General (including evidence of efficacy)

LCZ696 (sacubitril/valsartan) is a member of a new class of agents called angiotensin receptor-neprilysin inhibitors (ARNIs) which combine a neprilysin inhibitor and angiotensin receptor blocker (ARB). LCZ696 is currently indicated for treating patients with heart failure with reduced ejection fraction (HFrEF) in place of an angiotensin converting enzyme (ACE) inhibitor or ARB alone. LCZ696 (sacubitril/valsartan) was approved by the FDA in July 2015 to reduce the risk of death from cardiovascular causes and hospitalization for heart failure in patients with chronic heart failure, NYHA class II-IV, and reduced ejection fraction. The combination of neprilysin inhibition and renin-angiotensin aldosterone system (RAAS) effects have been shown to be superior to those of an ACE inhibitor. The trade name for LCZ696 is Entresto
^TM.

PARADIGM-HF was a phase III double-blind randomized trial which compared LCZ696 (sacubitril/valsartan) to enalapril in patients with heart failure with an ejection fraction of 40% or less and stable NYHA class II-IV symptoms while on what was considered to be optimal treatment. The primary outcome was a composite of cardiovascular death and hospitalizations for heart failure. Patients received either LCZ696 (sacubitril/valsartan) 200 mg twice daily (n=4187) or enalapril 10 mg twice daily (n=4212) in addition to guideline-directed medical therapy (GDMT) for chronic heart failure.

LCZ696 (sacubitril/valsartan) was superior to enalapril in reducing the risk of cardiovascular death or hospitalizations for heart failure (HR 0.80; 95% CI 0.73-0.87, p<0.001). The treatment effect was driven equally by reductions in cardiovascular death (HR: 0.80, 95% CI 0.71-0.89, p<0.001) and heart failure hospitalizations (HR: 0.79; 95% CI 0.71-0.89, p<0.001). There was also a significant reduction in all-cause mortality (HR 0.84; 95% CI 0.76 – 0.93, p<0.001) and an improvement in KCCQ-determined quality of life (HR 1.64, 95% CI 0.63-2.65, p=0.001) with LCZ696 (sacubitril/valsartan). The trial was stopped early due to significant benefit of LCZ696 (sacubitril/valsartan) over enalapril. Of note was the fact that enalapril at the dose used in PARADIGM-HF had been shown to improve outcomes including all-cause mortality in symptomatic heart failure patients with reduced ejection fraction in the Studies of Left Ventricular Dysfunction (SOLVD) treatment arm.

The 2013 ACC/AHA guidelines for the management of heart failure provides recommendations for GDMT to decrease morbidity and mortality. Neurohormonal blockade that targets the RAAS and sympathetic nervous system (SNS) has been the cornerstone of treatment and key classes of medications include: ACE inhibitors, ARBs, beta blockers, mineralocorticoid receptor antagonists (MRAs) and the combination therapy of hydralazine and isosorbide dinitrate. ACE inhibitors have long been the cornerstone of therapy for patients with HFrEF and ARBs are recommended as a substitution for patients who have intolerable side effects to ACE inhibitors. These guidelines were published prior to the PARADIGM-HF trial. However, the results of the PARADIGM-HF trial provide evidence that LCZ696 (sacubitril/valsartan) could be used in place of an ACE inhibitor or ARB as first-line therapy in many patients with heart failure and reduced ejection fraction.

Differences between drugs within the class

LCZ696 (sacubitril/valsartan) is the first approved agent of a novel class of agents combining a neprilysin inhibitor and an ARB. There are currently no alternatives in this class.

Administration

The recommended starting dose for LCZ696 (sacubitril/valsartan) is variable and depends on the dose of ACE inhibitor or ARB that the patient is taking and presence of severe renal dysfunction or moderate hepatic dysfunction (as defined below). LCZ696 (sacubitril/valsartan) is taken twice daily without regard to food. When switching from an ACE inhibitor, a washout period of 36 hours between drugs is required due to the increased risk of angioedema.

