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Update on Heart Failure Management: A Primer for Pharmacists

INTRODUCTION

Heart failure (HF) is a complex syndrome associated with a diminished quality of life and substantial rates of hospitalization and mortality. An understanding of the pathophysiologic mechanisms involved in the development of HF has evolved in recent decades, and this understanding has given rise to a sophisticated classification system and individualized treatment strategies for patients with HF. Although a majority of pharmacists indicate that they are routinely asked about HF medications, only a small percentage believe they are well informed about the broad range of medications and treatments used in the management of HF. This review will provide pharmacists with the knowledge needed to individualize drug treatment for patients with HF and will allow pharmacists to integrate new therapies with conventional management approaches.

PREVALENCE

Approximately 6 million adults in the United States (U.S.) are living with HF, and 915,000 new cases of HF are diagnosed each year.1 The prevalence of HF is projected to increase to more than 8 million adults by 2030.2 The prevalence of HF is higher in African Americans and Hispanics than in whites and Asian Americans. This higher prevalence of HF is likely due to higher rates of hypertension and diabetes |mellitus and lower socioeconomic status among African Americans and Hispanics. The lifetime risk of HF for patients with blood pressure (BP) greater than 160/90 mmHg is double that for patients with BP lower than 140/90 mmHg. The incidence of HF increases with age, approaching 10 cases per 1000 adults aged 65 years and older.1 Among people aged 80 or older, the remaining lifetime risk of HF is 20%, despite the relatively short life expectancy of this group.

HF is associated with a substantial burden on the U.S. health care system. Hospitalizations for HF totaled just over 1 million in 2010, and HF was the most common discharge diagnosis in patients older than 65 years. From 2006 to 2010, there were an average of 958,000 annual emergency room visits for HF.3 In 2010, the annual cost of HF was estimated to be $30.7 billion,1 and this cost is expected to increase to nearly $70 billion in 2030.2 Hospitalizations account for 80% of the direct medical care costs associated with HF.

Mortality after a diagnosis of HF has improved in recent years, but mortality remains high, with a rate of 43% at 5 years after diagnosis.1,4 When stratified by severity of HF, survival rates at 5 years for patients with stages A, B, C, and D HF (representing least severe to most severe symptoms) were 97%, 96%, 75%, and 20%, respectively.5 HF is mentioned as at least one cause of death in 1 of every 9 deaths,1 and, in 2011, HF was the primary cause of death for 65,000 individuals.

PATHOPHYSIOLOGY

HF is most commonly associated with a primary defect in ventricular function,6 such as decreased ejection of blood from the left ventricle or impaired ventricular filling. Both of these defects ultimately lead to a net reduction in the effective volume of blood delivered to the systemic circulation. This loss of blood volume and decreased cardiac output activates neurohormonal systems. Activation of neurohormonal systems results in the common clinical manifestations of HF, including shortness of breath (dyspnea), fatigue, and fluid retention. HF is not only associated with problems of ventricular function but may also be associated with primary abnormalities of the myocardium (cardiomyopathy), pericardium, pulmonary vasculature, or heart valves.7

HF is typically defined and stratified according to the left ventricular ejection fraction (LVEF). Patients with HF and a reduced ejection fraction (HFrEF) are typically identified as having systolic dysfunction.6 The specific threshold below which the LVEF is considered reduced is generally less than or equal to 35% or 40%. The predominant pathophysiologic defect in patients with HFrEF is an impairment in the ejection of blood from the left ventricle. Patients with HF and an LVEF greater than 50% are referred to as having HF with a preserved LVEF (HFpEF). The diagnosis of HFpEF is more complicated than that of HFrEF, in part because preserved LVEF had been defined by a variety of different thresholds (> 40%, > 45%, > 50%, and ≥ 55%).6 It is important to understand that HF cannot be diagnosed on the basis of LVEF alone. HF is a clinical diagnosis that is based on signs and symptoms that are determined by history and physical examination. Patients with HFpEF present with diastolic dysfunction as their primary cardiac defect. The primary pathophysiologic defect in diastolic dysfunction is left ventricular stiffening and impaired relaxation.6 It is not uncommon for patients with HF to have both systolic and diastolic dysfunction, and it is often difficult to categorize patients on the basis of systolic or diastolic dysfunction alone and to determine the source of the HF symptoms. In a population screening survey using echocardiography, approximately 1 in 4 individuals with evidence of diastolic dysfunction had no symptoms of HF.8

The most common causes of HF include conditions that damage or weaken the cardiac muscle. In the U.S., coronary artery disease and myocardial infarction are the most common causes of HF.7 Other causes include hypertension, valvular heart disease, viral or bacterial infections involving the heart, and toxic exposure to alcohol, cocaine, amphetamines, or cancer chemotherapy. Less common causes of HF include complications of human immunodeficiency virus infection, hyperthyroidism, hemochromatosis (iron overload), or amyloidosis. HF may also occur secondary to acromegaly and growth hormone deficiency, tachycardia-induced cardiomyopathy, peripartum cardiomyopathy, stress-induced (Takotsubo) cardiomyopathy, rheumatologic/connective tissue disorders, and Chagas disease.7 Cardiomyopathy resulting in HF may rarely be associated with genetic defects. Several drugs are also well known as etiologic agents that can worsen or precipitate HF due to an increase in sodium and water retention (i.e., thiazolidinediones, non-steroidal anti-inflammatory drugs, and corticosteroids) or a direct negative inotropic effect (antiarrhythmics and nondihydropyrine calcium channel blockers).9 There are many risk factors and conditions that increase the likelihood of development of HF, but the most obvious are those that increase the risk of coronary artery disease such as hypertension, diabetes mellitus, smoking, dyslipidemia, metabolic syndrome, sleep apnea, and obesity. Other factors that contribute to the development of HF include cardiac arrhythmias, pulmonary hypertension, and vascular stiffening.

