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Journal of Cardiovascular Nursing Vol. 31, No. 6, pp 545 Y554 xCopyright B2016 Wolters Kluwer Health, Inc. All rights reserved. Pharmacology: Evidence Meets Practice Foundations of Pharmacotherapy for Heart Failure With Reduced Ejection Fraction Evidence Meets Practice, Part II Colleen K. McIlvennan, DNP, ANP; Robert L. Page II, PharmD, MSPH, FAHA, BCPS Pharmacologic treatment for systolic heart failure, otherwise known as heart failure with reduced ejection fraction, has been established through clinical trials and is formulated into guidelines to standardize the diagnosis and treatment. Since the introduction of angiotensin-converting enzyme inhibitors and vasodilators in the 1980s, many guideline-recommended therapies have emerged over the past 20 years targeting specific neurohormones, aldosterone, and catecholamines to treat heart failure. Part 2 of this series will describe “-blockers, digoxin, and aldosterone antagonists in the context of the mechanism of action in heart failure, investigational trials that showed beneficial effects, and the practical applications for clinical use. KEY WORDS: “-adrenergic blockers, digoxin, heart failure, guideline, mineralocorticoid receptor antagonists H eart failure (HF) remains a worldwide epidemic and con- tinues to be associated with high morbidity and mortality. 1,2 Heart failure is categorized into cases of reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), primarily because patients with HFrEF seem to benefit from a variety of neurohormonal antagonist and device therapies, whereas most patients with HFpEF do not. Patients with clinical HF are divided roughly equally between HFrEF and HFpEF. 3There have been recent pharmacologic advances in HFrEF; however, there are several mainstay treatments with a strong evidence base that are recommended in the most recent American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) 2013 Guidelines for the Management of Heart Failure. 4 This article is the second in a series to describe pharmacologic agents named in the guidelines that impact the morbidity and mortality that is associated with HFrEF. In addition, practical applications for their use are described (see Table 1 for sum- mary of trials for the agents dis- cussed within this review). “-Adrenergic Antagonists Pharmacology/Pathophysiology Within the human myocyte, 3 dif- ferent adrenergic receptors exist: “1,”2,and !1, which are associated with a positive inotropic response and cell growth. 5Y7The “-adrenergic receptors are coupled to the enzyme adenylyl cyclase through G pro- teins, which convert adenosine tri- phosphate to cyclic adenosine monophosphate, which in turn is a positive inotropic and chrono- tropic secondary messenger. The heart has both “1and “2receptors, with “1as the predominant recep- tor type. In HFrEF, there is down- regulation in the “1receptor by overexposure to catecholamines, making the “2receptors more equiv- alent to the “1receptors. 8,9 These “2 receptors are present on the adren- ergic nerve terminals of the myocyte, where they stimulate an increase in cardiotoxic norepinephrine release. Overexpression of “2receptors even- tually leads to systolic dysfunction and a cardiomyopathy phenotype. Overexpression of !1receptor also occurs in the myocardium, leading to concentric hypertrophy. There- fore, continuous increased adren- ergic drive, which is seen in patients with HFrEF, has a devastating 545 Colleen K. McIlvennan, DNP, ANPAssistant Professor, Division of Cardiology,School of Medicine, University of Colorado,Aurora. Robert L. Page II, PharmD, MSPH,FAHA, BCPSProfessor, Clinical Specialist, Division ofCardiology, School of Pharmacy andMedicine,University of Colorado Skaggs,Aurora. The authors have no funding or conflicts ofinterest to disclose. CorrespondenceColleen K. McIlvennan, DNP, ANP, Sectionof Advanced Heart Failure and Transplant,Division of Cardiology, School of Medicine,University of Colorado, 12631 East 17thAve, B130, Aurora, CO 80045([email protected]). DOI: 10.1097/JCN.0000000000000335 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. TABLE 1 Summary of Major Clinical Trials With “-Blockers, Digoxin, and Aldosterone Antagonists in Patients With Heart Failure With Reduced Ejection Fraction Trial Date Study Design Treatment Arms Population Follow-upPeriod Primary Outcome “-BlockersMDC 11 1993 RCT Metoprolol ta rtrate (n = 194), placebo (n = 189) LVEF <40%, NYHA II YIV; mean age, 49 y 12 mo Metoprolol had a 34% reduction in death or need for transplantation compared with placebo(95% CI, 0.06 Y0.62; P= .058) CIBIS 12 1994 RCT Bisoprolol (n = 320), placebo (n = 321) LVEF <40%, NYHAIIIYIV; mean age, 60 y 1.9 y (mean) No difference in mortality between bisoprolol and placebo (RR, 0.80; 95% CI, 0.56 Y1.15; P= .22) CIBIS II a,13 1999 