Chapter 253: Heart Failure: Management

Distinctive phenotypes of presentation with diverse management targets exemplify the extensive syndrome of heart failure. These range from chronic heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), acute decompensated heart failure (ADHF), and advanced heart failure. Early management evolved from symptom control to disease-modifying therapy in HFrEF with the advent of renin-angiotensin-aldosterone system (RAAS)–directed therapy, beta receptor antagonists, mineralocorticoid receptor antagonists, cardiac resynchronization therapy, and implantable cardio-defibrillators. However, similar advances have been elusive in the syndromes of HFpEF and ADHF, which have remained devoid of convincing therapeutic advances to alter their natural history. In advanced heart failure, a stage of disease typically encountered in HFrEF, the patient remains markedly symptomatic with demonstrated refractoriness or inability to tolerate full-dose neurohormonal antagonism, often requires escalating doses of diuretics, and exhibits persistent hyponatremia and renal insufficiency with frequent episodes of heart failure decompensation requiring recurrent hospitalizations. Such individuals are at the highest risk of sudden or progressive pump failure–related deaths (Chap. 255). In contrast, early-stage asymptomatic left ventricular dysfunction is amenable to preventive care, and its natural history is modifiable by neurohormonal antagonism (not further discussed).

GENERAL PRINCIPLES

Therapeutic targets in HFpEF include control of congestion, stabilization of heart rate and blood pressure, and efforts at improving exercise tolerance. Addressing surrogate targets, such as regression of ventricular hypertrophy in hypertensive heart disease, and use of lusitropic agents, such as calcium channel blockers and beta receptor antagonists, have been disappointing. Experience has demonstrated that lowering blood pressure alleviates symptoms more effectively than targeted therapy with specific agents.

CLINICAL TRIALS IN HFpEF

The Candesartan in Heart Failure—Assessment of Mortality and Morbidity (CHARM) Preserved study showed a statistically significant reduction in hospitalizations but no difference in all-cause mortality in patients with HFpEF who were treated with the angiotensin receptor blocker (ARB), candesartan. Similarly, the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial demonstrated no differences in meaningful endpoints in such patients treated with irbesartan. An earlier analysis of a subset of the Digitalis Investigation Group (DIG) trial found no role for digoxin in the treatment of HFpEF. 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, the subgroup of elderly patients with prior hospitalization and HFpEF did not appear to benefit in terms of all-cause or cardiovascular mortality. Much smaller mechanistic studies in the elderly with the angiotensin-converting enzyme inhibitor (ACEI) enalapril showed no effect on peak exercise oxygen consumption, 6-min walk distance, aortic distensibility, left ventricular mass, or peripheral neurohormone expression.

NOVEL TARGETS

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 II trial, Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX), in HFpEF patients (left ventricular ejection fraction [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, quality of life (QOL), or other clinical and surrogate parameters. Conceptually targeting myocardial fibrosis in HFpEF, the large-scale Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) trial has been completed. This trial demonstrated no improvement in the primary composite endpoint, but did show a secondary signal of benefit on HF hospitalizations, counterbalanced, however, by an increase in adverse effects, particularly hyperkalemia. However, pessimism has been generated by the negative outcome of the Aldosterone Receptor Blockade in Diastolic Heart Failure (ALDO-DHF) study wherein spironolactone improved echocardiographic indices of diastolic dysfunction but failed to improve exercise capacity, symptoms, or QOL measures. On the premise that nitrates, which are nitric oxide donors, might improve preload, coronary perfusion, endothelial function and improved 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 sub-maximal exercise capacity, and decreased overall activity levels in treated patients. A unique molecule that hybridizes an ARB with an endopeptidase inhibitor, LCZ696, increases the generation of myocardial cyclic guanosine 3′,5′-monophosphate, enhances myocardial relaxation, and reduces ventricular hypertrophy. This dual blocker has been shown to reduce circulating natriuretic peptides and reduce left atrial size to a significantly greater extent than valsartan alone in patients with HFpEF. This molecule is currently being tested in a pivotal clinical trial (PARAGON-HF).

