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Hypertension continues to be the single most important cause of morbidity and mortality worldwide. The most recent United States National Health and Nutrition Examination Survey (NHANES) data suggests that blood pressure (BP) control continues to improve in all demographic groups, with 50% of all persons with hypertension and more than 65% of persons also being treated for hypertension currently controlled to the minimum goal of <140/90 mm Hg. Despite these successes, the pathogenesis of hypertension remains extremely heterogeneous and, since most patients require ≥2 antihypertensive agents to control BP, the hypertension community continues to look for new and innovative pathophysiologic approaches for BP control.

Vasopeptidase inhibitors simultaneously block 2 key enzymes involved in the regulation of cardiac function: (1) neprilysin (neutral endopeptidase [NEP]), which increases concentrations of natriuretic peptides and also inhibits the renin-angiotensin-aldosterone and sympathetic nervous system, and (2) angiotensin-converting enzyme (ACE). The most widely studied vasopeptidase inhibitor, omapatrilat, has been found to be a potent BP-lowering agent; however, since its use was associated with an increased risk for angioedema, believed to occur as a result of bradykinin upregulation, it was never approved for clinical use. Because angiotensin receptor blockers (ARBs) are believed to have less effect on bradykinin metabolism, agents that combine NEP inhibition with agents that block the angiotensin II receptor (ARBs) might be associated with the cardiac benefits of vasopeptidase inhibition without the increased risk for angioedema. Developed using a radiographic crystallographic technique, LCZ696 is a first-in-class dual-acting angiotensin II receptor and NEP inhibitor (ARNI) that combines the ARB valsartan with AHU377, its NEP inhibitor moiety. The present industry sponsored proof-of-concept trial was designed to establish whether LCZ696 leads to greater reduction of BP compared with the ARB valsartan.

Recruited from 134 sites in 18 countries (including the United States) between September 2007 and March 2008, eligible patients had to be aged between 18 and 75 years and have uncomplicated essential hypertension (mean sitting diastolic BP 90–109 mm Hg after antihypertensive drug washout or 95–109 mm Hg if untreated). Exclusion criteria included severe hypertension (mean sitting systolic BP ≥180 mm Hg), history of angioedema or allergy to an ARB or NEP inhibitor, type 1 or 2 diabetes, secondary hypertension, a serious structural or functional cardiac disorder, significant hepatic or renal disease, clinically important anemia, or abnormal serum sodium or potassium concentrations. In addition, use of certain medications were prohibited, including antihypertensives other than those specified in the protocol, antiarrhythmics, tricyclic antidepressants and monoamine oxidase inhibitors, systemic corticosteroids, nonsteroidal anti-inflammatory drugs, chronic sympathomimetic use, bile acid resins, α-blockers, and phosphodiesterase inhibitors taken within 48 hours of scheduled visits.

All 1328 participants underwent a 4-week introductory period, including a 2-week washout period and a subsequent 2-week placebo run-in period in which only patients were masked to treatment. Patients were then computer assigned in equal numbers in a double-blind fashion to 1 of 8 treatment groups: 100 mg LCZ696 (n=156); 200 mg LCZ696 (n=169); 400 mg LCZ696 (1 week on 200 mg then 7 weeks on 400 mg) (n=172); 80 mg valsartan (n=163); 160 mg valsartan (n=166); 320 mg valsartan (1 week on 160 mg followed by 7 weeks on 320 mg) (n=164); 200 mg AHU377 (n=165); or placebo (n=173). After 8 weeks of treatment, patients were again randomized double-blind in a 1:1 ratio to continue receiving their assigned treatment or switch to placebo for 1 additional week (withdrawal period). The primary outcome was the lowering of mean sitting diastolic BP during the 8-week treatment period (end point at week 12), which was calculated as the mean of the difference in BP between the 3 pairwise comparisons of LCZ696 and valsartan doses (100 mg LCZ696 vs 80 mg valsartan, 200 mg LCZ696 vs 160 mg valsartan, and 400 mg LCZ696 vs 320 mg valsartan). Secondary outcomes were lowering of mean sitting systolic BP across the 3 pairwise comparisons (calculated as for the primary outcome); single-dose pairwise comparisons for lowering of mean sitting diastolic and systolic BP during the 8-week treatment period; change in mean sitting diastolic and systolic BP during week 13 (withdrawal period); and single-dose pairwise comparisons of change in sitting pulse pressure during the 8-week treatment period to analyze dose response. Additional secondary outcomes included the percentage of patients in every group that had a successful response after 8 weeks of treatment for mean sitting diastolic BP (<90 mm Hg or a reduction of ≥10 mm Hg from baseline) and mean sitting systolic BP (<140 mm Hg or a reduction by ≥20 mm Hg from baseline); single-dose pairwise comparisons of control rates after 8 weeks of treatment in mean sitting diastolic BP (<90 mm Hg); mean sitting systolic BP (<140 mm Hg); and overall BP (<140/90 mm Hg). For each of the single pairwise comparisons, changes in 24-hour ambulatory BP for the 8-week treatment period were assessed in 24-hour, daytime (>600 to ≤2200 hours), and night-time (>2200 to ≤600 hour) mean ambulatory diastolic and systolic BP and pulse pressure (difference between mean ambulatory systolic and diastolic BP). Safety measurements were performed throughout the 13-week study for BP measurement, blood and biochemical tests (including creatinine and electrolyte determinations), electrocardiograms, physical examinations, and documentation of adverse events during the 8-week treatment period and the 1-week withdrawal period. Patients were withdrawn from the study at any study visit if they had a mean sitting diastolic BP ≥110 mm Hg or a mean sitting systolic BP ≥180 mm Hg during the 13 weeks of the study. Analysis was by intention to treat and included all randomized patients who had baseline data and at least one efficacy measurement taken during the 8-week core treatment period. While the study sponsor participated in the study design, data collection, data analysis, and interpretation and writing of the report, the authors had full access to the study data and took full responsibility for its content.