CLASSIFICATION

HF is typically a chronic, progressive syndrome with intermittent episodes of decompensation that may result in emergency department visits or hospitalizations. Therapy for HF is individualized on the basis of the severity of HF. The severity of HF is stratified according to the New York Heart Association (NYHA) functional classification system (Table 1).6 The primary limitation of the NYHA functional classification system is that it is primarily based on patients’ self-reported symptoms, which may lead to subjectivity in categorizing patients into a specific functional class. The American Heart Association (AHA) and the American College of Cardiology (ACC) developed a staging system that can be used in conjunction with the NYHA classification system (Table 1). The ACC/AHA staging system for HF is based on the presence or absence of structural heart disease and the presence or absence of symptoms, regardless of the severity of those symptoms. These classification systems are complimentary, and the NYHA classification can be used to stratify the severity of symptoms for patients who have ACC/AHA Stage C or D HF.

Table 1. NYHA functional classification and ACC/AHA stages of HF6,31
NYHA functional classifications ACC/AHA stages
I No limitation of physical activity; Ordinary physical activity does not cause HF symptoms A At high risk for HF but without structural heart disease or HF symptoms
II Slight limitation of physical activity; Comfortable at rest, but ordinary activity results in HF symptoms B Structural heart disease present but without signs or symptoms of HF
III Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes HF symptoms C Structural heart disease present with prior or current symptoms of HF
IV Unable to carry out any physical activity without HF symptoms or HF symptoms at rest D Refractory HF requiring specialized interventions
ACC = American College of Cardiology; AHA = American Heart Association; HF = heart failure; NYHA = New York Heart Association

DRUG THERAPY

The goals of treatment for patients with HF include improvement or alleviation of symptoms, improvement in quality of life, management of comorbidities, correction of precipitating factors, prevention of hospitalizations, and increased survival. The American College of Cardiology Foundation (ACCF)/AHA 2013 Guideline for the Management of HF makes recommendations for the use of specific drugs on the basis of stage of HF (Table 2).6 For patients with Stage A HF, therapy is directed at reducing the risk factors for the development of HF and includes therapy with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and a beta-blocker. Therapy for patients with Stage B HF is directed at treating structural heart disease, and therapy for patients with Stages C and D HF is directed at improving symptoms and reducing morbidity and mortality. Other factors must also be considered along with the recommendations made in the 2013 HF guidelines. Specifically, the general treatment recommendations that are based on HF stage are for patients with chronic HFrEF and do not address the management of patients with acute decompensated HF. Although a number of studies of drug therapy have been conducted in patients with HFpEF, none of the studies have demonstrated clinically significant reductions in morbidity or mortality.6 Therefore, management of patients with HFpEF cannot be based on available evidence-based trial data. The management of HFpEF will be discussed briefly later in this review.

Table 2. Drug therapy for chronic HFrEF stratified by ACC/AHA stage6,31
Drug or drug class ACC/AHA Stage B ACC/AHA Stage C ACC/AHA Stage D
ACEIs (ARBs) Yes Yes Yes
Beta-blockers Yes Yes Yes
Diuretics No Consider on the basis of symptoms Consider on the basis of symptoms
Digoxin No Consider on the basis of symptoms Consider on the basis of symptoms
Aldosterone receptor antagonists No Yes Yes
Hydralazine/isosorbide dinitrate No Yes for African Americans;
consider for others on the basis of symptoms		 Yes for African Americans;
consider for others on the basis of symptoms
Ivabradine* No Yes, if heart rate ≥ 70 bpm despite maximal beta-blocker therapy or if heart rate ≥ 70 bpm and there is a contraindication to beta-blocker therapy Yes, if heart rate ≥ 70 bpm despite maximal beta-blocker therapy or if heart rate ≥ 70 bpm and there is a contraindication to beta-blocker therapy
Sacubitril/valsartan* No Consider as alternative to ACEI/ARB Consider as alternative to ACEI/ARB
ACC = American College of Cardiology; ACEI = angiotensin converting enzyme inhibitor; AHA = American Heart Association; ARB = angiotensin receptor blocker; bpm = beats per minute; HFrEF = heart failure with reduced ejection fraction; *= not yet evaluated in any heart failure guideline

Drugs with demonstrated favorable effects on survival or quality of life in HF are typically referred to as evidence-based therapy or as guideline-directed medical therapy (GDMT).6 The effects of diuretics and digoxin on mortality in HF are unclear. These agents have not been demonstrated to have favorable effects on survival, but they are used to manage the symptoms of HF. Digoxin was evaluated in a large outcomes trial, which determined that the drug had a neutral effect on mortality in HF patients.10 Loop diuretics are commonly used to maintain normal volume status in patients with HF; many HF patients cannot be clinically stabilized without the use of loop diuretics. The ability to study clinical outcomes with loop diuretics using a placebo control is not feasible considering the high rates of clinical deterioration that would be expected in the group treated with placebo. Drugs from several classes, including endothelin receptor antagonists, vasopressin receptor antagonists, adenosine A1 receptor antagonists, imidazoline receptor agonists, tumor necrosis factor inhibitors, and phosphodiesterase 3 inhibitors, have been evaluated in outcomes trials in patients with HF; these drugs either had a negative impact on outcomes or a neutral effect on outcomes. Therefore, these drugs are not recommended for use in patients with HF.11