RCT Bisoprolol (n = 1327), placebo (n = 1320) LVEF e35%, NYHA III YIV; mean age, 61 y 1.3 y (mean) All-cause mortality was significantly lower with bisoprolol than placebo (11.8% vs 17.3%)(HR, 0.66; 95% CI, 0.54 Y0.81; P< .0001) MERIT-HF a,21 1999 RCT Metoprolol CR/XL (n = 1990), placebo (n = 2001) LVEF e40%, NYHA II YIV; mean age, 64 y 1 y (mean) All-cause mortality was significantly lower with metoprolol CR/XL than placebo (7.2%, perpatient-year of follow-up vs 11.0%) (RR, 0.66;95% CI, 0.53 Y0.81; P= .00009) COPERNICUS a,14 2001 RCT Carvedilol (n = 1156), placebo (n = 1133) LVEF <25%, mean age,63 y 10.4 mo (mean) Carvedilol had a 35% reduction in risk of death compared with placebo (95% CI, 0.19 Y0.48; P= .00013, unadjusted) COMET 15 2003 RCT Carvedilol (n = 1511) Metoprolol tartrate (n = 1518) LVEF e35%, NYHA II YIV; mean age, 62 y 58 mo (mean) All-cause mortality was 34% for carvedilol vs 40% for metoprolol (HR, 0.83; 95% CI, 0.74 Y0.93; P= .0017); the composite endpoint of mortalityor all-cause admission occurred in 74% ofcarvedilol group and 76% of metoprolol group(HR, 0.94; 95% CI, 0.86 Y1.02; P= .122) DigoxinDIG 30 1997 RCT Digoxin (n = 3397), placebo (n = 3403) LVEF e45%, NYHA II YIV; mean age, 62 y 37 mo (mean) No significant differences in mortality ( P= .80); in digoxin group, trend toward a decrease in risk ofdeath due to HF (RR, 0.88; 95% CI, 0.77 Y1.01; P= .06); in digoxin group, 6% fewer hospitalizationsand fewer patients hospitalized for HF (RR, 0.72;95% CI, 0.66 Y0.79; P< .001) DIG (High RiskSubstudy) 31 2013 Post-Hoc Analysis NYHA III-IV: Digoxin (n = 1118), placebo (n = 1105) LVEF e45%, NYHA II-IV; mean age, 62 y 37 mo (mean) Compared with placebo, those receiving digoxin had a significant reduction in the 2-y compositeendpoint of HF mortality or HF hospitalization:NYHA III YIV (HR, 0.65; 95% CI, 0.57 Y0.75; P< .001); LVEF <25% (HR, 0.61; 95% CI, 0.53 Y0.71; P< .001); and CTR >55% (HR, 0.65; 95% CI,0.57 Y0.75; P< .001) (continues ) 546 Journal of Cardiovascular Nursing xNovember/December 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. impact on the cardiac myocytes via the "and !adrenergic receptors. 5Y7 By blocking adrenergic receptors within the myocyte, " blockade can reduce the harmful effects of excessive and continuous increased adrenergic drive on the myocar- dium, which in turn can cause time- dependent improvements in systolic function, prevent progression of remodeling, decrease heart rate and blood pressure, reduce atrial and ventricular arrhythmias, and exert anti-ischemic effects. 5Y7 Currently, there are 3 classes of "-blockers available for clinical use (Table 2). 5Y7Introduced in 1968 as an antianginal agent, propranolol is considered to be the prototype nonselective "-blocker. Proprano- lol and timolol are first-generation "-blockers as they possess equal affinities for blocking both the "1 and "2receptors with no other ad- ditional pharmacological proper- ties. In the 1970s, cardioselective or second-generation "-blockers entered the market. These agents selectively antagonized the "1re- ceptor compared to the "2receptor without any additional pharmaco- logical properties. Metoprolol is approximately 74-fold selective for the "1receptor versus the "2 receptor, with bisoprolol being 119-fold selective. However, this selectivity can be lost with increas- ing doses. In the 1980s, the third- generation "-blockers were marketed, primarily for hyperten- sion. What separated these agents from their counterparts were their additional vasodilatory properties in addition to " blockade. For example, carvedilol, although only being 7-fold selective for the "1 receptor, is a potent !1blocking agent with 2- to 3-fold selectivity for the "1versus !1receptor. In addition, carvedilol also exerts antioxidant effects attributable to stimulation of nitric oxide produc- tion,aswellashavinganti- inflammatory and other metabolic effects such as small reductions in low-density lipoproteins. 5Y7 TABLE 1 Summary of Major Clinical Trials With "-Blockers, Digoxin, and Aldosterone Antagonists in Patients With Heart Failure With Reduced Ejection Fraction, Continued Trial Date Study Design Treatment Arms Population Follow-upPeriod Primary Outcome LVEF <25%: Digoxin (n = 1127),placebo (n = 1129)CTR > 55%: Digoxin (n = 1175),placebo (n = 1170) Aldosterone antagonistsRALES 49 1999 RCT Spironolactone (n = 822), placebo (841) LVEF e35%, NYHA III YIV; mean age, 62 y 24 mo (mean) Spir onolactone had a 30% reduction in risk of deathcompared with placebo (RR, 0.70; 95% CI,0.60 Y0.82; P< .001). EPHESUS 50 2003 RCT Eplerenone (n = 3319), placebo (n = 3313) LVEF e40%; mean age, 64 y 16 mo (mean) Eplerenone had a 15% reduction in risk of death compared with placebo (RR, 0.85; 95% CI,0.75 Y0.96; P= .008). EMPHASIS-HF a,51 2011 RCT Eplerenone (n = 1364), placebo (n = 1373) LVEF