Focused Treatment of Heart Failure with Reduced Ejection Fraction Using Sacubitril/Valsartan

Focused Treatment of Heart Failure with Reduced Ejection Fraction Using Sacubitril/Valsartan Am J Cardiovasc Drugs https://doi.org/10.1007/s40256-018-0280-5 REVIEW AR TICLE Focused Treatment of Heart Failure with Reduced Ejection Fraction Using Sacubitril/Valsartan Rex C. Liu The Author(s) 2018 Abstract The clinical syndrome of heart failure (HF) can be described as the reduced capacity of the heart to Key Points deliver blood throughout the body. To compensate for inadequate tissue perfusion, the renin–angiotensin aldos- Therapies targeting the renin–angiotensin terone system (RAAS) and the sympathetic nervous sys- aldosterone system (RAAS) and the sympathetic tem (SNS) become activated, resulting in increased blood nervous system reduce mortality risk for patients pressure, heart rate, and blood volume. Consequent acti- with heart failure with reduced ejection fraction. vation of the natriuretic peptide system (NPS) typically Angiotensin receptor/neprilysin inhibitor (ARNI) balances these effects; however, the NPS is unable to therapy targets both the natriuretic peptide system sustain compensation for excessive neurohormonal acti- and RAAS to further reduce the risk for mortality. vation over time. Until recently, mortality benefits have been provided to patients with HF only by therapies that Guidelines recommend switching appropriate target the RAAS and SNS, including angiotensin-con- patients from angiotensin-converting enzyme verting enzyme inhibitors (ACEIs), angiotensin receptor inhibitors/angiotensin receptor blockers treatment to blockers (ARBs), mineralocorticoid receptor antagonists, ARNI therapy. and beta-blockers. Sacubitril/valsartan, the first-in-class angiotensin receptor/neprilysin inhibitor (ARNI), targets both the NPS and RAAS to further improve clinical 1 Introduction outcomes. This review discusses the focused management of patients with HF with reduced ejection fraction With the advancements of medical therapy in treating (HFrEF) and suggests changes to current management infections, hypertension, diabetes mellitus, cancers, and paradigms. From this assessment, the evidence supports acute myocardial infarction, life expectancy has been favoring sacubitril/valsartan over ACEIs or ARBs, and steadily increasing [1]. However, along with this increase this therapy should be used in conjunction with beta- in longevity comes an associated increased risk for an blockers to further decrease morbidity and mortality in individual to develop other chronic conditions, particularly patients with HFrEF. chronic heart failure (HF) [2]. In 2012, HF affected more than 5 million Americans; by 2030, approximately 8.5 million adults may have HF in the United States [3, 4]. Thus, physicians can expect to see an increased number of patients who have or are at risk for chronic HF. & Rex C. Liu HF is a complex clinical syndrome that is traditionally rexcliujr@gmail.com considered to be caused by the heart not pumping effec- tively, thereby reducing its capacity to deliver blood PeaceHealth Medical Group - Whatcom, 2979 Squalicum throughout the body to achieve appropriate levels of tissue Parkway, Suite 101, Bellingham, WA 98225, USA R. C. Liu perfusion and resulting in dyspnea, edema, and fatigue With the diminished stroke volume in systolic dys- [5, 6]. Cardiac dysfunction caused by HF can be systolic, as function, there is reduced blood circulation and poor tissue a result of depressed myocardial contractility, or diastolic, perfusion [7]. The body responds to inadequate perfusion as a result of reduced ventricular relaxation and filling. by activating various compensatory neurohormonal Both types of dysfunction can contribute to the develop- mechanisms that are identical to those activated in response ment of HF and can coexist in many patients [5, 7]. to hemorrhage [7]. Blood pressure, heart rate, and However, for disease management purposes, HF that is blood volume are increased through activation of the predominantly systolic is classified as HF with reduced renin–angiotensin aldosterone system (RAAS) and the ejection fraction (HFrEF) [defined as left ventricular ejec- sympathetic nervous system (SNS) [9, 10]. In the context tion fraction (LVEF) B 40%], and predominantly diastolic of normal cardiac physiology, the RAAS and SNS are HF is classified as HF with preserved ejection fraction balanced by the natriuretic peptide system (NPS) to (HFpEF) (defined as LVEF C 50%). Patients with LVEF maintain homeostasis [7]. The volume overload associated between 41 and 49% are classified as having borderline with excessive neurohormonal activation, which also trig- HFpEF. Guideline-directed medical therapy (GDMT) dif- gers upregulation of the antidiuretic hormone vasopressin, fers based on this classification [5]. In this review, the results in myocardial stretch. Subsequently, this stretching recommended management of outpatients with New York triggers the release of natriuretic peptides to induce Heart Association (NYHA) class II–IV HFrEF and inpa- vasodilation, natriuresis, and diuresis [7, 10]. As HF pro- tients with HFrEF recovering from an acute episode will be gresses, the effects of the NPS become blunted through discussed and graded using the Strength of Recommenda- several proposed mechanisms, including reduced produc- tion Taxonomy (SORT) [8], with a focus on recent treat- tion of the biologically active forms of atrial natriuretic ment advances that may alter current management peptide (ANP) and B-type natriuretic peptide (BNP), paradigms. increased degradation of natriuretic peptides by neprilysin, increased receptor-mediated clearance of natriuretic pep- tides in circulation, and desensitization or reduced 2 Compensatory Mechanisms in Heart Failure expression of natriuretic peptide receptors in target organs [11]. As a result, the NPS is further stimulated, but even- The key biomechanical principle governing the function of tually, the NPS becomes unable to compensate for the the heart is the relationship between the degree of pressure overactivation of the RAAS and SNS [11]. The increased present in the heart, which is related to myocardial con- blood volume and pressure that results from neurohor- tractility, and the volume of blood circulated throughout monal activation forces fluid from blood vessels, resulting the body (Fig. 1)[7]. in congestive symptoms [7]. In addition, the chronic Fig. 1 Pressure–volume graphs illustrating the key biomechanical a normal heart. b Pressure–volume loop in a heart with systolic principle governing the function of the heart. In these illustrations, the dysfunction. In a heart with systolic dysfunction, the slope of the green curves represent the end diastolic pressure–volume relationship, yellow line is less steep, indicating depressed left ventricular (LV) which determines diastolic function. The yellow lines represent the contractility. The impaired contractility shifts the whole loop to the end systolic pressure–volume relationship, which determines the right because incomplete LV emptying leads to a higher remaining degree of systolic function. The slopes of the yellow lines are known volume at end systole. Altogether, the stroke volume is diminished as the end systolic slopes and the angle of the slopes indicates the (represented by a shorter and narrower loop with reduced total area) contractile function of the heart. a Pressure–volume loop representing as a result of systolic dysfunction Treatment of HFrEF with Sacubitril/Valsartan hemodynamic stress from neurohormonal activation further natriuretic-peptide-receptor-mediated clearance and enzy- strains the failing heart, stimulating cardiac remodeling [7]. matic degradation by neprilysin [21]. Neprilysin also Cardiac remodeling initially increases ventricular contrac- degrades the vasodilator peptides, adrenomedullin and tility and volume, but eventually the increased wall thick- bradykinin, as well as the vasoconstrictors, angiotensin I, ness and resultant fibrosis from prolonged neurohormonal angiotensin II, and endothelin-1 [21]. These actions to activation become detrimental, further limiting cardiac degrade regulators of opposing mechanisms of vasodilation function [7]. Altogether, neurohormonal activation and and vasoconstriction essentially neutralize each other, and subsequent cardiac remodeling propagates a vicious cycle as a result, monotherapy with a neprilysin inhibitor has that results in a cardiac crisis [7]. little effect on HF. Additionally, the increase in RAAS activation stimulated by neprilysin inhibitor-mediated upregulation of angiotensin II could actually worsen HF, 3 Treating Chronic Heart Failure with Reduced and the breakdown of bradykinin could increase risk of Ejection Fraction angioedema. Advances in treatment have led to improvements in sur- 3.1 Development of Sacubitril/Valsartan vival for many patients with HF [5, 12]. Until recently, reductions in mortality have been provided only by thera- Recognition of the need for a therapeutic agent that could pies that target the RAAS