Established drug therapy. A complete history of drug therapy in the management of HF is beyond the scope of this review. Loop diuretics and/or digoxin were the mainstay of treatment of HF until the availability of the ACEIs in the early 1980’s. Initially, ACEIs were typically added to baseline therapy that included loop diuretics with or without digoxin. In the last 3 decades, ACEIs have been shown to improve symptoms, improve exercise capacity, reduce progressive left ventricular remodeling, and improve survival in patients with HF, and they are now a cornerstone of HF management. The survival benefits of ACEIs have been demonstrated in patients with symptomatic HF and in patients with structural heart disease without signs or symptoms of HF (Stage B).11 The ARBs have also been shown to have favorable effects in HF. Comparisons of ARBs and ACEIs have demonstrated generally similar magnitudes of clinical benefits, including mortality benefits.11 However, there is no evidence that ARBs are superior to ACEIs in terms of efficacy. ARBs have been associated with fewer side effects than ACEIs, and, as a result, ARBs are primarily used in patients who cannot tolerate ACEIs. Although it is generally assumed that the benefit of ACEIs and ARBs is a class effect in HF, this assumption cannot be proven. Therefore, it is reasonable to use an ACEI or ARB that has been specifically studied in patients with HF. The ACCF/AHA HF guideline lists 8 ACEIs and 3 ARBs that are commonly used for the management of HFrEF: captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and trandolapril; and candesartan, losartan, and valsartan, respectively.6

Other therapies that have been shown to reduce mortality in HF include beta-blockers, aldosterone receptor antagonists, and the combination of hydralazine and isosorbide dinitrate.11 Beta-blocker outcomes trials were conducted in patients stabilized on an ACEI or ARB, and most patients received background diuretic therapy. Four beta-blockers have been shown to significantly improve cardiovascular (CV) outcomes in patients with HF: metoprolol succinate, carvedilol, bisoprolol, and nebivolol.6 Metoprolol succinate and carvedilol are approved by the U.S. Food and Drug Administration (FDA) for the treatment of HFrEF. The manufacturer of bisoprolol never sought FDA approval for HF, and the FDA declined to approve nebivolol for HF for several reasons related to trial design. The COMET trial compared carvedilol and metoprolol tartrate, which are both short-acting beta-blockers, in patients with HFrEF.12 Superior outcomes were achieved with carvedilol compared to metoprolol, including a significant 17% relative risk reduction in all-cause mortality. Although the magnitude of the effect of the individual beta-blockers on baseline heart rate differed between the treatment groups, the study remains the only adequately powered direct comparison of beta-blockers in HF. Beta-blocker use is guided by these findings and this class has become a standard of care in HF; the ACCF/AHA guideline lists 3 beta-blockers that are commonly used in HF: metoprolol succinate, carvedilol, or bisoprolol.6

Aldosterone (mineralocorticoid) receptor antagonists (i.e., spironolactone and eplerenone) have also been shown to reduce mortality in HFrEF.6,11,13 A study with spironolactone in patients with HFrEF was conducted at a time when beta-blockers were not considered the standard of care. Hence, the proportion of patients receiving beta-blockers was relatively low in that study.13 Aldosterone receptor antagonists are indicated for patients with NYHA class II, III, or IV HF with an LVEF less than or equal to 35% and for post-myocardial infarction patients with an LVEF less than or equal to 40% who have HF symptoms or a history of diabetes mellitus. GDMT dictates that these patients should be receiving an ACEI or ARB and a beta-blocker before adding an aldosterone receptor antagonist.6,11

The combination of hydralazine with isosorbide dinitrate has been compared against placebo and against enalapril in 2 small studies of patients with chronic HF. Patients treated with hydralazine and isosorbide dinitrate had improved functional capacity, but this drug combination was associated with a significantly smaller effect on mortality than enalapril.11 A fixed-dose combination of hydralazine and isosorbide dinitrate was also compared against placebo in African American patients with HF who were receiving standard HF therapy that included an ACEI or ARB.14 Hydralazine and isosorbide dinitrate improved quality of life, decreased hospitalizations, and reduced all-cause mortality compared to placebo. ACEIs and ARBs produce less hemodynamic effects and offer a lower mortality benefit for African Americans than for whites.14 The mechanism of this benefit is thought to be related to an altered response among African Americans to renin-angiotensin-aldosterone antagonism, but the exact mechanism of the benefit of hydralazine-isosorbide dinitrate in this race is not certain.

New drug therapies. Two new drug therapies for the management of HFrEF were approved in the U.S. in 2015: ivabradine (Corlanor) and the combination of sacubitril and valsartan (Entresto). Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated If channel blocker that reduces automaticity in the sinus node, which slows the heart rate.15 The effect of ivabradine on heart rate is both dose dependent and rate dependent. Ivabradine produces a greater reduction in heart rate in patients with a faster heart rate at baseline. The average reduction in heart rate at rest and during exercise is approximately 10 beats per minute (bpm). Although the predominant effect of the drug is in the sinus node, it may also prolong the AH and PR intervals. The drug has no effect on ventricular automaticity, repolarization, or contractility. Ivabradine may increase the QT interval by slowing heart rate, but it does not impact the QTc. Ivabradine can also block the Ih ion channel in the retina, which may result in the development of luminous phenomena (phosphenes) described as brightness in a limited part of the visual field.

