Time of administration important? Morning versus evening dosing of valsartan

Design

Multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group study 

N=1,082

Objective

To compare the antihypertensive effects and safety of morning (AM) and evening (PM) dosing of valsartan on 24-hour blood pressure (BP) to lisinopril

Study Groups

Valsartan AM (n= 359)

Valsartan PM (n= 367)

Lisinopril AM (n= 356)

Methods

Inclusion criteria: patients ages ≥18 years old, mean sitting systolic BP (msSBP) at least 150 mm Hg if untreated and more than 140 mm Hg if pretreated (not exceeding 160/95 mm Hg), a 24-h mean ambulatory BP (maBP) more than 130/80 mm Hg after washout, at least one additional cardiovascular risk factor

Exclusion criteria: patients with mean sitting SBP at least 180 mm Hg and/or mean sitting diastolic BP (msDBP) at least 110 mm Hg at any time during the pre-randomization phase, inability to discontinue prior medications safely for a period of 3 weeks, BMI >40 kg/m², untreated hypercholesterolemia, uncontrolled T2DM, secondary hypertension, unstable angina pectoris or arrhythmia, history of  stroke or MI within 12 months prior to screening visit

After a 1-week washout and 2-week single-blinded run-in, patients were randomized 1:1:1 to take valsartan 160 mg dosed AM or PM or lisinopril 20 mg AM for 4 weeks, then force-titrated to double the initial dose for 8 weeks. At week 12, hydrochlorothiazide (HCTZ) 12.5 mg was added for 14 weeks if office BP was more than 140/90 mm Hg and/or ambulatory BP more than 130/80 mm Hg.

Duration

26 weeks

Outcome Measures

Blood pressure control (defined as the percentage of patients at week 26 with a 24-h maBP ≤130/80 and change from baseline to week 12 in mean ambulatory BP) at weeks 12 and 26; office msBP

Baseline Characteristics

Valsartan AM (n= 359)

Valsartan PM (n= 367)

Lisinopril AM (n= 356)

Age, years

 ≥65 years

61.6

165 (46%)

61.2

170 (46.3%)

61.7

157 (44.1%)

Men

White

msSBP, mm Hg

msDBP, mm Hg

Results

Valsartan AM (n= 359)

Valsartan PM (n= 367)

Lisinopril AM (n= 356)

BP control at week 26

BP control at week 12 

36.7%

Change in maSBP at week 26, mm Hg

-13.3

Change in maSBP at week 12, mm Hg

-10.6

Adverse Events

Common adverse events: headache, nasopharyngitis, bronchitis, cough, nausea, vertigo, upper abdominal pain, diarrhea, and back pain

Study Author Conclusions

Once-daily dosing of valsartan 320 mg results in equally effective 24-hour BP efficacy, regardless of dosing time.

InpharmD Researcher Critique

There was no benefit of valsartan PM versus AM on night-time BP, early morning BP and morning BP surge. Evening dosing also did not improve BP lowering in patients requiring add-on HCTZ or in nondippers at baseline.

There were 99% white patients and 45.5% of patients aged at least 65 years, which means the result may not be applied to other populations. Also, the inability to precisely determine when the patients went to bed and when they awoke, as patient diaries were not maintained.

Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial

Design

Multicenter, controlled, non-blinded, prospective study

N= 19,084

Objective

To test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk  reduction

Study Groups

Awakening (n= 9,552)

Bedtime (n= 9,532)

Methods

Inclusion: caucasian Spanish men and women aged ≥18 years, diagnosis of hypertension 

Exclusion: pregnancy, history of alcoholism or narcotic dependency, acquired immunodeficiency syndrome, secondary hypertension, unstable angina pectoris, heart failure, life-threatening arrhythmia, atrial fibrillation, less than 1 year of follow-up

Patients were instructed to either ingest their entire daily dose of ≥1 prescribed BP-lowering medications of the major therapeutic classes (ARB, ACEI, CCB, β-blocker, and/or diuretic) at bedtime or upon awakening. Participating primary care physicians were allowed to prescribe without restriction any BP-lowering medication approved by the Spanish Agency of Medications and Health Products for once-daily dosing.

