Role of Neprilysin Inhibitor Combinations in Hypertension
Role of Neprilysin Inhibitor Combinations in Hypertension
Relevant articles were identified by searching MEDLINE using the following keywords and Medical Subject Headings (MeSH) terms: neprilysin inhibitor, LCZ696, angiotensin-receptor neprilysin inhibitor, hypertension, and/or heart failure. We screened the title and abstract of possibly relevant citations and retrieved all randomized control trials published until 2015, that studied or reported the effects of neprilysin inhibitors on BP.
Ruilope et al. reported the first proof-of-concept trial with LCZ696 that investigated the antihypertensive effects of LCZ696 when compared with the angiotensin-receptor blocker—valsartan. In the multi-centre, randomized, double-blinded, placebo-controlled, active-comparator study involving 1328 patients of 18–75 years of age with mild-to-moderate essential hypertension were randomly assigned to 8 weeks of double-blind treatment in one of eight groups of daily dose: 100, 200, and 400 mg LCZ696; 80, 160, and 320 mg valsartan; 200 mg AHU377; or placebo. The primary outcome of the trial was the mean sitting diastolic BP difference between the three single-dose 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).
The mean age of the trial population was 53 (±10.2) years, with 57% male and about 86% of patients younger than 65 years. The average duration of hypertension was 6.8 (±7.2) years. LCZ696 provided significantly superior reductions from baseline in mean sitting diastolic and systolic BP than valsartan at 8 weeks. When compared with 160 mg valsartan, 200 mg LCZ696 showed a higher reduction in mean sitting systolic BP (−11 vs. −5.69 mmHg, P = 0.0006) and mean sitting diastolic BP (−6.14 vs. −3.17 mmHg, P = 0.0023). Similarly, compared with 320 mg valsartan, 400 mg LCZ696 showed a significantly higher reduction in mean sitting systolic BP (−12.5 vs. −6.44 mmHg, P < 0.0001) and mean sitting diastolic BP (−6.85 vs. −4.15 mmHg, P = 0.0055). The reduction in mean sitting diastolic and systolic BP for 100 mg LCZ696 vs. 80 mg valsartan did not reach statistical significance. In a subgroup of 427 patients who underwent ambulatory BP monitoring, significant differences in 24-h mean ambulatory systolic BP were recorded for 200 mg LCZ696 vs. 160 mg valsartan (−3.23 mmHg) and 400 mg LCZ696 vs. 320 mg valsartan (−5.14 mmHg) for the 8-week treatment period (P < 0.05). However, differences in 24-h mean ambulatory diastolic BP between LCZ696 and corresponding valsartan doses were small and not significant.
Recently, Kario et al. published results of second hypertension trial of LCZ696 which was a multi-centre, randomized, double-blinded, placebo-controlled of 389 Asian patients aged ≥18 years with mild-to-moderate essential hypertension. After a 4-week run-in period, patients were randomized to 100, 200, or 400 mg LCZ696 or placebo for an 8-week double-blind period. The primary endpoint was mean difference across the three single-dose pairwise comparisons of LCZ696 vs. placebo (100, 200, and 400 mg LCZ696 vs. placebo) in clinic diastolic BP after the 8-week treatment period. When compared with placebo, the mean differences in change from baseline in clinic diastolic BP was −7.84, −7.29, and −8.76 mmHg for LCZ696 100, 200, and 400 mg, respectively. Likewise, compared with placebo, the mean differences in change from baseline in clinic systolic BP were −11.86, −12.57, and −15.38 mmHg for LCZ696 100, 200, and 400 mg, respectively. All doses of LCZ696 were associated with significant reductions in 24-h, daytime, and nighttime ambulatory systolic, diastolic, and pulse pressures (P < 0.0001).
Compared with Caucasian patients, BP reduction by LCZ696 tended to be greater in Asian patients with hypertension indicating that this drug may be particularly suitable in this population. Asian hypertensive patients are characterized by higher salt sensitivity and higher salt intake, resulting in suppression of renin–angiotensin system. These characteristics may result in higher prevalence of stroke, which is more directly associated with systolic BP. Thus, the increase in NPs by neprilysin inhibition in combination with ARB exerts an incremental effect on BP compared with ARB-monotherapy in Asian hypertensive patients (e.g. salt sensitive or elderly). In addition, LCZ696 may also be an effective drug in resistant hypertensive patients. Of note, compared with the same dose of valsartan, LCZ696 decreased systolic BP more than diastolic BP, resulting in a reduction of pulse pressure (Figure 2). Although the precise mechanism remains to be elucidated, the direct effect of NPs and ARB on the vascular properties and/or reduced circulating volume may play a part in the preferential effect of LCZ696 on systolic BP.
(Enlarge Image)
Figure 2.
Change in mean (A) systolic and (B) diastolic blood pressure from baseline in three randomized controlled trials. Ruilope et al. compared LCZ696 400 mg vs. valsartan 320 mg over 8 weeks. The PARAMOUNT trial compared LCZ696 200 mg twice daily vs. valsartan 160 mg twice daily over 12 weeks. Kario et al. compared LCZ696 400 mg vs. placebo over 8 weeks.