CLINICAL PEARLS

Even as efforts to control hypertension in HFpEF are critical, evaluation for and correction of underlying ischemia may be beneficial. Appropriate identification and treatment of sleep-disordered breathing should be strongly considered. Excessive decrease in preload with vasodilators may lead to underfilling the ventricle and subsequent hypotension and syncope. 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. 253-1).

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 aggregate outcomes remain poor, with a combined incidence of cardiovascular deaths, heart failure hospitalizations, myocardial infarction, strokes, or sudden death reaching 50% at 12 months after hospitalization. The management of these patients has remained difficult and principally revolves around volume control and decrease of vascular impedance while maintaining attention to end-organ perfusion (coronary and renal).

The first principle of management of these patients is to identify and tackle known precipitants of decompensation. Identification and management of medication nonadherence and use of prescribed medicines such as nonsteroidal anti-inflammatory drugs, cold and flu preparations with cardiac stimulants, and herbal preparations, including licorice, ginseng, and herbal forms of ephedrine (now banned in most places), are required. Active infection and overt or covert pulmonary thromboembolism should be sought, identified, and treated when clinical clues suggest such direction. When possible, arrhythmias should be corrected by controlling heart rate or restoring sinus rhythm in patients with poorly tolerated rapid atrial fibrillation and by correcting ongoing ischemia with coronary revascularization or by correcting offenders such as ongoing bleeding in demand-related ischemia. A parallel step in management involves stabilization of hemodynamics in those with instability. The routine use of a pulmonary artery catheter is not recommended and should be restricted to those who respond poorly to diuresis or experience hypotension or signs and symptoms suggestive of a low cardiac output where therapeutic targets are unclear. 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 an elevated troponin I level. A useful clinical schema to identify treatment targets for the various phenotypic presentations and management goals in ADHF is depicted in Fig. 253-2.

VOLUME MANAGEMENT

Intravenous Diuretic Agents

Intravenous 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 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 or 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. Addition of a thiazide diuretic agent such as metolazone in combination provides a synergistic effect and is often required in patients receiving long-term therapy with loop diuretic agents. 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. It is generally advisable to continue diuresis until euvolemia has been achieved. Physical examination findings, specifically the jugular venous pressure coupled with biomarker trends, are useful in timing discharge planning.

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 heart failure, 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 a pivotal study evaluating UF versus conventional therapy, fluid removal was improved and subsequent heart failure 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 worsening in creatinine in the UF group. Deaths and hospitalizations for heart failure 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 nonetheless responsive to diuretics. Whether UF is useful in states of diuretic unresponsiveness remains an open question, and this strategy continues to be employed judiciously in such situations.

VASCULAR THERAPY

Vasodilators including intravenous nitrates, nitroprusside, and nesiritide (a recombinant brain-type natriuretic peptide) have been advocated for upstream therapy in an effort to stabilize ADHF. The latter agent was introduced in a fixed dose for therapy after a comparison with intravenous nitrates suggested more rapid and greater reduction in pulmonary capillary wedge pressure. Enthusiasm for nesiritide waned due to concerns within the pivotal trials for development of renal insufficiency and an increase in mortality. To address these concerns, a large-scale morbidity and mortality trial, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) study was completed in 2011 and randomly enrolled 7141 patients with ADHF to nesiritide or placebo for 24–168 h in addition to standard care. Nesiritide was not associated with an increase or a decrease in the rates of death and rehospitalization and had a clinically insignificant benefit on dyspnea. Renal function did not worsen, but increased rates of hypotension were noted. Although this trial established the safety for this drug, the routine use cannot be advocated due to lack of significant efficacy. Recombinant human relaxin-2, or serelaxin, is a peptide upregulated in pregnancy and examined in ADHF patients with a normal or elevated blood pressure. In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin or placebo was added to a regimen of standard therapy in 1161 patients hospitalized with ADHF, evidence of congestion, and systolic pressure >125 mmHg. Serelaxin improved dyspnea, reduced signs and symptoms of congestion, and was associated with less early worsening of HF. Exploratory endpoints of hard outcomes at 6 months suggested positive signals in favor of mortality reduction. A subsequent larger study failed to demonstrate a benefit. Recently, the natriuretic peptide urodilatin was tested in a large trial (TRUE-AHF) in ADHF patients and while evidence for decongestion was forthcoming along with a reduction in net endogenous expression of natriuretic peptides, there was no improvement in clinical outcomes at 6 months. Urodilatin was associated with a higher rate of hypotension and worsening serum creatinine.