e30%, NYHA II; mean age, 69 y 21 mo (mean) Eplerenone had a 34% reduction in risk of death from cardiovascular causes or hospitalization forHF compared with placebo (HR, 0.66; 95% CI,0.56 Y0.78; P< .001). Abbreviations: CI, confidence interval; CIBIS, Cardiac Insufficiency Bisoprolol Study; COMET, Carvedilol or Metoprolol European Trial; COPERNI CUS, Carvedilol Prospective Randomized Cumulative Survival Study; CTR, cardiothoracic ratio; DIG, Digitalis Investigation Group; EMPHASIS-HF, Eplerenone in Mild Patients Hospitalization and Survival Study in He art Failure; EPHESUS, Eplerenone Post YAcute Myocardial Infarction Heart Failure Efficacy and Survival Study; HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; MDC, Metoprol ol in Dilated Cardiomyopathy; MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure; NYHA, New York Heart Association; RALES, Randomized Aldactone Evaluation Study; RCT, r andomized controlled trial; RR, relative risk. aTrial stopped early due to mortality benefit. Pharmacotherapy for HFrEF 547 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Summary of Clinical Trial Evidence The use of "-blockers in HF is a first-line therapy. Interestingly, the evolution of use of "-blockers in patients began with recommen- dations to avoid use in patients with HF. When a first-generation, nonselective "-blocker, proprano- lol, was first introduced to the market, it was found to contribute to worsening HF symptoms Va warning that was included in the package insert and led to "- blockers being contraindicated in HF. 10 However, clinical work con- tinued studying the effects of "- blockers in patients with HF. This preliminary research led to the landmark trial Metoprolol in Di- lated Cardiomyopathy (MDC), the first randomized controlled trial comparing the "1-antagonist met- oprolol tartrate with placebo in patients with symptomatic HF. 11 A total of 383 patients with idio- pathic dilated cardiomyopathy, who had a left ventricular ejection fraction (LVEF) less than 40% were randomized to either placebo or metoprolol tartrate and were uptitrated as tolerated to a maxi- mum dose of 100 to 150 mg daily. The metoprolol group had a 34% reduction in death or need for transplantation compared with the placebo group (95% confi- dence interval [CI], 0.06 Y0.62; P= .058). 11 Furthermore, exercise time at 12 months was significantly greater in the metoprolol group (P= .046) and LVEF in the meto- prolol group improved significantly more than in the placebo group from baseline to 12 months (0.13 vs 0.06; P< .0001). 11 After the MDC trial, several sub- sequent trials began testing addi- tional "-blockers. The first Cardiac Insufficiency Bisoprolol Study (CIBIS) compared the highly selec- tive "1-antagonist bisoprolol with placebo in patients with LVEF less than 40%. 12 In CIBIS, a nonsig- nificant 20% reduction in mortal- ity ( P= .22) between bisoprolol and placebo was found; however, it was also found that the bisoprolol group had significantly improved func- tional status and fewer hospitaliza- tions for HF (90 vs 61; P<.01). 12 Based on this trial, CIBIS II was con- ducted to test this evidence further with a larger sample size. The CIBIS II trial enrolled 2647 patients who had an LVEF of 35% or less and New York Heart Association (NYHA) functional class III to IV. It was the first "-blocker trial to be stopped early due to a significant mortality benefit of bisoprolol (hazard ratio [HR], 0.66; 95% CI, 0.54 Y0.81; P< .0001). 13 The Metoprolol CR/XL Ran- domised Intervention Trial in Con- gestive Heart Failure (MERIT-HF) was the next trial to be stopped prematurely because of the benefit of "-blockade. Long-acting meto- prolol succinate (CR/XL) was com- pared with placebo in 3991 patients with an LVEF of 40% or less and NYHA functional class II to IV. Its results mirrored those of the CIBIS II trial, with a 34% reduction in all- cause mortality in the metoprolol succinate CR/XL group (relative risk [RR], 0.66; 95% CI, 0.53 Y0.81; P= .00009). Based on the positive results of CIBIS II and MERIT-HF, metoprolol CR/XL was approved for use in patients with chronic HF in the United States in 2000. At the same time, Europe approved both metoprolol CR/XL and bisoprolol for this indication. 6 The Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) enrolled 2289 patients with symptomatic HF (dyspnea or fatigue at rest or on minimal exertion for 2 months) and an LVEF of less than 25% and were euvolemic. 14 Similar to CIBIS II and MERIT-HF, COPERNICUS showed a 35% reduction in risk of mortality with carvedilol compared with pla- cebo (95% CI, 0.19 Y0.48; P = .00013 [unadjusted] and P= .0014 [after adjustment for interim anal- yses]). 14 The COPERNICUS trial was the third trial that was stopped early because of mortality benefit of "-blockers. This led to the 2001 mortality reduction claim for car- vedilol in the United States and Europe. 