Efficacy and Safety of LCZ696, a First-in-Class Angiotensin Receptor Neprilysin Inhibitor, in Asian Patients With Hypertension

Abstract

Natriuretic peptides (NPs) have multiple biological effects, including natriuresis, vasodilatation, inhibition of the renin-angiotensin system (RAS) and the sympathetic nervous system, positive lusitropism, and inhibition of fibrosis. Levels of NPs may be decreased in some hypertensive states. 4 Neprilysin degrades NPs, and inhibition of neprilysin increases NP levels.5 However, the BP reductions observed with neprilysin inhibition alone are modest.6,7 Concomitant neprilysin inhibition and RAS suppression have effects on sodium and volume excretion and BP reductions to a greater extent compared with RAS inhibitors alone. 5,8Omapatrilat, a neprilysin and angiotensin-converting enzyme inhibitor, has been shown to have significantly better systolic Abstract-LCZ696 (Japanese adopted name: sucabitril valsartan sodium hydrate), a first-in-class angiotensin receptor neprilysin inhibitor, concomitantly inhibits neprilysin and blocks angiotensin type 1 receptor. This randomized, doubleblind, placebo-controlled study, the first in Asia for this drug, evaluated the dose-related efficacy and safety of LCZ696 in patients with hypertension using 24-hour ambulatory blood pressure (BP) monitoring. Asian patients aged ≥18 years (n=389) with hypertension were randomized to receive LCZ696 100 mg (n=100), 200 mg (n=101), 400 mg (n=96), or placebo (n=92) for 8 weeks. The primary end point was mean difference across the 3 single-dose pairwise comparisons of LCZ696 versus placebo in clinic diastolic BP after 8-week treatment. Key secondary efficacy variables included changes in clinic systolic BP and pulse pressure and changes in 24-hour, daytime, and nighttime ambulatory BPs and pulse pressure. Safety assessments included recording all adverse events and serious adverse events. A total of 362 patients completed the study. Reductions in clinic systolic BP, diastolic BP (P<0.0001), and pulse pressure (P<0.001) were significantly greater with all doses of LCZ696 than with placebo. There were also significant reductions in 24-hour, daytime, and nighttime ambulatory systolic BP, diastolic BP, and pulse pressure for all doses of LCZ696 compared with placebo (P<0.0001). LCZ696 was well tolerated, and no cases of angioedema were reported. In conclusion, LCZ696 is effective for the treatment of hypertension in Asian population and, in general, is safe and well tolerated. Clinical Trial Information-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01193101.

A prospective, randomized, double‐blind, placebo‐controlled pilot study of sacubitril/valsartan (Entresto) in dogs with cardiomegaly secondary to myxomatous mitral valve disease

“…On the other hand, clinically irrelevant systemic hypotension was seen more frequently in human patients taking S/V than in those taking enalapril, but S/V did not significantly alter SAP over time in the dogs of our study 24. Sacubitril/valsartan and related drugs have been shown to be a safe and effective treatment for systemic hypertension in humans and have been shown to delay the progression of chronic and proteinuric kidney diseases 46, 47, 48, 49, 50. Increased NEP concentrations are present in human patients with end‐stage renal dysfunction, suggesting an additional indication for use of S/V in patients with renal disease 51.…”

The Mechanism of Action of LCZ696

“…There were also significant reductions in 24-hour, daytime and nighttime ambulatory SBP, DBP and pulse pressure for all doses of LCZ696 compared with placebo (p<0.0001). 65 Although the mechanism is uncertain, this effect can be related to its vascular effects and/or to reduced effective circulating volume. In the PARAMOUNT trial the reduction from baseline in mean SBP/DBP was -9.3/-4.9 mmHg with LCZ699 (200 mg twice daily) and -2.9/-2.1 mmHg with valsartan (160 mg twice daily).…”

“…The most common adverse events were headache and pruritus, 64 nasopharyngitis and upper respiratory tract infection. 64,65 Hypotension or syncope occurred in five patients (one each in the placebo, 400 mg LCZ696 and 200 mg AHU377 groups; two in the 200 mg LCZ696 group). 64 Adverse events resulting in treatment discontinuation occurred in 1-2 % of patients on LCZ696, with the highest occurrence in the AHU377 and placebo groups.…”

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

“…67 Another similarly designed trial evaluating the effect of LCZ696 on hypertension studied 389 adult Asian patients with mild to moderate hypertension. 68 The study was also powered to detect a primary end point of a change in mean difference of DBP across 3 single-dose pairwise comparisons of LCZ696 versus placebo. Patients received either varying LCZ696 doses or placebo once daily.…”

“…Furthermore, the investigators failed to include an active comparator arm, making their data more predictable regarding to blood pressureelowering ability, and they did not report data on hard clinical outcomes. 68 …”