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 (dobutamine) and 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, improves perfusion, and relieves congestion acutely. Although milrinone and dobutamine have similar hemodynamic profiles, milrinone is slower acting and is renally excreted and thus requires dose adjustments in the setting of kidney dysfunction. Since milrinone acts downstream from the β₁-adrenergic receptor, it may provide an advantage in patients receiving beta blockers when admitted to the hospital. Studies are in universal agreement that long-term inotropic therapy increases mortality. However, the short-term use of inotropic agents in ADHF is also associated with increased arrhythmia, hypotension, and no beneficial effects on hard outcomes. Inotropic agents are currently indicated as bridge therapy (to either left ventricular assist device support or to transplant) or as selectively applied palliation in end-stage heart failure.

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 vasodilators in action. This makes the drug unsuitable in states of low output in the setting of hypotension. 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 non-inotropic therapy and found a modest improvement in symptoms with worsened short-term mortality and ventricular arrhythmias. Another drug that functions as a selective myosin activator, omecamtiv mecarbil, prolongs the ejection period and increases fractional shortening. Distinctively, the force of contraction is not increased, and as such, this agent does not increase myocardial oxygen demand. As a follow-up to early encouraging data, the COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure) study evaluated 448 patients with chronic heart failure and left ventricular systolic dysfunction, for 20 weeks of treatment, and observed improvements with this agent on cardiac function, left ventricular remodeling indices and natriuretic peptide expression. Other inotropic agents that increase myocardial calcium sensitivity through mechanisms that reduce cTnI phosphorylation or inhibit protein kinase A are being developed. (Table 253-1 depicts typical inotropic, vasodilator, and diuretic drugs used in ADHF.)

NEUROHORMONAL ANTAGONISTS

Other trials testing unique agents have yielded disappointing results in the situation of ADHF. 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 of selective adenosine antagonism and the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial of an oral selective vasopressin-2 antagonist in ADHF were both negative with respect to hard outcomes.

In patients who fail to respond adequately to medical therapy, mechanical assist devices may be required. This is covered in more detail in Chap. 255.

The last 50 years have witnessed great strides in the management of HFrEF. The treatment of symptomatic heart failure that evolved from a renocentric (diuretics) and hemodynamic therapy model (digoxin, inotropic therapy) ushered in the era of disease-modifying therapy with neurohormonal antagonism. In this regard, RAAS blockers and beta blockers form the cornerstone of pharmacotherapy and lead to attenuation of decline and 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. 253-3).

NEUROHORMONAL ANTAGONISM

Meta-analyses suggest a 23% reduction in mortality and a 35% reduction in the combination endpoint of mortality and hospitalizations for heart failure in patients treated with ACEIs. Patients treated with beta blockers provide a further 35% reduction in mortality on top of the benefit provided by ACEIs alone. Increased experience with both agents in a broad range of patients with HFrEF has demonstrated the safety of ACEIs in treating patients with mild renal insufficiency and the tolerability of beta blockers in patients with moderately controlled diabetes, asthma, and obstructive lung disease. The benefits of ACEIs and beta blockers extend to advanced symptoms of disease (NYHA class IIIb–IV). However, a substantial number of patients with advanced heart failure may not be able to achieve optimal doses of neurohormonal inhibitors and require cautious reduction in dose exposure to maintain clinical stability. Such individuals with lower exposure to ACEIs and beta blockers represent a high-risk cohort with poor prognosis.