and SNS, initially demonstrated target both the RAAS and the NPS without increasing risk with the angiotensin-converting enzyme inhibitor (ACEI) for angioedema led researchers to test the combination of a enalapril [10, 13]. The pivotal trials demonstrating the neprilysin inhibitor with an ARB. The first such combi- benefits with beta-blockers, mineralocorticoid receptor nation angiotensin receptor/neprilysin inhibitor (ARNI) to antagonists (MRAs), and angiotensin receptor blockers be developed is sacubitril/valsartan (Fig. 2)[21]. (ARBs) soon followed [5, 14–16]. In addition to reducing A pharmacodynamic study in patients with HFrEF the risk of mortality, these therapies offer other benefits for showed that, 21 days after receiving sacubitril/valsartan, patients with HFrEF, including antihypertensive effects plasma concentrations of the negative heart function mod- [5, 17] and reduced ventricular remodeling [18–20]. ulators aldosterone and endothelin-1 were significantly Despite the availability of effective treatments, the average decreased [22]. In addition, concentrations of N-terminal pro 5-year mortality for patients with HF remains at 24.4% for B-type natriuretic peptide (NT-proBNP) (the byproduct of those who are 60 years old and 54.4% for patients aged cleavage of pre-proBNP) were significantly decreased at all 80 years [4], indicating the need for additional options. time points assessed (7 and 21 days after sacubitril/valsartan treatment; all p \ 0.05). These results suggest that the ARNI Research has demonstrated that targeting only the increased activation of the RAAS and SNS eventually inhibits both the RAAS and neprilysin. leads to upregulation of other compensatory escape path- ways [9, 10]. Increased understanding of some of the 3.2 Efficacy of HF Treatments endogenous escape pathways and mechanisms that the body uses to try to compensate for increased activation of In 2015, sacubitril/valsartan was approved in Europe for the RAAS and SNS has yielded additional targets for the treatment of adults with chronic HFrEF and in the therapeutic intervention. For example, preservation of United States to reduce the risk of cardiovascular death and endogenous peptides such as natriuretic peptides, brady- hospitalization for HF in patients with chronic HFrEF kinin, and adrenomedullin could be beneficial by counter- (NYHA class II–IV) [23, 24]. These approvals occurred balancing neurohormonal activity [21]. following the results of the Prospective Comparison of Particular attention has been given to the NPS as a ARNI with ACEI to Determine Impact on Global Mortality therapeutic target [21]. Binding of ANP and BNP to and Morbidity in Heart Failure (PARADIGM-HF) trial natriuretic peptide receptor A stimulates an intracellular (NCT01035255), which compared sacubitril/valsartan with signaling pathway that leads to activation of protein kinase enalapril, an ACEI recognized as a standard-of-care med- G, resulting in vasorelaxation, natriuresis, and diuresis. ication for HFrEF [23–27]. The trial enrolled 8442 patients Other effects of ANP and BNP signaling include RAAS with stable HFrEF (EF B 40%) who were on GDMT, inhibition, enhancement of myocardial relaxation, reduced which included ACEIs, ARBs, beta-blockers, and/or MRAs cardiovascular remodeling, apoptosis, hypertrophy, and [26]. Patients received either enalapril 10 mg twice daily or fibrosis [21]. A third natriuretic peptide released primarily sacubitril/valsartan 97/103 mg twice daily (randomly from endothelial cells (and not found in high levels in the assigned in a 1:1 ratio) in addition to concomitant GDMT. blood) is C-type natriuretic peptide (CNP), which acts as a Compared with enalapril, sacubitril/valsartan showed a vasodilator [21]. These peptides are cleared through 20% reduction [hazard ratio (HR) 0.80; 95% confidence R. C. Liu Fig. 2 Mechanism of action of sacubitril/valsartan [21]. The inhibi- AT1R angiotensin II type 1 receptor, NEP neprilysin, NPS natriuretic tion of neprilysin works synergistically with the inhibition of peptide system, RAAS renin–angiotensin aldosterone system. Adapted angiotensin receptors by valsartan. ANP/BNP atrial natriuretic with permission from J Am Coll Cardiol 2015;65(10):1029–41. peptide/brain natriuretic peptide, ARB angiotensin receptor blocker, Copyright 2015: American College of Cardiology Foundation interval (CI) 0.73–0.87; p \ 0.001] in the primary endpoint including improvements in NYHA functional class, of composite cardiovascular death or first hospitalization for decreases in NT-proBNP, reduced requirements for diuretic HF [26]. Both drugs were reasonably well tolerated, although therapy, and improvements in exercise tolerance; significantly fewer patients in the sacubitril/valsartan group sacubitril/valsartan is generally safe and well tolerated in versus the enalapril group had to discontinue treatment patients with chronic symptomatic HFrEF [32–35]. In the because of an adverse event (10.7 vs. 12.3%; p = 0.03) or future, data from HF registries may be particularly useful renal impairment (0.7 vs. 1.4%; p = 0.002) [26]. sources of information for more acute gauging of the real- The potential of ARNI therapy to improve outcomes world effectiveness and safety of sacubitril/valsartan. may support recommendations for its broad adoption into Specifically, the PAtient RegisTry Assessing Effectiveness clinical practice. Using the number needed to treat calcu- and Safety of HEart Failure treatmeNt with LCZ696 acrOss lated for HF therapies in previous clinical trials, it has been CaNada (PARTHENON) (NCT02957409) will provide estimated that if ARNI therapy was initiated in all eligible observational, naturalistic data on rates of all-cause hospi- patients in the United States, 28,484 deaths per year could talization and all-cause mortality in relation to NT-proBNP be prevented or postponed [28]. The 2016 American Col- levels in approximately 1000 patients with HFrEF who lege of Cardiology (ACC)/American Heart Association initiate treatment with sacubitril/valsartan. Additionally, (AHA)/Heart Failure Society of America (HFSA) focused results from the ongoing Prospective Comparison of ARNI update of the 2013 American College of Cardiology with ARB Global Outcomes in HF with Preserved Ejection Foundation (ACCF)/AHA guideline for the management of Fraction (PARAGON-HF) trial (NCT01920711) may HF included the new findings from PARADIGM-HF, become available in the next year. PARAGON-HF is a adding the ARNIs as a treatment option in the class I large-scale, randomized, controlled, event-driven study recommendation for RAAS inhibition for patients with comparing morbidity and mortality outcomes in patients HFrEF, and also recommended switching from ACEI/ARB with HFpEF receiving treatment with sacubitril/valsartan to ARNI therapy for eligible patients to further reduce compared with those receiving valsartan treatment alone morbidity and mortality [29]. The guidelines also recom- [36]. If the results of PARAGON-HF show meaningful mend that only one ACEI/ARB/ARNI agent should be used benefits with sacubitril/valsartan, HFpEF treatment would in the treatment of HF [5, 29, 30], because combined have a significant advancement. RAAS inhibition causes excessive bradykinin accumula- tion, which increases the risk for angioedema [21]. Now that sacubitril/valsartan has been on the market for 4 Sacubitril/Valsartan Use in Clinical Practice several years, real-world data related to patient character- istics and clinical outcomes are emerging. Retrospective Effective change in clinical practice typically requires analyses of medical records have shown that patients thorough education of the clinicians who manage patients receiving sacubitril/valsartan in real-world settings typically with HF. This shift entails clinicians being comfort- had more severe disease than patients who were included in able with not only identifying which patients are candidates PARADIGM-HF [31]. Beneficial outcomes in the real for treatment with ARNIs, but also understanding the world are similar to those observed in PARADIGM-HF, proper use of these medications. Treatment of HFrEF with Sacubitril/Valsartan The approved target dose of sacubitril/valsartan is treatment with sacubitril/valsartan results in an increase in 97/103 mg twice per day. Treatment should be initiated at BNP because the degradation of this protein is inhibited a starting dose of sacubitril/valsartan 49/51 mg twice per [23]. Thus, caution should be taken when interpreting day for those patients already on an ACEI or ARB at increased BNP concentration with ARNI therapy [30]. C 50% of the target dose. Sacubitril/valsartan uptitration Alternatively, NT-proBNP levels can be monitored should be performed after 2–4 weeks to the target dose of because it is not a substrate for neprilysin and, therefore, 97/103 mg, as tolerated by the patient [23]. To initiate will more accurately reflect HF clinical status [38]. In the therapy with sacubitril/valsartan in patients who are not following sections, we describe two clinical settings— currently on an ACEI or ARB or who were previously