LCZ696 (Angiotensin–Neprilysin Inhibition)

Abstract

Angiotensin-converting enzyme inhibitors (ACEIs) have been the cornerstone in systolic heart failure (HF) regimens over the past 25 years. Their ability to block the renin–angiotensin–aldosterone system and their vasodilatory properties has repeatedly been shown to lower morbidity and mortality in patients with HF having reduced ejection fractions. In August 2014, the New England Journal of Medicine published a large trial studying a novel LCZ696 (angiotensin–neprilysin inhibition) agent against enalapril, an ACEI. In the phase III trial, LCZ696 demonstrated superiority to enalapril in composite death from cardiovascular causes and hospitalization for HF. The trial was stopped early due to overwhelming benefit of the study agent. This article provides an extensive review of the mechanism of action, pharmacokinetic properties, clinical efficacy, safety, and tolerability of LCZ696.

Keywords

LCZ696 angiotensin–neprilysin heart failure enalapril

Continuing Education Learning objectives

Describe the current classifications and cardinal symptoms of systolic heart failure

Design treatment regimens for managing systolic heart failure

Analyze the mechanism and discuss the relevant study data of LCZ696

Explain the PARADIGM-HF trial results and clinical outcomes

Evaluate the potential role of LCZ696 in the management of systolic heart failure

Introduction

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) heart failure guidelines classifies heart failure (HF) into 2 categories: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), also referred to as systolic and diastolic HF, respectively.¹ About 20% of Americans over 40 years of age will develop HF,² with a mortality rate of 50% within 5 years of diagnosis.^3,4 HF exacerbations are responsible for over 1 million annual hospitalizations, costing roughly US$40 billion.⁵ Systolic dysfunction is defined in patients with HFrEF of ≤40%.¹

Cardinal symptoms of HF are dyspnea and fatigue. This routinely leads to exercise intolerance, fluid retention, pulmonary congestion, and peripheral edema often resulting in hospitalizations. The structural heart disease and functional symptoms are described by the ACCF/AHA stages of HF and New York Heart Association (NYHA) functional classifications, respectively.^6,7 Primary risk factors for developing HF include hypertension, diabetes mellitus, metabolic syndrome, and atherosclerotic disease.¹

Treatment regimens for systolic HF took a leap forward in 1986 when the landmark Veterans Administration Cooperative Study (V-HeFT) I study showed the reduction of mortality in patients with systolic HF using vasodilation treatment.⁸ A few years later, the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) and Studies of Left Ventricular Dysfunction Treatment (SOLVD-T) studies highlighted the superior benefits of blocking the renin–angiotensin–aldosterone system (RAAS) in reducing the overall mortality and established angiotensin-converting enzyme inhibitors (ACEIs) as the cornerstone of treatment in patients with systolic HF.^9,10 The blockage of the RAAS compensation was further evaluated in angiotensin receptor blockers (ARBs) and potassium sparing diuretics trials, which continued to show benefits in improving mortality.^11,12 Beta-blockers, although initially considered counterintuitive, proved beneficial in turning off sympathomimetic innervation to reduced heart contractility.^13,14 These agents (along with diuretics and digoxin for symptom relief) have been accepted as the mainstay of treatment over the past 25 years (see Table 1).

Table 1.

Current Stages/Classification and Treatment Recommendations for Systolic Heart Failure.¹

ACCF/AHA stages of HF		NYHA functional classification	Treatment recommendations
A	High risk of HF without structure heart disease or symptoms	None	Control hypertension and lipid disorders Manage obesity, diabetes, and smoking cessation ACEIs/ARBs for all patients Beta-blocker for all patients ACEIs/ARBs for all patients Beta-blocker for all patients Aldosterone receptor antagonist if no renal insufficiency/hyperkalemia Hydralazine/isosorbide dinitrate in self-described African Americans already optimized on standard therapy Diuretics for fluid retention Digoxin to lower hospitalizations
B	Structural heart disease without symptoms	No limitation of physical activity
C	Structural heart disease with symptoms	No limitation of physical activity Slight limitation of physical activity, comfortable at rest Marked limitation of physical activity, comfortable at rest
D	Refractory HF requiring specialized interventions	IV Unable to perform physical activity without symptoms, symptoms at rest

Abbreviations: ACCF/AHA, American College of Cardiology Foundation/American Heart Association; NYHA, New York Heart Association; HF, heart failure; ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers.

In August of 2014, the New England Journal of Medicine published the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study, which compared the combination of an ARB + neprilysin (LCZ696) head-to-head against an ACEI (enalapril).¹⁵ The trial was terminated early after overwhelming benefits from LCZ696 were reviewed by an independent review board. The purpose of this article is to review the overall mechanism of action, pharmacokinetic properties, clinical efficacy, and safety of this novel agent as it may prove to open a new chapter in the treatment of systolic HF.