Of the 1328 patients randomized to treatment, 1215 (91%) completed the 8-week treatment period. Most were white (87%) and male (57%), with only 8% black. The mean age was 53 years, with 86% younger than 65 years. Baseline mean sitting BP was 156/100 mm Hg. LCZ696 provided significant reductions in sitting diastolic and systolic BP over valsartan (least-squares mean reduction of the mean change with the 3 LCZ696 doses compared with the 3 valsartan doses was 2.17 mm Hg for mean sitting diastolic BP and 4.20 mm Hg for mean sitting systolic BP). There were significant reductions with 200-mg LCZ696 compared with 160-mg valsartan and 400-mg LCZ696 vs 320-mg valsartan. Pairwise comparisons also showed superior reductions with 200-mg AHU377 than with placebo. BP began to be reduced at the end of the first week in all active treatment groups, and most of the antihypertensive effect from LCZ696 had occurred by the fourth week of treatment.

There was a nonlinear response during 8 weeks of treatment for the 3 doses of LCZ696 compared with placebo. Response rates were significantly higher in patients taking 200-mg LCZ696 than 160-mg valsartan and taking 400-mg PCZ696 compared with 320-mg valsartan. Response rates on AHU 377 were significantly lower than both 200 mg and 400 mg of LCZ696. The highest control rates were seen with 400-mg LCZ696 and were numerically greater but not statistically significant compared with those seen with 320-mg valsartan. The second highest control rates were recorded in patients taking 200-mg LCZ696 and were significantly greater than those taking 160-mg valsartan. The clinical characteristics and demographic indicators of the 427 patients who underwent 24-hour ambulatory BP monitoring (ABPM) were similar to those of the overall study population, with BP maintained thoughout the 24-hour period. For the 8-week treatment period, differences in ABPM for diastolic BP were small and not significant between LCZ696 and corresponding doses of valsartan. In contrast, systolic BP differences in ABPM were recorded for 200-mg LCZ696 and 160-mg valsartan and 400-mg LCZ696 and 320-mg valsartan, which were consistent with assessments of sitting systolic BP. The same differences were seen in the comparative groups with nighttime mean systolic ABPM values. No rebound effect was seen in any of the treatment groups during the 1-week withdrawal period.

Neurohormonal and biomarker assessments were also evaluated during the 8-week treatment period. Plasma atrial natriuretic peptide concentrations increased during treatment with all 3 doses of LCZ696 compared with placebo and with AHU377. Consistent with its ARB effect, plasma renin concentration significantly increased from baseline in all of the LCZ696 and valsartan groups compared with placebo, but the change was not significant in the AHU377 group compared with placebo. Plasma aldosterone concentration did not differ between any treatment groups nor did high-sensitivity C-reactive protein. The neurohormonal changes that did occur were poorly predictive of the BP changes that occurred. The mean urinary albumin-to-creatinine ratio was normal at baseline and significantly decreased in all LCZ696 and valsartan groups during treatment compared with placebo, with no difference between the active treatment groups. There was no reduction in the albumin-to-creatinine ratio noted in the AHU377 group compared with that of placebo. Overall, adverse events were infrequent, mild, and not dose-dependent. No serious adverse events were felt to be secondary to study drug. Discontinuation rates occurred in 1% of all patients treated, with the highest occurrence seen in the AHU377 and placebo groups. There were no cases of angioedema and no deaths recorded. Changes in hematology and chemistry values were small and not felt to be secondary to treatment. No changes in body weight were noted, and changes in orthostatic BP were not consistent across treatment groups, as the lowest frequency occurred in the 400-mg LCZ696 group.

