First neprilysin inhibitor approved for HF

Abstract

Morbidity and mortality in those with heart failure (HF) remain high,so effective therapies aimed at reducing HF burden are needed. Anovel combination therapy containing sacubitril, a neprilysin inhibitor,and valsartan (Entresto—Novartis) received FDA approval to reducethe risk of cardiovascular death and HF hospitalization in patients withHF with a reduced ejection fraction. Morbidity and mortality in those with heart failure (HF) remain high,so effective therapies aimed at reducing HF burden are needed. Anovel combination therapy containing sacubitril, a neprilysin inhibitor,and valsartan (Entresto—Novartis) received FDA approval to reducethe risk of cardiovascular death and HF hospitalization in patients withHF with a reduced ejection fraction. Neprilysin is a natural endopeptidase that degrades select vasoactive peptides such as natriuretic peptides, bradykinin, and adrenomedullin. Inhibition of neprilysin by the active moiety of sacubitril, known as LBQ657, results in increasing levels of these vasoactive peptides. These vasoactive peptides subsequently produce decreases in vasoconstriction and reductions in sodium retention and maladaptive remodeling. When given with valsartan for patients with HF, this new combination therapy has been shown to result in significant benefits in both cardiovascular morbidity and mortality.PARADIGM-HFThe PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial was a multinational, randomized, double-blind trial that compared the use of sacubitril/valsartan with enalapril in 8,442 adult patients with HF who had a reduced ejection fraction and were taking other HF therapies. After a median follow-up duration of 27 months, the use of sacubitril/valsartan resulted in a significant reduction in the risk of the primary composite endpoint of cardiovascular death or HF hospitalization (hazard ratio 0.80 [95% CI 0.73-0.87]). The number of events for each of these individual endpoints was lower in the sacubitril/valsartan group compared with enalapril (cardiovascular death 13.3% vs. 16.5%; HF hospitalizations 12.8% vs. 15.6%). More patients in the sacubitril/valsartan group had hypotension and angioedema, but fewer in this group had hyperkalemia and cough compared with the enalapril group.Place in therapyACE inhibitors have long been the standard of care for patients with HF and a reduced ejection fraction, with data from key trials showing this class of drugs reduces the risk of death. Subsequent studies then showed that use of beta-blockers and mineralocorti-coid-receptor antagonists, when added to ACE inhibitors, further improves mortality in this patient population. The results of the PARADIGM-HF trial now add yet another option with mortality and morbidity benefits for patients with HF and a reduced ejection fraction. Clinicians are encouraged to review the trial results and product labeling to determine if this new therapy is an ideal option for their patients with HF.Maria G. Tanzi, PharmD, contributing writerPatient counselingPatients should be given the FDA-approved patient labeling. Educate them on proper administration and potential adverse reactions. Inform patients that dosing is twice daily, and that missed doses should be taken as soon as they remember. If it’s almost time for the next dose, the missed dose should be skipped, and only the regularly scheduled dose should be taken. Educate patients on the potential for angio-edema to occur and symptoms such as swelling of the face, lips, tongue, and throat. If any of these symptoms occur, they should seek immediate medical help.Sacubitril/Valsartan (Entresto)Manufacturer: NovartisDrug class: Neprilysin inhibitor; angiotensin II receptor blocker (ARB)Indication: To reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with NYHA Class II—IV HF and a reduced ejection fraction.Dosage: An initial starting dose of 49/51 mg sacubitril/valsartan twice daily should be given, and the dose should be doubled to the target maintenance dose of 97/103 mg after 2–4 weeks as tolerated by the patient.■A lower starting dose of 24/26 mg sacubitril/valsartan given twice daily is recommended for patients not currently taking an angio-tensin-converting enzyme (ACE) inhibitor or an ARB or previously taking a low dose of these agents, for those with severe renal impairment, or for those with moderate hepatic impairment. Doses should also be doubled in these patients every 2–4 weeks as tolerated to get to the target maintenance dose of 97/103 mg.