Methods

An unfiltered search of PubMed and Google Scholar using the following key words: LCZ696, angiotensin–neprilysin, PARADIGM-HF, was performed to identify relevant information for review. Neither limits nor inclusion/exclusion criteria were applied. The results were thoroughly reviewed and evaluated.

Results

Indication and Dosage

The Food and Drug Administration approved a submission for a rolling new drug application and granted Fast Track designation for LCZ696 in July 2014 for the indication of HFrEF.¹⁶ LCZ696 was tested for oral administration at a dose of 200 mg twice daily, which provides an equivalent dose of valsartan 160 mg twice daily (the target dose used in the treatment of HF). The valsartan component of LCZ696 provides similar RAAS blockade as enalapril 10 mg twice daily, the target dose used in the SOLVD-T to show a reduction in mortality in patients with HFrEF. LCZ 200 mg twice daily also provides a near-complete inhibition of neprilysin, a neutral endopeptidase (NEP).¹⁷

Mechanism of Action

LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNi), is a single molecule entity consisting of 2 molecular moieties in a 1:1 molar ratio of valsartan, an ARB, and the NEP inhibitor prodrug AHU377, which is metabolized into the active moiety LBQ657 via enzymatic cleavage of its ethyl ester group.¹⁸ NEP inhibitors, candoxatril, omapatrilat, and LCZ696 all increase atrial natriuretic peptide (ANP) levels via the inhibition of NEP. Candoxatril and omapatrilat, however, were not approved due to efficacy and safety concerns.¹⁹ Candoxatril was ineffective in lowering blood pressure (BP) due to concomitant inhibition in the degradation of the potent vasoconstrictors, endothelin 1, and angiotensin II (AngII) by NEP.²⁰ This subsequently led to the development of omapatrilat, an NEPi combined with an ACEI (enalapril) to block the vasoconstrictor action of AngII. Omapatrilat provided superior antihypertensive activity; however, it was associated with a greater incidence of potentially life-threatening angioedema due to an increase in bradykinin and substance P secondary to the inhibition of ACE, NEP, and aminopeptidase P (APP).^18,21,22 Since ARBs inhibit the angiotensin (AT₁) receptor and do not directly inhibit ACE and APP, they are associated with a lower incidence of angioedema compared to ACEIs.²² Therefore, valsartan was chosen to replace the enalapril component of omapatrilat, resulting in the development of LCZ696.

In Vitro/In Vivo Activity

An in vitro study in cultured neonatal rat cardiac fibroblasts and myocytes showed superior dose-dependent antifibrosis and antihypertrophic effects with LCZ696 compared to valsartan alone.²² In vivo studies in rats with induced myocardial infarction (MI) showed significantly reduced cardiac hypertrophy indicating the possible use of LCZ696 in reducing cardiac remodeling after an MI. Both studies demonstrated a possible utilization of LCZ696 for patients with HFpEF, which is characterized by hypertension and ischemia leading to hypertrophy and myocardial fibrosis. Another in vivo study demonstrated that antagonism of NEPi/ARB in stroke-prone spontaneously hypertensive rats reduced BP, improved cardiac fibrosis, and vascular remodeling to a significantly similar degree as NEPi/ACEI. The study also showed that ARB blockade with NEPi/valsartan was slightly more effective than valsartan alone. However, NEPi alone was shown to be ineffective in lowering BP.²³

An in vivo study in spontaneously hypertensive rats and a phase II study, the Omapatrilat Cardiovascular Treatment versus Enalapril (OCTAVE), assessed the efficacy and safety of NEPi/ARB for the risk of angioedema. The results showed an increased risk of angioedema with NEPi/ACEI compared to NEPi/ARB. The mechanism for the increased risk of angioedema seen with NEPi/ACEI was possibly due to the accumulation of bradykinin. Many peptidases metabolize bradykinin with the following propensity, ACE > APP >> NEP = DDP-IV, therefore, NEPi/ACEI has the potential to significantly increase the concentration of bradykinin leading to an increased incidence of angioedema. ARBs prevent the action of AngII by blocking the AT₁ receptor, without affecting ACE, thus allowing it to metabolize bradykinin. Therefore, the accumulation of bradykinin is less likely with ARBs when compared to ACEIs, especially when combined with NEPi. It can be concluded that NEPi/ARB (ie, LCZ696) can produce antihypertensive efficacy similar to omapatrilat without the risk of life-threatening angioedema.¹⁹

