B-Type Natriuretic Peptide Testing in the Era of Neprilysin Inhibition: Are the Winds of Change Blowing?

Abstract

> There is nothing permanent except change. > > —Heraclitus of Ephesus The care of patients with heart failure (HF)2 and reduced ejection fraction has traditionally included therapies resulting in inhibition of the renin-angiotensin-aldosterone system; specifically, current clinical practice guidelines articulate use of either angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) as first-line therapy for patients with HF and left ventricular ejection fraction <40% (1). Accordingly, the use of ACEi or ARB therapy for such patients had been viewed as a foundation of HF care until recently. In spring 2014, however, the medical community received startling news of the premature suspension of the Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF). The trial was suspended because of overwhelming evidence that treatment of HF and reduced ejection fraction with the combination ARB (valsartan)/neprilysin inhibitor (sacubitril) resulted in substantial reduction in a wide array of cardiovascular complications compared with the gold standard ACEi comparator, enalapril. The magnitude of benefit from valsartan/sacubitril is hard to overstate: compared with well-dosed ACEi therapy, those treated with neprilysin inhibition in the PARADIGM-HF trial experienced 20% reduction in cardiovascular death or hospitalization for HF ( P = 4.0 × 10−7) and 16% reduction in all-cause mortality ( P < 0.001) (2). Results such as those from PARADIGM-HF are a rarity in HF trials, where development of new classes of therapeutics has been challenging. Neprilysin is a neutral endopeptidase that is responsible for the degradation of several endogenous vasoactive substances, including natriuretic peptides [atrial natriuretic peptide, B-type natriuretic peptide (BNP), and C-type natriuretic peptide], bradykinin, and adrenomedullin. Given that neprilysin degrades vascular peptides, its blockade results in a net vasodilatory effect, potentiated by its combination with an ACEi or ARB; …