Twenty‐Four‐Hour Blood Pressure‐Lowering Efficacy of Sacubitril/Valsartan Versus Olmesartan in Japanese Patients With Essential Hypertension Based on Nocturnal Blood Pressure Dipping Status: A Post Hoc Analysis of Data From a Randomized, Double‐Blind Multicenter Study

Background Nighttime blood pressure (BP) and an abnormal nocturnal BP dipping profile are important cardiovascular risk factors in patients with hypertension. This post hoc analysis investigated the effects of sacubitril/valsartan on 24‐hour BP in patients with mild‐to‐moderate hypertension and in patient subgroups based on nocturnal BP dipping status. Methods and Results Data from a randomized clinical trial comparing the BP‐lowering effects of 8 weeks of treatment with sacubitril/valsartan (200 or 400 mg/d) and olmesartan (20 mg/d) in Japanese patients with mild‐to‐moderate hypertension were analyzed. The primary end point was change in 24‐hour, daytime, and nighttime BP in patient subgroups based on nocturnal BP dipping status (dipper, nondipper). Six hundred thirty‐two patients with baseline and follow‐up ambulatory BP data were included. Both sacubitril/valsartan dosages reduced 24‐hour, daytime, and nighttime systolic BP, and 24‐hour and daytime diastolic BP, to a significantly greater extent than olmesartan in the dipper and nondipper groups. However, between‐group differences in nighttime systolic BP were more significant in the nondipper group (difference [95% CI] for sacubitril/valsartan 200 and 400 mg/d versus olmesartan 20 mg/d: –4.6 [95% CI, −7.3 to −1.8] and −6.8 [95% CI, −9.5 to −4.1] mm Hg, respectively; P<0.01 and P<0.001). Between‐group differences in the BP control rate were greatest in the nondipper subgroup (systolic BP control rate of 34.4% and 42.6% with sacubitril/valsartan 200 and 400 mg/d versus 23.1% with olmesartan 20 mg/d). Conclusions This analysis highlights the value of sacubitril/valsartan therapy in patients with a nondipper profile of nocturnal BP and confirms this agent's potent 24‐hour BP‐lowering effect in Japanese populations with hypertension. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01599104.

Change in NT-proBNP level from baseline to 8 weeks is summarized using geometric mean.
A paired t-test was used to analyze the difference in mean NT-proBNP level between baseline and 8 weeks for each treatment group for all patients and by nocturnal BP dipping status. Between-treatment differences in the change in NT-proBNP from baseline to 8 weeks was evaluated using an ANCOVA model with treatment as the fixed-effect and baseline NT-proBNP level as the covariate.

Changes from baseline to 8 weeks in 24-hour, daytime and nighttime BP in patient subgroups based on baseline characteristics
Data were analyzed using a repeated measure factorial ANCOVA model with treatment, baseline factor, post-dosing hours (hour 1, 2, 3, ..., 24), treatment by post-dosing hour interaction and treatment by baseline factor interaction as fixed-effect factors, and baseline mean 24-hour SBP as the repeated measure.

BP control rate at 8 weeks
The proportion of patients achieving control of 24-h ambulatory, daytime, and nighttime ambulatory SBP/DBP after 8 weeks is presented for the three treatment groups, and in patient subgroups based on nocturnal BP dipping status. An equality test was used to compare the proportion of patients achieving BP control between the sacubitril/valsartan and olmesartan groups.

Safety in patient subgroups based on nocturnal BP dipping status
Assessment of safety (in the safety analysis set) is based on the frequency of adverse events (AEs) and serious adverse events (SAEs) that were suspected by the investigators to be related to study medications. The incidence of any AEs, AEs leading to permanent treatment discontinuation, any SAEs, and SAEs leading to discontinuations are summarized using descriptive statistics, by treatment group and by nocturnal BP dipping status.
Between-group differences in change from baseline to 8 weeks in daytime and nighttime SBP Hourly post-dosing values for SBP were obtained over 24 hours by calculating the average of all readings taken in each hour. A repeated measure analysis of covariance (ANCOVA) method was used to assess effects of treatment on the change from baseline to 8 weeks in hourly SBP/DBP (hour 1, 2, 3, ..., 24) in patient subgroups based on nocturnal BP dipping status (dipper, non-dipper). The change from baseline to 8 weeks in SBP/DBP for each postdosing hour was calculated by comparing the value for a specific hour at baseline with the same hour at 8 weeks. In the repeated measure ANCOVA model, treatment, post-dosing hour (hour 1, 2, 3, ..., 24) and treatment by post-dosing hour interaction were fixed-effect factors, and baseline mean 24-hour SBP was the repeated measure.      SBP, systolic blood pressure. Figure S4. Change in early morning ambulatory systolic blood pressure (A) and diastolic blood pressure (B) from baseline to week 8 in the overall population and in patient subgroups based on nocturnal blood pressure dipping status (comparison between treatments). Data are least-squares mean change ± standard error (repeated-measures ANCOVA model). Early morning: 6am to 8am. *p<0.05, **p<0.01, ***p<0.001 vs. olmesartan.

A B
Abbreviations: ABP, ambulatory blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure. Figure S5. Change in early morning ambulatory systolic blood pressure (A) and diastolic blood pressure (B) from baseline to week 8 in patient subgroups based on nocturnal blood pressure dipping status (comparison between dipping status groups). Data are least-squares mean change ± standard error (repeated-measures ANCOVA model). Early morning: 6am to 8am.