■If switching from an ACE inhibitor to sacubitril/valsartan, a washout period of 36 hours is recommended between the administration of the two drugs.■Use in patients with severe hepatic impairment is not recommended.Of note:■The drug has a boxed warning for fetal toxicity, as drugs that act on the renin-angiotensin system can cause fetal harm, including death.■The drug is contraindicated in patients with hypersensitivity to any component of the drug, those with a history of angioedema related to previous ACE or ARB therapy, with concurrent use of an ACE inhibitor, or with concurrent use of aliskiren (Tekturna—Novartis) in patients with diabetes.■Warnings and precautions in the label include fetal toxicity, angio-edema, hypotension, impaired renal function, and hyperkalemia. Neprilysin is a natural endopeptidase that degrades select vasoactive peptides such as natriuretic peptides, bradykinin, and adrenomedullin. Inhibition of neprilysin by the active moiety of sacubitril, known as LBQ657, results in increasing levels of these vasoactive peptides. These vasoactive peptides subsequently produce decreases in vasoconstriction and reductions in sodium retention and maladaptive remodeling. When given with valsartan for patients with HF, this new combination therapy has been shown to result in significant benefits in both cardiovascular morbidity and mortality. PARADIGM-HFThe PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial was a multinational, randomized, double-blind trial that compared the use of sacubitril/valsartan with enalapril in 8,442 adult patients with HF who had a reduced ejection fraction and were taking other HF therapies. After a median follow-up duration of 27 months, the use of sacubitril/valsartan resulted in a significant reduction in the risk of the primary composite endpoint of cardiovascular death or HF hospitalization (hazard ratio 0.80 [95% CI 0.73-0.87]). The number of events for each of these individual endpoints was lower in the sacubitril/valsartan group compared with enalapril (cardiovascular death 13.3% vs. 16.5%; HF hospitalizations 12.8% vs. 15.6%). More patients in the sacubitril/valsartan group had hypotension and angioedema, but fewer in this group had hyperkalemia and cough compared with the enalapril group. The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial was a multinational, randomized, double-blind trial that compared the use of sacubitril/valsartan with enalapril in 8,442 adult patients with HF who had a reduced ejection fraction and were taking other HF therapies. After a median follow-up duration of 27 months, the use of sacubitril/valsartan resulted in a significant reduction in the risk of the primary composite endpoint of cardiovascular death or HF hospitalization (hazard ratio 0.80 [95% CI 0.73-0.87]). The number of events for each of these individual endpoints was lower in the sacubitril/valsartan group compared with enalapril (cardiovascular death 13.3% vs. 16.5%; HF hospitalizations 12.8% vs. 15.6%). More patients in the sacubitril/valsartan group had hypotension and angioedema, but fewer in this group had hyperkalemia and cough compared with the enalapril group. Place in therapyACE inhibitors have long been the standard of care for patients with HF and a reduced ejection fraction, with data from key trials showing this class of drugs reduces the risk of death. Subsequent studies then showed that use of beta-blockers and mineralocorti-coid-receptor antagonists, when added to ACE inhibitors, further improves mortality in this patient population. The results of the PARADIGM-HF trial now add yet another option with mortality and morbidity benefits for patients with HF and a reduced ejection fraction. Clinicians are encouraged to review the trial results and product labeling to determine if this new therapy is an ideal option for their patients with HF.Maria G. Tanzi, PharmD, contributing writerPatient counselingPatients should be given the FDA-approved patient labeling. Educate them on proper administration and potential adverse reactions. Inform patients that dosing is twice daily, and that missed doses should be taken as soon as they remember. If it’s almost time for the next dose, the missed dose should be skipped, and only the regularly scheduled dose should be taken. Educate patients on the potential for angio-edema to occur and symptoms such as swelling of the face, lips, tongue, and throat. If any of these symptoms occur, they should seek immediate medical help.Sacubitril/Valsartan (Entresto)Manufacturer: NovartisDrug class: Neprilysin inhibitor; angiotensin II receptor blocker (ARB)Indication: To reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with NYHA Class II—IV HF and a reduced ejection fraction.Dosage: An initial starting dose of 49/51 mg sacubitril/valsartan twice daily should be given, and the dose should be doubled to the target maintenance dose of 97/103 mg after 2–4 weeks as tolerated by the patient.