Duration

Median follow-up: 6.2 years

Outcome Measures

Blood pressure, CVD risk reduction CVD death, hemorrhagic stroke, heart failure, peripheral artery disease

Baseline Characteristics

Awakening (n= 9,552)

Bedtime (n= 9,532)

Age, years

Men 

Previous CVD events

Baseline blood pressure, mm Hg

Systolic

Diastolic

149.4 ± 20.5

86.3 ± 11.9

149.5 ± 19.9 

86.0 ± 12.3

Medications

ARB

ACEI

CCB

β-Blocker

Diuretic

53.1%

25.3%

32.7%

22.0%

46.5%

53.1%

23.4%

36.8%

17.5%

39.5%

Results

Awakening (n=9,552)

Bedtime (n=9,532)

Final blood pressure, mm Hg

Systolic

Diastolic

143.2 ± 20.9

82.4 ± 12.3

140 ± 20.6

81.4 ± 12.4

Sleep-time relative blood pressure decline, %

Systolic

Diastolic

8.5 ± 8.4

13.3 ± 9.4

12.2 ± 7.7

15.3 ± 8.6

Adverse Events

Study Author Conclusions

Routine ingestion by hypertensive patients of ≥1 prescribed blood pressure-lowering medications at bedtime, as opposed to upon wakening results in improved ambulatory blood pressure control (decrease in asleep BP and increased sleep-time relative BP decline) and a markedly diminished occurrence of major CVD events.

InpharmD Researcher Critique

The entire study population was Spanish caucasian and does not provide any insight towards other ethnic groups. The antihypertensive therapies were variable (some patients on more than one therapy) which resulted in an imbalanced number of patients in each medication class, which may have impacted the results. Additionally, this study was open-label but the primary endpoint was blinded.

Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial

Prospective, randomized, open-label, blinded-endpoint clinical trial

N= 21,104

To investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension

Evening dosing (n= 10,503)

Morning dosing (n= 10,601)

Adults aged ≥18 years with hypertension, taking at least one antihypertensive medication, UK residents, registered with a UK general practitioner, and having an email address

Participants were randomized 1:1 to continue their usual antihypertensive regimen in either the morning (6:00–10:00 AM) or the evening (8:00 PM–12:00 AM) and were followed primarily through an online study portal with regular questionnaires and linkage to national hospitalization and mortality records.

Enrollment period: December 17, 2011–June 5, 2018

Median follow-up: 5.2 years (interquartile range [IQR] 4.9–5.7)

Study follow-up ended: March 31, 2021

Primary: Composite of vascular death or hospitalization for non-fatal myocardial infarction or non-fatal stroke

Secondary: Hospitalization for non-fatal myocardial infarction, hospitalization for non-fatal stroke, vascular death, all-cause mortality, hospitalization or death from congestive heart failure, participant-reported adherence, and prespecified adverse events

Evening dosing group (n= 10,503)

65.0 ± 9.3

Female

White

134.8 ± 13.3

78.8 ± 9.3

28.4 ± 4.8

Abbreviations: BMI, body mass index.

12.9% of patients had a history of cardiovascular disease.

Evening dosing group (n= 10,503)

Primary composite endpoint

Hospitalization for non-fatal myocardial infarction

Hospitalization for non-fatal stroke

Vascular death

All-cause death

Hospitalization or death from congestive heart failure

Abbreviations: CI, confidence interval.

The prespecified ARB subgroup analysis did not demonstrate a significant difference in the effect of morning versus evening dosing (interaction p= 0.081).

Participants in the evening dosing group were slightly less likely to report falls than those in the morning dosing group (21.1% vs 22.2%; p= 0.048). Dizziness or light-headedness, upset stomach or indigestion, diarrhea, and muscle aches were more commonly reported with morning dosing. Excessive visits to the toilet during the day or night and other non-specified adverse events were more commonly reported with evening dosing.

In this pragmatic study, reflecting usual care, allocation to evening dosing of usual antihypertensive medication did not improve the primary composite endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke compared with morning dosing. Taking medication in the evening was not harmful but provided no additional benefit versus morning dosing. Therefore, patients should be advised that they need not change their antihypertensive medication dosing time but might choose to take their medication at a time that suits them best, because the timing makes no difference to cardiovascular outcomes.

The study was large and well-powered, providing robust evidence that evening dosing was not superior to morning dosing for cardiovascular outcomes. However, the open-label design may have introduced bias, and reliance on participant-reported data may have affected adverse event reporting. Although prespecified subgroup analyses included patients receiving ARBs, the trial was not designed or powered to evaluate ARB-specific dosing strategies, and no significant interaction between ARB use and dosing time was observed.

Antihypertensive Medication Timing and Cardiovascular Events and Death: The BedMed Randomized Clinical Trial

Multicenter, open-label, pragmatic randomized clinical trial with blinded end-point assessment

N= 3,357

To determine the effect of bedtime vs morning administration of antihypertensive medications on major cardiovascular events and death

Bedtime administration (n= 1,677)

Morning administration (n= 1,680)

Community-dwelling adult patients with hypertension taking at least 1 once-daily antihypertensive medication

Participants were randomized 1:1 to take all once-daily antihypertensive medications either at bedtime or in the morning. Follow-up included telephone interviews and email surveys to assess adherence and outcomes.

