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INTRODUCTION

Heart failure (HF) is a symptom complex associated with a diminished quality of life and a substantial burden of hospitalization and mortality. The understanding of the pathophysiology and clinical characteristics of heart failure have evolved over the past two decades. This has given rise to a more sophisticated classification system and more individualized treatment strategies for patients with HF. This review will provide pharmacists with updated treatment recommendations for patients with symptomatic Class C heart failure based on the 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure.¹

Definitions

HF is an abnormality in myocardial function typically occurring secondary to other diseases or risk factors. The primary abnormality is a relative reduction in cardiac output which results in activation of several neurohormonal systems including the sympathetic nervous system, the renin-angiotensin- aldosterone system, and other vasoactive and inflammatory mediators. HF is currently stratified based on patients’ left ventricular (LV) function.² Reduced ejection fraction (HFrEF), most commonly resulting from systolic dysfunction, is defined as ejection fraction (EF) ≤ 40%. Preserved EF (HFpEF), usually due to diastolic dysfunction, is defined as EF ≥ 50%. Mid-range or borderline LV function is EF between 41% and 49%. A final group of HF patients are those who at one time had documented HFrEF but who have recovered myocardial function such that their EF improved to > 40% (HFimpEF). The underlying pathophysiologic processes and natural history of patients with HFmEF and HFimpEF are currently not well understood.

Prevalence

Approximately 6 million adults in the U.S. are currently living with HF, with 915,000 new cases diagnosed each year.³ The prevalence of HF is projected to increase to over 8 million adults by 2030.³ The proportion of patients with HFrEF and HFpEF is approximately equal. Heart failure is associated with a substantial burden on the healthcare system. Hospitalizations for HF totaled just over 1 million in 2010. According to the Centers for Disease Control and Prevention, the cost of HF was estimated at $30.7 billion in 2010 with direct health care costs accounting for 68% of that total.

Mortality after a diagnosis of HF has improved in recent years, but remains at a high rate of 43% at 5 years after diagnosis.⁴ When stratified by severity of HF, survival at 5 years for patients with stage A, B, C, and D HF was 97%, 96%, 75%, and 20%, respectively.⁵ Heart failure was the primary cause of death in > 65,000 patients and a contributing factor to the cause of death in > 300,000 patients in 2013.³

Therapy

Therapy for HF is individualized based on severity according to ACC/AHA HF stage and symptoms based on the New York Heart Association (NYHA) functional classification (Table 1).⁶ The primary limitation of the NYHA functional classification system is that it is based on patients’ self-reported symptoms. This may lead to some subjectivity in placing patients into a specific functional class. Table 2 lists the drugs recommended for use in HF patients based on their ACC/AHA stage according to the 2013 HF guidelines.⁶

Table 1. NYHA Functional Classification and ACC/AHA Stages of Heart Failure (HF)6
NYHA Functional Classification		ACC/AHA Stages of Heart Failure
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.
NYHA=New York Heart Association; ACC/AHA = American College of Cardiology/American Heart Association

Table 2. Drug Therapy for Chronic Heart Failure with Reduced Ejection Fraction (HFrEF) Stratified by ACC/AHA Stage (2013 Guidelines)6
Drug/Drug Class	ACC/AHA Stage B	ACC/AHA Stage C	ACC/AHA Stage D
ACE inhibitor or ARB	Yes	Yes	Yes
Beta-blockers	Yes	Yes	Yes
Diuretics	No	Consider based on symptoms	Consider based on symptoms
Digoxin	No	Consider based on symptoms	Consider based on symptoms
Aldosterone antagonists	No	Yes	Yes
Hydralazine/isosorbide dinitrate	No	Yes for African Americans Consider for others based on symptoms	Yes for African Americans Consider for others based on symptoms
ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker. *not yet evaluated in any HF guideline

Drugs demonstrated to have favorable effects on survival or quality of life in HF are typically referred to as guideline-directed medical therapy (GDMT).⁶ Diuretics and digoxin have not been demonstrated to reduce mortality, but are used to manage the symptoms of HF. A large outcomes trial found that digoxin had a neutral effect on mortality in HF patients.⁷ The loop diuretics are commonly used to maintain normal volume status in the patient 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 placebo group.