Pharmacodynamics

Preclinical pharmacodynamic studies assessed the change in mean arterial pressure (MAP) from baseline, as well as the effects of NEP inhibition. LCZ696 was administered in 4 doses ranging from 2 to 60 mg/kg. Dose dependent and long lasting reduction in MAP and augmentation of plasma ANP immune reactivity levels, indicating NEP inhibition within 15 minutes was demonstrated.¹⁸ Human clinical studies measured cyclic guanosine monophosphate (cGMP levels and assessed RAAS blockade for NEP inhibition by measuring renin, Ang II, and plasma renin activity (PRA). A maximum 40% increase in mean cGMP was observed with 200 mg LCZ696. In addition, cGMP significantly increased 4 hours after administration for all doses. LCZ696 200 mg stimulated significant dose-dependent increases in renin (3.1-fold), PRA (4.9-fold), and Ang II (3.7-fold) concentrations compared with placebo, which indicated blockade of AT₁ receptor by LCZ696 to a similar extent as valsartan 320 mg.¹⁸

Pharmacokinetics

Pharmacokinetic parameters for LCZ696 were studied based on data obtained from a preclinical trial and 2 clinical studies conducted in 116 healthy human participants, which examined dose escalation pharmacokinetics in single and multiple dose administration, as well as a bioequivalence between LCZ696 and valsartan.¹⁸ The dose range was 200 to 1200 and 50 to 900 mg of LCZ696 for the single dose and multiple doses, respectively.

Systemic exposure and half-life are clinically relevant to the actions of LCZ696, since the beneficial effects of endogenous ANP in HF are limited by these factors. Time to maximum concentration for each LCZ696 component valsartan, AHU377, and LBQ657 was 1.7 to 2.2, 0.5 to 1.1, and 1.9 to 3.5 hours for single dose and 1.6 to 4.9, 0.6 to 0.9, and 1.8 to 2.7 hours for multiple dose administration. Similarly, mean half-life was 8.9 to 16.6, 1.1 to 3.6, and 9.9 to 11.1 hours, respectively. The short half-life of AHU377 demonstrated rapid metabolism to active NEPi moiety, LBQ657.

The bioequivalence criteria for the valsartan component of LCZ696 400 mg to valsartan 320 mg were achieved, and LCZ696 showed a 40% higher exposure to valsartan compared to valsartan alone. The relative bioavailability of valsartan following administration of LCZ696 compared to valsartan alone was determined from previous studies to be 1.67. LCZ696 200 twice daily also achieves a maximum neprilysin inhibition of 90% leading to sustained increases in the plasma cGMP concentration.²⁴

Certain drugs like warfarin, digoxin, carvedilol, and metformin are coadministered in patients with HF to manage comorbid conditions or HF itself. LCZ696 is a weak inhibitor of CYP2C9, and data show a lack of pharmacokinetic or pharmacodynamic interaction with warfarin.²⁵ Digoxin did not affect the pharmacokinetics of LCZ696.²⁶ Although LCZ696 exposure remained unaffected, exposure of metformin in the presence of LCZ696 decreased by 23%.²⁷ The C_max of valsartan was decreased by 12% when LCZ696 was coadministered with carvedilol.²⁸

Outcomes of phase II and III clinical trials are summarized in Table 2. Kobalava et al evaluated the changes due to LCZ696 on the concentration of natriuretic peptides ANP and its second messenger cGMP, BNP, and NT-proBNP in a 3-week phase II open-label study.²⁹ Although maintaining stable background therapy, a short washout period of ACEI therapy was followed by the administration of LCZ696 100 mg twice for 7 days, which was then followed by the administration of 200 mg twice for 14 days.

Table 2.

Summary of Phase II and III Outcomes for LCZ696.

Study author and design	Number of patients	Results						Significance
		LCZ696 100 mg twice a day × 7 days → 200 mg twice a day × 14 days—geometric mean (95% CI)
		Marker	Baseline	Day 7		Day 21
Kobalava et al and phase II²⁹	30	u-ANP, pg/mL	209.6 (182.3-240.3)	353.4 (293-462.1)		378.4 (333.1-430)		P < .001
		cGMP, nmol/L	11.13 (8.6-14.45)	13.83 (11.43-16.75)		15.07 (12.34-18.4)		P < .001
		BNP, pg/mL	127.7 (81.2-200.8)	95.9 (57.6-159.6)		99.6 (59.3-167.4)		P < .05
		NT-proBNP, pg/mL	522 (312.3-872.8)	274.9 (157.5-479.9)		283.8 (159.5-504.9)		P < .001

		LCZ696 100 mg twice a day × 7 days → 200 mg twice a day × 14 days—geometric mean (95% CI)
		Marker	Baseline	Day 7		Day 21

Jordaan et al. and phase II³¹	NR	Aldosterone, pg/mL	237.3 (200.5-280.5)	220 (184.7-262.5)		189.7 (159.2-226.1)		P < .05
		PRA, ng/mL/h	0.69 (0.42-1.13)	2.7 (1.4-5.18)		1.64 (0.71-3.8)		P < .05
		ARC, pg/mL	9.92 (8.15-12.08)	42.64 (25.66-70.85)		34.11 (17.5-66.49)		P < .001
		Endothelian-1, pg/mL	2.43 (2.06-2.86)	2.18 (1.87-2.53)		1.99 (1.75-2.26)		P < .001