Recruitment: March 31, 2017, to May 26, 2022

Final follow-up: December 22, 2023

Primary: Time to first occurrence of all-cause death or hospitalization/emergency department (ED) visit for stroke, acute coronary syndrome, or heart failure

Secondary: All-cause unplanned hospitalizations/ED visits, visual, cognitive, and fall- and/or fracture-related safety outcomes

Morning (n= 1,680)

Age, years (IQR)

Female

Diabetes

Coronary artery disease

Chronic kidney disease

Abbreviations: IQR, interquartile range.

Angiotensin-converting enzyme inhibitors were used by 36% of participants, angiotensin receptor blockers by 30%, calcium channel blockers by 29%, and diuretics by 27%.

Hazard Ratio (95% CI)

Composite of all-cause death and major cardiovascular events

81

27

48

30

Abbreviations: ACS, acute coronary syndrome; CI, confidence interval; MI, myocardial infarction.

Over a median follow-up of 4.6 years, the primary composite outcome of all-cause death and major cardiovascular events did not differ between the bedtime and morning dosing groups (2.3 vs 2.4 events per 100 patient-years; adjusted hazard ratio [HR] 0.96; 95% CI, 0.77–1.19; p= 0.70).

No significant differences were observed for the individual components of the primary outcome, predefined subgroup analyses, or secondary and safety outcomes. Self-reported adherence was lower in the bedtime group than in the morning group, although ambulatory blood pressure monitoring demonstrated lower overnight systolic and diastolic blood pressure with bedtime dosing.

No difference in falls or fractures, new glaucoma diagnoses, or 18-month cognitive decline between groups.

Among adults with hypertension in primary care, bedtime administration of antihypertensive medications was safe but did not reduce cardiovascular risk. Antihypertensive medication administration time did not affect the risks and benefits of BP-lowering medication and instead should be guided by patient preferences.

The study was well designed with a pragmatic approach and broad inclusion criteria, enhancing generalizability. However, adherence to medication timing was self-reported, which may have introduced bias. Although ARBs were commonly used at baseline, the study did not report ARB-specific analyses, limiting conclusions regarding the optimal timing of ARB administration.

Comparison of the Efficacy of Morning Versus Evening Administration of Telmisartan in Essential Hypertension

Prospective, randomized, open-label, blinded endpoint, parallel-group chronotherapy trial

N= 215

To investigate the administration time-dependent antihypertensive efficacy of telmisartan

Telmisartan on awakening (n= 107)

Telmisartan at bedtime (n= 108)

Age ≥18 years; diagnosis of grade 1 or 2 essential hypertension based on European Society of Hypertension-European Society of Cardiology guidelines; corroboration by ABPM

Shift workers, heavy drinkers (alcohol intake >80 g/d), heavy smokers (>20 cigarettes per day), heavy exercisers, severe arterial hypertension (grade 3), type 1 diabetes, secondary arterial hypertension, cardiovascular disorders, unstable angina pectoris, heart failure, stroke, life-threatening arrhythmia, nephropathy, retinopathy, previous myocardial infarction or coronary revascularization within the last year

Patients were randomly assigned according to a computer-generated allocation table to receive one telmisartan 80-mg tablet daily either upon awakening or at bedtime for 12 weeks; personnel conducting the statistical analyses were blinded to treatment assignment. Compliance was assessed by tablet count and patient interview at the final visit.

Clinic BP was measured six times at each study visit after patients had been seated for at least 5 minutes. Forty-eight-hour ABPM was performed immediately before treatment and after 12 weeks, with SBP, DBP, and heart rate measured every 20 minutes from 7 AM to 11 PM and every 30 minutes overnight. Participants wore wrist actigraphs throughout ABPM to determine individual activity and sleep periods and accurately calculate diurnal and nocturnal BP means.

ABPM records were excluded if ≥30% of readings were missing, data were missing for a 2-hour interval, or monitoring occurred during an irregular rest–activity schedule or an ineligible sleep duration. Daily, diurnal, and nocturnal BP means were compared between groups using analysis of variance; within-group before-and-after comparisons were conducted using paired analyses.