6 The only trial to attempt to compare mortality benefit between "-blockers was the Carvedilol or Metoprolol European Trial. 15Atotal of 3029 patients with an LVEF of 35% or less and NYHA functional class II to IV, previously admitted for a cardiovascular reason, and treated with diuretics and angiotensin- converting enzyme (ACE) inhibi- tors were randomized to treatment with either carvedilol (target dose 25 mg twice daily) or metoprolol tartrate (target dose 50 mg twice daily). Carvedilol had a 17% lower mortality rate compared with met- oprolol ( P = .0017); however, there is debate over the conclusion that carvedilol is superior to met- oprolol owing to the suboptimal dosing of metoprolol based on the MDC trial. 7 TABLE 2 Description of "-Blockers by Generations Studied in Patients With Heart Failure With Reduced Ejection Fraction 5 Generation "-Blocker (Examples) "1/"2Selectively "1/!1Selectively Additional Properties First generation/nonselective Propranolol 2.1 0 NoneSecond generation/selective "1 Metoprolol 74 0 NoneBisoprolol 119 0 Third generation/vasodilator Carvedilol 7.3 2.4 Antioxidant Nebivolol 293 0 Potentiation of NO Abbreviation: NO, nitric oxide. 548 Journal of Cardiovascular Nursing xNovember/December 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Pharmacotherapeutics in Heart Failure With Reduced Ejection Fraction According to the ACC/AHA 2013 Guidelines, the use of bisoprolol, carvedilol, or sustained-release metoprolol succinate is recom- mended for all patients with current or previous symptoms of HFrEF, un- less contraindicated, to reduce mor- bidity and mortality (Class I, Level of Evidence: A). 4These 3"-blockers have been shown to improve mor- tality, reduce hospitalizations, and improve quality of life; however, it is important that these findings not be generalized to all"-blockers. 4 Several"-blockers have been shown to be less effective in certain HF patient populations or worsen HF symptoms, as was with the case with bucindolol. 16 Clinical Considerations Initiation/Titration "-Blockers should be initiated in all patients with HFrEF, unless there is a valid contraindication. Valid re- lative contraindications include heart rate less than 60 beats per minute, second- or third-degree heart block, and symptomatic hypotension. Pa- tients should be started on"-blocker therapy at the time of HFrEF diag- nosis. Patients do not need to be on other disease-modifying HF therapy before initiation; however, studies have shown that the addition of "-blocker therapy to low ACE in- hibitor dose results in increased symptom relief and decreased mor- tality than do increases in dosage of ACE inhibitor alone. 17,18 Initiation of"-blockers in patients who are acutely decompensated should be avoided; patients should be stabi- lized and euvolemic at the time of starting"-blockers. Furthermore, "-blockers have been shown to be safe to prescribe in stabilized hospi- talized HF patients. 19,20 Initial doses should be low and the"-blocker should be uptitrated gradually, over the course of weeks to months. Target doses of the 3"-blockers ap- proved for HFrEF include meto-prolol succinate 200 mg daily, bisoprolol 10 mg daily, and carve- dilol 25 mg twice daily (or 50 mg twice daily for patients >80 kg). Every effort should be made to achieve target doses of”-blockers given the benefits reported in large clinical trials. 13,14,21 Abrupt with- drawal of”-blocker therapy should be avoided because of the increased risk of clinical decompensation. 22 Adverse Drug Reactions and Interactions It is important that patients be stabilized and compensated before initiation of”-blockers. Attention should be paid to the adverse reac- tions of”-blockers, including worsening HF, fluid retention, bronchospasm, hypotension, de- pression, and bradycardia. 23,24 Most of these symptoms should not limit”-blocker use indefinitely but should be treated with dose reduc- tion or modification of the admin- istration schedule. For example, for patients on concomitant ACE inhibitor therapy, separating the”- blocker and ACE inhibitor admin- istration may help with symptoms of fatigue or hypotension. Caution should be taken when treating pa- tients with”-blockers who have reactive airway disease or symp- tomatic bradycardia given the po- tential to exacerbate these conditions. Patients should be informed that symptoms may worsen or they may experience significant fatigue after initiation of”-blockers, but symp- toms have been shown to decrease 2 months after beginning therapy. 25 Digoxin Pharmacology/Pathophysiology Cardiac glycosides have played a prominent role in the pharmaco- therapy of HF since Sir William Withering codified their use in his monograph on the efficacy of flox- glove leaves in 1785. Although one of the most common medications prescribed for HF in the 1990s, the use of digoxin has remained contro- versial in HFrEF in recent years. 