		LCZ696 100 mg twice a day × 7 days → 200 mg twice a day × 14 days (mean ± SD, 90% CI)
			Mean BP, mm Hg	HR, bpm		PP	RPP

Kobalava et al and phase II³⁰	30	Baseline	135.5 ± 14.2/80.0 ± 9.1	65.5 ± 10.3		55.5 ± 6.4	8875	Clinically significant decreases of 15% in both the pulse pressure (PP) from baseline to day 7 and 21, and in the rate pressure product (RPP) from baseline to day 7 and day 21 were documented
		2 h	122.9 ± 15.7/74.7 ± 10.5 (Δ −12.6/−5.3)	62.5 ± 10.0
		4 h	123.2 ± 16.7/73.0 ± 12.6 (Δ −12.2/−7.0)	64.0 ± 11.4
		12 h	118.7 ± 15.8/71.6 ± 12.5 (Δ −16.8/−8.5)	65.6 ± 11.3
		Day 1-7	119.1 ± 17.3/71.9 ± 10.4	64.6 ± 8.2		47.2 ± 4.4	7693
		Day 7-21	121.2 ± 16.2/73.6 ± 10.6	62.8 ± 9.7		47.6 ± 5.0	7611

		NT-pro-BNP, pg/mL	LCZ696 (n = 134)	95% CI	Valsartan (n = 132)	95% CI	Ratio LCZ696/valsartan

Solomon et al and phase II³²	266	Baseline	783	670-914	862	733-1012	0.77	P = .005
		12 weeks	605	512-714	835	710-981	95% CI (0·64-0·92)	P = .005
		Left atrial volume reduction with LCZ696 after 36 weeks						P = .003
		Improvement in LCZ696 NYHA class at week 36 (not week 12)						P = .05

		Outcome, no. (%)	LCZ696 (N = 4187)	Enalapril (N = 4212)		Hazard ratio or difference (95% CI)

McMurray et al and phase III³³	8399	Death from CV cause or first hospitalization 2/2 HF	914 (21.8)	1117 (26.5)		0.80 (0.73-0.87)		P < .001
		Death from cardiovascular causes	558 (13.3)	693 (16.5)		0.80 (0.71-0.89)		P < .001
		First hospitalization for worsening HF	537 (12.8)	658 (15.6)		0.79 (0.71-0.89)		P < .001
		Death from any cause	711 (17.0)	835 (19.8)		0.84 (0.76-0.93)		P < .001
		Δ in KCCQ clinical summary score at 8 months	−2.99 ± 0.36	−4.63 ± 0.36		1.64 (0.63-2.65)		P = .001
		LCZ696 reduced risk of hospitalization for heart failure by 21% compared to enalapril						P < .001
		LCZ696 decreased the symptoms and physical limitation of heart failure						P = .001

Abbreviations: LCZ696, angiotensin receptor-neprilysin inhibitor; u-ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; NT-proBNP, N-terminal pro brain natriuretic peptide; PRA, plasma renin activity; ARC, active renin concentration; KCCQ, Kansas City Cardiomyopathy Questionnaire; CI, confidence interval; cGMP, cyclic guanosine monophosphate; SD, standard deviation; BP, blood pressure; HR, hazards ratio; CV, cardiovascular; NYHA, New York Heart Association; HF, heart failure.

Thirty patients with stable chronic HFrEF defined as NYHA class II or III, with an LVEF <40% on optimal background treatment, were eligible for study participation. The efficacy parameters measured were the changes in natriuretic peptides ANP, cGMP, BNP, and NT-proBNP from baseline, following 7 and 21 days of treatment with LCZ696.

LCZ696 significantly increased ANP in urine and cGMP in serum, which is consistent with NEP inhibition. LCZ696 also significantly decreased serum BNP and NT-proBNP after 7 days (100 mg twice daily) and 21 days (200 mg twice daily) of treatment suggesting unloading of the heart.

Kobalava et al also conducted a phase II open-label, nonrandomized study with 30 patients to evaluate BP and heart rate (HR) responses to LCZ696 100 mg followed by 200 mg twice daily.³⁰ Persons aged 62 ± 9.3 years with stable chronic HFrEF defined as NYHA class II to III and LVEF ≤40% on stable background treatment for at least a month were included in the study (86.7% of the patients had a history of hypertension). A short washout period of ACEI therapy while maintaining stable background therapy was followed by LCZ696 100 mg twice daily for 7 days followed by 200 mg twice daily for 14 days. The primary efficacy assessments were supine rest BP and HR after a 3-minute rest. LCZ696 treatment was stopped if the patient experienced symptomatic or orthostatic hypotension or uncontrolled hypertension (systolic BP > 160 mm Hg). Treatment with LCZ696 100 and 200 mg twice a day was associated with a BP reduction that was well tolerated. A clinically significant decrease in both pulse pressure and in rate pressure product of 15% reflects a reduction in myocardial oxygen demand, indicating a potential beneficial effect in patients with chronic HFrEF.