January 2005 to October 2006

24-hour blood pressure reduction; nocturnal blood pressure reduction, sleep time–relative blood pressure decline, prevalence of nondipping

Telmisartan on Awakening (n= 107)

54.2%

46.4 ± 11.5

164.2 ± 10.0

73.4 ± 15.6

27.1 ± 4.2

89.8 ± 13.3

102.1 ± 8.5

151.8 ± 16.2

90.9 ± 11.6

60.9 ± 8.6

74.6 ± 10.1

99.6 ± 21.4

0.97 ± 0.24

5.5 ± 1.7

215.4 ± 37.3

116.4 ± 77.1

Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; HR, heart rate.

After 12 weeks, telmisartan 80 mg once daily significantly reduced diurnal, nocturnal, and 24-hour systolic and diastolic blood pressure from baseline regardless of administration time.

Compared with morning dosing, bedtime administration produced greater reductions in nocturnal systolic blood pressure (11.1% vs 6.5%; p< 0.001) and nocturnal diastolic blood pressure (13.0% vs 8.3%; p< 0.001), while reductions in 24-hour systolic and diastolic blood pressure were similar between groups (p= 0.327 and p= 0.554, respectively).

Bedtime dosing also resulted in lower post-treatment nocturnal systolic and diastolic blood pressure (108.3 vs 112.2 mm Hg; p= 0.011 and 63.4 vs 67.3 mm Hg; p< 0.001), greater nocturnal blood pressure decline, and a lower prevalence of nondipping (8.3% vs 36.5%; p< 0.001).

The proportion of patients achieving controlled ambulatory blood pressure was higher with bedtime administration than with morning administration (64.8% vs 49.5%; p= 0.023), whereas morning blood pressure surge did not differ significantly between groups.

No adverse events reported.

The results of this ingestion time study on subjects with grade 1 or 2 essential hypertension randomly assigned to receive the 80-mg daily dose of telmisartan either on awakening or at bedtime demonstrate a normalization of the circadian BP profile toward a more dipper pattern only when telmisartan is administered at bedtime. Results raise the possibility that the dosing time of telmisartan should be chosen in relation to the baseline dipper status of each patient to improve therapeutic benefit and to increase BP control, as defined by an adequate reduction in both diurnal and nocturnal means of BP. Whether converting a nondipper to dipper pattern with bedtime administration of telmisartan could also reduce cardiovascular risk is a hypothesis that merits investigation.

The randomized, blinded-endpoint design, use of individualized sleep periods determined by actigraphy, and duplicate 48-hour ABPM assessments strengthen the comparison of telmisartan administration times. However, the trial was open-label, evaluated only telmisartan 80 mg as monotherapy for 12 weeks, excluded patients with severe hypertension and substantial cardiovascular comorbidity, and assessed surrogate BP outcomes rather than cardiovascular events; therefore, the findings primarily support improved nocturnal BP control with bedtime telmisartan and do not establish a universally optimal dosing time for all ARBs or patient populations.

Treatment of Non-Dipper Hypertension with Bedtime Administration of Valsartan

Prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group chronotherapy trial

N= 148

To investigate the administration time-dependent antihypertensive efficacy of valsartan in non-dipper patients

Valsartan on awakening (n= 72)

Valsartan at bedtime (n= 76)

Grade 1–2 essential hypertension, aged 53.0 ± 12.6 years, non-dipper status confirmed by ambulatory blood pressure monitoring (ABPM), 24-h mean systolic blood pressure/diastolic blood pressure (SBP/DBP) above 130/80 mmHg, diurnal mean above 135/85 mmHg, or nocturnal mean above 120/70 mmHg

Shift-workers, heavy drinkers (> 80 g/day), smokers (> 20 cigarettes/day), heavy exercisers, severe arterial hypertension (grade 3), secondary arterial hypertension, cardiovascular disorders (angina, heart failure, stroke, nephropathy, retinopathy, previous myocardial infarction or coronary revascularization)

After a 2- to 4-week washout period when required, participants were randomized according to a computer-generated allocation table to receive valsartan 160 mg once daily as monotherapy either upon awakening from nighttime sleep or at bedtime. Treatment allocation was concealed from the investigator performing clinical blood pressure measurements and the personnel conducting statistical analyses. Blood pressure and heart rate were assessed at baseline and after treatment using 48-hour ABPM, with measurements obtained every 20 minutes from 07:00 to 23:00 and every 30 minutes overnight; physical activity was simultaneously recorded every minute using wrist actigraphy to establish each participant’s individualized diurnal activity and nocturnal rest periods.