Class Effect and Sequence of Administration

ACEIs 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 investigations, 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 when either agent was initiated first. 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

A trial has indicated that higher tolerated doses of ACEIs achieve greater reduction in hospitalizations without materially improving survival. Beta blockers demonstrate a dose-dependent improvement in cardiac function and reductions in mortality and hospitalizations. Clinical experience suggests that, in the absence of symptoms to suggest hypotension (fatigue and dizziness), pharmacotherapy may be up-titrated every 2 weeks in stable ambulatory patients as tolerated.

MINERALOCORTICOID ANTAGONISTS

Aldosterone antagonism is associated with a reduction in mortality in all stages of symptomatic NYHA class II to IV HFrEF. Elevated aldosterone levels in HFrEF promote sodium retention, electrolyte imbalance, and endothelial dysfunction and may directly contribute to myocardial fibrosis. The selective agent eplerenone (tested in NYHA class II and post–myocardial infarction heart failure) and the nonselective antagonist spironolactone (tested in NYHA class III and IV heart failure) reduce mortality and hospitalizations, with significant reductions in sudden cardiac death (SCD). 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.

RAAS THERAPY AND NEUROHORMONAL “ESCAPE”

Neurohormonal “escape” has been witnessed in patients with HFrEF by the finding that circulating levels of angiotensin II return to pretreatment levels with long-term ACEI therapy. ARBs blunt this phenomenon by binding competitively to the AT₁ receptor. Meta-analysis of 24 randomized trials demonstrated the superiority of ARBs to placebo in patients with intolerable adverse effects with ACEIs and their non-inferiority in all-cause mortality or hospitalizations when compared with ACEIs. The Valsartan Heart Failure Trial (Val-HeFT) suggested that addition of valsartan in patients already receiving treatment with ACEIs and beta blockers was associated with a trend toward worse outcomes. Similarly, adding valsartan to captopril in patients with heart failure after myocardial infarction who were receiving background beta blocker therapy was associated with an increase in adverse events without any added benefit compared with monotherapy for either group. Thus, the initial clinical strategy should be to use a two-drug combination first (ACEI and beta blocker; if beta blocker intolerant, then ACEI and ARB; if ACEI intolerant, then ARB and beta blocker). In symptomatic patients (NYHA class II–IV), an aldosterone antagonist should be strongly considered, but four-drug therapy should be avoided.

A recent trial called the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) tested a direct renin inhibitor, aliskiren, in addition to other heart failure medications, within a week after discharge from a hospitalization for decompensated HFrEF. No significant difference in cardiovascular death or hospitalization at 6 or 12 months was noted. Aliskiren was associated with a reduction in circulating natriuretic peptides, but any disease-modifying effect was overcome by excessive adverse events including hyperkalemia, hypotension, and renal dysfunction. These studies point to the limits achieved with RAAS modulation in this clinical syndrome.

ARTERIOVENOUS VASODILATION

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 nitric oxide, which stimulates cyclic guanosine monophosphate production and consequent arterial-venous vasodilation. This combination improves survival, but not to the magnitude evidenced by ACEIs or ARBs. 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. The study demonstrated benefit in survival and hospitalization recidivism in the treatment group. Adherence to this regimen is limited by the thrice-daily dosing schedule.

NOVEL NEUROHORMONAL ANTAGONISM

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 heart failure in HFrEF despite demonstrating benefits in right-sided heart failure due to pulmonary arterial hypertension. Similarly, the centrally acting sympatholytic agent moxonidine worsens outcomes in left heart failure. The combined drug omapatrilat hybridizes an ACEI with a neutral endopeptidase 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 heart failure requiring intravenous treatment. The risk of angioedema was notably higher with omapatrilat than ACEIs alone.

More recently, the introduction of LCZ696, an ARB (valsartan) with an endopeptidase inhibitor (sacubitril), has shown a survival benefit in a large trial versus ARB alone. The drug, referred to as an angiotensin receptor–neprilysin inhibitor (ARNI) (and denoted Entrezto), was tested in the PARADIGM-HF trial as an alternate to optimally dosed ACEI and demonstrated an incremental improvement in survival when compared to ACEI alone. Most guidelines now advocate switching ACEI to this drug as a standard in patients with mild-moderate systolic heart failure when they remain symptomatic despite fully tolerated doses of conventional therapy.