outpatient and inpatient (post-acute episode)—and discuss taking low doses of these agents, the US prescribing how ARNI use may be applicable. information recommends starting at a lower dose of 24/26 mg twice daily and uptitrating every 2–4 weeks to 4.1 Prescribing Sacubitril/Valsartan for Outpatients the target dose [23]. A starting dose of 24/26 mg twice daily is also recommended for patients with severe renal In the PARADIGM-HF study, patients enrolled exhibited impairment (i.e., estimated glomerular filtration rate medical histories that may have been related to their dis- \ 30 mL/min/1.73 m ) or moderate hepatic impairment ease, including prior hospitalization for HF (63%), (Child–Pugh class score B), with uptitration every myocardial infarction (43%), and/or atrial fibrillation/flut- 2–4 weeks, as tolerated [23]. ter (37%), in addition to risk factors for HF such as Sacubitril/valsartan is contraindicated in patients with hypertension (71%) and diabetes mellitus (35%) [39]. concurrent ACEI use and in patients with a history of Baseline LVEF varied widely in the study, from 5 to 42% angioedema [23]. The risk of angioedema is comparable [40]. Thus, the trial assessed the use of ARNI therapy on a with ACEIs and with sacubitril, and as such, combining diverse outpatient HFrEF population, with the primary goal these agents poses a safety risk [37]. Consequently, for of preventing occurrences of acute episodes and decreasing those patients who are already on ACEI therapy, a 36-h mortality. Notably, a post hoc analysis showed that base- washout period is required to decrease the risk for line LVEF did not significantly impact clinical outcomes angioedema [23]. In patients being treated with an ARB, no [40]. However, prescribers should review a number of washout period is necessary because the risk of angioe- factors when considering optimal outpatient GDMT for dema is typically low with these agents [37], and the reg- chronic symptomatic HFrEF. The first is to ensure inhibi- ular dose initiation and uptitration schedule can be tion of the SNS and the RAAS with combined beta- followed [23]. blocker, ACEI/ARB/ARNI, and MRA therapy [strength of recommendation (SOR) A; level of evidence (LOE) 1] The same precautions/contraindications that are associ- ated with ACEIs and ARBs apply to ARNIs; however, [5, 29, 30, 41]. ARNIs decrease intravascular volume, which may result in After patients have demonstrated tolerability to con- an increased risk of symptomatic hypotension [21, 26]. current therapy with a RAAS antagonist and beta-blocker When using any medication that can lower blood pressure, at low doses, each agent prescribed should be uptitrated to patients’ cardiac performance should be monitored based the target or highest tolerated dose (SOR A; LOE 1), with on mean arterial pressure [(2 9 diastolic ? systolic blood beta-blockers uptitrated until the target heart rate is pressure)/3]. To maintain adequate total body perfusion, achieved [42–44]. In a post hoc analysis of data from mean arterial pressure should be maintained at PARADIGM-HF, patients treated with sacubitril/valsartan C 65 mmHg; if it falls below this threshold, uptitration of experienced lower risk for mortality compared with sacubitril/valsartan should be stopped. If symptomatic enalapril, both at target doses (HR 0.79; 95% CI 0.71–0.88) hypotension occurs in a patient who is on a combination and at suboptimal doses between 50 and 100% of the target therapy of sacubitril/valsartan and a diuretic, the diuretic dose (HR 0.79; 95% CI 0.67–0.92); however, patients dose should be decreased prior to decreasing the sacubi- treated at target doses experienced greater reductions for tril/valsartan dosage or discontinuing therapy [23]. If nec- the risk for mortality, irrespective of therapy [44]. Upti- essary, the diuretic dose should either be decreased by 50% tration should be performed in small increments, dictated or discontinued completely, depending on the current dose by orthostatic vital signs and physical examination findings of diuretic and the individual patient’s known response to (SOR C; LOE 3) [5]. For example, if the resting heart rate diuretics (personal observation). Close follow-up should be is not considered to be at goal (i.e.,\ 70 beats per minute), provided to ensure that the clinical responses to such then the beta-blocker should be uptitrated first [5]. changes are not detrimental. A phone call to follow-up Once the goal resting heart rate is achieved, then RAAS should be performed within 24 hours, and an office visit antagonist therapy should be uptitrated (SOR C; LOE 3). In should be conducted within one week. In addition, contrast, if beta-blocker uptitration to achieve the target R. C. Liu heart rate results in symptomatic hypotension, thereby complete management of a patient’s hypertension and HF, limiting the initiation or uptitration of a RAAS antagonist, negative long-term effects associated with HFrEF (in- then it is reasonable to switch from a nonselective beta- cluding cardiac remodeling) may be avoided and contrac- blocker such as carvedilol, which may increase risk of tility may be improved. Although it has not yet been vasodilation as a result of alpha-1 blockade, to a beta-1- established whether sacubitril/valsartan can prevent or selective beta-blocker (e.g., metoprolol succinate or reverse cardiac remodeling, the Prospective Study of bisoprolol) [45]. Blood pressure should be reduced to the Biomarkers, Symptom Improvement, and Ventricular lowest tolerable level for each patient (SOR C; LOE 3), Remodeling During Sacubitril/Valsartan Therapy for Heart which may limit the maximum dosage of therapy [5, 30]. Failure (PROVE-HF) (NCT02887183) is underway to To guide uptitration, clinicians may consider assessing determine whether the benefits of this drug extend from mean arterial pressure—which contributes to perfusion improved clinical outcomes and into measurable changes pressure and systemic vascular resistance—rather than in cardiac health [48]. Additional potential benefits include systolic blood pressure alone [46]. As a point of clarifica- the cessation or reversal of damage to other organs caused tion, when substitution for or initiation of an ARNI is being by hypoperfusion. considered, patients do not need to be on the maximal recommended dose of GDMT, but rather on the highest 4.2 Prescribing Sacubitril/Valsartan for Inpatients doses of GDMT that they are able to tolerate. These doses After an Acute Episode can be far below the recommended doses in the US pre- scribing information [23]. One can consider an ARNI to be Acute episodes of worsening HF may be attributed to either a ‘‘super ACEI’’ or ‘‘super ARB’’ and address its use a lack of treatment in patients previously undiagnosed with accordingly, as one would use an ACEI or ARB. HF or inadequate treatment of HF in patients with a con- Patients with chronic symptomatic NYHA class II or III firmed diagnosis. For patients who are not responding as HFrEF already receiving an ACEI or ARB should also be expected to GDMT, consultation with an HF cardiologist is switched to an ARNI (SOR A; LOE 1), in line with the advisable. Inadequate responses could include no signifi- 2016 and subsequent 2017 ACC/AHA/HFSA focused cant diuresis as defined by a urine output of \ 100 mL/h guideline updates [26, 29, 30]. Patients with NYHA class while on intravenous loop diuretics, worsening renal func- IV HFrEF were underrepresented in the PARADIGM-HF tion with diuretic therapy, hypotension with use of GDMT trial [60 (\ 1%) of 8442 subjects were enrolled with at low doses, or persistent signs and symptoms of HF (e.g., NYHA class IV HFrEF] [26]. In European market autho- dyspnea/edema/tachycardia) despite appropriate GDMT. rizations, this lack of clinical experience is cited as a reason Following resolution of an acute episode of HF, a patient must receive appropriate medications as part of the to exercise caution when using sacubitril/valsartan in patients with NYHA class IV HFrEF [24]. However, in the discharge planning (SOR B; LOE 2) [49, 50], which should United States, sacubitril/valsartan is indicated for the include assessment of the risk for future episodes, and treatment of patients with chronic NYHA class II–IV evaluation of a patient’s ability to adhere to therapy HFrEF [23], and results suggest that treatment with (SOR C; LOE 3) [5]. It may be prudent to initiate therapies sacubitril/valsartan, compared with enalapril, may reduce the prior to discharge to ensure tolerability, particularly with risk of cardiovascular death in this patient population [26]. delayed follow-up care (SOR B; LOE 2) [51, 52]. The Thus, it is reasonable for clinicians to consider initiating Organized Program to Initiate Lifesaving Treatment in sacubitril/valsartan therapy in patients with NYHA class IV Hospitalized Patients with Heart Failure (OPTIMIZE-HF) HFrEF. One additional important consideration is the trial (NCT00344513) observed that initiation of carvedilol potential for drug interactions, mainly those that involve at discharge in patients hospitalized for acute HF (AHF) the