The relative bioavailability of ivabradine is nearly 40% and peak plasma concentrations are achieved in 1 hour when taken on an empty stomach. The drug is recommended to be taken with food, since food delays peak absorption by 1 hour and increases absorption by 20% to 40%.15 Approximately 70% of ivabradine is bound to circulating plasma protein. Ivabradine is extensively metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme, and only 4% of unchanged drug is cleared by the kidneys. The primary metabolite is N-desmethylated ivabradine, which is equipotent to ivabradine and has a plasma concentration that is approximately 40% of that of the parent drug. The half-life of ivabradine is 6 hours; the half-life of the metabolite is approximately twice as long as the parent drug. The metabolite is cleared via both feces and urine. Because the drug is extensively metabolized via CYP3A4, potent CYP3A4 inducers and inhibitors can have a substantial impact on the effect of ivabradine. Other potential interactions could occur with drugs that impact heart rate such as beta-blockers, amiodarone, digoxin, diltiazem, and drugs likely to impact conduction in the atria.

Three large outcomes trials have been conducted that evaluated the benefits of the heart rate- lowering effects of ivabradine.16-18 The BEAUTIFUL trial randomized almost 11,000 patients with coronary artery disease, left ventricular systolic dysfunction (LVEF < 40%), and a resting heart rate greater than or equal to 60 bpm to ivabradine or placebo.16 Patients with angina or HF were required to have stable symptoms for at least 3 months and stable doses of CV medications for at least 1 month. Beta-blocker therapy was not mandatory and, for patients taking beta-blockers, there was no specific target dose. The composite efficacy endpoint was CV death, hospitalization for myocardial infarction, or hospitalization for worsening HF. After a median treatment duration of 19 months, ivabradine had no effect on the primary outcome (hazard ratio [HR] 1.00; 95% confidence interval [CI] 0.91-1.10; p = 0.94).

The SIGNIFY trial randomized just over 19,000 patients with stable coronary artery disease who did not have HF to ivabradine or placebo.17 Patients were included in this study if they had an LVEF of at least 40% and a resting heart rate greater than or equal to 70 bpm. Beta-blocker therapy was not required. The primary composite endpoint was CV death or nonfatal myocardial infarction. After a median follow-up of 2 years, ivabradine did not favorably impact the primary outcome (HR 1.08; 95% CI 0.96-1.20; p = 0.20).

The SHIFT trial was a randomized, double-blind, placebo-controlled study comparing ivabradine to placebo in 6558 patients with symptomatic HF (NYHA class II-IV), an LVEF less than or equal to 35%, and a resting heart rate greater than or equal to 70 bpm who had been hospitalized in the previous year for worsening HF.18 During the 4 weeks prior to study enrollment, all patients were required to be clinically stable, to be in sinus rhythm, and to be taking a stable medication regimen that included maximally tolerated doses of beta-blockers, unless contraindicated. The majority of patients were also taking a diuretic, an ACEI or ARB, and an aldosterone antagonist. Of the 89% of patients taking a beta-blocker, 26% were taking a guideline-defined target dose. Ivabradine was started at 5 mg twice daily; at 2 weeks, the dose was titrated to either 2.5 or 7.5 mg twice daily to achieve a heart rate between 50 and 60 bpm. The doses of ivabradine at 1 month were 7.5 mg, 5 mg, and 2.5 mg twice daily in 63%, 26%, and 8% of patients, respectively. The primary composite outcome was hospitalization for worsening HF or CV death.

After a 2-year median follow-up, the primary outcome occurred in 24.5% of the ivabradine group and in 28.7% of the placebo group (HR 0.82; 95% CI 0.75-0.90; p < 0.001). The reduction in the primary composite outcome was driven entirely by a reduction in hospitalizations for worsening HF (HR 0.74; 95% CI 0.66-0.83). The reduction in total CV death over the median follow-up was not statistically significant with the use of ivabradine (HR 0.91; 95% CI 0.80-1.03).

Discontinuation of the study drug occurred in 21% of ivabradine patients and 19% of placebo patients (HR 1.14; 95% CI 1.02-1.27; p = 0.017). Serious adverse events occurred at a significantly lower rate in patients receiving ivabradine (45%) than in patients receiving placebo (48%; p = 0.025). However, it appears that this reduction occurred primarily as a result of fewer "cardiac events," which may have been due to fewer episodes of HF decompensation and HF hospitalizations. Bradycardia, atrial fibrillation, phosphenes, and blurred vision occurred at significantly higher rates with ivabradine than with placebo. Bradycardia was the only adverse event that was associated with a significantly greater rate of treatment discontinuation with ivabradine than with placebo.

On the basis of the results of SHIFT, the FDA approved ivabradine to reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF (LVEF ≤ 35%) who are in sinus rhythm with a heart rate of at least 70 bpm and are either on maximally tolerated beta-blocker therapy or have a contraindication to beta-blocker therapy.15 The FDA did not require that patients be hospitalized in the prior year for worsening HF as part of the drug’s indication. The recommended dosing regimen is identical to that in SHIFT. The starting dose is typically 5 mg twice daily, although a starting dose of 2.5 mg twice daily may be considered in patients in whom a risk of bradycardia is anticipated. The dose is then titrated after 2 weeks to achieve a target heart rate of 50 to 60 bpm. Patients who fail to achieve the target heart rate or who develop symptoms of bradycardia in the target heart rate range should discontinue the drug. Ivabradine is contraindicated in patients with acute or decompensated HF, a BP less than 90/50 mmHg, sick sinus syndrome or other atrioventricular conduction defects unless a functioning demand pacemaker is present, a resting heart rate less than 60 bpm, severe hepatic dysfunction, pacemaker dependence, or concomitant use of strong CYP3A4 inhibitors or inducers.