■A lower starting dose of 24/26 mg sacubitril/valsartan given twice daily is recommended for patients not currently taking an angio-tensin-converting enzyme (ACE) inhibitor or an ARB or previously taking a low dose of these agents, for those with severe renal impairment, or for those with moderate hepatic impairment. Doses should also be doubled in these patients every 2–4 weeks as tolerated to get to the target maintenance dose of 97/103 mg.■If switching from an ACE inhibitor to sacubitril/valsartan, a washout period of 36 hours is recommended between the administration of the two drugs.■Use in patients with severe hepatic impairment is not recommended.Of note:■The drug has a boxed warning for fetal toxicity, as drugs that act on the renin-angiotensin system can cause fetal harm, including death.■The drug is contraindicated in patients with hypersensitivity to any component of the drug, those with a history of angioedema related to previous ACE or ARB therapy, with concurrent use of an ACE inhibitor, or with concurrent use of aliskiren (Tekturna—Novartis) in patients with diabetes.■Warnings and precautions in the label include fetal toxicity, angio-edema, hypotension, impaired renal function, and hyperkalemia. ACE inhibitors have long been the standard of care for patients with HF and a reduced ejection fraction, with data from key trials showing this class of drugs reduces the risk of death. Subsequent studies then showed that use of beta-blockers and mineralocorti-coid-receptor antagonists, when added to ACE inhibitors, further improves mortality in this patient population. The results of the PARADIGM-HF trial now add yet another option with mortality and morbidity benefits for patients with HF and a reduced ejection fraction. Clinicians are encouraged to review the trial results and product labeling to determine if this new therapy is an ideal option for their patients with HF. Maria G. Tanzi, PharmD, contributing writerPatient counselingPatients should be given the FDA-approved patient labeling. Educate them on proper administration and potential adverse reactions. Inform patients that dosing is twice daily, and that missed doses should be taken as soon as they remember. If it’s almost time for the next dose, the missed dose should be skipped, and only the regularly scheduled dose should be taken. Educate patients on the potential for angio-edema to occur and symptoms such as swelling of the face, lips, tongue, and throat. If any of these symptoms occur, they should seek immediate medical help.Sacubitril/Valsartan (Entresto)Manufacturer: NovartisDrug class: Neprilysin inhibitor; angiotensin II receptor blocker (ARB)Indication: To reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with NYHA Class II—IV HF and a reduced ejection fraction.Dosage: An initial starting dose of 49/51 mg sacubitril/valsartan twice daily should be given, and the dose should be doubled to the target maintenance dose of 97/103 mg after 2–4 weeks as tolerated by the patient.■A lower starting dose of 24/26 mg sacubitril/valsartan given twice daily is recommended for patients not currently taking an angio-tensin-converting enzyme (ACE) inhibitor or an ARB or previously taking a low dose of these agents, for those with severe renal impairment, or for those with moderate hepatic impairment. Doses should also be doubled in these patients every 2–4 weeks as tolerated to get to the target maintenance dose of 97/103 mg.■If switching from an ACE inhibitor to sacubitril/valsartan, a washout period of 36 hours is recommended between the administration of the two drugs.■Use in patients with severe hepatic impairment is not recommended.Of note:■The drug has a boxed warning for fetal toxicity, as drugs that act on the renin-angiotensin system can cause fetal harm, including death.■The drug is contraindicated in patients with hypersensitivity to any component of the drug, those with a history of angioedema related to previous ACE or ARB therapy, with concurrent use of an ACE inhibitor, or with concurrent use of aliskiren (Tekturna—Novartis) in patients with diabetes.