Jordaan et al conducted an open-label, 2-dose phase study in patients with stable chronic HFrEF defined as NYHA class II or III and LVEF <40% to assess the efficacy and safety of short-term treatment with LCZ696 on RAAS and other biomarkers.³¹ A brief washout period of ACEI or ARB was allowed prior to administration of LCZ696 100 mg twice daily for 7 days followed by uptitrated to 200 mg twice daily for 14 days while maintaining background therapy. Efficacy parameters were determined by measuring plasma levels of aldosterone, active renin concentration (ARC), PRA, and endothelin 1 at baseline, day 7, and day 21 at the end of each dose treatment period. PRA and ARC increased significantly indicating AT₁ receptor blockade by the valsartan component of LCZ696. LCZ696 200 mg twice daily significantly reduced plasma levels of aldosterone and endothelin 1. These results supported the development of LCZ696 in HF due to the significant inhibition of multiple components of the RAAS.

Solomon et al conducted a phase II randomized, double-blind, parallel group, active controlled study in patients with HFpEF defined as NYHA class II to III HF with LVEF ≥ 45% and NT-proBNP greater than 400 pg/mL to assess the efficacy and safety of LCZ696 compared to valsartan.³² The study design included a 2-week, single blind, placebo run-in period during which patients continued background treatment and were required to discontinue ACEI and ARBs 24 hours prior to randomization. A total of 266 randomized participants were titrated to either LCZ696 200 mg twice daily or valsartan 160 mg twice daily for 36 weeks duration and were included in the analysis. Efficacy was determined based on the primary end point of change in NT-proBNP at 12 weeks from baseline. LCZ696 reduced NT-proBNP significantly compared to valsartan at 12 weeks. At the end of 36 weeks, BP and left atrial volume were significantly decreased.

McMurray et al in collaboration with Novartis personnel conducted a phase III, randomized, double-blind, double-dummy parallel group, active-controlled, 2-arm, event-driven trial comparing the long-term efficacy and safety of enalapril and LCZ696 in patients with chronic symptomatic HFrEF.³³ The study consisted of 4 phases. An initial screening followed by a single blind run-in with enalapril 10 mg twice daily with allowable uptitration to the target dose after 1 to 2 weeks. Safety monitoring criteria for hyperkalemia, renal dysfunction, BP, and adverse events needed to be met prior to the single-blind LCZ696 run-in. During the LCZ696 run-in period, ACEI or ARBs were discontinued a day prior to starting LCZ696 100 mg twice daily followed by uptitration to 200 mg twice daily after 1 to 2 weeks for an additional 2 to 4 weeks of therapy. If patients tolerated both enalapril and LCZ696 run-in periods then they were randomized in a 1:1 ratio to a double-blind treatment with either enalapril 10 mg twice daily or LCZ696 200 mg twice daily, where LCZ696 was stopped a day prior to randomization to minimize the potential risk of angioedema.

The study enrolled 8346 patients for randomization at 985 centers in 47 countries across major geographical regions. Persons aged ≥18 years with NYHA functional class II to IV, LVEF ≤35% decreased from original ≤40%, plasma BNP ≥150 pg/mL (or NT-proBNP ≥600 pg/mL), or BNP ≥100 pg/mL (or NT-proBNP ≥400 pg/mL) and a hospitalization for HF within the past 12 months, treatment with a stable dose of ACEI or ARB (equivalent to 10 mg/d), beta-blocker (unless contraindicated or not tolerated), and an aldosterone antagonist (not required, but should be considered taking into account renal function, serum potassium, and tolerability) for at least 4 weeks before screening visit were included. Key exclusion criteria were extensive but included known history of angioedema, history of intolerance to recommended target doses of ACEIs or ARBs, current acute decompensated HF, requirement for treatment with both ACEI and ARB, and more.

The purpose of the study was to evaluate the superiority of LCZ696 200 mg twice daily compared to enalapril 10 mg twice daily in addition to standard of care for HrEF in delaying time to first occurrence of either cardiovascular death or HF hospitalization. Secondary efficacy parameters were testing the superiority of LCZ696 to enalapril in improving Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score for HF symptoms and physical limitations at 8 months and delaying time to all-cause mortality. PARADIGM-HF was an event-driven trial, all randomized patients were to remain in the trial until 2410 patients had experienced a cardiovascular death or HF hospitalization, unless Data Monitoring Committee (DMC) recommended the study be stopped earlier for efficacy or safety reasons. Three interim efficacy analyses were planned, when approximately one-third, one-half, and two-thirds of the primary events occurred. Time-to-event data were evaluated with the use of Kaplan-Meier estimates and Cox proportional hazard models.