Table 253-2 lists the common neurohormonal and vasodilator regimens for HFrEF.

HEART RATE MODIFICATION

Ivabradine, an inhibitor of the I_f current in the sinoatrial node, slows the heart rate without a negative inotropic effect. The Systolic Heart Failure Treatment with Ivabradine Compared with Placebo Trial (SHIFT) was conducted in patients with class II or III HFrEF, a heart rate >70 beats/min, and history of hospitalization for heart failure during the previous year. Ivabradine reduced hospitalizations and the combined endpoint of cardiovascular-related death and heart failure hospitalization. The study population was not necessarily representative of North American patients with HFrEF since, with a few exceptions, most did not receive internal cardioverter-defibrillation or cardiac resynchronization therapy and 40% did not receive a mineralocorticoid receptor antagonist. Although 90% received beta blockers, only a quarter were on full doses. Whether this agent would have been effective in patients receiving robust, guideline-recommended therapy for heart failure remains unclear. In the 2012 European Society of Cardiology guidelines for the treatment of heart failure, clinically, Ivabradine should be considered in patients who remain symptomatic after guideline-based ACEIs, beta blockers, and mineralocorticoid receptor antagonists and with residual heart rate >70 beats/min. Another group in whom potential benefit may be expected includes those unable to tolerate beta blockers.

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 DIG trial demonstrated a reduction in heart failure hospitalizations in the treatment group (patients with heart failure 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 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. Loop diuretic agents are often required because of their increased potency, and frequent dose adjustments may be necessary because of variable oral absorption and fluctuations in renal function. Importantly, clinical trial data confirming efficacy are limited, and no data suggest that these agents improve survival. Thus, diuretic agents should ideally be used in tailored dosing schedules to avoid excessive exposure. Indeed, diuretics are essential at the outset to achieve volume control before neurohormonal therapy is likely to be well tolerated or titrated.

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. Their use should be discouraged.

INFLAMMATION

Targeting inflammatory cytokines such as tumor necrosis factor α (TNF-α) by using anticytokine agents such as infliximab and etanercept has been unsuccessful and associated with worsening heart failure. Use of intravenous immunoglobulin therapy in nonischemic etiology of heart failure 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 heart failure 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 heart failure) showed signals in favor of immunomodulation.

STATINS

Potent lipid-altering and pleiotropic effects of statins reduce major cardiovascular events and improve survival in non–heart failure populations. Once heart failure 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 coronary artery disease in the background setting of heart failure, then they should be employed. However, no rationale appears to exist for routine statin therapy in nonischemic heart failure.

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 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. 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.

FISH OIL

Treatment with long-chain omega-3 polyunsaturated fatty acids (ω-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 ω-3 PUFAs in plasma phospholipids at baseline and after 3 months. Three-month treatment with ω-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 heart failure and micronutrient status. Reversible heart failure has been described as a consequence of severe thiamine and selenium deficiency. Thiamine deficiency has received attention in heart failure 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 of thiamine in HFrEF with evidence of improved cardiac function. This finding is restricted to chronic heart failure 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 (EECP)

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 heart failure. 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 heart failure.

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 micro- and 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.

Anemia is common in heart failure patients, reduces functional status and QOL, and is associated with increased proclivity for hospital admissions and mortality. Anemia in heart failure 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 heart failure. 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 heart failure.

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 Failure (SADHART-CHF) trial, showed that although sertraline was safe, it did not provide greater reduction in depression or improve cardiovascular status among patients with heart failure and depression compared with nurse-driven multidisciplinary management.