Sacubitril/valsartan is a fixed-dose combination of a neprilysin inhibitor and an ARB.19 Valsartan is an ARB that has FDA-approved indications for the treatment of HF and for left ventricular dysfunction following myocardial infarction. ARBs inhibit the effect of angiotensin II at the angiotensin type 1 receptor, which leads to decreased sympathetic tone, vasodilation, decreased hypertrophy, fibrosis and remodeling in the myocardium and vasculature, and decreased aldosterone secretion, which reduces sodium and water retention. Neprilysin (previously referred to as neutral endopeptidase) is an enzyme that metabolizes several different peptides, including atrial natriuretic peptide, B-type natriuretic peptide, bradykinin, adrenomedullin, substance P, and angiotensin II. Sacubitril (previously referred to as LCZ696) inhibits neprilysin, which leads to increased circulating concentrations of the peptides that neprilysin metabolizes. The net effect is that sacubitril produces many of the same pharmacologic effects as valsartan but via a different mechanism of action.

Sacubitril and valsartan are present in the Entresto tablet in a 1:1 molar ratio.19 Sacubitril and valsartan dissociate from each other after oral administration. Sacubitril is a prodrug that is rapidly converted to the active neprilysin inhibitor, LBQ657, by plasma esterases. The bioavailability of sacubitril is estimated to be at least 60%. The bioavailability of valsartan from the Entresto formulation is higher than the bioavailability from the Diovan formulation. The 26 mg, 51 mg, and 103 mg of valsartan in Entresto tablets are bioequivalent to the 40 mg, 80 mg, and 160 mg of valsartan in Diovan tablets. This increase in bioavailability is thought to be due to differences in the manufacturing process. Sacubitril, LBQ657, and valsartan are all highly plasma protein bound (> 90%). The half-lives of sacubitril, LBQ657, and valsartan are 1.1 to 3.6 hours, 9.9 to 11.1 hours, and 8.9 to 16.6 hours, respectively. LBQ657 is not further metabolized to a significant extent. Valsartan is not substantially metabolized, with only about 20% of the drug recovered as metabolites. CYP450-mediated metabolism of sacubitril and valsartan is minimal. Hence, CYP450-mediated drug interactions are not clinically important with sacubitril/valsartan.

A single, large, adequately designed clinical trial (PARADIGM-HF) compared sacubitril/valsartan against enalapril in patients with HFrEF.20 PARADIGM-HF included patients with symptomatic, chronic HF (LVEF ≤ 40%) who were treated with a stable dose of an ACEI or ARB and a beta-blocker for a minimum of 4 weeks prior to study enrollment. The study included 2 single-blind run-in phases during which 10,513 eligible patients initially received enalapril 10 mg twice daily for 2 weeks. Patients who tolerated enalapril were then treated with sacubitril/valsartan starting at 49 mg/51 mg twice daily, which was then titrated to 97 mg/103 mg twice daily. During the enalapril run-in, 10.5% of patients discontinued therapy and were excluded from the study. During the sacubitril/valsartan run-in, 10.4% of patients discontinued therapy and were excluded from the study. The most common adverse events that occurred during both run-in periods were hypotension, hyperkalemia, and renal dysfunction. As a result, 8442 patients were randomized in a double-blind manner to enalapril 10 mg twice daily or sacubitril/valsartan 97 mg/103 mg twice daily. The primary composite outcome of the PARADIGM-HF trial was CV death or hospitalization for HF.

After a median follow-up of 27 months, the primary composite outcome occurred in 21.8% of sacubitril/valsartan patients and 26.5% of enalapril patients (HR 0.80; 95% CI 0.73-0.87; p < 0.001). Sacubitril/valsartan significantly reduced the individual components of the composite outcome and all-cause mortality. The reduction in all-cause mortality was driven entirely by the reduction in CV mortality. Quality of life and changes in functional capacity favored sacubitril/valsartan patients over enalapril patients.

Discontinuation of the study drug due to adverse reactions occurred in 10.7% of sacubitril/valsartan and 12.3% of enalapril patients (p = 0.03). Discontinuation for renal impairment occurred in 0.7% of sacubitril/valsartan patients and 1.4% of enalapril patients (p = 0.002). Symptomatic hypotension occurred in 14% of the sacubitril/valsartan treatment group and 9% of the enalapril group (p < 0.001). Hypotension with a systolic blood pressure less than 90 mmHg occurred in 2.7% of the sacubitril/valsartan group and 1.4% of the enalapril group (p < 0.001). A significantly greater number of enalapril patients had serum creatinine levels greater than 2.5 mg/dl and serum potassium levels greater than 6.0 mEq/L compared to sacubitril/valsartan patients. Angioedema occurred twice as frequently with sacubitril/valsartan than with enalapril (0.2% vs 0.1%; p = 0.19), but no patient experienced airway compromise in either treatment group. Cough occurred significantly less frequently with sacubitril/valsartan than with enalapril (11.3% vs 14.3%; p < 0.001).