Participants continued their usual activities during monitoring, followed a similar schedule during both ABPM days, and avoided daytime naps. Blood pressure series were excluded if >30% of measurements were missing, data were absent for >2 consecutive hours, the participant had an irregular rest–activity schedule, or nighttime sleep lasted <6 or >12 hours. Absolute and relative changes in diurnal, nocturnal, and 24-hour mean blood pressure were compared between groups using repeated-measures analysis of variance; trough-to-peak ratios, smoothness indices, blood pressure control, and changes in dipping status were also evaluated.

October 2003 to March 2004

Change in diurnal: nocturnal ratio of blood pressure; percentage of patients reverting to dippers, percentage of patients with controlled blood pressure over 24 h, reduction in urinary albumin excretion

Never treated, n

Previously treated with

Beta-blocker

Angiotensin II receptor blocker

Angiotensin-converting enzyme inhibitor

Calcium channel blocker

3

7

7

2

5

7

4

2

Male

Age, years

Height, cm

Weight, kg

Body mass index, kg/m2

Waist, cm

Hip, cm

SBP, mmHg

DBP, mmHg

Pulse pressure, mmHg

Glucose, mg/dl

Creatinine, mg/dl

Uric acid, mg/dl

Cholesterol, mg/dl

Triglycerides, mg/dl

Fibrinogen, mg/dl

Albumin, mg/24 h urine

Creatinine clearance, ml/min

24-h mean SBP reduction, mmHg

24-h mean DBP reduction, mmHg

Posttreatment 24-hour mean SBP, mmHg

Posttreatment 24-hour mean DBP, mmHg

Posttreatment diurnal mean SBP, mmHg

Posttreatment diurnal mean DBP, mmHg

Posttreatment nocturnal mean SBP, mmHg

Posttreatment nocturnal mean DBP, mmHg

Diurnal:nocturnal ratio increase

Percentage of patients reverting to dippers

No specific adverse events reported in the study.

In non-dipper hypertensive patients, dosing time with valsartan should be chosen at bedtime for improved efficacy during the nocturnal resting hours and potential associated reduction in cardiovascular risk. The results of this chronotherapy study on non-dipper subjects with grade 1 or 2 essential hypertension, who were randomly assigned to receive the daily dose of valsartan either upon awakening or at bedtime, demonstrate a normalization of the circadian blood pressure profile only when valsartan is administered at bedtime. The results raise the possibility that the dosing time of valsartan should be chosen in relation to the baseline dipper status of each patient to improve therapeutic benefit and to increase blood pressure control, as defined by an adequate reduction in both diurnal and nocturnal means of blood pressure. Whether converting a non-dipper to dipper pattern with bedtime administration of valsartan will also reduce cardiovascular risk is a hypothesis that deserves further investigation.

The randomized, blinded-endpoint design, individualized actigraphy-defined sleep periods, and 48-hour ABPM strengthen the assessment of administration-time effects and demonstrate that bedtime valsartan improved nocturnal blood pressure and dipping status without compromising 24-hour blood pressure reduction. However, the open-label design, short 3-month follow-up, exclusively White population, restriction to non-dipper patients receiving valsartan 160 mg, absence of reported safety outcomes, and reliance on blood pressure and surrogate outcomes limit applicability to other patient populations, ARBs, doses, and cardiovascular outcomes; the authors also acknowledged that it was unknown whether the administration-time effect represented an ARB class effect or was specific to valsartan.

ADMINISTRATION-TIME-DEPENDENT EFFECTS OF OLMESARTAN ON THE AMBULATORY BLOOD PRESSURE OF ESSENTIAL HYPERTENSION PATIENTS

Prospective, randomized, open-label, parallel-group, blinded endpoint (PROBE) trial

N= 123

To determine whether the administration-time-dependent efficacy is a class-related feature of angiotensin II receptor blocker (ARB) medications, specifically assessing the effects of olmesartan administered either upon awakening or at bedtime on ambulatory blood pressure in patients with essential hypertension

Awakening (n= 67)

Bedtime (n= 66)

Age ≥18 yrs; diagnosis of previously untreated grade 1 or 2 uncomplicated essential hypertension; systolic BP 140–179 mmHg and/or diastolic BP 90–109 mmHg; corroborated by 48 h ambulatory blood pressure monitoring (ABPM)

Pregnant women, shift-workers, heavy alcohol drinkers, heavy smokers, heavy exercisers, severe arterial hypertension, type 1 diabetes, secondary arterial hypertension, cardiovascular disorders, unstable angina, heart failure, stroke, life-threatening arrhythmia, nephropathy, retinopathy, recent myocardial infarction or coronary revascularization

Patients were randomly assigned to receive olmesartan (20 mg/day) either upon awakening or at bedtime for three months. BP was measured by ambulatory monitoring for 48 consecutive hours before and after treatment. The study was conducted at the Hospital Clínico Universitario, Santiago de Compostela, Spain.