Atrial arrhythmias, especially atrial fibrillation, are common and serve as a harbinger of worse prognosis in patients with heart failure. When rate control is inadequate or symptoms persist, pursuing a rhythm control strategy is reasonable. Rhythm control may be achieved via pharmacotherapy or by percutaneous or surgical techniques, and referral to practitioners or centers experienced in these modalities is recommended. Antiarrhythmic drug therapy should be restricted to amiodarone and dofetilide, both of which have been shown to be safe and effective but do not alter the natural history of the underlying disease. The Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) studied the effects of the novel antiarrhythmic agent dronedarone and found an increased mortality due to worsening heart failure. Catheter ablation and pulmonary vein isolation appear to be safe and effective in this high-risk cohort and compare favorably with the more established practice of atrioventricular node ablation and biventricular pacing.

Diabetes mellitus is a frequent co-morbidity in heart failure. Prior studies using thiazolidinediones (activators of peroxisome proliferator-activated receptors) have been associated with worsening heart failure. Glucagon-like peptide 1 (GLP-1) agonists such as liraglutide have also been tested and do not lead to greater post-hospitalization clinical stability or worsening in heart failure. Recently, the drug empagloflozin was tested in the EMPA-REG study and demonstrated a decrease in cardiovascular mortality as well as hospitalizations for heart failure. This drug, a sodium–glucose cotransporter 2 (SGLT2), induces an osmotic diuresis as well as ketosis. This drug class may represent a viable therapeutic avenue in diabetics with heart failure.

NEUROMODULATION USING DEVICE THERAPY

Autonomic dysfunction is common in heart failure and attempts at using devices to modulate the sympathetic and parasympathetic systems have been undertaken. Broadly, devices that achieve vagal nerve stimulation, baroreflex activation, renal sympathetic denervation, spinal cord stimulation, or left cardiac sympathetic denervation have been employed. While small preclinical and clinical studies have demonstrated benefits, large-sized randomized trials, when conducted, have failed. The INOVATE-HF study tested vagal nerve stimulation versus optimal medical therapy among individuals with stable HF. Vagus nerve stimulation did not reduce the rate of death or hospitalization for HF. However, functional capacity and QOL were favorably affected by vagus nerve stimulation.

Nonsynchronous contraction between the walls of the left ventricle (intraventricular) or between the ventricular chambers (interventricular) impairs systolic function, decreases mechanical efficiency of contraction, and adversely affects ventricular filling. Mechanical dyssynchrony results in an increase in wall stress and worsens functional mitral regurgitation. The single most important association of extent of dyssynchrony is a widened QRS interval on the surface electrocardiogram, particularly in the presence of a left bundle branch block pattern. With placement of a pacing lead via the coronary sinus to the lateral wall of the ventricle, cardiac resynchronization therapy (CRT) enables a more synchronous ventricular contraction by aligning the timing of activation of the opposing walls. Early studies showed improved exercise capacity, reduction in symptoms, and evidence of reverse remodeling. The Cardiac Resynchronization in Heart Failure Study (CARE-HF) trial was the first study to demonstrate a reduction in all-cause mortality with CRT placement in patients with HFrEF on optimal therapy with continued moderate-to-severe residual symptoms of NYHA class III or IV heart failure. More recent clinical trials have demonstrated disease-modifying properties of CRT in even minimally symptomatic patients with HFrEF, including the Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) and Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), both of which sought to use CRT in combination with an implantable defibrillator. Most benefit in mildly symptomatic HFrEF patients accrues from applying this therapy in those with a QRS width of >149 ms and a left bundle branch block pattern. Attempts to further optimize risk stratification and expand indications for CRT using modalities other than electrocardiography have proven disappointing. In particular, echocardiographically derived measures of dyssynchrony vary tremendously, and narrow QRS dyssynchrony has not proven to be a good target for treatment. Uncertainty surrounds the benefits of CRT in those with ADHF, a predominant right bundle branch block pattern, atrial fibrillation, and evidence of scar in the lateral wall, which is the precise location where the CRT lead is positioned.

