Angiotensin 2 Type 1 Receptor Blockade with Neprilysin Inhibition for Chronic Heart Failure: A New Paradigm?

Abstract

A new treatment for heart failure (HF) combining angiotensin 2 type 1 receptor blockade with inhibition of the widespread membrane-bound enzyme, neprilysin (NEP), seems likely to take treatment of chronic heart failure (CHF) a major step forward. Neurohormonal pathways are central to the evolution and progression of HF irrespective of the exact initial triggering cardiac injury or overload, and our current evidence-based treatments for this condition depend upon antagonism of the renin-angiotensin-aldosterone (RAAS) and sympathetic nervous (SNS) systems through prescription of angiotensin converting enzyme inhibitors (ACEIs), angiotensin 2 type 1 receptor blockers (ARBs), mineralocorticoid antagonists (MRAs) and blockers of beta-adrenoceptors (beta blockers). Properly deployed, these therapies reduce 1-year mortality to less than half than that suffered by patients with HF in the pre-1980s era. 1,2 However, despite this clear impact upon the outcome of this deadly syndrome, 5-year mortality in CHF remains greater than 50%. This poor outlook plus the continuing high prevalence of HF mandates an ongoing search for more effective treatments. 3 The therapeutic advances outlined above were established by the turn of the 21st century and until now, trials of new neurohormonal interventions over the last 15 years have been largely disappointing. Examples include therapeutic trials, all based on impeccable rationales and supported by encouraging preclinical data and positive phase 1 and 2 clinical data of endothelin 1 antagonists, arginine vasopressin blockers and direct renin inhibitors. 4-6 When subjected to the test of full phase 3 randomised controlled clinical trials, none of these approaches has proven to reduce cardiovascular or all-cause mortality in HF, although some secondary end-points such as readmission with recurrent, acute decompensated HF may show a benefi cial trend and useful niche applications have developed such as the use of endothelin antagonists in pulmonary hypertension and of AVP blockers in accelerating correction of hyponatraemia complicating HF. In the 1990s, an effort was made to add enhancement of benefi cial endogenous adaptive responses