additive pharmacodynamic effects of hypotension and was associated with a reduced risk for mortality at hyperkalemia between guideline-recommended therapies 60–90 days (HR 0.46; p = 0.0006) and mortality or that suppress angiotensin stimulation [5, 30]. Because rehospitalization [odds ratio (OR) 0.71; p = 0.0175] com- RAAS inhibitors are known to inhibit renal potassium pared with patients who were not initiated on beta-blocker excretion, patients with HFrEF treated with ACEI/ARB/ therapy prior to discharge [51]. In an analysis of 16,052 ARNI are at increased risk for hyperkalemia, especially if patients hospitalized with HF from the Get With The they have comorbid kidney disease. If hyperkalemia Guidelines -Heart Failure registry, patients who discon- develops in such patients, outpatient therapy with the tinued or did not start ACEI/ARB therapy at the time of potassium binder patiromer is a reasonable treatment hospital discharge had significantly higher 1-year mortality option to reduce serum potassium levels [47]. (all p B 0.001) and higher 30-day hospital readmission Consideration should also be given to improving the rates (all p \ 0.05) compared with patients who continued overall cardiac health of the patient. Through proper and or initiated treatment [52]. Furthermore, medication Treatment of HFrEF with Sacubitril/Valsartan reconciliation and counseling at discharge improves tran- needs to get the first prescription refill at the pharmacy. sitions of care [5, 53]. Although the cost of sacubitril/valsartan is high, data from Multidisciplinary HF clinic-based interventions should PARADIGM-HF indicate that benefits for patients can be be performed to improve patient outcomes (SOR A; tremendous, and the financial costs must be weighed rel- LOE 1) [54]. It is useful for patients to receive financial ative to benefits. The relative risk reduction of death with and social evaluation and counseling prior to discharge; sacubitril/valsartan is comparable to that with an having a lower socioeconomic status has been associated implantable cardioverter defibrillator, which can cost tens of with increased risk for poor clinical outcomes and adher- thousands of dollars to implant and replace [63]. In this author’s ence in patients with HF [55, 56]. In addition, referrals to opinion, physicians have a responsibility to offer ARNI therapy healthcare professionals for outpatient care should be to those patients who have clear indications for its use, because planned. HF specialist or cardiologist referral may improve data from PARADIGM-HF were so compelling. adherence to GDMT and ensure the timely initiation of The guidelines do not specify that ARNI therapy should invasive cardiac therapies when indicated [57]. Similarly, not be used in an inpatient setting [29, 30]; therefore, the referrals to dietitians and pharmacists for further education initiation of sacubitril/valsartan prior to discharge for sta- after discharge may improve adherence to interventions bilized patients with acute HF exacerbation may be con- [58, 59]. Moreover, multidisciplinary care improves out- sidered. Two trials will evaluate the safety and efficacy of comes in patients with HF, and hospitalization presents an sacubitril/valsartan initiated prior to hospital discharge opportunity to coordinate care [6, 57]. after stabilization for AHF: Comparison of Sacubitril/ While pending discharge following stabilization of Valsartan Versus Enalapril on Effect on NT-proBNP in AHF, careful thought must be given to the chronic Patients Stabilized From an AHF Episode (PIONEER-HF) HF treatments prescribed, as this regimen is the first (NCT02554890) and Comparison of Pre- and Post-Dis- line of defense against rehospitalization. Although the charge Initiation of LCZ696 Therapy in HFrEF Patients PARADIGM-HF study population did not include inpa- After an Acute Decompensation Event (TRANSITION) tients, the occurrence of hospitalizations during the study (NCT02661217) [62]. allowed for some insight into the use of sacubitril/valsartan After discharge, it is important to follow up with in this population. In particular, it is worth noting that patients to assess adherence, monitor clinical status, and patients receiving sacubitril/valsartan experienced a optimize GDMT (SOR A; LOE 1) [5, 64]. It is reasonable reduced risk for HF readmission within 30 days (OR 0.62; to schedule a follow-up visit within 7–14 days post-dis- 95% CI 0.45–0.87; p = 0.006) and 60 days (OR 0.68; 95% charge and an early telephone call within 3 days of hospital CI 0.50–0.92; p = 0.01) compared with those patients discharge to improve transitions of care [5]. receiving enalapril [60]. In addition, an analysis of Medi- care data observed that patients with a discharge order for ACEI therapy had higher prescription-fill rates within 5 Conclusions 30 days of discharge (HR 10.93; 95% CI 5.28–22.61) [61]; thus, discharge orders for ARNI therapy may similarly To adequately reduce the mortality and morbidity associ- improve adherence [62]. Also, cost, insurance coverage ated with chronic HF, it is important to treat both mecha- and/or requirement for preauthorization, and tolerability for nisms of disease associated with it, i.e., the increased the medication are adherence factors. However, in real- activation of the RAAS and the adrenergic system. world practice, these issues can usually be managed with Sacubitril/valsartan is designed to target both systems, and relative ease. In many cases, inpatient hospital manage- clinical data support its use for reducing mortality in ment teams can provide patients with a manufacturer’s patients with HFrEF. voucher for a free 30-day prescription trial of ARNI ther- In the largest trial to date for HFrEF patients apy prior to discharge. During this first month of therapy, (PARADIGM-HF), sacubitril/valsartan was shown to be the team schedules a follow-up visit at an outpatient HF superior over enalapril in improving both mortality and clinic, where tolerance of the ARNI is evaluated, with morbidity [26], which led to the current guideline recom- particular attention paid to weight gain, hypotension (de- mendation to initiate ARNI therapy in all appropriate fined as mean arterial pressure \ 65 mmHg), orthostatic patients with RAAS-antagonist–naı ¨ve HFrEF and also to symptoms, and signs of decompensated HF. If tolerance to substitute an ARNI for an ACEI/ARB in patients with therapy is demonstrated, a prescription for continued NYHA class II–III HFrEF [30]. For appropriate patients therapy will be issued. Once the prescription is received by with HFrEF, sacubitril/valsartan therapy to target both the the patient’s pharmacy, a prior authorization form is usu- RAAS and NPS should, therefore, be the drug of choice ally generated automatically. Thus, prior authorization is in over ACEIs and ARBs—in combination with beta-blocker place after tolerability is confirmed and before the patient therapy for the SNS—to decrease morbidity and mortality. R. C. Liu Acknowledgements Medical writing assistance was provided by 9. Lymperopoulos A, Rengo G, Koch WJ. Adrenergic nervous Marcel Kuttab, PharmD, of Oxford PharmaGenesis Inc., which was system in heart failure: pathophysiology and therapy. Circ Res. funded by Novartis Pharmaceuticals Corporation. 2013;113:739–53. 10. Reed BN, Street SE, Jensen BC. Time and technology will tell: the pathophysiologic basis of neurohormonal modulation in heart Data availability Data sharing is not applicable to this article as no failure. Heart Fail Clin. 2014;10:543–57. datasets were generated or analyzed during the current study. 11. Dı ´ez J. Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy. Eur J Compliance with Ethical Standards Heart Fail. 2017;19:167–76. 12. Loh JC, Creaser J, Rourke DA, Livingston N, Harrison TK, Funding Medical writing assistance for this manuscript was provided Vandenbogaart E, et al. Temporal trends in treatment and out- by Oxford PharmaGenesis Inc., Newtown, Pennsylvania, USA, which comes for advanced heart failure with reduced ejection fraction was funded by Novartis Pharmaceuticals Corporation, East Hanover, from 1993–2010: findings from a university referral center. Circ New Jersey, USA. The author was fully responsible for all content and Heart Fail. 2013;6:411–9. editorial decisions and received no financial support or other form of 13. The CONSENSUS Trial Study Group. Effects of enalapril on compensation related to the development of this manuscript. mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study Conflict of interest Dr. Liu has received a consultant fee from Novartis. (CONSENSUS). N Engl J Med. 1987;316:1429–35. 14. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Ethical approval This article does not contain any studies with Gilbert EM, et al. The effect of carvedilol on morbidity and human participants or animals performed by the author. mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349–55. Open Access This article is distributed under the terms of the 15. 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Focused Treatment of Heart Failure with Reduced Ejection Fraction Using Sacubitril/Valsartan