The standard starting dose is 49/51 mg twice daily.

A reduced initial dose of LCZ696 (sacubitril/valsartan) 24/26 mg twice daily is recommended for the following patients:

ACE Inhibitor or ARB naive
Low dose ACE inhibitor or ARB therapy

Low dose ACE inhibitor equivalent: enalapril <=10 mg daily

Low dose ARB equivalent: valsartan <=160mg daily
Severe renal function (GFR <30ml/min/1.73m ²)
Moderate hepatic impairment (Child-Pugh class B)

LCZ696 (sacubitril/valsartan) is not recommended for the following patients:

Severe hepatic impairment (Child-Pugh class C)
Concomitant ARB therapy: LCZ696 (sacubitril/valsartan) contains the ARB valsartan.

The dose should be doubled every 2-4 weeks to achieve the target dose of 97/103 mg twice daily or the maximally-tolerated dose.

The tablets are oval shaped and not scored; therefore, it is not recommended to split the tablets.

Pharmacokinetics:

Oral bioavailability is >=60%
Steady-state is reached in 3 days
Highly protein bound 94-97%
Volume of distribution is 75 L for sacubitril and 103 L for valsartan
Sacubitril component is primarily excreted in the urine (52-68%) and feces (37-48%)
Valsartan component is primarily excreted in the feces (86%) and to a lesser extent in the urine (13%)

Pharmacologic action

LCZ696 (sacubitril/valsartan) is a first in class ARNI. Sacubitril is a neprilysin inhibitor and valsartan is an ARB. Through its inhibition of neprilysin, LCZ696 increases several endogenous vasoactive peptides, including natriuretic peptides (e.g., atrial natriuretic peptide, B-type natriuretic peptide, and others), adrenomedullin, and bradykinin. Increases in these vasoactive peptides leads to vasodilation, increased natriuresis, increased diuresis, and inhibition of fibrosis. Valsartan, the ARB component, inhibits angiotensin II at the AT
₁ receptor, thereby blocking angiotensin effects including vasoconstriction, salt and water retention, and chronic structural changes in the myocardium including fibrosis and hypertrophy. Angiotensin II also stimulates the release of aldosterone and release of this agent is also blocked to some extent by an ARB. Thus, the combined effects of neprilysin and RAAS inhibition are synergistic and act to block the deleterious effects of RAAS activation while enhancing levels of counter-regulatory peptides that have beneficial effects.

Indications and contraindications

LCZ696 (sacubitril/valsartan) is indicated to decrease risk of cardiovascular death and heart failure hospitalizations for heart failure in patients with chronic HFrEF, NYHA class II-IV. LCZ696 (sacubitril/valsartan) should be used in conjunction with other GDMTs in place of an ACE inhibitor or ARB.

Contraindications include:

Hypersensitivity to any of the components.
Concomitant use of ACE inhibitor: LCZ696 (sacubitril/valsartan) should not be administered within 36 hours of receiving an ACE inhibitor.
Concomitant use of aliskiren in patients with diabetes mellitus.
History of angioedema related to previous treatment with ACE inhibitor or ARB therapy.

