Entresto

Entresto. It is a combination medication used for the treatment of heart failure with reduced ejection fraction. The drug combines sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker. Its approval and use are based on landmark clinical trials demonstrating significant benefits in reducing cardiovascular death and hospitalization compared to previous standard therapies.

Medical uses

Entresto is indicated to reduce the risk of cardiovascular death and heart failure hospitalization in adult patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is typically used as a replacement for an angiotensin-converting enzyme inhibitor or another angiotensin II receptor blocker in patients who meet specific clinical criteria. The pivotal PARADIGM-HF trial established its superiority over enalapril in this patient population. Guidelines from the American College of Cardiology and the American Heart Association recommend it as a foundational therapy for eligible patients.

Adverse effects

Common adverse effects include hypotension, hyperkalemia, cough, and dizziness. A serious potential risk is angioedema, which occurred more frequently in patients of African descent during clinical trials. Due to its mechanism of action, it is contraindicated in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy. Concomitant use with aliskiren in patients with diabetes mellitus is also contraindicated. Monitoring of serum potassium, renal function, and blood pressure is recommended during treatment.

Pharmacology

The pharmacological action is a dual combination of sacubitril, which inhibits the enzyme neprilysin, and valsartan, which blocks the angiotensin II type 1 receptor. Inhibition of neprilysin increases levels of beneficial peptides such as natriuretic peptides, bradykinin, and adrenomedullin, promoting vasodilation, natriuresis, and reduced fibrosis. Valsartan inhibits the deleterious effects of the renin–angiotensin–aldosterone system, including vasoconstriction and aldosterone secretion. This dual mechanism provides complementary neurohormonal modulation in heart failure.

History

The development of Entresto followed research into augmenting the protective natriuretic peptide system while blocking the renin–angiotensin–aldosterone system. The key Phase III trial, PARADIGM-HF, was stopped early in 2014 due to overwhelming efficacy. Based on these results, the U.S. Food and Drug Administration granted approval in July 2015. The European Medicines Agency provided marketing authorization in November 2015. Its development and success marked a significant shift in the pharmacotherapy of heart failure, leading to updates in major international guidelines.

Society and culture

The high cost of Entresto has been a subject of discussion within healthcare systems, including debates over formulary coverage by entities like the National Health Service in the United Kingdom and insurers in the United States. It has been featured in medical education programs from institutions like the Cleveland Clinic and the Mayo Clinic. The drug's brand name is recognized in popular media, sometimes referenced in discussions about pharmaceutical innovation and healthcare economics.