Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial

Rouleau, Jean L.; Pfeffer, Marc A.; Stewart, Duncan J.; Isaac, Debra; Sestier, F; Kerut, Edmund Kenneth; Porter, Charles B.; Proulx, Guy; Qian, Chunlin; Block, A. Jay

doi:10.1016/s0140-6736(00)02602-7

Cited by 370 publications

(220 citation statements)

References 17 publications

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“…Clinical hypertension trials have shown broadly Next generation multifunctional angiotensin receptor blockers TW Kurtz and U Klein superior antihypertensive efficacy of omapatrilat relative to enalapril, 47 and good efficacy was also shown in heart failure. 48,49 However, the 3-fold higher incidence of angioedema observed for omapatrilat relative to enalapril, and the incidence of life-threatening angioedema in the late-stage clinical studies led to the discontinuation of omapatrilat in 2002 because of the unfavorable risk-benefit profile. 50 As both ACE and neprilysin are key enzymes in the metabolism of bradykinin, it is hypothesized that dual inhibition of ACE and neprilysin by omapatrilat and other vasopeptidase inhibitors results in a significantly greater elevation of bradykinin levels relative to ACE inhibition alone, which in a subset of patients can lead to excessive vascular leakage, fluid extravasation and angioedema, explaining the unfavorable tolerability issues observed for omapatrilat.…”

Section: Next Generation Arbs That Inhibit Neprilysin Activitymentioning

confidence: 99%

Next generation multifunctional angiotensin receptor blockers

Kurtz

Klein

2009

Hypertens Res

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Angiotensin receptor blockers (ARBs) are well-tolerated drugs that are known to be useful for inhibiting activity of the reninangiotensin (RAS) system, treating hypertension and reducing the risk for cardiovascular disease. However, inhibition of the RAS does not control all pathophysiological mechanisms of hypertension or cardiovascular risk and many patients continue to suffer from cardiovascular events and metabolic disturbances despite being treated with an ARB, an angiotensin-converting enzyme inhibitor or both, in addition to other standard therapies for cardiovascular disease. Recently, it has become apparent that bifunctional molecules can be designed that do more than just block AT 1 receptors and that can target additional mechanisms of hypertension, cardiovascular disease and diabetes besides just increased activity of the renin-angiotensin system. Specifically, next generation ARBs are becoming available that are intended to not only antagonize AT 1 receptors, but also block endothelin receptors, function as nitric oxide donors, inhibit neprilysin activity and increase natriuretic peptide levels, or stimulate the peroxisome proliferator-activated receptor c (PPARc). In this review, we: (1) discuss the potential importance of multifunctional ARBs that can reduce cardiovascular and metabolic risk through multiple mechanisms that go beyond just inhibition of the renin-angiotensin system and (2) describe specific examples of next generation ARBs in development that are intended to do more than simply block AT 1 receptors.

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Section: Next Generation Arbs That Inhibit Neprilysin Activitymentioning

confidence: 99%

Next generation multifunctional angiotensin receptor blockers

Kurtz

Klein

2009

Hypertens Res

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“…Vasopeptidase inhibition could have an advantage over selective ACE inhibition for the treatment of patients with congestive heart failure. However, the beneficial effect of omapatrilat on cardiovascular morbidity compared with lisinopril in patients with congestive heart failure suggested by the IMPRESS study (4) has not been confirmed by the results of the OVERTURE study (12), in which no significant difference in terms of cardiovascular morbidity or mortality between 40 mg of omapatrilat daily and 10 mg of enalapril twice daily was reported.…”

mentioning

confidence: 94%

“…This drug is designed to treat hypertension (2) and congestive heart failure (3,4). In animal models, NEP inhibition may have additional beneficial effects on target organs damage beyond ACE inhibition (5)(6)(7)(8).…”

mentioning

confidence: 99%

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Azizi

Lamarre-Cliché²,

Labatide-Alanore³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodiumdepleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.Omapatrilat is a vasopeptidase inhibitor that has a similar nanomolar inhibitory constant for both neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) in vitro (1). This drug is designed to treat hypertension (2) and congestive heart failure (3,4). In animal models, NEP inhibition may have additional beneficial effects on target organs damage beyond ACE inhibition (5-8). Omapatrilat was shown to have a greater antihypertensive efficacy in hypertensive patients than ACE inhibitors, such as lisinopril (9,10) or enalapril (11). Vasopeptidase inhibition could have an advantage over selective ACE inhibition for the treatment of patients with congestive heart failure. However, the beneficial effect of omapatrilat on cardiovascular morbidity compared with lisinopril in patients with congestive heart failure suggested by the IMPRESS study (4) has not been confirmed by the results of the OVERTURE study (12), in which no significant difference in terms of cardiovascular morbidity or mortality between 40 mg of omapatrilat daily and 10 mg of enalapril twice daily was reported.We have previously reported the BP and hormonal effects of a single oral dose of 10 mg of omapatrilat in sodium-depleted normotensive subjects (13). Omapatrilat (10 mg) had a shorter BP-lowering effect than a single oral dose of 20 mg of fosinopril, despite the fact that, at the dose used, both drugs appeared to have a similar potency in inhibiting ACE, whereas omapatrilat, by inhibiting NEP, increased urinary atrial natriuretic peptide (ANP) and blunted the decrease in plasma ANP due to ACE inhibition (13).The doses of omapatrilat subsequently used in the clinical development program were high...

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“…54 Initial trials of omapatrilat in HF patients reported no major adverse side effects, 55e57 improvement in reported functional status, 55 improved left ventricular ejection fraction (LVEF), natriuresis, and diuresis, 55 and even a nonsignificant trend favoring omapatrilat in rates of death and HF-related admissions compared with lisinopril. 57 Again, when compared with lisinopril, similar effects were found regarding levels of the substrates Ang II and endothelin-1. 57 The OVERTURE trial consisted of 5,770 New York Heart Association (NYHA) class IIeIV HF patients randomized to omapatrilat or enalapril for 14.5 months (Table 1).…”

Section: Omapatrilatmentioning

confidence: 58%

“…57 Again, when compared with lisinopril, similar effects were found regarding levels of the substrates Ang II and endothelin-1. 57 The OVERTURE trial consisted of 5,770 New York Heart Association (NYHA) class IIeIV HF patients randomized to omapatrilat or enalapril for 14.5 months (Table 1). 58 The trial was designed to detect a primary end point of death or hospitalization for HF requiring intravenous treatment and found omapatrilat to be noninferior, but a post hoc analysis that used a broader definition for HF-related hospitalizations found a statistically significant decrease in the end point among patients taking omapatrilat.…”

Section: Omapatrilatmentioning

confidence: 58%

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

Buggey

Mentz

DeVore

et al. 2015

Journal of Cardiac Failure

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Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future. (J Cardiac Fail 2015;21:741e750)

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Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial

Cited by 370 publications

References 17 publications

Next generation multifunctional angiotensin receptor blockers

Next generation multifunctional angiotensin receptor blockers

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

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