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Am J Cardiovasc Drugs https://doi.org/10.1007/s40256-018-0280-5 REVIEW AR TICLE Focused Treatment of Heart Failure with Reduced Ejection Fraction Using Sacubitril/Valsartan Rex C. Liu The Author(s) 2018 Abstract The clinical syndrome of heart failure (HF) can be described as the reduced capacity of the heart to Key Points deliver blood throughout the body. To compensate for inadequate tissue perfusion, the renin–angiotensin aldos- Therapies targeting the renin–angiotensin terone system (RAAS) and the sympathetic nervous sys- aldosterone system (RAAS) and the sympathetic tem (SNS) become activated, resulting in increased blood nervous system reduce mortality risk for patients pressure, heart rate, and blood volume. Consequent acti- with heart failure with reduced ejection fraction. vation of the natriuretic peptide system (NPS) typically Angiotensin receptor/neprilysin inhibitor (ARNI) balances these effects; however, the NPS is unable to therapy targets both the natriuretic peptide system sustain compensation for excessive neurohormonal acti- and RAAS to further reduce the risk for mortality. vation over time. Until recently, mortality benefits have been provided to patients with HF only by therapies that Guidelines recommend switching appropriate target the RAAS and SNS, including angiotensin-con- patients from angiotensin-converting enzyme verting enzyme inhibitors (ACEIs), angiotensin receptor inhibitors/angiotensin receptor blockers treatment to blockers (ARBs), mineralocorticoid receptor antagonists, ARNI therapy. and beta-blockers. Sacubitril/valsartan, the first-in-class angiotensin receptor/neprilysin inhibitor (ARNI), targets both the NPS and RAAS to further improve clinical 1 Introduction outcomes. This review discusses the focused management of patients with HF with reduced ejection fraction With the advancements of medical therapy in treating (HFrEF) and suggests changes to current management infections, hypertension, diabetes mellitus, cancers, and paradigms. From this assessment, the evidence supports acute myocardial infarction, life expectancy has been favoring sacubitril/valsartan over ACEIs or ARBs, and steadily increasing [1]. However, along with this increase this therapy should be used in conjunction with beta- in longevity comes an associated increased risk for an blockers to further decrease morbidity and mortality in individual to develop other chronic conditions, particularly patients with HFrEF. chronic heart failure (HF) [2]. In 2012, HF affected more than 5 million Americans; by 2030, approximately 8.5 million adults may have HF in the United States [3, 4]. Thus, physicians can expect to see an increased number of patients who have or are at risk for chronic HF. & Rex C. Liu HF is a complex clinical syndrome that is traditionally rexcliujr@gmail.com considered to be caused by the heart not pumping effec- tively, thereby reducing its capacity to deliver blood PeaceHealth Medical Group - Whatcom, 2979 Squalicum throughout the body to achieve appropriate levels of tissue Parkway, Suite 101, Bellingham, WA 98225, USA R. C. Liu perfusion and resulting in dyspnea, edema, and fatigue With the diminished stroke volume in systolic dys- [5, 6]. Cardiac dysfunction caused by HF can be systolic, as function, there is reduced blood circulation and poor tissue a result of depressed myocardial contractility, or diastolic, perfusion [7]. The body responds to inadequate perfusion as a result of reduced ventricular relaxation and filling. by activating various compensatory neurohormonal Both types of dysfunction can contribute to the develop- mechanisms that are identical to those activated in response ment of HF and can coexist in many patients [5, 7]. to hemorrhage [7]. Blood pressure, heart rate, and However, for disease management purposes, HF that is blood volume are increased through activation of the predominantly systolic is classified as HF with reduced renin–angiotensin aldosterone system (RAAS) and the ejection fraction (HFrEF) [defined as left ventricular ejec- sympathetic nervous system (SNS) [9, 10]. In the context tion fraction (LVEF) B 40%], and predominantly diastolic of normal cardiac physiology, the RAAS and SNS are HF is classified as HF with preserved ejection fraction balanced by the natriuretic peptide system (NPS) to (HFpEF) (defined as LVEF C 50%). Patients with LVEF maintain homeostasis [7]. The volume overload associated between 41 and 49% are classified as having borderline with excessive neurohormonal activation, which also trig- HFpEF. Guideline-directed medical therapy (GDMT) dif- gers upregulation of the antidiuretic hormone vasopressin, fers based on this classification [5]. In this review, the results in myocardial stretch. Subsequently, this stretching recommended management of outpatients with New York triggers the release of natriuretic peptides to induce Heart Association (NYHA) class II–IV HFrEF and inpa- vasodilation, natriuresis, and diuresis [7, 10]. As HF pro- tients with HFrEF recovering from an acute episode will be gresses, the effects of the NPS become blunted through discussed and graded using the Strength of Recommenda- several proposed mechanisms, including reduced produc- tion Taxonomy (SORT) [8], with a focus on recent treat- tion of the biologically active forms of atrial natriuretic ment advances that may alter current management peptide (ANP) and B-type natriuretic peptide (BNP), paradigms. increased degradation of natriuretic peptides by neprilysin, increased receptor-mediated clearance of natriuretic pep- tides in circulation, and desensitization or reduced 2 Compensatory Mechanisms in Heart Failure expression of natriuretic peptide receptors in target organs [11]. As a result, the NPS is further stimulated, but even- The key biomechanical principle governing the function of tually, the NPS becomes unable to compensate for the the heart is the relationship between the degree of pressure overactivation of the RAAS and SNS [11]. The increased present in the heart, which is related to myocardial con- blood volume and pressure that results from neurohor- tractility, and the volume of blood circulated throughout monal activation forces fluid from blood vessels, resulting the body (Fig. 1)[7]. in congestive symptoms [7]. In addition, the chronic Fig. 1 Pressure–volume graphs illustrating the key biomechanical a normal heart. b Pressure–volume loop in a heart with systolic principle governing the function of the heart. In these illustrations, the dysfunction. In a heart with systolic dysfunction, the slope of the green curves represent the end diastolic pressure–volume relationship, yellow line is less steep, indicating depressed left ventricular (LV) which determines diastolic function. The yellow lines represent the contractility. The impaired contractility shifts the whole loop to the end systolic pressure–volume relationship, which determines the right because incomplete LV emptying leads to a higher remaining degree of systolic function. The slopes of the yellow lines are known volume at end systole. Altogether, the stroke volume is diminished as the end systolic slopes and the angle of the slopes indicates the (represented by a shorter and narrower loop with reduced total area) contractile function of the heart. a Pressure–volume loop representing as a result of systolic dysfunction Treatment of HFrEF with Sacubitril/Valsartan hemodynamic stress from neurohormonal activation further natriuretic-peptide-receptor-mediated clearance and enzy- strains the failing heart, stimulating cardiac remodeling [7]. matic degradation by neprilysin [21]. Neprilysin also Cardiac remodeling initially increases ventricular contrac- degrades the vasodilator peptides, adrenomedullin and tility and volume, but eventually the increased wall thick- bradykinin, as well as the vasoconstrictors, angiotensin I, ness and resultant fibrosis from prolonged neurohormonal angiotensin II, and endothelin-1 [21]. These actions to activation become detrimental, further limiting cardiac degrade regulators of opposing mechanisms of vasodilation function [7]. Altogether, neurohormonal activation and and vasoconstriction essentially neutralize each other, and subsequent cardiac remodeling propagates a vicious cycle as a result, monotherapy with a neprilysin inhibitor has that results in a cardiac crisis [7]. little effect on HF. Additionally, the increase in RAAS activation stimulated by neprilysin inhibitor-mediated upregulation of angiotensin II could actually worsen HF, 3 Treating Chronic Heart Failure with Reduced and the breakdown of bradykinin could increase risk of Ejection Fraction angioedema. Advances in treatment have led to improvements in sur- 3.1 Development of Sacubitril/Valsartan vival for many patients with HF [5, 12]. Until recently, reductions in mortality have been provided only by thera- Recognition of the need for a therapeutic agent that could pies that target the RAAS and SNS, initially demonstrated target both the RAAS and the NPS without increasing risk with the