Two new drug therapies for the management of HFrEF were approved in the U.S. in 2015.^8,9 These include ivabradine (Corlanor) and the fixed-dose combination of valsartan and sacubitril (Entresto) referred to as an angiotensin receptor/neprilysin inhibitor, or ARNI. The benefit of these drugs in HF prompted revised guidelines, including the ACC/AHA/HFSA 2016 Focused Update on New Pharmacological Therapy for Heart Failure.¹ This update also included a new class of recommendation/level of evidence (COR/LOE) (Table 3).¹

Table 3. Class of Recommendation and Level of Evidence for Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care1
Class (Strength) of Recommendation (COR)	Level (Quality) of Evidence (LOE)
Class I (strong)                                Benefit >>> Risk Indicated, recommended, useful, effective, beneficial	Level A High quality evidence from > 1 randomized trial Meta-analysis of high quality randomized trials
Class IIa (moderate)                          Benefit >> Risk Reasonable/can be useful, effective, beneficial	Level B-R Moderate quality evidence from ≥ 1 randomized trials
Class IIb (weak)                                   Benefit ≥ Risk May/might be reasonable Usefulness/effectiveness not well established	Level B-NR Moderate quality evidence from ≥1 well-designed well-executed non-randomized, observational, or registry trials
Class III No Benefit (moderate)             Benefit = Risk Not recommended Not useful/effective/beneficial	Level C-LD Randomized or non-randomized observational or registry trials with design or execution limitations Physiological or mechanistic studies in patients
Class III Harm (strong)                         Risk > Benefit Harmful Associated with excess morbidity/mortality	Level C-EO Consensus of expert opinion based on clinical experience

Ivabradine. Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated (HCN) If channel blocker that reduces automaticity in the sinus node, which slows heart rate.¹⁰ The effect of ivabradine on heart rate is both dose dependent and rate dependent. Ivabradine produces a greater reduction in heart rate in patients who have a faster heart rate at baseline. The average decrease at rest and during exercise is about 10 bpm. Although the predominant effect of the drug is in the sinus node, it may also prolong the AH and PR interval. 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. This has been associated with development of luminous phenomena (phosphenes) described as brightness in a limited part of the visual field.⁸

The relative bioavailability of ivabradine is about 40% with peak plasma concentrations achieved in 1 hour when taken on an empty stomach. Food delays peak absorption by 1 hour and increases absorption by 20% to 40%.⁸ The drug is recommended to be taken with food. Approximately 70% of ivabradine is bound to circulating plasma protein. Ivabradine is extensively metabolized by CYP3A4 with only about 4% of unchanged drug cleared by the kidney.⁸ The primary metabolite is N-desmethylated ivabradine which is equipotent to ivabradine, with a plasma concentration that is about 40% of that of the parent drug. The half-life of ivabradine ranges from 6 hours to 11 hours.^8,11 The role of the major metabolite on the duration of action of the drug is uncertain. 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. Pharmacodynamic drug interactions with other drugs—such as beta-blockers, amiodarone, digoxin, diltiazem, and other drugs that affect the sinoatrial node—may potentiate the effect of ivabradine on heart rate.

Three large outcomes trials have been conducted to evaluate the heart rate lowering effects of ivabradine.^12-14 The BEAUTIFUL trial randomized almost 11,000 patients with coronary artery disease, LV systolic dysfunction (EF < 40%), and a resting heart rate ≥ 60 bpm to ivabradine or placebo.¹² Patients with angina or HF had to have stable symptoms for at least 3 months and stable doses of cardiovascular 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 cardiovascular 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 (HR 1.00; 95% CI 0.91 to 1.10; P = 0.94).

The SIGNIFY trial randomized just over 19,000 patients with stable coronary artery disease who did not have symptomatic HF to ivabradine or placebo.¹³ Patients had to have a LVEF ≥ 40% and a resting heart rate ≥ 70 bpm. Beta-blocker therapy was not required. The primary composite endpoint was cardiovascular 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 to 1.20; P = 0.20).

SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) was a randomized, double- blind, placebo-controlled study comparing ivabradine to placebo in 6,558 patients with symptomatic HF (NYHA class II-IV), LVEF ≤ 35%, and a resting heart rate ≥ 70 bpm who had been hospitalized in the prior year for worsening HF.¹⁴ During the 4 weeks prior to study enrollment, all patients had to be clinically stable, in normal sinus rhythm, and taking a stable medication regimen which included maximally tolerated doses of beta-blockers. A majority of patients were taking diuretics, an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), beta-blockers, and an aldosterone antagonist. Of the 89% of patients taking a beta-blocker, 26% were on a guideline-defined target dose. Ivabradine was started at 5 mg twice daily for 2 weeks at which time 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%, respectively. The primary composite endpoint was the first occurrence of hospitalization for worsening HF or cardiovascular death.

