Real-world use patterns of angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) among patients with heart failure within a large integrated health system.

BACKGROUND: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that is now preferred in guidelines over angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for patients with heart failure with reduced ejection fraction (HFrEF). However, it has not been broadly adopted in clinical practice. OBJECTIVE: To characterize ARNI use within a large diverse real-world population and assess for any racial disparities. METHODS: We conducted a cross-sectional study within Kaiser Permanente Southern California. Adult patients with HFrEF who received ARNIs, ACEIs, or ARBs between January 1, 2014, and November 30, 2020, were identified. The prevalence of ARNI use among the cohort and patient characteristics by ARNIs vs ACEIs/ARBs use were described. Multivariable regression was performed to estimate odds ratios and 95% CIs of receiving ARNI by race and ethnicity. RESULTS: Among 12,250 patients with HFrEF receiving ACEIs, ARBs, or ARNIs, 556 (4.54%) patients received ARNIs. ARNI use among this cohort increased from 0.02% in 2015 to 7.48% in 2020. Patients receiving ARNIs were younger (aged 62 vs 69 years) and had a lower median ejection fraction (27% vs 32%) compared with patients receiving ACEIs/ARBs. They also had higher use of mineralocorticoid antagonists (24.1% vs 19.8%) and automatic implantable cardioverterdefibrillators (17.4% vs 13.3%). There were no significant differences in rate of ARNI use by race and ethnicity. CONCLUSIONS: Within a large diverse integrated health system in Southern California, the rate of ARNI use has risen over time. Patients given ARNIs were younger with fewer comorbidities, while having worse ejection fraction. Racial minorities were no less likely to receive ARNIs compared with White patients. DISCLOSURES: Dr Huang had stock ownership in Gilead and Pfizer. Dr Liang received support for article processing and medical writing.

Mechanism of vasopeptidase inhibitor-induced plasma extravasation: comparison of omapatrilat and the novel neutral endopeptidase 24.11/angiotensin-converting enzyme inhibitor GW796406.

We describe N-[(2S)-2-(mercaptomethyl)-3-methylbutanoyl]-4-(1H-pyrazol-1-yl)-L-phenylalanine (GW796406), a vasopeptidase inhibitor (VPI) that possessed approximately 3-fold selectivity for neutral endopeptidase 24.11 (NEP) versus angiotensin-converting enzyme (ACE) in in vitro assays using rat and human enzymes. In the same assays, omapatrilat, the most extensively studied VPI, displayed approximately 3-fold selectivity for ACE. The in vivo ACE and NEP inhibition profile and the liability of the compounds to increase plasma extravasation were compared at two (low and high) therapeutically equivalent intravenous doses in the rat. At the low dose, both agents inhibited ACE activity by approximately 85%. Consistent with their in vitro ACE/NEP selectivity, omapatrilat produced 49% inhibition, whereas GW796406 produced >95% inhibition of NEP. Neither compound increased plasma extravasation. When the low dose was administered to rats pretreated with the NEP inhibitor ecadotril to normalize NEP background to <5% of control, only omapatrilat significantly increased plasma extravasation. At the high dose, omapatrilat and GW796406 produced profound, nonselective inhibition of ACE (>90%) and NEP (>95%), and they significantly increased plasma extravasation. The activity of the agents as inhibitors of dipeptidylpeptidase IV (DPP IV) and aminopeptidase P (APP) was also investigated. Neither compound inhibited DPP IV. Interestingly, omapatrilat, but not GW796406, was a relatively potent inhibitor of APP (IC50 = 260 nM). We investigated whether APP inhibition increased the plasma extravasation liability of GW796406. The low dose of GW796406 administered with apstatin, an APP inhibitor, did not increase plasma extravasation. This finding inferred that APP inhibition is not involved in plasma extravasation in the rat and that APP inhibition does not explain the increased plasma extravasation produced by omapatrilat in NEP-inhibited rats.

Metabolism of endothelin-1 and big endothelin-1 by recombinant neutral endopeptidase EC.3.4.24.11.

1. Inhibitors of neutral endopeptidase EC.3.4.24.11 (NEP) have been shown to attenuate the hypertensive effect of big-endothelin-1 (BET-1) in rats. To determine whether NEP converts BET-1 to endothelin-1 (ET-1), the effect of a recombinant NEP (rNEP) on BET-1 and on ET-1 was assessed in vitro. 2. Incubation of [125I]-ET-1 with 1 microgram ml-1 of rNEP resulted in degradation of the peptide within minutes. Increase in the amount of rNEP to 10 micrograms ml-1 led to total cleavage of [125I]-ET-1 within seconds. 3. Phosphoramidon (10 microM) or SQ-28,603 (100 microM) totally suppressed the degradation of [125I]-ET-1 by rNEP. 4. The degradation of [125I]-BET-1 by either 1 or 10 micrograms ml-1 of rNEP was much slower than that of [125I]-ET-1. Again, both phosphoramidon and SQ 28,603 protected the peptide from degradation. 5. Intact [125I]-ET-1 was not observed when [125I]-BET-1 was incubated with rNEP. 6. These data show that neutral endopeptidase EC.3.4.24.11 is not an endothelin converting enzyme.

Effects of UK 69 578: a novel atriopeptidase inhibitor.

UK 69 578 is a competitive inhibitor of endopeptidase 24.11 (the enzyme that degrades atrial natriuretic factor) in vitro. In vivo, UK 69 578 has renal and cardiovascular effects similar to low-dose atrial natriuretic factor infusion, and may be a useful agent in hypertension and heart failure.