26Y29 Digoxin’s primary mechanism of action lies in its ability to inhibit membrane-bound!subunits of the sodium-potassium ATPase (so- dium pump) in the myocyte. This leads to an accumulation of intra- cellular sodium. Intracellular sodium is, in turn, exchanged for calcium through the membrane-bound so- dium calcium exchanger, which increases calcium availability for contractile proteins, resulting in an increase in the force of myocardial contraction. Inhibition of the sodium pump may also improve barore- ceptor sensitivity, which is decreased in patients with HFrEF, possibly leading to additional neurohor- monal effects. More specifically, these neurohormonal benefits con- sist of decreased activation of the sympathetic nervous system, in- creased vagal tone (ie, decreased sinoatrial and atrioventricular con- duction), and reduced serum nor- epinephrine concentrations and plasma renin activity. 26Y29 Summary of Clinical Trial Evidence While digoxin has been used in patients with HF for more than 200 years, its effects on morbidity and mortality were not elucidated until the late 1990s. The Digitalis Investigation Group (DIG) trial, was a double blind, placebo con- trolled study composed of 302 centers in both the United States and Canada including 6800 pa- tients. 30 Patients were required to be in normal sinus rhythm with an LVEF of 45% or less and HF as determined by preset signs, symp- toms, or radiographic criteria. The use of ACE inhibitors was strongly encouraged but not mandated. The primary endpoint was all-cause mortality and secondary endpoints were mortality due to cardiovascu- lar causes, mortality due to wors- ening HF, and hospitalization due to worsening HF. After a mean follow-up of 37 months, no differ- ence existed in all-cause or cardio- vascular mortality; however, a trend in a reduction in death from Pharmacotherapy for HFrEF 549 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. HF did exist (RR, 0.88; 95% CI, 0.77Y1.01). The pivotal difference between digoxin and placebo was the reduction in HF hospitalizations (RR, 0.72; 95% CI, 0.66Y0.79). In a subanalysis of the DIG trial, high- risk patients defined as NYHA functional class II to IV (n = 2223), with LVEF less than 25% (n = 2256), and with a cardiothoracic ratio of greater than 55% (n = 2345) ex- hibited the greatest benefits from digoxin. 31 Compared with placebo, those receiving digoxin had a signif- icant reduction in the 2-year com- posite endpoint of HF mortality or HF hospitalization: NYHA III to IV (HR, 0.65; 95% CI, 0.57Y0.75;P< .001), LVEF less than 25% (HR, 0.61; 95% CI, 0.53Y0.71;P< .001), and cardiothoracic ratio greater than 55% (HR, 0.65; 95% CI, 0.57Y0.75;P< 0.001). 31 In terms of monitoring digoxin, a post hoc analysis of the DIG trial found that higher serum digoxin concentrations were associated with an increase in crude all-cause mortality rates (0.5Y0.8 ng/mL, 29.9%; 0.9Y1.1 ng/mL, 38.8%; andQ1.2 ng/mL, 48.0%;P=.006 for trend). 32 Patients with serum digoxin concentrations of 0.5 to 0.8 ng/mL had a 6.3% (95% CI, 2.1Y10.5) lower mortality rate com- pared with patients receiving pla- cebo. This study was one of the first analyses to establish a therapeutic range for digoxin in HFrEF. Neu- rohormonal modulation is believed to contribute to digoxin’s therapeu- tic benefits. Reasons for the adverse effects seen at higher concentrations have been hypothesized to be from the inotropic-associated increases in myocardial oxygen consumption and arrhythmogesesis. 32 Nonetheless, several controver- sies have arisen with digoxin over the years. In 2002, a post hoc analysis by Rathore et al 32 found that women who received digoxin had a higher rate of death than women who received placebo (ad- justed HR, 1.23; 95% CI, 1.02Y1.47), a finding that was not seen in men.However, a 2005 post hoc analysis of the DIG trial by Adams et al 33 demonstrated that the beneficial effect of digoxin on morbidity was seen in women at serum concentra- tions from 0.5 to 0.9 ng/mL, whereas serum concentrations greater than 1.2 ng/mL were harmful. Therefore, many have concluded that the re- sults of the initial post hoc analysis by Rathore et al were primarily the result of higher serum digoxin con- centrations in women. 32 Finally, a number of retrospective and observational studies, as well as a meta-analysis of patients with atrial fibrillation (with and without HF), have questioned the safety and efficacy of digoxin therapy. 