Analysis of the primary efficacy parameter was performed according to the intention-to-treat principle. The PARADIGM-HF was terminated early due to statistically significant reduction in relative risk reduction of 20% in the primary composite outcome of death from cardiovascular causes or first hospitalization for worsening HF in the LCZ696 group compared to the enalapril group (HR 0.80, 95% confidence interval, CI [0.73-0.87], P < .001). Individual components of the primary outcome composite were also found to be statistically significant; death from cardiovascular death (HR 0.80, 95% CI [0.71-0.89], P < .001) and first hospitalization for worsening HF (HR 0.79, 95% CI [0.71-0.89], P < .001). LCZ696 was superior to enalapril in reducing the risk of death and of hospitalization for HF (Table 3). Statistically significant secondary end points included death from any cause (HR 0.84, 95% CI [0.76-0.93], P < .001) and change in KCCQ clinical summary score at 8 months (HR 1.64, 95% CI [0.63-2.65], P < .001). LCZ696 also reduced risk of hospitalization for HF by 21% compared to enalapril. LCZ696 resulted in a statistically significant decrease in the symptoms and physical limitations of HF (P = .001).

Table 3.

Results of Primary Outcomes in PARADIGM-HF.³³

Outcome, no. (%)	LCZ696, N = 4187	Enalapril, N = 4212	Hazard ratio or difference (95% CI)	P value
Death from cardiovascular causes or first hospitalization for worsening heart failure	914 (21.8)	1117 (26.5)	0.80 (0.73-0.87)	<.001
Death from cardiovascular causes	558 (13.3)	693 (16.5)	0.80 (0.71-0.89)	<.001
First hospitalization for worsening heart failure	537 (12.8)	658 (15.6)	0.79 (0.71-0.89)	<.001

Abbreviations: PARADIGM-HF, Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; CI, confidence interval; LCZ696, angiotensin–neprilysin inhibition.

LCZ696 was generally safe and well tolerated following administration of single doses up to 1200 mg and up to 900 mg in multiple doses (Table 4).³³ In a PARAMOUNT trial, LCZ696 had similar tolerability and adverse effect profile as valsartan; however, LCZ696 had fewer numerical adverse events.³⁴ In the PARADIGM-HF study, which provides a more comprehensive safety and tolerability profile for LCZ696, 10.7% of patients in the LCZ696 group discontinued treatment compared to 12.3% of patients in the enalapril group (P = .03). LCZ696 study arm was more likely to have symptomatic hypotension and nonserious angioedema compared to the enalapril group, which had a greater proportion of patients with renal impairment, hyperkalemia, and cough. A statistically significant number of patients discontinued enalapril due to renal impairment compared to LCZ696 (59 [1.4%] vs 29 [0.7%] P = .002).

Table 4.

Safety and Tolerability in PARADIGM-HF.³³

Parameter	Solomon et al³²		P value	McMurray et al³³		P value
Parameter	LCZ696	Valsartan	P value	LCZ696	Enalapril	P value
Any Adverse Events (AEs)	96 (64%)	111 (73%)	.14	3419	3503	NR
Serious AEs	22 (15%)	30 (20%)	.32	1937 (46%)	2142 (51%)	NR
AE resulting in discontinuation	15 (10%)	17 (11%)	.90	10.7%	12.3%	.03
Death	1 (1%)	2 (1%)	.99	274	339	NR
Angioedema	1 (0.67%)	0	NR	19 (0.45)	9 (0.21)	NR^a
Symptomatic hypotension	28 (19%)	27 (18%)	.88	588 (14)	388 (9.2)	<.001
Symptomatic SBP <90 mm Hg	NR	NR	NR	112 (2.7)	59 (1.4)	<.001
K ≥ 6 mmol/L	5 (3%)	6 (4%)	.97	181 (4.3)	236 (5.6)	.007
SrCr ≥ 2.5 mg/dL	NR	NR	NR	139 (3.3)	188 (4.5)	.007
Cough	NR	NR	NR	474 (11.3)	601 (14.3)	<.001

Abbreviations: NR, not reported; PARADIGM-HF, Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; SBP, systolic blood pressure; LCZ696, angiotensin–neprilysin inhibition; SrCr, serum creatinine.

^aStratified based on no treatment or use of antihistamines only, use of catecholamines or glucocorticoids without hospitalization, and hospitalization without airway compromise were all not significant.

Concluding Remarks

Data from clinical trials of angiotensin–neprilysin inhibition have demonstrated statistical significance in reducing cardiovascular mortality and hospitalizations due to HF. However, the importance of the landmark PARADIGM-HF trial on treatment approaches for systolic HF remains to be determined.