angiotensin-converting enzyme inhibitor (ACEI) for angioedema led researchers to test the combination of a enalapril [10, 13]. The pivotal trials demonstrating the neprilysin inhibitor with an ARB. The first such combi- benefits with beta-blockers, mineralocorticoid receptor nation angiotensin receptor/neprilysin inhibitor (ARNI) to antagonists (MRAs), and angiotensin receptor blockers be developed is sacubitril/valsartan (Fig. 2)[21]. (ARBs) soon followed [5, 14–16]. In addition to reducing A pharmacodynamic study in patients with HFrEF the risk of mortality, these therapies offer other benefits for showed that, 21 days after receiving sacubitril/valsartan, patients with HFrEF, including antihypertensive effects plasma concentrations of the negative heart function mod- [5, 17] and reduced ventricular remodeling [18–20]. ulators aldosterone and endothelin-1 were significantly Despite the availability of effective treatments, the average decreased [22]. In addition, concentrations of N-terminal pro 5-year mortality for patients with HF remains at 24.4% for B-type natriuretic peptide (NT-proBNP) (the byproduct of those who are 60 years old and 54.4% for patients aged cleavage of pre-proBNP) were significantly decreased at all 80 years [4], indicating the need for additional options. time points assessed (7 and 21 days after sacubitril/valsartan treatment; all p \ 0.05). These results suggest that the ARNI Research has demonstrated that targeting only the increased activation of the RAAS and SNS eventually inhibits both the RAAS and neprilysin. leads to upregulation of other compensatory escape path- ways [9, 10]. Increased understanding of some of the 3.2 Efficacy of HF Treatments endogenous escape pathways and mechanisms that the body uses to try to compensate for increased activation of In 2015, sacubitril/valsartan was approved in Europe for the RAAS and SNS has yielded additional targets for the treatment of adults with chronic HFrEF and in the therapeutic intervention. For example, preservation of United States to reduce the risk of cardiovascular death and endogenous peptides such as natriuretic peptides, brady- hospitalization for HF in patients with chronic HFrEF kinin, and adrenomedullin could be beneficial by counter- (NYHA class II–IV) [23, 24]. These approvals occurred balancing neurohormonal activity [21]. following the results of the Prospective Comparison of Particular attention has been given to the NPS as a ARNI with ACEI to Determine Impact on Global Mortality therapeutic target [21]. Binding of ANP and BNP to and Morbidity in Heart Failure (PARADIGM-HF) trial natriuretic peptide receptor A stimulates an intracellular (NCT01035255), which compared sacubitril/valsartan with signaling pathway that leads to activation of protein kinase enalapril, an ACEI recognized as a standard-of-care med- G, resulting in vasorelaxation, natriuresis, and diuresis. ication for HFrEF [23–27]. The trial enrolled 8442 patients Other effects of ANP and BNP signaling include RAAS with stable HFrEF (EF B 40%) who were on GDMT, inhibition, enhancement of myocardial relaxation, reduced which included ACEIs, ARBs, beta-blockers, and/or MRAs cardiovascular remodeling, apoptosis, hypertrophy, and [26]. Patients received either enalapril 10 mg twice daily or fibrosis [21]. A third natriuretic peptide released primarily sacubitril/valsartan 97/103 mg twice daily (randomly from endothelial cells (and not found in high levels in the assigned in a 1:1 ratio) in addition to concomitant GDMT. blood) is C-type natriuretic peptide (CNP), which acts as a Compared with enalapril, sacubitril/valsartan showed a vasodilator [21]. These peptides are cleared through 20% reduction [hazard ratio (HR) 0.80; 95% confidence R. C. Liu Fig. 2 Mechanism of action of sacubitril/valsartan [21]. The inhibi- AT1R angiotensin II type 1 receptor, NEP neprilysin, NPS natriuretic tion of neprilysin works synergistically with the inhibition of peptide system, RAAS renin–angiotensin aldosterone system. Adapted angiotensin receptors by valsartan. ANP/BNP atrial natriuretic with permission from J Am Coll Cardiol 2015;65(10):1029–41. peptide/brain natriuretic peptide, ARB angiotensin receptor blocker, Copyright 2015: American College of Cardiology Foundation interval (CI) 0.73–0.87; p \ 0.001] in the primary endpoint including improvements in NYHA functional class, of composite cardiovascular death or first hospitalization for decreases in NT-proBNP, reduced requirements for diuretic HF [26]. Both drugs were reasonably well tolerated, although therapy, and improvements in exercise tolerance; significantly fewer patients in the sacubitril/valsartan group sacubitril/valsartan is generally safe and well tolerated in versus the enalapril group had to discontinue treatment patients with chronic symptomatic HFrEF [32–35]. In the because of an adverse event (10.7 vs. 12.3%; p = 0.03) or future, data from HF registries may be particularly useful renal impairment (0.7 vs. 1.4%; p = 0.002) [26]. sources of information for more acute gauging of the real- The potential of ARNI therapy to improve outcomes world effectiveness and safety of sacubitril/valsartan. may support recommendations for its broad adoption into Specifically, the PAtient RegisTry Assessing Effectiveness clinical practice. Using the number needed to treat calcu- and Safety of HEart Failure treatmeNt with LCZ696 acrOss lated for HF therapies in previous clinical trials, it has been CaNada (PARTHENON) (NCT02957409) will provide estimated that if ARNI therapy was initiated in all eligible observational, naturalistic data on rates of all-cause hospi- patients in the United States, 28,484 deaths per year could talization and all-cause mortality in relation to NT-proBNP be prevented or postponed [28]. The 2016 American Col- levels in approximately 1000 patients with HFrEF who lege of Cardiology (ACC)/American Heart Association initiate treatment with sacubitril/valsartan. Additionally, (AHA)/Heart Failure Society of America (HFSA) focused results from the ongoing Prospective Comparison of ARNI update of the 2013 American College of Cardiology with ARB Global Outcomes in HF with Preserved Ejection Foundation (ACCF)/AHA guideline for the management of Fraction (PARAGON-HF) trial (NCT01920711) may HF included the new findings from PARADIGM-HF, become available in the next year. PARAGON-HF is a adding the ARNIs as a treatment option in the class I large-scale, randomized, controlled, event-driven study recommendation for RAAS inhibition for patients with comparing morbidity and mortality outcomes in patients HFrEF, and also recommended switching from ACEI/ARB with HFpEF receiving treatment with sacubitril/valsartan to ARNI therapy for eligible patients to further reduce compared with those receiving valsartan treatment alone morbidity and mortality [29]. The guidelines also recom- [36]. If the results of PARAGON-HF show meaningful mend that only one ACEI/ARB/ARNI agent should be used benefits with sacubitril/valsartan, HFpEF treatment would in the treatment of HF [5, 29, 30], because combined have a significant advancement. RAAS inhibition causes excessive bradykinin accumula- tion, which increases the risk for angioedema [21]. Now that sacubitril/valsartan has been on the market for 4 Sacubitril/Valsartan Use in Clinical Practice several years, real-world data related to patient character- istics and clinical outcomes are emerging. Retrospective Effective change in clinical practice typically requires analyses of medical records have shown that patients thorough education of the clinicians who manage patients receiving sacubitril/valsartan in real-world settings typically with HF. This shift entails clinicians being comfort- had more severe disease than patients who were included in able with not only identifying which patients are candidates PARADIGM-HF [31]. Beneficial outcomes in the real for treatment with ARNIs, but also understanding the world are similar to those observed in PARADIGM-HF, proper use of these medications. Treatment of HFrEF with Sacubitril/Valsartan The approved target dose of sacubitril/valsartan is treatment with sacubitril/valsartan results in an increase in 97/103 mg twice per day. Treatment should be initiated at BNP because the degradation of this protein is inhibited a starting dose of sacubitril/valsartan 49/51 mg twice per [23]. Thus, caution should be taken when interpreting day for those patients already on an ACEI or ARB at increased BNP concentration with ARNI therapy [30]. C 50% of the target dose. Sacubitril/valsartan uptitration Alternatively, NT-proBNP levels can be monitored should be performed after 2–4 weeks to the target dose of because it is not a substrate for neprilysin and, therefore, 97/103 mg, as tolerated by the patient [23]. To initiate will more accurately reflect HF clinical status [38]. In the therapy with sacubitril/valsartan in patients who are not following sections, we describe two clinical settings— currently on an ACEI or ARB or who were previously outpatient and inpatient (post-acute episode)—and discuss taking low doses of these agents, the