34Y38 In the Atrial Fibrillation Follow-up In- vestigation of Rhythm Manage- ment study, digoxin was associated with a 1.14-fold increase in all-cause mortality in patients with atrial fibrillation after correcting for clin- ical characteristics and comorbidities, regardless of gender or of the pre- sence or absence of HF. 32 Pharmacotherapeutics in Heart Failure With Reduced Ejection Fraction According to the ACC/AHA 2013 Guidelines, digoxin can be beneficial in patients with HFrEFVregardless of rhythmVto decrease hospitaliza- tions (Class IIa, Level of Evidence: B). 4 Although no mortality benefit has been shown, digoxin has been reported to reduce hospitalizations, improve symptoms, and increase quality of life in patients with HF. 30,39 Clinical Considerations Initiation/Titration Digoxin is indicated in patients with chronic, stable, HF and should not be initiated in patients with an acute HF exacerbation. The initiation of digoxin does not require a loading dose, as is sometimes used in pa- tients with atrial fibrillation. A main- tenance dose of digoxin is generally 0.125Y0.2502g daily. Lower doses should be used in older patients (>70 years), patients with impairedrenal function, and patients with low lean body mass. 40 It is contra- indicated in patients with signifi- cant sinus or atrioventricular block. Digoxin has a narrow therapeu- tic window. As discussed above, the optimal therapeutic range re- mains somewhere between 0.5 and 0.9 ng/mL. 32,33 Whereas digoxin toxicity can be associated with lower digoxin levels, overt toxicity is usu- ally associated with levels greater than 2 ng/mL. Trough digoxin con- centrations should be obtained 3 to 5 days after initiation of therapy and 5 to 7 days after any dosing changes. Adverse Drug Reactions and Interactions Most adverse reactions occur in response to large doses of digoxin. These include cardiac arrhythmias (eg, heart block), gastrointestinal symptoms (eg, nausea, anorexia), and neurologic symptoms (eg, vi- sual disturbances). 4 Digoxin can be initiated in addition to goal- directed medical management in patients with persistent HF symp- toms; however, caution should be taken when administering digoxin along with other medications that depress sinus or atrioventricular function. As digoxin is a substrate for P-glycoprotein, the dose of di- goxin should be reduced in drugs that are substrates of P-glycoprotein to decrease the chance of toxicity. These medications include clarith- romycin, dronedarone, erythro- mycin, amiodarone, itraconazole, cyclosporine, propafenone, verap- amil, or quinidine. 4 Aldosterone Antagonists Pharmacology/Pathophysiology More than 50 years ago, Luetscher and Johnson 41 discovered that pa- tients with HF secreted a hormone in the urine that had sodium- retaining properties. In the 1960s, this hormone was found to be aldosterone. Subsequently, studies have suggested that plasma aldo- sterone concentrations are higher in patients with HFrEF despite maximal renin-angiotensinogen 550 Journal of Cardiovascular Nursing xNovember/December 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. blockade (eg, aldosterone escape), which has correlated to increased HF severity and higher risks for mortality. 41,42 Aldosterone is pri- marily synthesized by the adrenal cortex and serves to preserve sodium, potassium, and water homeostasis; however, aldosterone can also be produced by the vascular endothe- lium, adipocytes, and cardiac myocytes. 43,44 By binding to min- eralocorticoid receptors in the kidney, aldosterone induces sodium and in turn water reabsorption with con- comitant potassium excretion. 45,46 In patients with HFrEF, triggers for aldosterone release include an- giotensin II (especially with signif- icant intravascular volume depletion with diuretics), increased serum po- tassium concentrations, corticotro- pin, vasopressin, and endothelin. Aldosterone promotes several neg- ative pleotropic effects within the heart, kidney, and vasculature. In the heart, aldosterone stimulates growth-promoting and profibrotic effects on myocytes, which could lead to ventricular remodeling, myo- cardial fibrosis, and premature myocyte cell death. 44Y46 Outside of its effects on the reabsorption of sodium and water from tubular fluid in the kidney, stimulation of mineralocorticoid receptors in the renal cortex can contribute to ische- mic injury, mesangial cell prolifera- tion, and nephrosclerosis. 45,46 Finally, in the coronary and peripheral arteries, aldosterone has been associated with proatherogenic effects, endothelial cell hypertrophy, and reduced nitric oxide bioavailability. 45,46 Currently, 2 agents competitively inhibit aldosterone at the mineral- ocorticoid receptor sites: spironolac- tone and eplerenone. Structurally similar to progesterone, spironolac- tone is a nonselective mineralocorti- coid receptor antagonist. However, spironolactone additionally inhibits dihydrotestosterone receptors, thus blunting its effects, and increases the peripheral conversion of testos- terone into estradiol, leading to its antiadrogenic and progestogenicside effects. 