Table 4. Clinical Characteristics of Sacubitril/Valsartan and Ivabradine8,9
Variable	Angiotensin receptor/neprilysin inhibitor (ARNI)		Ivabradine
	Valsartan	Sacubitril
Mechanism of action	Angiotensin receptor blocker	Prodrug converted to LBQ657 which is a neprilysin inhibitor	If channel blocker
Indication	Reduction in the risk of cardiovascular death and HF hospitalization in patients with chronic HF (NYHA Class II-III) and reduced ejection fraction		Reduction in the risk of hospitalization for worsening HF in patients with stable, symptomatic HF with an EF ≤ 35% who are in sinus rhythm with a resting heart rate ≥ 70 bpm
Bioavailability (%)		≥ 60	40
Food Interaction			Food delays Tmax by about 1 hour, but ⬆ AUC by 20% to 40%; take dose with food
Time to peak plasma concentration (Tmax)	1.5 hours	0.5 hours	0.75-1.5 hours
Half-life (hours)			6 to 11
Plasma protein binding	94% to 97%	94% to 97%	70%
Unchanged drug cleared via renal clearance	13%		Minimal
Metabolism		Metabolized by non-specific esterases to the active moiety (LBQ657)	Extensive metabolism by CYP 3A4 to a major metabolite (N-desmethylated ivabradine (equipotent to ivabradine and circulates at plasma concentrations 40% of ivabradine
Drug interactions			Strong to moderate CYP 3A4 inhibitors/inducers effect plasma concentrations
*1:1 molar complex of sacubitril and valsartan

After a 2-year median follow-up period, the primary outcome occurred in 24.5% of the ivabradine group compared to 28.7% of the placebo group (HR 0.18; 95% CI 0.75-0.90; P < 0.0001). The reduction in the primary composite outcome was driven entirely by a reduction in hospitalizations which included time to a first HF hospitalization (HR 0.82; 95% CI 0.75-0.90) and for total hospitalizations for HF (HR 0.74; 95% CI 0.66-0.83). The reduction in total cardiovascular deaths over the median follow-up period was not statistically significant (HR 0.91; 95% CI 0.80-1.03).¹⁴

Discontinuation of 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 were significantly fewer with ivabradine (45%) than with placebo (48%; P = 0.025). However, it appears that this reduction occurred primarily because of fewer cardiac events, which may have been due to fewer episodes of HF decompensation and HF hospitalizations. The adverse events that occurred at significantly greater rate with ivabradine compared to placebo were bradycardia, atrial fibrillation, phosphenes, and blurred vision. The only adverse event that was associated with a significantly greater rate of treatment discontinuation with ivabradine was bradycardia.¹⁴

Based on the results of SHIFT, the FDA approved ivabradine with an indication to reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with LVEF ≤ 35% who are in sinus rhythm with a heart rate ≥ 70 bpm and are either on maximally tolerated beta-blocker therapy or have a contraindication to beta-blocker therapy.⁸ The FDA did not require that patients be hospitalized in the prior year for worsening HF as part of the drug’s indication. The approved 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 for 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. Patients who fail to achieve the target heart rate or develop symptoms of bradycardia in the target range should discontinue the drug. Ivabradine is contraindicated in patients with acute or decompensated HF, blood pressure < 90/50m mmHg, sick sinus syndrome or other atrioventricular conduction defects unless a functioning permanent pacemaker is present, resting heart rate < 60 bpm, severe hepatic dysfunction, pacemaker dependence, or concomitant use of strong CYP3A4 inhibitors or inducers.⁸

Limitations to consider based on the design of SHIFT include a lack of data in patients with HFrEF other than those with NYHA Class II/III HF. Fewer than 1 in 4 patients were treated with beta-blockers at target doses. The use of beta-blockers was not standardized in SHIFT. Beta-blockers not demonstrated to reduce mortality in HF were included in the study. The SHIFT does not report the inclusion of any black patients. There are no data with ivabradine available in patients receiving the combination of hydralazine plus a nitrate.¹⁴

The ACC/AHA/HFSA 2016 Focused Update recommends that ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic NYHA Class II/III stable chronic HFrEF (LVEF ≤ 35%) who are receiving guideline-directed medical therapy, including a beta-blocker at a maximum tolerated dose, and who are in sinus rhythm with a heart rate of ≥ 70 bpm at rest.¹ The COR/LOE for ivabradine in HF is IIa/B-R. The class or recommendation of IIa is most likely a result of the fact that ivabradine did not reduce cardiovascular or total mortality in SHIFT. It is important to note that ivabradine is used in addition to guideline-directed medical therapy for HF.