US prescribing how ARNI use may be applicable. information recommends starting at a lower dose of 24/26 mg twice daily and uptitrating every 2–4 weeks to 4.1 Prescribing Sacubitril/Valsartan for Outpatients the target dose [23]. A starting dose of 24/26 mg twice daily is also recommended for patients with severe renal In the PARADIGM-HF study, patients enrolled exhibited impairment (i.e., estimated glomerular filtration rate medical histories that may have been related to their dis- \ 30 mL/min/1.73 m ) or moderate hepatic impairment ease, including prior hospitalization for HF (63%), (Child–Pugh class score B), with uptitration every myocardial infarction (43%), and/or atrial fibrillation/flut- 2–4 weeks, as tolerated [23]. ter (37%), in addition to risk factors for HF such as Sacubitril/valsartan is contraindicated in patients with hypertension (71%) and diabetes mellitus (35%) [39]. concurrent ACEI use and in patients with a history of Baseline LVEF varied widely in the study, from 5 to 42% angioedema [23]. The risk of angioedema is comparable [40]. Thus, the trial assessed the use of ARNI therapy on a with ACEIs and with sacubitril, and as such, combining diverse outpatient HFrEF population, with the primary goal these agents poses a safety risk [37]. Consequently, for of preventing occurrences of acute episodes and decreasing those patients who are already on ACEI therapy, a 36-h mortality. Notably, a post hoc analysis showed that base- washout period is required to decrease the risk for line LVEF did not significantly impact clinical outcomes angioedema [23]. In patients being treated with an ARB, no [40]. However, prescribers should review a number of washout period is necessary because the risk of angioe- factors when considering optimal outpatient GDMT for dema is typically low with these agents [37], and the reg- chronic symptomatic HFrEF. The first is to ensure inhibi- ular dose initiation and uptitration schedule can be tion of the SNS and the RAAS with combined beta- followed [23]. blocker, ACEI/ARB/ARNI, and MRA therapy [strength of recommendation (SOR) A; level of evidence (LOE) 1] The same precautions/contraindications that are associ- ated with ACEIs and ARBs apply to ARNIs; however, [5, 29, 30, 41]. ARNIs decrease intravascular volume, which may result in After patients have demonstrated tolerability to con- an increased risk of symptomatic hypotension [21, 26]. current therapy with a RAAS antagonist and beta-blocker When using any medication that can lower blood pressure, at low doses, each agent prescribed should be uptitrated to patients’ cardiac performance should be monitored based the target or highest tolerated dose (SOR A; LOE 1), with on mean arterial pressure [(2 9 diastolic ? systolic blood beta-blockers uptitrated until the target heart rate is pressure)/3]. To maintain adequate total body perfusion, achieved [42–44]. In a post hoc analysis of data from mean arterial pressure should be maintained at PARADIGM-HF, patients treated with sacubitril/valsartan C 65 mmHg; if it falls below this threshold, uptitration of experienced lower risk for mortality compared with sacubitril/valsartan should be stopped. If symptomatic enalapril, both at target doses (HR 0.79; 95% CI 0.71–0.88) hypotension occurs in a patient who is on a combination and at suboptimal doses between 50 and 100% of the target therapy of sacubitril/valsartan and a diuretic, the diuretic dose (HR 0.79; 95% CI 0.67–0.92); however, patients dose should be decreased prior to decreasing the sacubi- treated at target doses experienced greater reductions for tril/valsartan dosage or discontinuing therapy [23]. If nec- the risk for mortality, irrespective of therapy [44]. Upti- essary, the diuretic dose should either be decreased by 50% tration should be performed in small increments, dictated or discontinued completely, depending on the current dose by orthostatic vital signs and physical examination findings of diuretic and the individual patient’s known response to (SOR C; LOE 3) [5]. For example, if the resting heart rate diuretics (personal observation). Close follow-up should be is not considered to be at goal (i.e.,\ 70 beats per minute), provided to ensure that the clinical responses to such then the beta-blocker should be uptitrated first [5]. changes are not detrimental. A phone call to follow-up Once the goal resting heart rate is achieved, then RAAS should be performed within 24 hours, and an office visit antagonist therapy should be uptitrated (SOR C; LOE 3). In should be conducted within one week. In addition, contrast, if beta-blocker uptitration to achieve the target R. C. Liu heart rate results in symptomatic hypotension, thereby complete management of a patient’s hypertension and HF, limiting the initiation or uptitration of a RAAS antagonist, negative long-term effects associated with HFrEF (in- then it is reasonable to switch from a nonselective beta- cluding cardiac remodeling) may be avoided and contrac- blocker such as carvedilol, which may increase risk of tility may be improved. Although it has not yet been vasodilation as a result of alpha-1 blockade, to a beta-1- established whether sacubitril/valsartan can prevent or selective beta-blocker (e.g., metoprolol succinate or reverse cardiac remodeling, the Prospective Study of bisoprolol) [45]. Blood pressure should be reduced to the Biomarkers, Symptom Improvement, and Ventricular lowest tolerable level for each patient (SOR C; LOE 3), Remodeling During Sacubitril/Valsartan Therapy for Heart which may limit the maximum dosage of therapy [5, 30]. Failure (PROVE-HF) (NCT02887183) is underway to To guide uptitration, clinicians may consider assessing determine whether the benefits of this drug extend from mean arterial pressure—which contributes to perfusion improved clinical outcomes and into measurable changes pressure and systemic vascular resistance—rather than in cardiac health [48]. Additional potential benefits include systolic blood pressure alone [46]. As a point of clarifica- the cessation or reversal of damage to other organs caused tion, when substitution for or initiation of an ARNI is being by hypoperfusion. considered, patients do not need to be on the maximal recommended dose of GDMT, but rather on the highest 4.2 Prescribing Sacubitril/Valsartan for Inpatients doses of GDMT that they are able to tolerate. These doses After an Acute Episode can be far below the recommended doses in the US pre- scribing information [23]. One can consider an ARNI to be Acute episodes of worsening HF may be attributed to either a ‘‘super ACEI’’ or ‘‘super ARB’’ and address its use a lack of treatment in patients previously undiagnosed with accordingly, as one would use an ACEI or ARB. HF or inadequate treatment of HF in patients with a con- Patients with chronic symptomatic NYHA class II or III firmed diagnosis. For patients who are not responding as HFrEF already receiving an ACEI or ARB should also be expected to GDMT, consultation with an HF cardiologist is switched to an ARNI (SOR A; LOE 1), in line with the advisable. Inadequate responses could include no signifi- 2016 and subsequent 2017 ACC/AHA/HFSA focused cant diuresis as defined by a urine output of \ 100 mL/h guideline updates [26, 29, 30]. Patients with NYHA class while on intravenous loop diuretics, worsening renal func- IV HFrEF were underrepresented in the PARADIGM-HF tion with diuretic therapy, hypotension with use of GDMT trial [60 (\ 1%) of 8442 subjects were enrolled with at low doses, or persistent signs and symptoms of HF (e.g., NYHA class IV HFrEF] [26]. In European market autho- dyspnea/edema/tachycardia) despite appropriate GDMT. rizations, this lack of clinical experience is cited as a reason Following resolution of an acute episode of HF, a patient must receive appropriate medications as part of the to exercise caution when using sacubitril/valsartan in patients with NYHA class IV HFrEF [24]. However, in the discharge planning (SOR B; LOE 2) [49, 50], which should United States, sacubitril/valsartan is indicated for the include assessment of the risk for future episodes, and treatment of patients with chronic NYHA class II–IV evaluation of a patient’s ability to adhere to therapy HFrEF [23], and results suggest that treatment with (SOR C; LOE 3) [5]. It may be prudent to initiate therapies sacubitril/valsartan, compared with enalapril, may reduce the prior to discharge to ensure tolerability, particularly with risk of cardiovascular death in this patient population [26]. delayed follow-up care (SOR B; LOE 2) [51, 52]. The Thus, it is reasonable for clinicians to consider initiating Organized Program to Initiate Lifesaving Treatment in sacubitril/valsartan therapy in patients with NYHA class IV Hospitalized Patients with Heart Failure (OPTIMIZE-HF) HFrEF. One additional important consideration is the trial (NCT00344513) observed that initiation of carvedilol potential for drug interactions, mainly those that involve at discharge in patients hospitalized for acute HF (AHF) the additive pharmacodynamic effects of hypotension and was associated with a reduced risk for mortality