■Warnings and precautions in the label include fetal toxicity, angio-edema, hypotension, impaired renal function, and hyperkalemia. Patient counselingPatients should be given the FDA-approved patient labeling. Educate them on proper administration and potential adverse reactions. Inform patients that dosing is twice daily, and that missed doses should be taken as soon as they remember. If it’s almost time for the next dose, the missed dose should be skipped, and only the regularly scheduled dose should be taken. Educate patients on the potential for angio-edema to occur and symptoms such as swelling of the face, lips, tongue, and throat. If any of these symptoms occur, they should seek immediate medical help.Sacubitril/Valsartan (Entresto)Manufacturer: NovartisDrug class: Neprilysin inhibitor; angiotensin II receptor blocker (ARB)Indication: To reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with NYHA Class II—IV HF and a reduced ejection fraction.Dosage: An initial starting dose of 49/51 mg sacubitril/valsartan twice daily should be given, and the dose should be doubled to the target maintenance dose of 97/103 mg after 2–4 weeks as tolerated by the patient.■A lower starting dose of 24/26 mg sacubitril/valsartan given twice daily is recommended for patients not currently taking an angio-tensin-converting enzyme (ACE) inhibitor or an ARB or previously taking a low dose of these agents, for those with severe renal impairment, or for those with moderate hepatic impairment. Doses should also be doubled in these patients every 2–4 weeks as tolerated to get to the target maintenance dose of 97/103 mg.■If switching from an ACE inhibitor to sacubitril/valsartan, a washout period of 36 hours is recommended between the administration of the two drugs.■Use in patients with severe hepatic impairment is not recommended.Of note:■The drug has a boxed warning for fetal toxicity, as drugs that act on the renin-angiotensin system can cause fetal harm, including death.■The drug is contraindicated in patients with hypersensitivity to any component of the drug, those with a history of angioedema related to previous ACE or ARB therapy, with concurrent use of an ACE inhibitor, or with concurrent use of aliskiren (Tekturna—Novartis) in patients with diabetes.■Warnings and precautions in the label include fetal toxicity, angio-edema, hypotension, impaired renal function, and hyperkalemia. Patient counseling Patients should be given the FDA-approved patient labeling. Educate them on proper administration and potential adverse reactions. Inform patients that dosing is twice daily, and that missed doses should be taken as soon as they remember. If it’s almost time for the next dose, the missed dose should be skipped, and only the regularly scheduled dose should be taken. Educate patients on the potential for angio-edema to occur and symptoms such as swelling of the face, lips, tongue, and throat. If any of these symptoms occur, they should seek immediate medical help. Sacubitril/Valsartan (Entresto) Manufacturer: Novartis Drug class: Neprilysin inhibitor; angiotensin II receptor blocker (ARB) Indication: To reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with NYHA Class II—IV HF and a reduced ejection fraction. Dosage: An initial starting dose of 49/51 mg sacubitril/valsartan twice daily should be given, and the dose should be doubled to the target maintenance dose of 97/103 mg after 2–4 weeks as tolerated by the patient.■A lower starting dose of 24/26 mg sacubitril/valsartan given twice daily is recommended for patients not currently taking an angio-tensin-converting enzyme (ACE) inhibitor or an ARB or previously taking a low dose of these agents, for those with severe renal impairment, or for those with moderate hepatic impairment. Doses should also be doubled in these patients every 2–4 weeks as tolerated to get to the target maintenance dose of 97/103 mg.■If switching from an ACE inhibitor to sacubitril/valsartan, a washout period of 36 hours is recommended between the administration of the two drugs.■Use in patients with severe hepatic impairment is not recommended. Of note:■The drug has a boxed warning for fetal toxicity, as drugs that act on the renin-angiotensin system can cause fetal harm, including death.■The drug is contraindicated in patients with hypersensitivity to any component of the drug, those with a history of angioedema related to previous ACE or ARB therapy, with concurrent use of an ACE inhibitor, or with concurrent use of aliskiren (Tekturna—Novartis) in patients with diabetes.■Warnings and precautions in the label include fetal toxicity, angio-edema, hypotension, impaired renal function, and hyperkalemia.