Combined inhibition of the RAAS and neprilysin is thought to offer potential benefits for the treatment of hypertension and HF. The success demonstrated in the PARADIGM-HF study suggests that the novel drug combination surpasses the standard of care treatment with an ACEI in a relative risk reduction cardiovascular mortality and HF hospitalizations by 20% and 21%, respectively. This is especially important because the study drug was compared with an ACE inhibitor, a gold standard treatment that was proven to reduce mortality by roughly 18% in early trials.³⁴ As a cardiovascular mortality trial, the 20% risk reduction in cardiovascular deaths is significant because LCZ696 effectively doubled the survival benefit of enalapril on cardiovascular mortality. However, this is the relative risk reduction; the absolute benefit was only approximately 3% better.

The phase III PARADIGM-HF trial, the largest ever trial of an HF treatment, randomized over 8000 patients with class II, III, or IV HF. Almost all of the patients were NYHA class II to III, with an overwhelming 70% of patients in class II. Less than 1% of study patients were in class IV, which demonstrates that the effect of angiotensin–neprilysin inhibition in severe disease remains unknown. PARADIGM-HF also looked at clinically stable patients with HF. The role of initiating LCZ696 after hospitalization due to HF also remains unknown. Furthermore, additional research needs to be done to assess the drug in patients who were underrepresented in PARADIGM-HF. The average age of study participants was 63.8 years old, with women representing roughly 22% of patients and African Americans representing only 5% of patients. Of the 8399 patients who completed the trial, only 602 were from North America. A more diverse study with an older population may give a more accurate representation of patients who could potentially benefit from the study drug.

The run-in phase of the study design ensured that participants were able to tolerate both treatment options. However, of the 10 513 patients initially enrolled, a total of 2079 stopped participating in the study due to intolerance to enalapril or LCZ696. Because 20% of patients could not tolerate either treatment option and were subsequently dropped from the trial, the rates of adverse events may be drastically underestimated and not reflective of what would happen after transitioning the use of LCZ696 from trial to clinical practice. It would be interesting to see a side effect profile generated for the 20% of patients who were not candidates for inclusion into the study. Additionally, being that only patients who were able to tolerate a full dose of enalapril or LCZ696 were included, the study results may be more applicable toward healthier patients who were able to tolerate higher doses of the study drugs.

The combined angiotensin receptor–neprilysin inhibition as compared to ACE inhibition alone is interesting in terms of the dosing of study drugs. Enalapril was used at a dose of 10 mg orally twice a day, when it can be further titrated to a maximum of 40 mg/d in patients with HF. However, in the study group, valsartan was used at a dose of 160 mg orally twice a day, which is the maximum dose. It is possible that patients in the ACE inhibitor group did not receive as much benefit from enalapril as they could have with properly titrated doses. Perhaps the adverse event profile for enalapril might have also been underestimated as more patients might have experienced side effects at an increased dose. Additionally, prior to beginning the study, patients who were on ACEIs/ARBs were required to discontinue their current medications, which often had a higher, more therapeutic equivalent dose of enalapril. Other study designs are available that could have accounted for this confounding variable.

The PARADIGM-HF is one of the first contemporary trials to propose a new drug for substitution rather than an add-on strategy in chronic HF. Many patients with HF remain at risk of hospitalization, death, and poor quality of life. The advent of a novel drug brings excitement to an otherwise unchanging approach to treatment. Is it possible that LCZ696 may be a potential new option for the treatment of HF? Will LCZ696 eventually replace ACEIs? As of now, it remains unknown. Although PARADIGM-HF is promising, there were limitations within the trial. Additional studies are needed to truly assess the effectiveness and safety of implementing a change in the treatment of HF. The magnitude of relative risk reduction and the minimal number needed to treat to prevent outcomes suggest that LCZ696 may be cost-effective; however, pricing will play a crucial role in the treatment of patients with HF as well. When the standard of care with generic ACEIs is readily available, the need for economic studies also becomes apparent.³⁵ Although this study had an approximate 2-year follow-up, assessing long-term benefits and risks associated with treatment with LCZ696 is still warranted.

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Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

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References

Yancy

Jessup

Bozkurt

. ACCF/AHA guideline for the management of heart failure. Circulation. 2013;128 (16):e240–e327.

Rizzello

Poldermans

Biagini

. Prognosis of patients with ischaemic cardiomyopathy after coronary revascularization: relation to viability and improvement in left ventricular ejection fraction. Heart. 2009;95 (15):1273–1277.

Pagley

Beller

Watson

. Improved outcome after coronary bypass surgery in patients with ischemic cardiomyopathy and residual myocardial viability. Circulation. 1997;96 (3):793–800.

Fowles

Mason

. Endomyocardial biopsy. Ann Intern Med. 1982;97 (6):885–894.

