clinical importance of this finding remains unclear.

Current guidelines support the use of aspirin in patients with ischemic

cardiomyopathy who do not have a contraindication.

■ FISH OIL

Treatment with long-chain omega-3 polyunsaturated fatty acids (w-3

PUFAs) has been shown to be associated with modestly improved

clinical outcomes in patients with HFrEF. This observation from the

GISSI-HF trial was extended to measurements of w-3 PUFAs in plasma

phospholipids at baseline and after 3 months. Three-month treatment

with w-3 PUFAs enriched circulating eicosapentaenoic acid (EPA) and

docosahexaenoic acid (DHA). Low EPA levels are inversely related to

total mortality in patients with HFrEF.

■ MICRONUTRIENTS

A growing body of evidence suggests an association between HF and

micronutrient status. Reversible HF has been described as a consequence of severe thiamine and selenium deficiency. Thiamine deficiency has received attention in HF due to the fact that malnutrition

and diuretics are prime risk factors for thiamine loss. Small exploratory

randomized studies have suggested a benefit of supplementation with

thiamine in HFrEF with evidence of improved cardiac function. This

finding is restricted to chronic HF states and does not appear to be beneficial in the ADHF phenotype. Due to the exploratory nature of the

evidence, no recommendations for routine supplementation or testing

for thiamine deficiency can be made.

■ ENHANCED EXTERNAL COUNTERPULSATION

Peripheral lower extremity therapy using graded external pneumatic

compression at high pressure is administered in 1-h sessions for 35

treatments (7 weeks) and has been proposed to reduce angina symptoms and extend time to exercise-induced ischemia in patients with

coronary artery disease. The Prospective Evaluation of Enhanced

External Counterpulsation in Congestive Heart Failure (PEECH) study

assessed the benefits of enhanced external counterpulsation in the

treatment of patients with mild-to-moderate HF. This randomized trial

improved exercise tolerance, QOL, and NYHA functional classification

but without an accompanying increase in peak oxygen consumption.

A placebo effect due to the nature of the intervention simply cannot

be excluded.

■ EXERCISE

The Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study investigated short-term (3-month)

and long-term (12-month) effects of a supervised exercise training

program in patients with moderate HFrEF. Exercise was safe, improved

patients’ sense of well-being, and correlated with a trend toward mortality reduction. Maximal changes in 6-min walk distance were evident at 3 months with significant improvements in cardiopulmonary

exercise time and peak oxygen consumption persisting at 12 months.

Therefore, exercise training is recommended as an adjunctive treatment in patients with HF.

■ MANAGEMENT OF SELECTED COMORBIDITY

Sleep-disordered breathing is common in HF and particularly in

HFrEF. A range of presentations exemplified by obstructive sleep

apnea, central sleep apnea, and its extreme form of Cheyne-Stokes

breathing are noted. Frequent periods of hypoxia and repeated microand macro-arousals trigger adrenergic surges, which can worsen

hypertension and impair systolic and diastolic function. A high index

of suspicion is required, especially in patients with difficult-to-control

hypertension or with predominant symptoms of fatigue despite reverse

remodeling in response to optimal medical therapy. Worsening of right

heart function with improvement of left ventricular function noted on

medical therapy should immediately trigger a search for underlying

sleep-disordered breathing or pulmonary complications such as occult

embolism or pulmonary hypertension. Treatment with nocturnal

positive airway pressure improves oxygenation, LVEF, and 6-min walk

distance. However, no conclusive data exist to support this therapy as a

disease-modifying approach with reduction in mortality. A recent trial

using adaptive servo-ventilation in patients who had HFrEF and predominantly central sleep apnea increased all-cause and cardiovascular

mortality, so this approach should be avoided.

Anemia is common in HF patients, reduces functional status and

QOL, and is associated with increased proclivity for hospital admissions and mortality. Anemia in HF is more common in the elderly,

in those with advanced stages of HFrEF, in the presence of renal

insufficiency, and in women and African Americans. The mechanisms

include iron deficiency, dysregulation of iron metabolism, and occult

gastrointestinal bleeding. Intravenous iron using either iron sucrose or

carboxymaltose (Ferric Carboxymaltose Assessment in Patients with

Iron Deficiency and Chronic Heart Failure [FAIR-HF] trial) has been

shown to correct anemia and improve functional capacity. Another

trial, CONFIRM-HF, enrolled similar patients with iron deficiency

(ferritin <100 ng/mL or 100–300 ng/mL if transferrin saturation <20%)

and demonstrated that use of ferric carboxymaltose in a simplified

high-dose schedule resulted in improvement in functional capacity,

symptoms, and QOL. Oral iron supplementation does not appear to

be effective in treating iron deficiency in HF. Erythropoiesis-regulating

agents such as erythropoietin analogues have been studied with disappointing results. The Reduction of Events by Darbepoetin Alfa in Heart

Failure (RED-HF) trial demonstrated that treatment with darbepoetin

alfa did not improve clinical outcomes in patients with systolic HF and

may increase risk of stroke.

Depression is common in HFrEF, with a reported prevalence of one

in five patients, and is associated with a poor QOL, limited functional

status, and increased risk of morbidity and mortality in this population. However, the largest randomized study of depression in HFrEF,

the Sertraline Against Depression and Heart Disease in Chronic Heart