The investigators conclude that compared with valsartan, dual inhibition of the angiotensin II receptor and neprilysin with LCZ696 provides complementary and additive reductions in BP.— Ruilope LM, Dukat A, Bohm M, et al. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomized, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375:1255–1266.

Comment

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  3. Disclosures:

Vasopeptidase inhibitors are novel investigational agents that simultaneously block both the renin-angiotensin system (RAS) and the degradation of natriuretic peptides (NEP inhibition). When pure NEP inhibitors have been investigated, they have not demonstrated a significant BP effect, but, nonetheless, through other mechanisms, NEP inhibition is felt to be cardioprotective. The first extensively studied dual vasopeptidase inhibitor was omapatrilat, which combined an ACE inhibitor with an NEP inhibitor. In the Omapatrilat Cardiovascular Treatment Vs Enalapril (OCTAVE) trial, more than 25,000 patients received either omapatrilat 80 mg or enalapril 40 mg. In OCTAVE, patients assigned to omapatrilat achieved a greater reduction in systolic BP (mean difference, 3.6 mm Hg), an effect that was especially seen in what were considered to be difficult-to-treat populations. Unfortunately, its use was also associated with an increased risk of angioneurotic edema (2.17% ompatrilat vs 0.68% enalapril), especially in blacks. The increased risk of angioedema is felt to occur due to increased inhibition of the breakdown of bradykinin, and largely because of this adverse effect, omapatrilat was never approved for use in the United States. In an effort to minimize the angioedema seen with omapatrilat and still provide the benefits of dual vasopeptidase inhibition, there has been enthusiasm to combine NEP inhibitors with ARBs rather than ACE inhibitors. LCZ696 is a first-in-class vasopeptidase inhibitor that combines the ARB valsartan with AHU377, its NEP inhibitor moiety.

In the current study referenced above, dual inhibition of the angiotensin II receptor and the NEP neprilysin with LCZ696 demonstrated complementary and modestly greater effects on BP reduction than use of the ARB valsartan alone, and it was safe, effective, and well tolerated with no episodes of angioedema and no deaths seen in the 1215 patients who completed the 8-week treatment period. In addition, the neprilsyin inhibitor, AHU377, when given alone, had a minimal effect on BP reduction, suggesting that the ARB component of the combination drug is the driving force behind the BP reduction seen with this vasopeptidase inhibitor. Of interest, the neurohormone concentrations did not predict BP response to LCZ696. Because only 8% of the current study population were black, a group more prone to angioedema with both ACE inhibitors and omapatrilat, the safety of LCZ696 and related compounds needs to be confirmed in future studies that include a larger black population. In addition, in order to confirm these initial results, further clinical trials need to be conducted in a variety of patients with difficult-to-treat hypertension and related cardiovascular disorders, including hypertensive patients with diabetes and chronic kidney disease and the elderly, none of whom were well-represented in the present study.

Moreover, further studies need to be conducted that examine the overall cardiovascular effect of vasopeptidase inhibitors such as LCZ696. The additional BP reduction seen with this agent was modest, and the hypothesis is that the addition of NEP inhibition to blockade of the RAS will lead to cardiovascular benefits over and above the effect on BP. However, this hypothesis has certainly not been proven, and these agents will need to be studied in a wide range of cardiovascular disorders and with end points other than just BP. Based on the unique mechanism of action of vasopeptidase inhibitors, the most promising areas of research include conditions where excess vascoconstriction, volume overload, and neurohormonal activation play a key pathophysiologic role, perhaps including resistant hypertension and idiopathic pulmonary hypertension. As several novel agents with unique mechanisms of action developed for the control of hypertension have recently been withdrawn from further clinical development, the hypertension community anxiously awaits future studies involving this and potentially other dual-acting ARB-NEP (ARNI) inhibitors.

Disclosures:

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  3. Disclosures:

Both Dr Bloch and Dr Basile report receiving honoraria, consulting fees, and research support from Novartis Pharmaceuticals, which is developing the investigational agent LCZ696.