Three months

24 h BP reduction; nocturnal BP mean reduction; sleep-time relative BP decline; awake/asleep BP ratio; morning BP surge

Awakening (n= 67)

Male

Age, years

Height, cm

Weight, kg

BMI, kg/m2

Waist, cm

Abbreviations: BMI, body mass index.

Baseline demographic characteristics and laboratory parameters were comparable between the morning and bedtime treatment groups.

Bedtime (n= 66)

24 h mean of SBP, mmHg

Awake mean of SBP, mmHg

Asleep mean of SBP, mmHg

Awake/asleep ratio of SBP

Non-dipper

After 3 months of treatment, morning and bedtime olmesartan produced similar reductions in 24-hour ambulatory blood pressure and similar rates of blood pressure control (74% vs 75%). Compared with morning dosing, bedtime dosing produced greater reductions in asleep systolic and diastolic blood pressure, increased the awake/asleep blood pressure ratio, reduced the proportion of patients with a non-dipping blood pressure pattern (19% vs 40%; p= 0.009), and reduced the diastolic morning blood pressure surge. Heart rate and laboratory parameters remained unchanged in both groups.

Three patients withdrew due to adverse effects: two with gastric intolerance, one with nausea in the awakening group; one with nausea in the bedtime group.

Nocturnal BP regulation was significantly better achieved with bedtime as compared to morning dosing of olmesartan. These effects are comparable to those previously reported for valsartan and telmisartan, thus suggesting that they may be class-related features of ARB medications in spite of differences in their half-life kinetics. These administration-time-dependent effects should be taken into account when prescribing ARB medications for treatment of essential hypertension.

The study's strengths include its randomized design and use of ambulatory blood pressure monitoring. However, the open-label nature and potential for selection bias due to exclusion criteria may limit generalizability. The study did not explore long-term cardiovascular outcomes, which would be valuable for understanding the clinical significance of the findings.

Effect of Dosing Time of Angiotensin II Receptor Blockade Titrated by Self-Measured Blood Pressure Recordings on Cardiorenal Protection in Hypertensives: The Japan Morning Surge-Target Organ Protection (J-TOP) Study

Open-label multicenter trial

N= 450

To study the impact of the dosing time of an angiotensin II receptor blocker (ARB) titrated by self-measured home blood pressure (HBP) on cardiorenal damage in hypertensives

Awakening dosing (n= 229)

Bedtime dosing (n= 221)

Hypertensive patients with self-measured systolic HBP more than 135 mmHg

Patients with arrhythmia, history of congestive heart failure, recent history of coronary artery disease, stroke, aortic dissection, peripheral artery disease, dementia, malignancy, chronic inflammatory disease, bilateral renal arterial stenosis, or contraindication for candesartan

Participants measured home blood pressure for 14 days before randomization and were stratified according to the morning–evening difference in systolic home blood pressure as having morning hypertension (difference ≥15 mmHg), morning and evening hypertension (difference ≥0 to <15 mmHg), or evening hypertension (difference <0 mmHg). Within these strata, participants were randomly assigned by an independent research center to receive candesartan immediately after breakfast or immediately before bedtime, titrated to achieve both morning and evening systolic home blood pressure <135 mmHg. Participants not receiving an ARB began candesartan 4 mg/day, whereas those already receiving an ARB were switched to candesartan 8 mg/day; doses were increased monthly in 4-mg increments to a maximum of 12 mg/day, and a diuretic was added when blood pressure remained uncontrolled.

Other baseline antihypertensive medications and their administration times were maintained. Participants measured morning blood pressure after awakening but before breakfast and antihypertensive medication, evening blood pressure before medication and bedtime, and, when possible, nighttime blood pressure at 2:00, 3:00, and 4:00 AM. The home monitoring device automatically obtained three measurements per occasion and calculated weekly averages; primary analyses were conducted according to the intention-to-treat principle in 450 participants with complete baseline data.

6 months

Primary: 6-month change in urinary albumin/creatinine ratio (UACR) and plasma B-type natriuretic peptide level

Secondary: 6-month changes in home blood pressure (HBP), dose of candesartan, percentage of diuretic use

Age, years

Male

BMI, kg/m²

Duration of hypertension, years

Diabetes

CKD

Geometric mean UACR, mg/gCr (range)

Albuminuria

Geometric mean BNP, pg/mL (range)

Morning systolic BP, mmHg

Evening systolic BP, mmHg

Receiving antihypertensive medication

Abbreviations: BMI, body mass index; CKD, chronic kidney disease.