SCD due to ventricular arrhythmias is the mode of death in approximately half of patients with heart failure and is particularly proportionally prevalent in HFrEF patients with early stages of the disease. Patients who survive an episode of SCD are considered to be at very high risk and qualify for placement of an implantable cardioverter-defibrillator (ICD). Although primary prevention is challenging, the degree of residual left ventricular dysfunction despite optimal medical therapy (≤35%) to allow for adequate remodeling and the underlying etiology (post–myocardial infarction or ischemic cardiomyopathy) are the two single most important risk markers for stratification of need and benefit. Currently, patients with NYHA class II or III symptoms of heart failure and an LVEF <35%, irrespective of etiology of heart failure, are appropriate candidates for ICD prophylactic therapy. In patients with a myocardial infarction and optimal medical therapy with residual LVEF ≤30% (even when asymptomatic), placement of an ICD is appropriate. A recent Danish trial suggested that prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. In this trial, benefits were noted in those aged <60 years. In patients with a terminal illness and a predicted life span of <6 months or in those with NYHA class IV symptoms who are refractory to medications and who are not candidates for transplant, the risks of multiple ICD shocks must be carefully weighed against the survival benefits. If a patient meets the QRS criteria for CRT, combined CRT with ICD is often employed (Table 253-3).

Coronary artery bypass grafting (CABG) is considered in patients with ischemic cardiomyopathy with multivessel coronary artery disease. The recognition that hibernating myocardium, defined as myocardial tissue with abnormal function but maintained cellular function, could recover after revascularization led to the notion that revascularization with CABG would be useful in those with living myocardium. Revascularization is most robustly supported in individuals with ongoing angina and left ventricular failure. Revascularizing those with left ventricular failure in the absence of angina remains controversial. The Surgical Treatment for Ischemic Heart Failure (STICH) trial in patients with an ejection fraction of ≤35% and coronary artery disease amenable to CABG demonstrated no significant initial benefit compared to medical therapy. However, patients assigned to CABG had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes over 10 years than among those who received medical therapy alone. An ancillary study of this trial also determined that the detection of hibernation pre-revascularization did not materially influence the efficacy of this approach, nor did it help to define a population unlikely to benefit if hibernation was not detected.

Surgical ventricular restoration (SVR), a technique characterized by infarct exclusion to remodel the left ventricle by reshaping it surgically in patients with ischemic cardiomyopathy and dominant anterior left ventricular dysfunction, has been proposed. However, in a 1000-patient trial in patients with HFrEF who underwent CABG alone or CABG plus SVR, the addition of SVR to CABG had no disease-modifying effect. However, left ventricular aneurysm surgery is still advocated in those with refractory heart failure, ventricular arrhythmias, or thromboembolism arising from an akinetic aneurysmal segment of the ventricle. Other remodeling procedures, such as use of an external mesh-like net attached around the heart to limit further enlargement, have not been shown to provide hard clinical benefits, although favorable cardiac remodeling was noted.

Mitral regurgitation (MR) occurs with varying degrees in patients with HFrEF and dilated ventricles. Annular dilatation and leaflet noncoaptation in the setting of anatomically normal papillary muscles, chordal structures, and valve leaflets characterize functional MR. In patients who are not candidates for surgical coronary revascularization, mitral valve repair remains controversial. Ischemic MR (or infarct-related MR) is typically associated with leaflet tethering and displacement related to abnormal left ventricular wall motion and geometry. No evidence to support the use of surgical or percutaneous valve correction for functional MR exists as disease-modifying therapy even though MR can be corrected.

The cardiomyocyte possesses regenerative capacity and such renewal is accelerated under conditions of stress and injury, such as an ischemic event or heart failure. Investigations that use either bone marrow–derived precursor cells or autologous cardiac-derived cells have gained traction but have not generally improved clinical outcomes in a convincing manner. More promising, however, are cardiac-derived stem cells. Two preliminary pilot trials delivering cells via an intracoronary approach have been reported. In one, autologous c-kit–positive cells isolated from the atria obtained from patients undergoing CABG were cultured and reinfused. In another, cardiosphere-derived cells grown from endomyocardial biopsy specimens were used. These small trials demonstrated improvements in left ventricular function but require far more work to usher in a clinical therapeutic success. The appropriate route of administration, the quantity of cells to achieve a minimal therapeutic threshold, the constitution of these cells (single source or mixed), the mechanism by which benefit accrues, and short- and long-term safety remain to be elucidated.