Angiotensin receptor/neprilysin inhibitor (ARNI). Sacubitril/valsartan is a fixed-dose combination of a neprilysin inhibitor and an ARB.⁹ Valsartan is an ARB approved by the FDA for the treatment of HF and for LV dysfunction following myocardial infarction. ARBs inhibit the effect of angiotensin II at the angiotensin type 1 receptor which leads to a decrease in sympathetic tone, vasodilation, decreased hypertrophy, fibrosis and remodeling in the myocardium and vasculature, and a decrease in aldosterone secretion which reduces sodium and water retention.¹⁵ Neprilysin (previously referred to as a neutral endopeptidase) is an enzyme that metabolizes several different peptides, including atrial natriuretic peptide (ANP), b-type natriuretic peptide (BNP), bradykinin, adrenomedullin, substance P, and angiotensin II.¹⁶ Sacubitril inhibits neprilysin which leads to increases in 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.

The fixed-dose combination contains sacubitril and valsartan in a 1:1 molar ratio.⁹ Sacubitril and valsartan dissociate from each other after oral administration. Sacubitril is a prodrug which is rapidly converted to the active neprilysin inhibitor LBQ657 by plasma esterases. The bioavailability of sacubitril is estimated to be > 60%.¹⁷ The bioavailability of valsartan in the sacubitril combination is greater than that associated with combination of valsartan and hydrochlorothiazide (Diovan^®). The 26 mg, 51 mg, and 103 mg of valsartan in sacubitril/valsartan is bioequivalent to 40 mg, 80 mg, and 160 mg of valsartan in the hydrochlorothiazide combination tablet. 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 1.1–3.6 hours, 9.9.–11.1 hours, and 8.9–16.6 hours, respectively. Sacubitril is rapidly metabolized to LBQ657 while 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.⁹

A single large adequately designed clinical trial has compared sacubitril/valsartan against enalapril in patients with HFrEF (PARADIGM-HF).¹⁸ This study included patients with symptomatic, chronic HF with LVEF ≤ 40% treated with a stable dose of an ACE inhibitor or an ARB and a beta-blocker for a minimum of 4 weeks prior to study enrollment. This 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 tolerating enalapril were then treated with sacubitril/valsartan starting at 49 mg/51 mg twice daily titrated to 97 mg/103 mg twice daily. The run-in phase with sacubitril/valsartan occurred over 4 to 6 weeks. 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. The adverse events occurring most commonly during both run-in periods were hypotension, hyperkalemia, and renal dysfunction. Thus, 8442 patients were randomized in double-blind fashion to enalapril 10 mg twice daily or sacubitiril/valsartan 97 mg/103 mg twice daily. The primary composite endpoint of PARADIGM-HF trial was cardiovascular death or hospitalization for HF.¹⁸

After a median follow-up of 27 months, the primary composite outcome occurred in 21.8% of sacubitril/valsartan patients compared to 26.5% of enalapril patients (HR 0.80; 95% CI 0.73-0.87; P < 0.001). Sacubitril/valsartan also significantly reduced the individual components of the composite outcome (cardiovascular death and time to first HF hospitalization) as well as all-cause mortality. PARADIGM trial findings included a statistically significant 20% reduction in the primary composite endpoint of cardiovascular death or HF hospitalization and a 16% reduction in the risk of death from any cause (P < 0.001 for both). The reduction in all-cause mortality was driven entirely by the reduction in cardiovascular mortality. Quality of life and changes in functional capacity favored sacubitril/valsartan patients compared to enalapril patients.¹⁸

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 dysfunction occurred in 0.7% of sacubitril/valsartan patients and 1.4% of enalapril patients (P = 0.002). Symptomatic hypotension occurred in 14% and 9% of sacubitril/valsartan and enalapril treatment groups, respectively (P < 0.001). Hypotension with a systolic BP < 90 mmHg occurred in 2.7% and 1.4% of sacubitril/valsartan and enalapril groups, respectively (P < 0.001). A significantly greater number of enalapril patients had serum creatinine levels > 2.5 mg/dl and serum potassium levels > 6.0 mEq/L than with sacubitril/valsartan. Angioedema occurred twice as frequently with sacubitril/valsartan compared to enalapril (0.2% vs 0.1%; P = 0.19), but no patient experienced airway compromise in either treatment group. Cough occurred significantly less with sacubitril/valsartan than with enalapril (11.3% vs 14.3%; P < 0.001).¹⁸