Clinical Trials of Angiotensin II-Receptor Neprilysin Inhibitor in Hypertension
Relevant articles were identified by searching MEDLINE using the following keywords and Medical Subject Headings (MeSH) terms: neprilysin inhibitor, LCZ696, angiotensin-receptor neprilysin inhibitor, hypertension, and/or heart failure. We screened the title and abstract of possibly relevant citations and retrieved all randomized control trials published until 2015, that studied or reported the effects of neprilysin inhibitors on BP.
Ruilope et al. reported the first proof-of-concept trial with LCZ696 that investigated the antihypertensive effects of LCZ696 when compared with the angiotensin-receptor blocker—valsartan. In the multi-centre, randomized, double-blinded, placebo-controlled, active-comparator study involving 1328 patients of 18–75 years of age with mild-to-moderate essential hypertension were randomly assigned to 8 weeks of double-blind treatment in one of eight groups of daily dose: 100, 200, and 400 mg LCZ696; 80, 160, and 320 mg valsartan; 200 mg AHU377; or placebo. The primary outcome of the trial was the mean sitting diastolic BP difference between the three single-dose 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).
The mean age of the trial population was 53 (±10.2) years, with 57% male and about 86% of patients younger than 65 years. The average duration of hypertension was 6.8 (±7.2) years. LCZ696 provided significantly superior reductions from baseline in mean sitting diastolic and systolic BP than valsartan at 8 weeks. When compared with 160 mg valsartan, 200 mg LCZ696 showed a higher reduction in mean sitting systolic BP (−11 vs. −5.69 mmHg, P = 0.0006) and mean sitting diastolic BP (−6.14 vs. −3.17 mmHg, P = 0.0023). Similarly, compared with 320 mg valsartan, 400 mg LCZ696 showed a significantly higher reduction in mean sitting systolic BP (−12.5 vs. −6.44 mmHg, P < 0.0001) and mean sitting diastolic BP (−6.85 vs. −4.15 mmHg, P = 0.0055). The reduction in mean sitting diastolic and systolic BP for 100 mg LCZ696 vs. 80 mg valsartan did not reach statistical significance. In a subgroup of 427 patients who underwent ambulatory BP monitoring, significant differences in 24-h mean ambulatory systolic BP were recorded for 200 mg LCZ696 vs. 160 mg valsartan (−3.23 mmHg) and 400 mg LCZ696 vs. 320 mg valsartan (−5.14 mmHg) for the 8-week treatment period (P < 0.05). However, differences in 24-h mean ambulatory diastolic BP between LCZ696 and corresponding valsartan doses were small and not significant.
Recently, Kario et al. published results of second hypertension trial of LCZ696 which was a multi-centre, randomized, double-blinded, placebo-controlled of 389 Asian patients aged ≥18 years with mild-to-moderate essential hypertension. After a 4-week run-in period, patients were randomized to 100, 200, or 400 mg LCZ696 or placebo for an 8-week double-blind period. The primary endpoint was mean difference across the three single-dose pairwise comparisons of LCZ696 vs. placebo (100, 200, and 400 mg LCZ696 vs. placebo) in clinic diastolic BP after the 8-week treatment period. When compared with placebo, the mean differences in change from baseline in clinic diastolic BP was −7.84, −7.29, and −8.76 mmHg for LCZ696 100, 200, and 400 mg, respectively. Likewise, compared with placebo, the mean differences in change from baseline in clinic systolic BP were −11.86, −12.57, and −15.38 mmHg for LCZ696 100, 200, and 400 mg, respectively. All doses of LCZ696 were associated with significant reductions in 24-h, daytime, and nighttime ambulatory systolic, diastolic, and pulse pressures (P < 0.0001).
Compared with Caucasian patients, BP reduction by LCZ696 tended to be greater in Asian patients with hypertension indicating that this drug may be particularly suitable in this population. Asian hypertensive patients are characterized by higher salt sensitivity and higher salt intake, resulting in suppression of renin–angiotensin system. These characteristics may result in higher prevalence of stroke, which is more directly associated with systolic BP. Thus, the increase in NPs by neprilysin inhibition in combination with ARB exerts an incremental effect on BP compared with ARB-monotherapy in Asian hypertensive patients (e.g. salt sensitive or elderly). In addition, LCZ696 may also be an effective drug in resistant hypertensive patients. Of note, compared with the same dose of valsartan, LCZ696 decreased systolic BP more than diastolic BP, resulting in a reduction of pulse pressure (Figure 2). Although the precise mechanism remains to be elucidated, the direct effect of NPs and ARB on the vascular properties and/or reduced circulating volume may play a part in the preferential effect of LCZ696 on systolic BP.
(Enlarge Image)
Figure 2.
Change in mean (A) systolic and (B) diastolic blood pressure from baseline in three randomized controlled trials. Ruilope et al. compared LCZ696 400 mg vs. valsartan 320 mg over 8 weeks. The PARAMOUNT trial compared LCZ696 200 mg twice daily vs. valsartan 160 mg twice daily over 12 weeks. Kario et al. compared LCZ696 400 mg vs. placebo over 8 weeks.