Targeting molecular aberrations using gene transfer therapy, mostly with an adenoviral vector, has been tested in HFrEF. A cellular target includes calcium cycling proteins such as inhibitors of phospholamban such as SERCA2a which is deficient in patients with HFrEF. Primarily responsible for reincorporating calcium into the sarcoplasmic reticulum during diastole, this target was tested in the CUPID (Efficacy and Safety Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure) trial. This study used coronary arterial infusion of adeno-associated virus type 1 carrying the gene for SERCA2a and initially demonstrated that natriuretic peptides were decreased, reverse remodeling was noted, and symptomatic improvements were forthcoming. However, a confirmatory trial failed to meet its primary efficacy endpoint.

More advanced therapies for late-stage heart failure such as left ventricular assist devices and cardiac transplantation are covered in detail in Chap. 255.

Despite stellar outcomes with medical therapy, admission rates following heart failure hospitalization remain high, with nearly half of all patients readmitted to hospital within 6 months of discharge. Recurrent heart failure and related cardiovascular conditions account for only half of readmissions in patients with heart failure, whereas other comorbidity-related conditions account for the rest. The key to achieving enhanced outcomes must begin with the attention to transitional care at the index hospitalization with facilitated discharge through comprehensive discharge planning, patient and caregiver education, appropriate use of visiting nurses, and planned follow-up. Early postdischarge follow-up, whether by telephone or clinic-based, may be critical to ensuring stability because most heart failure–related readmissions tend to occur within the first 2 weeks after discharge. Although routinely advocated, intensive surveillance of weight and vital signs with use of telemonitoring has not decreased hospitalizations. Intrathoracic impedance measurements have been advocated for the identification of early rise in filling pressure and worsened hemodynamics so that preemptive management may be employed. However, this has not been successful and may worsen outcomes in the short term. Implantable pressure monitoring systems do tend to provide signals for early decompensation, and in patients with moderately advanced symptoms, such systems have been shown to provide information that can allow implementation of therapy to avoid hospitalizations by as much as 39% (in the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients [CHAMPION] trial). Once heart failure becomes advanced, regularly scheduled review of the disease course and options with the patient and family is recommended including discussions surrounding end-of-life preferences when patients are comfortable in an outpatient setting. As the disease state advances further, integrating care with social workers, pharmacists, and community-based nursing may be critical in improving patient satisfaction with the therapy, enhancing QOL, and avoiding heart failure hospitalizations. Equally important is attention to seasonal influenza vaccinations and periodic pneumococcal vaccines that may obviate non–heart failure hospitalizations in these ill patients. When nearing end of life, facilitating a shift in priorities to outpatient and hospice palliation is key, as are discussions around advanced therapeutics and continued use of ICD prophylaxis, which may worsen QOL and prolong death.

Substantial differences exist in the practice of heart failure therapeutics and outcomes by geographic location. The penetrance of CRT and ICD is higher in the United States than in Europe. Conversely, therapy unavailable in the United States, such as levosimendan, is designated as useful in Europe. Variation in the benefits of beta blockers based on world region remains an area of controversy. In oral pharmacologic therapy trials of HFrEF, patients from southwest Europe have a lower incidence of ischemic cardiomyopathy and those in North America tend to have more diabetes and prior coronary revascularization. There is also regional variation in medication use even after accounting for indication. In trials of heart failure, disparate effects are noted across populations. As a recent example, in TOPCAT, the drug spironolactone was effective when used in the US population while patients recruited from Russia and contiguous territories showed no difference. Whether this represents population differences or trial conduct disparity remains to be investigated. ADHF, patients in Eastern Europe tend to be younger, with higher ejection fractions and lower natriuretic peptide levels. Patients from South America tend to have the lowest rates of comorbidities, revascularization, and device use. In contrast, patients from North America have the highest comorbidity burden with high revascularization and device use rates. Given geographic differences in baseline characteristics and clinical outcomes, the generalizability of therapeutic outcomes in patients in the United States and Western Europe may require verification.