Undesirable effects

Fetal toxicity: All drugs that work on the RAAS can cause harm to the fetus when given during pregnancy. They can decrease fetal renal function in the second and third trimester of pregnancy and increase fetal and neonatal morbidity and mortality. LCZ696 (sacubitril/valsartan) should be discontinued if pregnancy is detected.
Angioedema: Angioedema was reported as 0.5% with LZC696 (sacubitril/valsartan) and 0.2% with enalapril during the double-blind period in PARADIGM-HF. There was also an increased rate in Blacks vs. non-Blacks and in those with prior history of angioedema. If angioedema occurs, LCZ696 (sacubitril/valsartan) should be discontinued and should
NOT be rechallenged. LCZ696 (sacubitril/valsartan) should not be used in those with a history of angioedema related to previous ACE inhibitor or ARB therapy. If switching to or from an ACE inhibitor, a 36-hour washout period is required between drugs.
Hypotension: LCZ696 (sacubitril/valsartan) lowers blood pressure through its inhibition of the RAAS and can cause symptomatic hypotension. In the double-blind period of PARADIGM-HF, 18% of patients on LCZ696 (sacubitril/valsartan) reported an adverse effect of hypotension vs. 12% on patients on enalapril. Since there is a greater risk in those patients with an activated RAAS, it is recommended to correct salt or volume depletion prior to initiation. If symptomatic hypotension occurs, adjust diuretics and other antihypertensives, and treat other causes of hypovolemia and/or reduce the dose of LCZ696 (sacubitril/valsartan). If symptomatic hypotension persists despite a decrease in LCZ696 (sacubitril/valsartan), the drug may need to be stopped.
Impaired renal function: LCZ696 (sacubitril/valsartan) is a RAAS blocking agent; therefore, decreases in renal function may be expected in high risk individuals including those with renal artery stenosis. In the double-blind period of PARADIGM-HF, 5% of those treated with LCZ696 (sacubitril/valsartan) and enalapril reported renal failure as an adverse event. In addition, increases in Scr >=50% were observed in 16% of those treated with both LCZ696 (sacubitril/valsartan) and enalapril. Renal function should be monitored closely and the LCZ696 (sacubitril/valsartan) dose should be decreased or stopped for clinically significant decreases in renal function.
Hyperkalemia: Through its effects on RAAS blockade, LCZ696 (sacubitril/valsartan) has the potential to cause hyperkalemia. In the double-blind period of PARADIGM-HF, 12% of patients treated with LCZ696 (sacubitril/valsartan) reported an adverse effect of hyperkalemia. In addition, potassium concentrations >5.5 mEq/L were observed in 16% of those treated with both LCZ696 (sacubitril/valsartan) and enalapril. Close monitoring is advised in patients with risk factors such as severe renal impairment, diabetes mellitus, hypoaldosteronism, or high potassium diet. Dose reductions or discontinuation of the drug may be necessary for clinically significant increases in potassium.

Based on the trial design of PARADIGM-HF in which patients were required to be able to tolerate both enalapril and LCZ696 (sacubitril/valsartan) during the single blind run in phase, it is likely that these side effects are under-reported and may be higher in clinical practice.

Alternative approaches

If patients develop symptomatic hypotension on LCZ696 (sacubitril/valsartan), there are a few strategies to consider. If the patient is hypovolemic, the dose of diuretic can be decreased. Decreasing the dose of other anti-hypertensives or LCZ696 (sacubitril/valsartan) may be warranted. If symptomatic hypotension persists after decreasing the dose of LCZ696 (sacubitril/valsartan), the medication should be withdrawn.

If patients cannot tolerate LCZ696 (sacubitril/valsartan), their ACE inhibitor or ARB therapy should be restarted as per the 2013 ACC/AHA Heart Failure guidelines.

References

McMurray, JVJ, Packer, M, Desai, AS. “Angiotensin-neprilysin inhibition versus enalapril in heart failure”. NEJM. vol. 371. 2015. pp. 993-1004. (PARADIGM-HF: trial which got LCZ696 [sacubitril/valsartan] regulatory approval in the US.)

2015. (Full prescribing information including FDA-labeled indication, dosing, administration, clinical pharmacology, contraindications, precautions, etc.)

Yancy, CW, Jessup, M, Bozkurt, B. “ACC/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practical guidelines”. Circulation. vol. 128. June 2013. pp. 240-327. (Current ACC/AHA Guidelines for the management of patients with heart failure.)

Vardeny, O, Miller, R, Solomon, SD. “Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure”. JACC. vol. 2. 2104. pp. 663-70. (Summarizes the effect of natriuretic peptides in heart failure, natriuretic peptides as therapeutic targets, and clinical trials with LCZ696 [sacubitril/valsartan].)

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