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New treatments for hypertension
Published in H. Gavras, The Year in Hypertension 2004, 2004
CARMINE SAVOIA, ERNESTO L SCHIFFRIN
Hypertension is a major risk factor for cardiovascular disease, including ischaemic cardiomyopathy and congestive heart failure. Optimal treatment of hypertension must be coupled to an understanding of haemodynamic, humoral and renal effects of pharmacological agents. Many findings from studies published in the last year show that treatment with BP-lowering regimens based on ACE/NEP inhibitors, which exert favourable effects on the RAAS as well as on natriuretic peptides and other vasodilator systems, may result in greater clinical benefit than conventional therapy. Omapatrilat improved morbidity and mortality in patients with ischaemic heart disease and congestive heart failure. In the latter, vasopeptidase inhibition had a favourable effect on neurohormonal parameters that are known to be predictive of outcome. Thus the benefits achieved with omapatrilat, particularly in high-risk patients, could outweigh the disadvantage of the high incidence of angio-oedema. However, further studies are necessary to clarify the mechanisms whereby survival is improved, as well as those involved in the side effects of this new class of drugs. Indeed, beyond the increase of vasodilators such as bradykinin that could be involved in the pathogenesis of angio-oedema, addition of NEP to ACE inhibition reduces angiotensin 1-7 levels and may modulate endothelin levels. These additional effects of combined ACE/NEP inhibition could counteract benefits of ACE inhibition in the long run that may be mediated by increased angiotensin 1-7.
Advanced heart failure with reduced ejection fraction
Published in Baylor University Medical Center Proceedings, 2020
Albert Hicks, Jorge F. Velazco, Salman Gohar, Ahmed Seliem, Shelley A. Hall, Jeffrey B. Michel
Endogenous peptides such as brain natriuretic peptide (BNP) have vasodilatory and preload-reducing properties and are released in response to elevated left ventricular pressures, making them attractive targets for heart failure therapy. Neprilysin is a naturally occurring enzyme that degrades BNP. In 2002 omapatrilat, a combination of an ACEI and a neprilysin inhibitor, was compared to enalapril in the OVERTURE trial for treatment of heart failure.11 The primary endpoint was a composite of death and heart failure hospitalization. Omapatrilat was found to be noninferior to enalapril but demonstrated worse outcomes in black patients and higher rates of angioedema compared to the enalapril group. In 2005 nesiritide, a recombinant form of human BNP, in a meta-analysis demonstrated an increased risk of mortality in acutely decompensated heart failure patients compared to the control group.12 Despite the negative results of these endogenous peptide trials, further attempts to utilize this treatment pathway continued. To reduce the risk of angioedema, a neprilysin inhibitor in combination with an angiotensin receptor blocker (ARB) was studied.
New pharmacotherapy for heart failure with reduced ejection fraction
Published in Expert Review of Cardiovascular Therapy, 2020
Sara Sotirakos, Peter Wheen, James Spiers, Richard Armstrong
A study conducted in dogs with experimental HF showed some promise for NEP-I on heart failure [24]. NEP-I is capable of raising plasma BNP levels in humans with HF; however, in humans with HFrEF given ecadotril, a NEP-I, in addition to their traditional therapy with ACE-I showed little to no benefit [25,26]. Additionally, incidence of drug-induced aplastic anemia in the ecadotril study was particularly high, a risk that is normally low with the use of ACE-I [25]. Furthermore, the key reason why ACE-I combined with NEP-I is not recommended is due to the increased risk of angioedema, as observed in the OVERTURE trial [27]. OVERTURE assessed the efficacy of omapatrilat, an ACE-I and NEP-I combination therapy which showed to be an effective antihypertensive agent, but was not more effective than ACE-I alone at decreasing hospitalization and mortality, in addition to having a 0.9% higher risk of adverse event compared to ACE-I [27]. The changes in blood pressure from omapatrilat after the up-titration period were not significantly different from enalapril, unlike sacubitril/valsartan which found a significantly lower systolic blood pressure compared to the enalapril group [12,27]. Overall NEP-I has not shown promise as an effective therapy in the past and has not been studied to a great extent as a monotherapy due to limited success seen.
Will we ever use angiotensin receptor neprilysin inhibition (ARNi) for the treatment of hypertension?
Published in Blood Pressure, 2019
Sverre E. Kjeldsen, Krzysztof Narkiewicz, Michel Burnier, Suzanne Oparil
Omapatrilat, a dual ACE-NEP inhibitor (a class of drugs termed vasopeptidase inhibitors) was the first agent to be evaluated in clinical trials of hypertension and heart failure treatment [2]. Omapatrilat lowered BP more than stand-alone ACE inhibitor treatment in hypertension. In the OCTAVE study, the efficacy of omapatrilat versus enalapril to reduce clinical events was evaluated in approximately 25,000 untreated or uncontrolled hypertensives. Participants randomized to omapatrilat exhibited improved systolic BP control compared to enalapril. However, further development of omapatrilat was discontinued because of an increased risk of angioedema in OCTAVE, possibly explained by excessive accumulation of bradykinin which normally would be hydrolysed by NEP, ACE and also (potentially) aminopeptidase-P and dipeptidyl peptidase-4. Substance P, which is also hydrolyzed by these enzymes, has also been coupled with angioedema.