45,46 Compared with spironolactone, eplerenone is a selective mineralocorticoid recep- tor antagonist with a 100- to 1000- fold lower affinity for androgen, glucocorticoid, and progesterone receptors. 47,48 In terms of metab- olism, eplerenone is a substrate of the cytochrome P-450 (CYP) 3A4 isoenzyme; thus, serum concentra- tions could be affected by inhibitors and inducers of this isoenzyme. Spi- ronolactone is a potent inhibitor of P-glycoprotein and in turn can in- fluence the systemic exposure of drugs that are P-glycoprotein substrates. 45,46 Summary of Clinical Trial Evidence Several robust studies have been conducted evaluating aldosterone antagonists in patients with HFrEF. In the Randomized Aldactone Evaluation Study (RALES), 1663 patients with NYHA functional class III to IV with an LVEF of 35% or less receiving background ther- apy with an ACE inhibitor were randomized to receive 25 mg daily of spironolactone (which could be increased after 8 weeks to 50 mg daily) or placebo. 49 Patients with a serum creatinine level greater than 2.5 mg/dL and a serum potassium level greater than 5.0 mEq/L were excluded. Of note, only 11% of patients were receiving a”-blocker at time of enrollment. After a mean follow-up of 24 months, patients receiving spironolactone had a 31% reduction in the primary end- point of all-cause mortality compared with those who received placebo (RR, 0.69; 95% CI, 0.58Y0.82;P< .001). In addition, spironolactone was associated with a 31% reduc- tion in cardiac death (P<.001), 36% reduction in death due to pro- gression of HF (P< .001), a 29% reduction in sudden cardiac death (P< .02), as well as a 30% reduc- tion in hospitalization for cardiac causes (P< .001). Based on these data, the number need to treat with spironolactone for 2 years to save 1 life was 9 patients.In the Eplerenone Post-Acute Myocardial Infarction Heart Fail- ure Efficacy and Survival Study (EPHESUS), 6632 patients 3 to 14 days postYmyocardial infarction with an LVEF of 40% or less and signs and symptoms of HF were randomized to eplerenone 25 mg daily (which was increased to 50 mg daily after 4 weeks) or placebo. 50 Patients who were postYmyocardial infarction with concomitant diabe- tes and an LVEF of 40% or less did not have to have signs and symp- toms of HF to be included in the study. The exclusion criteria were similar to those of the RALES trial. Unlike the RALES trial, 75% of pa- tients were receiving background "-blocker therapy. After a mean follow-up of 16 months, eplerenone reduced the co-primary endpoints of all-cause mortality by 15% (RR, 0.85; 95% CI, 0.75Y0.96) and car- diovascular death or cardiovascular hospitalization by 13% (RR, 0.87; 95% CI, 0.79Y0.95). In the diabetes cohort, eplerenone was associated with a 17% reduction in the com- posite endpoint of cardiovascular mortality or any hospitalization (RR, 0.83; 95% CI, 0.71Y0.98;P= .31). The estimated number to treat to save 1 life per year was 50; 33 were needed to treat to prevent cardiovascular death or 1 cardio- vascular hospitalization. Because the RALES trial consisted of patients with HFrEF and NYHA functional class III to IV, the question remained whether the benefit of aldosterone antago- nism in patients with NYHA func- tional II also showed benefit. In the Eplerenone in Mild Patients Hos- pitalization and Survival Study in Heart Failure, 2737 patients with NYHA functional class II and an LVEF of 35% or less were random- ized to receive either eplerenone 25 mg daily (titrated to 50 mg daily after 4 weeks) or placebo. 51 Pa- tients with an estimated glomeru- lar filtration rate (eGFR) less than 30 mL/min/1.73 m 2and a serum potassium greater than 5.0 mEq/L Pharmacotherapy for HFrEF 551 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. were excluded. As with EPHESUS, a larger percentage (87%) of pa- tients were receiving a"-blocker at time of enrollment. After a mean of 21 months follow-up, eplerenone exhibited a 37% reduction in the primary endpoint of cardiovascular death or HF hospitalization (HR, 0.63; 95% CI, 0.54Y0.74;P< .001) and a 24% reduction in all-cause mortality (HR, 0.76; 95% CI, 0.62Y0.93;P< .008). Additional reductions were seen in all-cause, cardiac, and HF hospitalizations. Overall, the number needed to treat with eplerenone to save 1 life per year was 51 patients. Pharmacotherapeutics in Heart Failure With Reduced Ejection Fraction According to the ACC/AHA 2013 Guidelines, aldosterone receptor antagonists are recommended in pa- tients with NYHA functional class II to IV and who have an LVEF of 35% or less to reduce morbidity and mortality (Class I, Level of Evidence: A). 4In addition, aldosterone antag- onists are recommended to reduce morbidity and mortality after an acute myocardial infarction in pa- tients who have an LVEF of 40% or less who develop symptoms of HF or who have a history of diabetes (Class I, Level of Evidence: A). 