On the basis of the results of the PARADIGM-HF trial, the FDA approved sacubitril/valsartan to reduce the risk of CV death and hospitalization for HF in patients with chronic HF (NYHA class II-IV) and a reduced LVEF; it is used in place of an ACEI or an ARB.17 Initiation of sacubitril/valsartan is somewhat complicated. In patients already taking an ACEI, ACEI therapy must be discontinued for 36 hours prior to initiation of sacubitril/valsartan. The initial dose of sacubitril/valsartan is based on the magnitude of the ACEI dose. Patients taking a "high" dose of an ACEI can start sacubitril/lvalsartan at the 49 mg/51 mg dose twice daily. Characterization of a "high" dose is somewhat subjective; daily doses greater than enalapril 10 mg, lisinopril 10 mg, or ramipril 5 mg are generally considered "high" doses, but no recommendations defining "high" doses of other ACEIs are available. Patients taking lower than a "high" dose of an ACEI should start sacubitril/valsartan at the 24 mg/26 mg dose twice daily. Regardless of the starting dose, the sacubitril/valsartan dose should be titrated at 2- to 4-week intervals to the maintenance dose of 97 mg/103 mg twice daily. Patients taking an ARB do not need to undergo the 36-hour washout period, but the initial dose of sacubitril/valsartan is based on the magnitude of the ARB dose. Patients taking daily doses greater than valsartan 160 mg, losartan 50 mg, or olmesartan 10 mg should initiate sacubitril/valsartan at the 49 mg/51 mg twice daily dose. Patients taking lower doses of ARBs should start sacubitril/valsartan at the 24 mg/26 mg twice daily dose. Titration to the recommended maintenance dose of sacubitril/valsartan should occur at 2- to 4-week intervals. Patients not taking an ACEI or an ARB must start sacubitril/valsartan at the lowest dose (24 mg/26 mg twice daily) and titrate to the recommended maintenance dose at 2- to 4-week intervals.

In patients with mild to moderate renal impairment, no dosage adjustment is required with sacubitril/valsartan. In patients with severe renal impairment (creatinine clearance < 30 mL/min), the starting dose of sacubitril/valsartan should be 24 mg/26 mg twice daily. No dosage adjustment is required with sacubitril/valsartan in patients with mild hepatic impairment. In patients with moderate hepatic impairment, the starting dose should be 24 mg/26 mg twice daily. Sacubitril/valsartan is not recommended in patients with severe hepatic impairment.

Since ivabradine and sacubitril/valsartan were only recently approved by the FDA, these agents have not yet been added to the HF guidelines. It is anticipated that both of these drugs will be included in the next edition of the HF guidelines on the basis of their favorable impacts on outcomes in HF. There are several classes of drugs used in HF that are GDMT for HFrEF (Table 2). These drugs should be used according to the ACCF/AHA recommendations unless patients have a contraindication to their use or a complication while using these drugs. Additionally, the use of diuretics and digoxin are added to manage symptoms after consideration of GDMT. Ultimately, drug therapy in patients with HFrEF is individualized on the basis of response to medical therapy.

Drug therapy in HFpEF. No therapy has been shown to improve outcomes in patients with HFpEF.6 Several studies with drugs shown to improve survival in HFrEF have been conducted in patients with HFpEF. Studies with perindopril, candesartan, and irbesartan compared to placebo failed to demonstrate benefits in patients with HFpEF.21 No studies have specifically evaluated the effect of beta-blockers in patients with HFpEF, but a subgroup analysis of the SENIORS trial found that nebivolol did not favorably impact mortality in patients with an LVEF greater than 40%. In the OPTIMIZE-HF registry, the use of beta-blockers in patients with HFpEF did not improve hospitalizations or mortality. The TOPCAT study compared spironolactone and placebo in patients with HFpEF.22 The composite outcome of CV death, aborted cardiac arrest, or HF hospitalization was not significantly reduced by spironolactone, but HF hospitalizations were significantly reduced by spironolactone. A post-hoc analysis of TOPCAT found significant regional differences in outcomes and reasons for study inclusion.23 In the analysis, the primary composite outcome was significantly better with spironolactone in patients in countries in the Western Hemisphere than in patients in other countries and in patients who qualified for the study on the basis of B-type natriuretic levels rather than a history of prior HF hospitalizations.

There is a lack of data demonstrating improved outcomes with any specific drug therapy in patients with HFpEF. Therefore, guidelines suggest focusing on the management of the most common risk factors associated with HFpEF, including aggressive BP and heart rate control.6 It is reasonable to consider beta-blockers, ACEIs, ARBs, or aldosterone receptor antagonists for BP control in patients with HFpEF. Maintenance of sinus rhythm in patients with atrial fibrillation or adequate rate control in patients with permanent atrial fibrillation is recommended. Patients with volume overload should be managed with diuretics. Managing the risk factors for and treating diabetes mellitus and ischemic heart disease are also priorities. Additional data concerning the optimal medical management of patients with HFpEF is needed.

REDUCING HF HOSPITALIZATIONS AND COMPLICATIONS

Hospitalizations may represent an initial event leading to a diagnosis of HF or hospitalizations may occur in patients with chronic HF and represent disease progression with negative prognostic implications. The natural history of hospitalizations over the lifespan of the patient with HF has been referred to as a "three-phase terrain."24,25 One-third of all hospital readmissions occur in the first 2 months after an HF hospitalization, which is referred to as the "vulnerable" or "transition" period; approximately 60% of these readmissions occur in the first 15 days after hospital discharge. One-half of hospital readmissions occur during the 2 months prior to death, which is referred to as the "palliative" phase. The remaining 20% of readmissions occur in the time frame between those 2 periods, which is referred to as the "plateau" phase. It is important to note that approximately 50% of all readmissions are estimated to be secondary to HF or CV causes and the other 50% are secondary to non-CV causes.