Allman

Shaw

Hachamovitch

. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol. 2002;39 (7):1151–1158.

Schmidt

Shah

. Accurate detection of elevated left ventricular filling pressure by a simplified bedside application of the Valsalva maneuver. Am J Cardiol. 1993;71 (5):462–465.

Gorodeski

Chu

Chow

. Application of the Seattle Heart Failure Model in ambulatory patients presented to an advanced heart failure therapeutics committee. Circ Heart Fail. 2010;3 (6):706–714.

Cohn

Archibald

Ziesche

. Effect of vasodilator therapy on mortality in chronic congestive heart failure. N Engl J Med. 1986;314 (24):1547–1552.

CONSENSUS. The Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med. 1987;316 (23):1429–1435.

10.

SOLVD-Treatment. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325 (5):293–302.

11.

Pitt

Zannad

Remme

. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341 (10):709–717.

12.

US Carvedilol Heart Failure Study Group; Packer

Bristow

Cohn

. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334 (21):1349–1355.

13.

COPERNICUS; Packer

Coats

AJS

Fowler

. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344(22):1651–1658.

14.

Val-He

Cohn

Tognoni

. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345 (23):1667–1675.

15.

McMurray

JJV

Packer

Desai

. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371 (11):993–1004.

16.

Novartis. Pharmaceuticals Corporate Fact Sheet. Novartis Newsroom; 2014. Web site. http://www.novartis.com/downloads/newsroom/corporate-fact-sheet/2a_Pharmaceuticals_EN.pdf. Accessed September 20, 2014.

17.

McMurray

Packer

Desai

. Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. 2014;16 (7):817–825.

18.

Noe

Chandra

. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010;50 (4):401–414.

19.

Hedge

Renner

. Concomitant angiotensin AT₁ receptor antagonism and neprilysin inhibition produces omapatrilat-like antihypertensive effects without promoting tracheal plasma extravasation in the rat. J Cardiovasc Pharmacol. 2011;57 (4):495–504.

20.

McDowell

Coutie

Shaw

. The effect of the neutral endopeptidase inhibitor drug, candoxatril, on circulating levels of two of the most potent vasoactive peptides. Br J Clin Pharmacol. 1997;43 (3):329–332.

21.

Kostis

Packer

Black

. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) Trial. Am J Hypertens. 2004;17 (2):103–111.

22.

Von Lueder

Sangaralingham

Wang

. Renin–angiotensin blockade combined with natriuretic peptide system augmentation: novel therapeutic concepts to combat heart failure. Circ Heart Fail. 2013;6 (3):594–605.

23.

Brassard

Javeshghani

. Effects of combined AT₁ receptor antagonist/NEP inhibitor on vascular remodeling and cardiac fibrosis in SHRSP. J Hypertens. 2008;26 (2):322–333.

24.

McMurray

Packer

Desai

. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison and ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial. Eur J Heart Fail. 2013;15 (9):1062–1073.

25.

Ayalasomayajula

Jordaan

Pal

. Assessment of drug interaction potential between LCZ696 and warfarin. Hypertension. 2013;62:A448.

26.

Ayalasomayajula

Jordaan

Pal

. Assessment of pharmacokinetic drug interaction between LCZ696 and digoxin. Hypertension. 2013;62:A449.

27.

Mendonza

Mizuki

Langenickel

. Assessment of pharmacokinetic drug interaction between LCZ696 and metformin. Hypertension. 2013;62:A456.

28.

Hsui-Ling

Greeley

Pal

. Assessment of pharmacokinetic drug–drug interaction between LCZ696 and carvedilol. Hypertension. 2013;62:A457.

29.

Kobalava

Kotovskaya

Meray

. Clinic blood pressure in stable heart failure patients treated with the dual-acting neprilysin and angiotensin receptor inhibitor LCZ696. Eur Heart J. 2011;32 (abstract suppl.):788.

30.

Kobalava

Kotovskaya

Meray

. Natriuretic peptide inhibition in the presence of angiotensin receptor blockade following short-term treatment with LCZ696 in heart failure patients: effect on ANP, BNP, NT-proBNP and cGMP. Eur Heart J. 2011;32 (abstract suppl):784–785.

31.

Jordaan

. Changes in RAAS (renin angiotensin aldosterone system) biomarkers in patients with stable chronic heart failure following short-term angiotensin receptor neprilysin inhibitor (ARNI) treatment. SA Heart. 2011;8:236.

32.

Solomon

Zile

Pieske

. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized controlled trial. Lancet. 2012;380 (9851):1387–1395.

33.

McMurray

Packer

Desai

. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371 (11):993–1004.

34.

Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigators. N Engl J Med. 1992;327 (10):685–691.

35.

Cook

Cole

Asaria

. The annual global economic burden of heart failure. Int J Cardiol. 2014;171 (3):368–376.