The serum concentration of endogenous BNP rises in heart failure, and monitoring this peptide has been shown to have prognostic value. Natriuretic peptides may be administered as recombinant ANP (carperitide), recombinant BNP (nesiritide), or ularitide, the synthetic form of urodilatin (see above). These peptides produce vasodilation and natriuresis and have been investigated for the treatment of congestive heart failure. Nesiritide is approved for the treatment of decompensated acute heart failure (see Chapter 13). Ularitide has demonstrated beneficial effects in animal models of heart failure and in phase 1 and 2 studies in heart failure patients (Figure 17–6). It is in phase 3 development as an infusion treatment for acute decompensated heart failure.
The circulating levels of natriuretic peptides can also be increased by drugs that inhibit their breakdown by neprilysin 7.5 ng/kg/min
FIGURE 17–6 Hemodynamic effects of infusion of three doses of ularitide and placebo in patients with acute decompensated heart failure. (Modified from Anker SD et al: Ularitide for the treatment of acute decompensated heart failure: From preclinical to clinical studies. Eur Heart J 2015;36:715.) (NEP 24.11). The resulting increase in ANP and BNP causes natriuresis and vasodilation, as well as a compensatory increase in renin secretion and plasma ANG II levels. Because of the increase in ANG II, these drugs are not effective as monotherapy in the treatment of heart failure. However, they led to the development of drugs that combine neprilysin inhibition with an ACE inhibitor in order to prevent the increase in plasma ANG II, or with an ARB to block the actions of ANG II.
Drugs that combine neprilysin inhibition with ACE inhibition, known as vasopeptidase inhibitors, include omapatrilat, sampatrilat, and fasidotrilat. Omapatrilat, which received the most attention, lowers blood pressure in animal models of hypertension as well as in hypertensive patients, and improves cardiac function in patients with heart failure. Unfortunately, omapatrilat causes a significant incidence of angioedema and cough, apparently as a result of decreased metabolism of bradykinin, and is not approved for clinical use.
The combination of an ANG II receptor antagonist with a neprilysin inhibitor (ARNI) increases endogenous natriuretic peptide levels while simultaneously blocking the effects of the increase in plasma ANG II. The first-in-class ARNI, LCZ696, is a single molecule composed of the neprilysin inhibitor prodrug sacubitril and the ANG II receptor antagonist valsartan.
In healthy subjects, LCZ696 increased plasma ANP and –8 cGMP levels in combination with increases in plasma renin and ANG II levels. Clinical trials in patients with heart failure demonstrated many beneficial effects of LCZ696, and it was superior to ACE inhibition or angiotensin receptor blockade in reducing the risk of death and hospitalization from heart failure (Figure 17–7). Side effects included hypotension, hyperkalemia, renal impairment, and angioedema. LCZ696, marketed as
Entresto, is approved by the US Food and Drug Administration