The most common modifiable risk factors leading to hospital readmissions for HF are summarized in Table 3. The reasons for HF readmission vary somewhat depending on when they occur.26 During the vulnerable or transition period, factors associated with readmission in patients with HF include incomplete treatment during hospitalization, poor coordination of care plans at discharge, and inadequate access to early follow-up care. During the plateau phase, reasons for hospital readmission in patients with HF include non-adherence to GDMT or device therapy, failure to identify and treat early signs of congestion, and failure to adequately manage comorbidities that can result in hospitalizations. Hospitalizations occurring during the palliative phase are thought to be less preventable, partly because patients are less responsive to standard HF therapies during this phase. Decisions concerning reassessment of treatment options and end-of-life care will ultimately need to be made during this phase.

Table 3. Avoidable causes of heart failure hospital readmissions25,31
  1. Inadequate education and counseling provided to the patient, family, and/or caregiver
  2. Inadequate discharge planning by the health care team
  3. Failure of the health care team to provide adequate follow-up care
  4. Failure of the patient to follow non-pharmacologic  therapy recommendations, such as diet, activity, and symptom monitoring or appropriate self-care measures
  5. Failure to address the complex issues that impact patient care, including:
    • Medical issues (medication adherence, multiple comorbidities)
    • Behavioral issues (barriers to change, readiness to change, internal motivation)
    • Psychosocial issues (depression, anxiety, cognitive impairment, social isolation, low health literacy)
    • Environmental issues (physical or geographic isolation, physical barriers in home)
    • Financial issues (poverty, lack of health insurance, lack of prescription insurance)
  6. Failure of health care providers to prescribe guideline-directed medical therapy, including pharmacological, non-pharmacological, and device therapy, and disease management programs when indicated

Lack of adherence to GDMT and lifestyle modifications are a cause of approximately one-third of HF hospitalizations.27,28 Overall, 40% to 60% of HF patients are non-adherent to recommended therapy.29 In the CHARM program, adherence to evidence-based therapy was associated with a 35% relative risk reduction in mortality.30 Outcomes can also be improved by pharmacist involvement in care. A systematic analysis of 12 studies evaluating pharmacist involvement in the care of patients with HF showed a significant reduction in hospitalizations with a trend in mortality reduction compared to when pharmacists are not involved in patient care.31 An even greater effect on outcomes, including reduced HF hospitalizations, improved quality of life, and increased exercise capacity, was observed when pharmacists were included as part of the collaborative care team for the HF patient. The majority of studies evaluating the impact of pharmacists on the use of GDMT in patients with HF revealed a significant improvement in adherence, which dissipated when pharmacist involvement stopped.32

Discharge counseling. The Heart Failure Society of America (HFSA) recommends that all patients with HF and their families/caregivers receive education and counseling about HF and its processes.33 This counseling may occur during hospitalizations, care transitions, or in the community setting. Regardless of where or when it occurs, the HFSA guidelines state that individualized education and counseling should be multidisciplinary and emphasize adherence to pharmacologic and non-pharmacologic therapy and self-care. To be effective, education must lead to skill building and changes in targeted critical behaviors. The goals and objectives for the education of patients with HF are summarized in Table 4. Patient health literacy, cognitive state, psychological state, culture, and access to social and financial resources must be considered during counseling. Educational programs should begin with an assessment of the patient’s knowledge of HF, and the intensity of education and counseling should vary according to the severity of disease. During hospitalization, only essential education, such as post-hospitalization treatment and follow-up appointments, should be provided. More extensive education should occur in the immediate post-discharge phase and continue over a minimum of 3 to 6 months. Patient preferences for educational formats should be evaluated and may include videos, print materials, one-on-one or group sessions, and the Internet. Patients should be able to demonstrate an understanding of their education (by using the "teach back" technique) about diet, exercise, medications, and disease processes.

Table 4. Educational goals and objectives for patients with heart failure (HF)6,31
1. Define HF
  • Educate patients about the causes of and risk factors for HF 
  • Discuss the signs and symptoms associated with HF
2. Recognize the signs and symptoms associated with worsening HF
  • Discuss specific plans for responding to changes in particular signs and symptoms
  • Formulate an action plan for contacting health care providers
3. Understand the indication of and how to use each medication
  • Identify each medication
  • Explain the purpose of each medication
  • Clarify the dose and timing of the dose of each medication
  • Recognize potential side effects of each medication
  • Understand actions to take in the event of a missed dose of a medication
4. Manage risk factors for the progression of HF (per treatment guidelines)
  • Stop smoking
  • Control blood pressure
  • Control blood glucose levels
  • Control lipid levels
  • Maintain a healthy body weight
5. Follow specific diet recommendations
  • Identify high- and low-sodium foods and restrict sodium intake
  • Restrict fluid intake, if needed
  • Limit intake of alcoholic beverages
  • Consume appropriate caloric intake and an appropriate balance of protein, carbohydrate, and fat
6. Adhere to exercise/activity recommendations
  • Participate in a prescribed exercise and/or activity plan
  • Complete activities of daily living
  • Maintain desired level of sexual activity
7. Promote adherence to treatment
  • Plan a regimen that promotes medication adherence and fits the patient's lifestyle
  • Design a strategy to obtain prescription refills
  • Discuss goals of treatment appropriate for the stage of HF 

Disease management programs. The HFSA recommends that high-risk HF patients or patients hospitalized for HF be considered for enrollment in a disease management program (DMP).33 Patients who have high-risk HF (Table 5) should also be considered for referral to an HF DMP. The recommended components of an HF DMP are summarized in Table 6. A substantial number of studies have been conducted to evaluate the effectiveness of a variety of HF DMPs on hospitalizations and mortality,34 and the majority of these studies focused on a primary intervention that included in-home visits, outpatient visits, structured telephone support, non-invasive telemonitoring, and invasive telemonitoring. A systematic review of these DMPs found substantial heterogeneity in the results of the randomized controlled trials evaluating the effectiveness of these programs.34 The inconsistent results among the different DMPs cannot be interpreted to indicate that HF DMPs are ineffective. Rather, the most effective HF DMPs need to be flexible enough to incorporate a variety of medical care monitoring interventions selected on the basis of the preferences or needs of the individual patient. The one-size-fits-all approach to the application of an HF DMP has not been shown to be effective.

