Table 1.
Effects of time-dependent dosing for treatment of HTN: reviewed studies (2013-2017) of the general populations without emphasis on comorbid conditions.
| Reference | Country | Study Design | Participants details | HTN definition | Follow up (month) |
Morning
anti- hypertensive medications |
Evening
anti- hypertensive medications |
Measures of BP |
Ancillary Measures | Results |
|---|---|---|---|---|---|---|---|---|---|---|
| Ayala et al. 2013 (81). | Spain. | Prospective, open-label, blinded endpoint, single-center RCT; replacement of one antihypertensive medication with a new medication ingested upon awakening (group 1) vs. at bedtime (group 2). | 50% male; aged 61 ± 11 y; groups had similar distributions of T2D (33-34%); OSA (7-8%); metabolic syndrome (70-73%); obesity (53-60%); previous CV events (<8%), otherwise free from CV disorders. (Total participants, n=776; group 1, n=391). | Resistant HTN: SBP/DBP awake mean ≥ 135/85 mmHg and/or asleep mean ≥120/70 mmHg (48h ABPM) AND compliant to 3 HTN medications (unspecified) OR treated with ≥4 HTN medications. | 64.8 (6-102). | Group 1: All in morning; average 3.2a at start and 3.5a by end of study. Combination of diuretic with ARB, or ACEI at start, with new medication usually being a CCB or α-blocker. Group 2: Varied | Group 1: None Group 2: ≥1 at bedtime; average 3.2a at start and 3.4a by end of study. 26% ARB, 13% ACEI, 55% CCB, 17% β-blockers, 13% diuretic, and 41% or α-blocker. | 48 h ABPM recorded annually (or quarterly if treatment was adjusted). | CV events; CV death; total death. | Group 2 ↓ asleep SBP/DBP mean, sleep-time relative SBP/DBP decline, prevalence of non-dipping BPb, hazard ratio of total events and ↑ BP control and increased survival compared to group 1. Ingesting CCB, β-blocker, or ARB at bedtime compared to morning ↓CVD risk; non-significance with other drug classes likely due to limited sample size of individual treatment-class. |
| Bonten et al. 2015 (89). | The Netherlands. | Prospective, randomized, open-label, blinded end point, 2-period crossover study; comparison of low-dose aspirin administered in the morning vs bedtime. | 73% male; aged 64±7 y; previous use of 80-100 mg aspirin for CVD prevention; no antiplatelet, anticoagulant or NSAID medications. (n=290). | Baseline BP ≥ 120/70 or ≥160/100 mm Hg (average of 6 BP measured 2 minutes apart after 10 minutes of rest). | 3. | Aspirin within 1 hour of waking. | Same as morning (crossover design); 1 hour before bedtime. | 24h ABPM. | Platelet reactivity. | No significant differences in ABPM between morning and bedtime aspirin administration. Bedtime administration ↓morning platelet reactivity. |
| Farah et al. 2013 (94). | Israel. | Prospective RCT; medication upon awakening (group 1) vs. at bedtime (group 2); unclear blinding. | 67% male; aged 50 ± 2 y; uncontrolled HTN; non-dipping BPb; BMI<30 kg/m2; no evidence of target organ damage or systemic disease. (Total participants, n=60; group 1, n=30). | Uncontrolled HTN: Sitting SBP >140 mmHg, sitting DBP> 90 mmHg (mean of 3 outpatient visits); and awake BP >135/85 mmHg or nocturnal BP > 120/70 mmHg (24h ABPM). | 4. | Group 1: Long-acting CCB or ACEI; 5 of 30 received combined tablet of CCB and ACEI. Group 2: None. | Group 1: None. Group 2: Long-acting CCB or ACEI; 5 of 30 received combined tablet of CCB and ACEI. | 24 h ABPM and office BP. | Cholesterol, triglycerides, HDL, LDL, glucose, and creatinine. | Group 2 ↓BP, more prominently at night, and controlled 24h SBP and DBP. Four participants with monotherapy were unresponsive to bedtime dosing, but their BP was controlled by the addition of a 2nd drug at bedtime. |
| Fujiwara et al. 2017 (97). | Japan. | Prospective, multicenter, open-label, crossover, noninferiority, RCT; morning vs. bedtime administration; blinded by independent research center. | 35% male; aged 68 ± 9 y; 17% T2D; 65% CKD; no HF, coronary heart disease, or cerebrovascular disease at baseline; 17% extreme dipper; 22% non-dipper; and 9% reverse dipperb. (n=23). | Office SBP ≥140 mmHg or DBP ≥90 mmHg (mean of 2 consecutive BP measurements after ≥2 minutes of seated rest). | 2. | ARB and CCB combination therapy. | Same as morning (crossover design). | Nocturnal brachial (ABPM) and central SBP. | Adverse events and adherence to medication. | Morning administration ↓brachial and central SBP/DBP and bedtime administration ↓ central DBP only compared to baseline. Need to say something about adherence. |