at hyperkalemia between guideline-recommended therapies 60–90 days (HR 0.46; p = 0.0006) and mortality or that suppress angiotensin stimulation [5, 30]. Because rehospitalization [odds ratio (OR) 0.71; p = 0.0175] com- RAAS inhibitors are known to inhibit renal potassium pared with patients who were not initiated on beta-blocker excretion, patients with HFrEF treated with ACEI/ARB/ therapy prior to discharge [51]. In an analysis of 16,052 ARNI are at increased risk for hyperkalemia, especially if patients hospitalized with HF from the Get With The they have comorbid kidney disease. If hyperkalemia Guidelines -Heart Failure registry, patients who discon- develops in such patients, outpatient therapy with the tinued or did not start ACEI/ARB therapy at the time of potassium binder patiromer is a reasonable treatment hospital discharge had significantly higher 1-year mortality option to reduce serum potassium levels [47]. (all p B 0.001) and higher 30-day hospital readmission Consideration should also be given to improving the rates (all p \ 0.05) compared with patients who continued overall cardiac health of the patient. Through proper and or initiated treatment [52]. Furthermore, medication Treatment of HFrEF with Sacubitril/Valsartan reconciliation and counseling at discharge improves tran- needs to get the first prescription refill at the pharmacy. sitions of care [5, 53]. Although the cost of sacubitril/valsartan is high, data from Multidisciplinary HF clinic-based interventions should PARADIGM-HF indicate that benefits for patients can be be performed to improve patient outcomes (SOR A; tremendous, and the financial costs must be weighed rel- LOE 1) [54]. It is useful for patients to receive financial ative to benefits. The relative risk reduction of death with and social evaluation and counseling prior to discharge; sacubitril/valsartan is comparable to that with an having a lower socioeconomic status has been associated implantable cardioverter defibrillator, which can cost tens of with increased risk for poor clinical outcomes and adher- thousands of dollars to implant and replace [63]. In this author’s ence in patients with HF [55, 56]. In addition, referrals to opinion, physicians have a responsibility to offer ARNI therapy healthcare professionals for outpatient care should be to those patients who have clear indications for its use, because planned. HF specialist or cardiologist referral may improve data from PARADIGM-HF were so compelling. adherence to GDMT and ensure the timely initiation of The guidelines do not specify that ARNI therapy should invasive cardiac therapies when indicated [57]. Similarly, not be used in an inpatient setting [29, 30]; therefore, the referrals to dietitians and pharmacists for further education initiation of sacubitril/valsartan prior to discharge for sta- after discharge may improve adherence to interventions bilized patients with acute HF exacerbation may be con- [58, 59]. Moreover, multidisciplinary care improves out- sidered. Two trials will evaluate the safety and efficacy of comes in patients with HF, and hospitalization presents an sacubitril/valsartan initiated prior to hospital discharge opportunity to coordinate care [6, 57]. after stabilization for AHF: Comparison of Sacubitril/ While pending discharge following stabilization of Valsartan Versus Enalapril on Effect on NT-proBNP in AHF, careful thought must be given to the chronic Patients Stabilized From an AHF Episode (PIONEER-HF) HF treatments prescribed, as this regimen is the first (NCT02554890) and Comparison of Pre- and Post-Dis- line of defense against rehospitalization. Although the charge Initiation of LCZ696 Therapy in HFrEF Patients PARADIGM-HF study population did not include inpa- After an Acute Decompensation Event (TRANSITION) tients, the occurrence of hospitalizations during the study (NCT02661217) [62]. allowed for some insight into the use of sacubitril/valsartan After discharge, it is important to follow up with in this population. In particular, it is worth noting that patients to assess adherence, monitor clinical status, and patients receiving sacubitril/valsartan experienced a optimize GDMT (SOR A; LOE 1) [5, 64]. It is reasonable reduced risk for HF readmission within 30 days (OR 0.62; to schedule a follow-up visit within 7–14 days post-dis- 95% CI 0.45–0.87; p = 0.006) and 60 days (OR 0.68; 95% charge and an early telephone call within 3 days of hospital CI 0.50–0.92; p = 0.01) compared with those patients discharge to improve transitions of care [5]. receiving enalapril [60]. In addition, an analysis of Medi- care data observed that patients with a discharge order for ACEI therapy had higher prescription-fill rates within 5 Conclusions 30 days of discharge (HR 10.93; 95% CI 5.28–22.61) [61]; thus, discharge orders for ARNI therapy may similarly To adequately reduce the mortality and morbidity associ- improve adherence [62]. Also, cost, insurance coverage ated with chronic HF, it is important to treat both mecha- and/or requirement for preauthorization, and tolerability for nisms of disease associated with it, i.e., the increased the medication are adherence factors. However, in real- activation of the RAAS and the adrenergic system. world practice, these issues can usually be managed with Sacubitril/valsartan is designed to target both systems, and relative ease. In many cases, inpatient hospital manage- clinical data support its use for reducing mortality in ment teams can provide patients with a manufacturer’s patients with HFrEF. voucher for a free 30-day prescription trial of ARNI ther- In the largest trial to date for HFrEF patients apy prior to discharge. During this first month of therapy, (PARADIGM-HF), sacubitril/valsartan was shown to be the team schedules a follow-up visit at an outpatient HF superior over enalapril in improving both mortality and clinic, where tolerance of the ARNI is evaluated, with morbidity [26], which led to the current guideline recom- particular attention paid to weight gain, hypotension (de- mendation to initiate ARNI therapy in all appropriate fined as mean arterial pressure \ 65 mmHg), orthostatic patients with RAAS-antagonist–naı ¨ve HFrEF and also to symptoms, and signs of decompensated HF. If tolerance to substitute an ARNI for an ACEI/ARB in patients with therapy is demonstrated, a prescription for continued NYHA class II–III HFrEF [30]. For appropriate patients therapy will be issued. Once the prescription is received by with HFrEF, sacubitril/valsartan therapy to target both the the patient’s pharmacy, a prior authorization form is usu- RAAS and NPS should, therefore, be the drug of choice ally generated automatically. Thus, prior authorization is in over ACEIs and ARBs—in combination with beta-blocker place after tolerability is confirmed and before the patient therapy for the SNS—to decrease morbidity and mortality. R. C. Liu Acknowledgements Medical writing assistance was provided by 9. Lymperopoulos A, Rengo G, Koch WJ. Adrenergic nervous Marcel Kuttab, PharmD, of Oxford PharmaGenesis Inc., which was system in heart failure: pathophysiology and therapy. Circ Res. funded by Novartis Pharmaceuticals Corporation. 2013;113:739–53. 10. Reed BN, Street SE, Jensen BC. Time and technology will tell: the pathophysiologic basis of neurohormonal modulation in heart Data availability Data sharing is not applicable to this article as no failure. Heart Fail Clin. 2014;10:543–57. datasets were generated or analyzed during the current study. 11. Dı ´ez J. Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy. Eur J Compliance with Ethical Standards Heart Fail. 2017;19:167–76. 12. Loh JC, Creaser J, Rourke DA, Livingston N, Harrison TK, Funding Medical writing assistance for this manuscript was provided Vandenbogaart E, et al. Temporal trends in treatment and out- by Oxford PharmaGenesis Inc., Newtown, Pennsylvania, USA, which comes for advanced heart failure with reduced ejection fraction was funded by Novartis Pharmaceuticals Corporation, East Hanover, from 1993–2010: findings from a university referral center. Circ New Jersey, USA. The author was fully responsible for all content and Heart Fail. 2013;6:411–9. editorial decisions and received no financial support or other form of 13. The CONSENSUS Trial Study Group. Effects of enalapril on compensation related to the development of this manuscript. mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study Conflict of interest Dr. Liu has received a consultant fee from Novartis. (CONSENSUS). N Engl J Med. 1987;316:1429–35. 14. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Ethical approval This article does not contain any studies with Gilbert EM, et al. The effect of carvedilol on morbidity and human participants or animals performed by the author. mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349–55. Open Access This article is distributed under the terms of the 15. 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Journal

American Journal of Cardiovascular DrugsSpringer Journals

Published: May 31, 2018

References

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