Table 5. Characteristics of high-risk heart failure6,7,31
  • MVO2 uptake < 14 mL/kg/min
  • Repeat hospitalization
  • Worsening renal function
  • Diuretic resistance
  • Cardiorenal syndrome
  • Hypotension-limiting guideline-directed medical therapy
  • Seattle Heart Failure Risk Calculator score > 15%
  • Reaching < 300 feet during a 6-min walk
  • Persistent hyponatremia
  • Cardiac cachexia
MVO2 = mixed venous oxygen saturation

Table 6. Components of an effective heart failure disease management program6,31
1. Individualized comprehensive education and counseling for each patient
2. Promotion of self-care, which may allow self-adjustment of diuretic and/or potassium supplement
doses
3. Emphasis on behavioral changes that improve adherence to pharmacologic and non-pharmacologic
treatments
4. Increased access to health care providers
5. Early recognition and follow-up for signs and symptoms of fluid overload
6. Early follow-up after hospitalization or decompensation
7. Flexible and individualized strategy for long-term follow-up (home or office visits, telemonitoring)
8. Emphasis on guideline-directed medical therapy
9. Attention to social and financial barriers

It is important to recognize that all HF DMPs include an educational and counseling component. The majority also include on-going in-home or outpatient clinic visits as a standard of care. A few HF DMPs rely solely on telephone follow-up or telemonitoring. DMPs that incorporate face-to-face interactions show similar outcomes to more advanced DMP strategies that incorporate non-invasive telemonitoring or structured telephone support. Pharmacists’ should play an important role in the DMP process, especially in terms of education, counseling, and clinical follow-up.

Patient adherence. A substantial amount of research has focused on predictors of adherence in HF patients. This data is important because it will inform pharmacists about patients with barriers to adherence.32 Variables that predict increased and decreased adherence to treatment regimens are summarized in Table 7. Although predictors of adherence may be useful in prioritizing the intensity and type of education and counseling in patients with HF, altering the variables that affect adherence is typically difficult. Even though specific variables are associated with poor adherence, the presence of a single variable that impacts adherence does not guarantee poor adherence. A predictive tool that can be used as a reliable indicator of poor adherence has yet to be identified. An evaluation of the utility of a number of tools created to predict nonadherence in HF patients has recently been published,32 and the adherence tools associated with the best practical value in HF patients were the Morisky Medication Adherence Scale and the Merck Adherence Estimator.35,36 These tools can be used in conjunction with an assessment of the previously aforementioned variables to help predict adherence and identify patients who have a high risk for non-adherence.

Table 7. Factors that impact medication adherence in patients with heart failure (HF)30
Increased adherence Decreased adherence Variable adherence
(studies report conflicting results)
Age > 65 years old Belonging to a racial minority (Non-white, African American) Female gender
Increased education level (number of years) Severe HF Prior HF hospitalization
Current use of other cardiovascular medications Increased number of comorbidities  
Patient knowledge of correct medication use (demonstrated by the "teach back" method) Depression  
Prior use of HF medications Cognitive decline  
Adequate health literacy High baseline heart rate  
Satisfactory reading ability Renal impairment/use of dialysis  
Being married High medication copay  
  Frequent medication dosing  
  Changes in daily routine to accommodate taking medications  
  Use of antiarrhythmics  
  Living alone  
  Lack of health insurance  

QUALITY IMPROVEMENT INITIATIVES

Several large-scale quality improvement initiatives have demonstrated improvement in quality measures and outcomes over time for the institutions participating in these registries.37 The ADHERE, OPTIMIZE-HF, and the GWTG-HF registries found that participating institutions improved their use of GDMT in patients with HF and observed improvements related to hospitalizations, lengths of hospital stay, and risk-adjusted hospital mortality.38-40 These findings suggest that quality improvement initiatives designed for large-scale use can increase adherence to quality measures and standardized clinical decision-making tools. Registries currently being implemented that involve patients with HF are focusing on interventions directed at the transition of care from hospital to home.41 Pharmacists must be knowledgeable about these registries since they focus on improvements in the use of GDMT therapy for HF and for standardized treatment of common comorbidities observed in patients with HF such as atrial fibrillation and diabetes mellitus. Pharmacist involvement in and understanding of institution-specific performance relative to benchmarks established by these registries is strongly encouraged.

SUMMARY

Substantial improvements in the understanding of the pathophysiology of HF have led to refinements in the use of pharmacologic therapies, as well as non-pharmacologic approaches and device therapies, for the treatment of HF. Despite these advances, HF remains a complex, progressive, and ultimately fatal syndrome. Pharmacists can play a crucial role in ensuring that patients with HF receive optimal medical management. Pharmacists must be able to educate and counsel patients not only about the use of GDMT but also about drugs that are either of no benefit or potentially harmful to the patient with HF. Pharmacists must also be educated about the benefits and risks of new drug therapies that have not yet been incorporated into the HF guidelines. HF hospitalizations are clinically and economically important and pharmacists must be part of the multidisciplinary approach to reduce readmissions for HF. Pharmacist involvement in caring for patients with HF requires an on-going commitment to continually monitoring and evaluating an individual patient’s adherence and response to the prescribed pharmaceutical care plan.

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