CHF and arrhythmias:
Indications for: ENTRESTO
To reduce risk of cardiovascular death and hospitalization for heart failure in adults with chronic heart failure (benefits are most clearly evident in those with LVEF below normal). To treat symptomatic heart failure with systemic left ventricular systolic dysfunction in children aged ≥1yr.
Adult Heart Failure
- A multinational, randomized, double-blind trial comparing Entresto versus enalapril in 8,442 adult patients with symptomatic chronic heart failure (NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤40%).
- Patients had to have been on an ACE inhibitor or ARB for at least 4 weeks and on maximally tolerated doses of beta-blockers.
- Patients with a systolic blood pressure of <100mmHg at screening were excluded.
- The primary objective of PARADIGM-HF was to determine whether Entresto, a combination of sacubitril and a RAS inhibitor (valsartan), was superior to a RAS inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF).
Patients who successfully completed the sequential run-in periods were randomized to receive either Entresto 200mg (N=4,209) twice-daily or enalapril 10mg (N=4,233) twice-daily. The primary endpoint was the first event in the composite of CV death or hospitalization for HF. The median follow-up duration was 27 months and patients were treated for up to 4.3 years.
PARADIGM-HF demonstrated that Entresto was superior to enalapril alone based on a time-to-event analysis (hazard ratio [HR] 0.80; 95% confidence interval [CI], 0.73, 0.87, P <0.0001). The treatment effect reflected a reduction in both cardiovascular death and heart failure hospitalization. Entresto also improved overall survival (HR 0.84; 95% CI [0.76, 0.93], P =0.0009). This finding was driven entirely by a lower incidence of cardiovascular mortality on Entresto.
- A multicenter, randomized, double-blind trial comparing Entresto versus valsartan in 4,796 adult patients with symptomatic heart failure with left ventricular ejection fraction ≥45%, and structural heart disease [either left atrial enlargement (LAE) or left ventricular hypertrophy (LVH)].
- Patients with a systolic blood pressure of <110mmHg and patients with any prior echocardiographic LVEF <40% at screening were excluded.
- The primary objective of PARAGON-HF was to determine whether Entresto reduced the rate of the composite endpoint of total (first and recurrent) heart failure (HF) hospitalizations and cardiovascular (CV) death.
Patients who successfully completed the sequential run-in periods were randomized to receive either Entresto 200mg (N=2,419) twice-daily or valsartan 160mg (N=2,403) twice-daily. The median follow-up duration was 35 months and patients were treated for up to 4.7 years.
PARAGON-HF demonstrated that Entresto had a numerical reduction in the rate of the composite endpoint of total HF hospitalizations and CV death, based on an analysis using a proportional rates model (rate ratio [RR] 0.87; 95% CI [0.75, 1.01], P =0.06). The treatment effect was primarily driven by the reduction in total HF hospitalizations in patients randomized to Entresto (RR 0.85; 95% CI [0.72, 1.00]).
Pediatric Heart Failure
- A multinational, randomized, double-blind trial comparing Entresto versus enalapril based on an analysis in 110 pediatric patients 1 to <18 years old with heart failure (NYHA/Ross class II-IV) due to systemic left ventricular systolic dysfunction (LVEF ≤40%).
- Patients with systemic right ventricles and single ventricles were excluded from the trial.
- The Entresto target maintenance dose in pediatric patients 1 to <18 years old was 3.1mg/kg twice daily.
The endpoint was the between-group difference in the change in plasma NT-proBNP from baseline to 12 weeks. The reduction from baseline in NT-proBNP was 44% and 33% in the Entresto vs enalapril groups, respectively. While the between-group difference was not statistically significant, the reductions for Entresto and enalapril were similar to or greater than what was seen in adults; these reductions did not appear to be attributable to post-baseline changes in background therapy.
Since Entresto improved outcomes and reduced NT-proBNP in PARADIGM-HF, the effect on NT-proBNP was considered a reasonable basis to infer improved cardiovascular outcomes in pediatric patients.
Initially 49mg/51mg twice daily; double the dose after 2–4 weeks to target maintenance dose of 97mg/103mg twice daily as tolerated. Not currently on ACEI/ARB, previously on low doses of ACEI/ARB, severe renal impairment (eGFR <30mL/min/1.73m2), or moderate hepatic impairment (Child-Pugh B): initially 24mg/26mg twice daily; double the dose every 2–4 weeks to target maintenance dose of 97mg/103mg twice daily as tolerated. If switching from or to an ACEI: allow 36 hour wash-out period between taking the two drugs.
<1yr: not established. Administer twice daily; adjust dose every 2 weeks as tolerated. ≥1yr: <40kg (use oral susp; see full labeling): initially 1.6mg/kg, titrate to 2.3mg/kg, then to target dose of 3.1mg/kg; ≥40–<50kg: initially 24mg/26mg, titrate to 49mg/51mg, then to target dose of 72mg/78mg; ≥50kg: initially 49mg/51mg, titrate to 72mg/78mg, then to target dose of 97mg/103mg. Not currently on ACEI/ARB, previously on low doses of ACEI/ARB, severe renal impairment (eGFR <30mL/min/1.73m2), or moderate hepatic impairment (Child-Pugh B): initiate at half the usual dose (for 40–50kg: initially 0.8mg/kg with oral susp); follow recommended dose escalation every 2 weeks. If switching from or to an ACEI: allow 36 hour wash-out period between taking the two drugs.
History of angioedema related to previous ACE inhibitor or ARB therapy. Concomitant ACE inhibitors. Concomitant aliskiren in patients with diabetes.
Fetal toxicity may develop; discontinue if pregnancy is detected. Discontinue if angioedema occurs; do not re-administer. Give SC epinephrine for airway obstruction if indicated. Black patients may have higher risk of angioedema than non-Black patients. Avoid in hereditary angioedema. May cause symptomatic hypotension. Correct salt/volume depletion prior to initiation or start at a lower dose. Adjust concomitant diuretic or antihypertensive doses if hypotension occurs. Reduce dose or temporarily discontinue if hypotension persists. Monitor renal function in renal artery stenosis, severe CHF. Monitor serum creatinine and down-titrate or interrupt dose if significant renal dysfunction develops. Monitor for hyperkalemia esp. in severe renal impairment, diabetes, hypoaldosteronism, or high K+ diet. Severe hepatic impairment: not recommended. Neonates. Pregnancy (2nd & 3rd trimesters); consider alternative therapy. Nursing mothers: not recommended.
Neprilysin inhibitor + angiotensin II receptor blocker.
See Contraindications. Dual inhibition of the renin-angiotensin system: avoid concomitant with an ARB. Concomitant aliskiren in renal impairment (eGFR <60mL/min/1.73m2); avoid. Concomitant K+ supplements, K+ -sparing diuretics, K+ -containing salt substitutes may cause hyperkalemia. Worsening renal function and possible acute renal failure with NSAIDs, including selective COX-2 inhibitors (monitor renal function periodically in elderly and/or volume depleted). May increase lithium levels; monitor.
Hypotension, hyperkalemia, cough, dizziness, renal failure, increased serum creatinine, decreased hemoglobin/hematocrit.
Following oral administration, 52–68% of sacubitril (primarily as LBQ657) and ~ 13% of valsartan and its metabolites are excreted in urine; 37-48% of sacubitril (primarily as LBQ657), and 86% of valsartan and its metabolites are excreted in feces.
Mean elimination half-life: ~1.4 hours (sacubitril), 11.5 hours (LBQ657), and 9.9 hours (valsartan).
Generic Drug Availability: