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Treatment of heart failure: the path to Entresto, an angiotensin receptor antagonist-neprilysin inhibitor


The PARADIGM-HF ( Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure ) trial has demonstrated that a new angiotensin receptor antagonist - neprilysin inhibitor was superior to an angiotensin-converting enzyme inhibitor in reducing mortality in patients with heart failure and reduced ejection fraction.

The research path culminated in the development of angiotensin receptor antagonist-neprilysin inhibitor.

The first phase, elucidation of the renin-angiotensin-aldosterone system, began with Tigerstedt's discovery of renin, followed by isolation of angiotensin, isolation of angiotensin-converting enzyme, and synthesis of its inhibitors and of angiotensin receptor blockers.

Phase 2 began with de Bold's discovery of atrial natriuretic peptide, followed by isolation of the enzyme that degrades it ( neprilysin ) and its inhibitors.

Phase 3 consists of blocking both the renin-angiotensin-aldosterone and atrial natriuretic peptide-degrading systems simultaneously. A molecular complex, LCZ696 ( Entresto ), developed by scientists at Novartis, combines an angiotensin receptor blocker ( Valsartan ) with a neprilysin inhibitor ( Sacubitril ), is well tolerated, and represents an important step in the management of heart failure and reduced ejection fraction. ( Xagena )

Braunwald E, J Am Coll Cardiol 2015;65:1029-1041

XagenaMedicine_2015



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