Limitations of the PARADIGM-HF trial include a lack of data concerning the impact of the study drug on changes in exercise capacity. A study currently in progress (AWAKE-HF) is evaluating the effect of sacubitril/valsartan compared with enalapril on mean activity counts as measured by wrist-worn accelerometer.¹⁹ It does not appear that this study is evaluating the 6-minute walk test or exercise capacity using treadmill time. Seventy-five percent of patients in PARADIGM-HF had NYHA class II HF and about 23% had NYHA class III HF. Little or no data are available concerning the use of sacubitril/valsartan in patients outside of these functional classes. Only about 5% of the patients enrolled in PARADIGM-HF were African American. It is unknown what proportion of these patients were treated with hydralazine plus a nitrate. Neprilysin increases levels of amyloid beta, the protein thought to be involved in the development of Alzheimer’s disease. Although no substantial reports of neurocognitive toxicity were reported in PARADIGM-HF, testing with sufficient sensitivity to detect subtle changes in cognitive function was not part of the study protocol. Neurocognitive testing has been added to the study design of the PARAGON study, which is evaluating sacubitril/valsartan in patients with HFpEF.²⁰

Based on the results of the PARADIGM-HF trial, the FDA approved sacubitril/valsartan for use in place of an ACEI or an ARB to reduce the risk of cardiovascular death and hospitalization for HF in patients with HFrEF (NYHA class II-IV).⁹ Initiation of sacubitril/valsartan is somewhat complicated in patients already receiving therapy with an ACE inhibitor or ARB. The ACE inhibitor must be discontinued for 36 hours prior to initiation of sacubitril/valsartan. The initial dose of sacubitril/valsartan is based on the size of the ACE inhibitor dose. Patients taking “high” doses of an ACE inhibitor (enalapril 10 mg, lisinopril 10 mg, or ramipril 5 mg) can start sacubitril/valsartan at the 49 mg/51 mg dose twice daily. The size of what is considered a high dose of an ACE inhibitor appears to be somewhat subjective. No recommendation is made in the labeling concerning what are considered “high” doses of other available ACE inhibitors. Patients taking lower doses of an ACE inhibitor 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 size 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 ARB therapy should start sacubitril/valsartan at the lowest dose. Titration to the recommended maintenance dose of sacubitril/valsartan should occur at 2- to 4-week intervals. According to the prescribing information, patients not taking an ACEI or an ARB must start sacubitril/valsartan at the lowest dose (24 mg/26 mg) and titrate to the recommended maintenance dose at 2- to 4-week intervals.⁹ In patients with mild to moderate renal dysfunction, no dose adjustment is required with sacubitril/valsartan. In patients with severe renal dysfunction (CrCl < 30 ml/min), the starting dose of sacubitril/valsartan should be 24 mg/26 mg twice daily. No dose 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. Sacubitril/valsartan is not recommended in patients with severe hepatic impairment.⁹

Based on the results of the PARADIGM-HF study, the ACC/AHA/HFSA 2016 Focused Update guideline recommends the following.¹ Inhibition of the renin-angiotensin system with an ACE inhibitor or an ARB (evidence level I/A) or an ARNI (evidence level I/B-R) should be used in conjunction with evidenced- based beta-blockers and aldosterone antagonists in selected patients with chronic HFrEF to reduce morbidity and mortality. ACE inhibitors and ARBs are beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality. In patients with chronic symptomatic HFrEF (NYHA class II/III) who tolerate an ACE inhibitor or ARB, replacement of these drugs with an ARNI is recommended to further reduce morbidity and mortality. The implication is that in order for patients to receive an ARNI, they must tolerate an ACE inhibitor or an ARB and must remain symptomatic despite such therapy. The 2016 guidelines also indicate that an ARNI should not be administered concomitantly with an ACE inhibitor or within 36 hours of the last dose of an ACE inhibitor (III/B-R). In addition, the 2016 update indicates that an ARNI should not be given to a patient with a history of angioedema (III/E-O).

Summary

Substantial improvements in the understanding of the pathophysiology of HF have led to the study and approval of two new pharmacologic therapies that improve outcomes in patients with HF. With the availability of these two new drug therapies, pharmacists must be educated about the benefit and risk of these agents. Given the clinical and economic importance of HF, pharmacists must be a part of the multidisciplinary approach to the treatment of HF. Each of these new drugs must be used on an individualized basis to improve the care of the patient with HF. This requires an ongoing commitment to monitoring and evaluation of the individual patient’s plan for pharmacologic therapy.

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