Change in UACR

Change in BNP

At 6 months, mean reductions in clinic, morning, evening, and nighttime systolic blood pressure were similar between the awakening- and bedtime-dosing groups, respectively (−13.1 vs −13.0 mmHg, p= 0.93; −14.2 vs −16.9 mmHg, p= 0.054; −13.9 vs −14.6 mmHg, p= 0.67; and −8.8 vs −6.4 mmHg, p= 0.35); nighttime blood pressure data were available for 80 and 81 patients, respectively.

Morning diastolic blood pressure decreased to a greater extent with bedtime dosing than awakening dosing (−7.6 vs −5.9 mmHg; p= 0.03), whereas evening diastolic blood pressure reductions were comparable (−6.4 vs −6.2 mmHg; p= 0.75). In prespecified subgroup analyses, bedtime dosing produced a greater reduction in UACR than awakening dosing among patients with morning hypertension (−50.6% vs −31.3%; p= 0.02), while no significant between-group differences were observed in the morning-and-evening hypertension subgroup (−43.4% vs −35.3%; p= 0.31) or evening hypertension subgroup (−40.4% vs −38.8%; p= 0.87).

At study end, mean candesartan doses were identical between groups (9.9 ± 3.1 mg/day each; p= 0.960), and diuretic use was not significantly different with bedtime versus awakening dosing (57.0% vs 51.5%; p= 0.243).

Adverse events were comparable between the two groups. No major events in the bedtime-dosing group, four major events in the awakening-dosing group.

In HBP-guided antihypertensive treatment in hypertensives, bedtime dosing of an ARB may be superior to awakening dosing for reducing microalbuminuria. This study clarified that even in patients with relatively mild hypertension, more strict 24-h BP control as targeted BP both at morning and evening self-measured at home less than 130/80 mmHg allowed a major reduction in albuminuria. The bedtime dosing of RAS inhibitors may be one of the options to achieve a more protective effect on the target organ damage and subsequent cardiovascular events through suppression of both the BP level and RAS activation during sleep-early morning period, particularly in high-risk patients with morning hypertension.

The randomized multicenter design, home blood pressure-guided dose titration, comparable achieved blood pressure and candesartan doses, and prespecified analyses by morning–evening blood pressure pattern strengthen the assessment of whether dosing time independently affected albuminuria. However, the open-label design, use of a surrogate renal outcome rather than clinical cardiovascular events, baseline imbalance in albuminuria, morning-only urine collection, incomplete nighttime blood pressure data, allowance of diuretic add-on therapy, and inclusion of many patients already receiving an ARB limit conclusions regarding a universally optimal administration time for ARB tablets.

Morning vs Bedtime Dosing and Nocturnal Blood Pressure Reduction in Patients With Hypertension: The OMAN Randomized Clinical Trial

Prospective, multicenter, randomized, open-label, parallel-group, superiority clinical trial

N= 720

To compare the effects of morning vs bedtime antihypertensive medication administration on nocturnal blood pressure reduction and circadian rhythm among patients with hypertension

Morning dosing (n= 352)

Bedtime dosing (n= 368)

Patients with hypertension aged 18 to 75 years without prior antihypertensive treatment or who had discontinued antihypertensive agents for 2 weeks

Patients with extreme BP decrease at night, white coat hypertension, working at night, chronic renal insufficiency, hypertensive urgency, age >75 years

Participants were randomized 1:1 to take a single olmesartan/amlodipine tablet containing olmesartan 20 mg and amlodipine 5 mg once daily in the morning between 6:00 and 10:00 AM or at bedtime between 6:00 and 10:00 PM. Ambulatory blood pressure monitoring was performed at baseline, week 4, and week 12, with measurements every 20 minutes from 6:00 AM to 10:00 PM and every 30 minutes from 10:00 PM to 6:00 AM; office blood pressure was measured at baseline and every 4 weeks. At week 4, the dose could be increased to 1.5 tablets daily in patients with masked or sustained uncontrolled hypertension, and at week 8 it could be increased by an additional 0.5 tablet if office blood pressure remained uncontrolled. Outcomes were assessed primarily in the intention-to-treat population using analysis of covariance adjusted for the corresponding baseline blood pressure, with per-protocol and sensitivity analyses also performed.