4A Class III (harm), Level of Evidence B recommendation is included in the guidelines, which states that aldosterone antagonists should not be used when serum creatinine level is greater than 2.5 mg/dL in men or greater than 2.0 mg/dL in women (or eGFR < 30 mL/min/ 1.73 m 2) or when potassium level is greater than 5.0 mEq/L because of risk of life-threatening hyper- kalemia or renal insufficiency. 4 Clinical Considerations Initiation/Titration Aldosterone antagonists are indi- cated in patients with NYHA func- tional class II to IV heart failure. Because of the proven mortalitybenefit, aldosterone antagonists should be initiated in patients with HFrEF and already taking an ACE inhibitor or angiotensin II receptor antagonists and"-blockers. When considering NYHA functional class II patients for aldosterone anta- gonists, they should have a history of cardiovascular hospitalization or elevated plasma natriuretic pep- tide levels. 4 When initiating an aldosterone antagonist, renal func- tion should be assessed and started only if creatinine level is less than 2.5 mg/dL in men and less than 2.0 mg/dL in women (or eGFR >30 mL/min/1.73 m 2).4Aldoste- rone antagonists are safe to start in hospitalized patients; observa- tional data have shown long-term survival benefit of spironolactone initiated before discharge from the hospital. 52 Aldosterone antagonists should be started at low dose and increased as potassium levels allow (spi- ronolactone: initial dose of 12.5 mg daily uptitrated to 25 mg daily; eplerenone: initial dose of 25 mg daily uptitrated to 50 mg daily). In patients with decreased glomerular filtration rates, initiation should be started with every other day dos- ing. Monitoring of renal function, potassium, and diuretic dosing should be performed at initiation and followed closely on a regular basis to minimize risk of hyper- kalemia and renal insufficiency. 49,51 General guidelines include drawing labs within 2 to 3 days of initiation and again 7 days after starting the medication. Thereafter, monitor- ing should occur at least monthly for the first 3 months and then once every 3 months. Adverse Drug Reactions and Interactions The major risk of using an aldoste- rone antagonist is hyperkalemia. Therefore, concurrent use of both ACE inhibitors and angiotensin II receptor antagonists is contrain- dicated. An analysis from the EPH- ESUS trial described 4 independent predictors of hyperkalemia: eGFRless than 60 mL/min/1.73 m 2, his- tory of diabetes mellitus, serum potas- sium level greater than 4.3 mEq/L, and previous use of antiarrhythmic agents. 53 At the time of initiation, potassium supplementation should be discontinued and patients should be counseled to avoid potassium- containing foods. Close monitor- ing and dose adjustments based on renal function and potassium con- centrations can help minimize the risk of hyperkalemia. In addition, adverse endocrine effects, such as gynecomastia, are more common in spironolactone owing to its non- selective properties. Eplerenone has greater specificityfor the mineralo- corticoid receptor, resulting in fewer adverse endocrine effects. 47 Because of its metabolism, eplerenone should be avoided with potent inhibitors of CYP3A4 in- hibitors such as grape fruit juice, erythromycin, clarithromycin, ke- toconazole, conovaptain, and rito- navir. Inducers of CYP3A4 such as phenytoin, rifampin, and St. John’s wort can lower eplerenone levels; however, the clinical significance of this interaction has not been well defined. If spironolactone is added to a substrate of P-glycoprotein, in- creased systemic exposure of the con- comitant drug could exist. As digoxin is a substrate for P-glycoprotein, spironolactone can reduce the re- nal clearance of digoxin. However, this interaction is complex, as spi- ronolactone can cross-react with some digoxin assays and provide digoxin concentrations that are falsely elevated. Both spironolactone and eplerenone should be avoided in patients receiving potassium- sparing diuretics and the dose re- duced in drugs that could increase serum potassium (eg, trimetho- prim, tolvaptan, cyclosporine, and tacrolimus). 45 Conclusion At the end of the 1990s, a revolution in HF pharmacotherapies emerged with the introduction of”-blockers 552 Journal of Cardiovascular Nursing xNovember/December 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. and aldosterone antagonists, which targeted specific neurohormones and catecholamines. Based on the studies presented, these drugs not only significantly reduce mortality but also decreased HF hospitaliza- tions when added to background HF pharmacotherapy. In the case of digoxin, its role in HFrEF still remains controversial, although it has been shown to decrease HF hospitalization. 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