June 1, 2022, to April 30, 2024, with a 12-week follow-up

Primary: Change in nighttime systolic blood pressure from baseline to 12 weeks

Secondary: Changes in office and other ambulatory blood pressure indicators

Mean age, years

Male

Mean BMI, kg/m²

Total cholesterol, mg/dL

LDL cholesterol, mg/dL

HDL cholesterol, mg/dL

Median triglycerides, mg/dL (IQR)

Median plasma glucose, mg/dL (IQR)

Current smoker

Current drinker

Diabetes

Median duration of hypertension, years (IQR)

History of antihypertensive medications use

Hypertension treatment

ACEI

ARB

β-Blocker

CCB

Diuretic

17 (4.3%)

226 (57.2%)

40 (10.1%)

258 (65.3%)

29 (7.3%)

8 (4.2%)

112 (59.3%)

18 (9.5%)

120 (63.5%)

14 (7.4%)

9 (4.4%)

114 (55.3%)

22 (10.7%)

138 (67.0%)

15 (7.3%)

Baseline BP, mm Hg

Office SBP

Office PP

24-h SBP

24-h DBP

24-h PP

Daytime SBP

Daytime DBP

Nighttime SBP

Nighttime DBP

Morning SBP

Morning DBP

154.3 ± 12.4

94.9 ± 10.7

78.3 ± 11.1

147.8 ± 11.0

91.5 ± 9.1

76.0 ± 9.7

151.9 ± 11.3

94.0 ± 9.5

138.4 ± 14.1

85.6 ± 9.9

149.8 ± 15.2

93.5 ± 11.6

154.4 ± 12.2

94.6 ± 10.3

78.3 ± 11.0

148.0 ± 11.1

91.4 ± 9.0

76.0 ± 9.8

152.3 ± 11.0

94.0 ± 9.2

138.4 ± 15.1

85.4 ± 10.4

150.0 ± 15.2

93.0 ± 11.6

154.3 ± 12.5

95.1 ± 11.1

78.3 ± 11.2

147.6 ± 11.0

91.6 ± 9.2

76.1 ± 9.7

151.5 ± 11.6

94.0 ± 9.8

138.3 ± 13.0

85.8 ± 9.4

149.5 ± 15.2

93.9 ± 11.5

No nocturnal SBP decrease <10% of daytime mean BP or with increase in nocturnal SBP

No nocturnal DBP decrease <10% of daytime mean BP or with increase in nocturnal DBP

Abbreviations: IQR, interquartile range; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; CCB, calcium-channel blocker; DBP, diastolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PP, pulse pressure; SBP, systolic blood pressure.

At 12 weeks, bedtime dosing resulted in a significantly greater reduction in nighttime systolic blood pressure than morning dosing (mean standard deviation [SD] −25.3 [15.0] vs −22.3 [16.8] mm Hg; between-group difference, −3.0 mm Hg; 95% confidence interval [CI] −5.1 to −1.0; p= 0.004).

Bedtime dosing also produced greater reductions in nighttime diastolic blood pressure (between-group difference, −1.4 mm Hg; 95% CI −2.8 to −0.1; p= 0.04), morning systolic blood pressure (−3.1 mm Hg; 95% CI −5.6 to −0.5), and morning diastolic blood pressure (−2.7 mm Hg; 95% CI −4.4 to −1.0).

Nighttime systolic blood pressure control was achieved in 79.0% of patients receiving bedtime dosing versus 69.8% receiving morning dosing (p= 0.01), while office systolic blood pressure control was achieved in 88.7% versus 82.2%, respectively (p= 0.02).

The proportion of patients with an inadequate nocturnal systolic blood pressure decline or an increase in nocturnal systolic blood pressure decreased from 53.3% to 36.9% in the bedtime group (p< 0.001), compared with 50.9% to 45.3% in the morning group (p= 0.35).

No significant differences in the prevalence of reported adverse effects and nocturnal hypotension between the groups.

In this randomized clinical trial of antihypertensive chronotherapy, bedtime dosing provided better control of nocturnal blood pressure and improved the circadian rhythm, without reducing the efficacy on mean daytime or 24-hour blood pressure, or increasing the risk of nocturnal hypotension. These findings support the potential advantages of bedtime administration and offer new evidence to guide future research on antihypertensive chronotherapy.

This multicenter randomized trial used prespecified dosing windows, repeated ambulatory blood pressure monitoring, and protocol-directed dose titration, providing comparatively strong evidence that bedtime olmesartan/amlodipine may modestly improve nocturnal blood pressure control over morning administration. However, the open-label design, 12-week duration, self-reported dosing adherence, restriction to Chinese patients without cardiovascular disease, and use of an ARB–calcium channel blocker combination limit application of the findings to ARB monotherapy, other antihypertensive agents, diverse populations, and long-term cardiovascular outcomes.