| Hermida et al. 2013 (82). | Spain. | Cross-sectional; all medications upon awakening (group 1), full daily dose of ≥1 medications at bedtime (group 2), or split twice daily dose of medications (group 3). | 58% male; aged 64±12 y. Resistant HTN: Failed to sufficiently lower SBP/DBP with lifestyle changes and prescription of ≥3 HTN medications. (Group 1, n=1084; group 2, n=1436; group 3, n=379). | Awake SBP/DBP mean ≥135/85 mm Hg and/or asleep SBP/DBP mean ≥120/70 mmHg. | N/A | Group 1: all medications (3†±1). Group 2: some medications (3†±1). Group 3: Split twice daily dose of ≥1 Medication (4†±1) | Group 1: none. Group 2: full daily dose of ≥1 medication. Group 3: Split twice daily dose of ≥1 medication. | 48h ABPM. | Markers of CVD risk: microalbuminuria, CKD, albumin/creatinine ratio, glucose, cholesterol, eGFR. | Bedtime dose (group 2) ↓non-dipping and reverse dipping BPb and CVD risk compared to group 1 or 2. |
| Huangfu et al. 2015 (95). | China. | Randomized, single-blinded and parallel-controlled; comparison of morning, evening, and split administration of diuretic and ARB. | 45% male; aged 56±13 y; grade II or III HTN untreated ≥ 2 weeks. (Group 1, n= 20; group 2, n=21; group 3, n=23; group 4, n=22). | 24h mean SBP/DBP ≥130/80 mmHg, the diurnal mean value ≥135/85 mmHg, or the nocturnal mean value ≥120/70 mmHg. | 3. | Morning medications taken 6-8 AM. Group 1: diuretic and ARB. Group 2: none. Group 3: diuretic. Group 4: ARB. | Bedtime medications taken 7-9 PM. Group 1: none. Group 2: diuretic and ARB. Group 3: ARB. Group 4: diuretic. | 24h ABPM. | N/A. | Group 2 ↓morning surge in BP from baseline. No significant changes in dippingb status or 24h mean BP. |
| Kario et al. 2016 (96). | Japan. | Prospective, multicenter, open-label, RCT; morning (group 1) vs. bedtime (group 2) administration; unclear blinding. | 62% male; aged 75 ± 9 y; HTN patients with paroxysmal AF confirmed with electrocardiography; free from severe liver or kidney disease, persistent or permanent AF prior to randomization; no HF, stroke or MI within 6 months of study initiation. (Total completing study, n=81; group 1, n=41; 91% completed study) | SBP ≥140 mm Hg (office) or SBP ≥135 mm Hg (home), and/or DBP ≥90 mm Hg (office) or DBP ≥85 mm Hg (home). Office BP: mean of 3 consecutive measures. Home BP: mean of morning or evening BP for 5 consecutive days. | 3. | Group 1: ARB + CCB combination tablet. Group 2: none. | Group 1: none. Group 2: ARB + CCB combination tablet. | 24 h ABPM. | High-sensitivity troponin T, plasminogen activator inhibitor-1, N-terminal pro-brain natriuretic peptide, and the urinary albumin/creatinine ratio from baseline. | Compared to baseline, group 1 and 2 ↓ 24 h, nighttime, morning, pre-awake, morning and evening home SBP/DBP and home BP variability. Group 2 ↓ high-sensitivity troponin T, N-terminal pro-brain natriuretic peptide, and the urinary albumin/creatinine ratio. |
| Lafeber et al. 2014 (90). | The Netherlands. | Open blinded end-point, three-period cross-over, RCT; comparison of a fixed dose combination pill (polypill) administered in the morning (period 1) vs. evening (period 2) vs. individual pill components administered in morning and evening (period 3). | 85% male; aged 67±8 y; 100% established atherosclerotic CVD + indication for the use of CV medication. (n=81). | N/A | 1.5-2. | Morning administration between 5-11AM. Period 1: Polypill (containing aspirin, statin, ACEI, and diuretic) Period 2: none Period 3: aspirin, ACEI, and diuretic. | Evening administration between 9PM-12AM. Period 1: none Period 2: Polypill4 Period 3: statin. | 24h ABPM. | LDL cholesterol, anti-platelet function, medication adherence. | No difference in ABPM between polypill dose time (period 1 and 2) compared to individual agents. Polypill (period 1 and 2) ↑ adherence compared to individual agents. Polypill in evening (period 2) ↓ LDL compared to morning dosing. |
| Mori et al. 2013 (85). | Japan. | Prospective RCT; morning (group 1) vs. bedtime (group 2) administration of ARB with increasing dosing and/or addition of long acting CCB for BP control; blinded by numbered containers. | 56% male; aged 62 y; untreated primary HTN; 9% on diabetic medications; 6% CKD. Participants were free from secondary HTN, severe liver dysfunction, stroke, bilateral renal artery stenosis, hyperpotassemia, and had >1 kidney present. Groups did not vary on baseline characteristics. (Total completing study, n=188; group 1, n=96). | Office SBP ≥140 mmHg, DBP ≥90 mmHg-measured after sitting ≥10 minutes. Excluded if SBP ≥180 mmHg. | 6. | Group 1: Baseline dose of ARB, 14 ± 5 mg; 6 month dose, 22 ± 11 mg. Baseline #number. of antihypertensive drugs, 1.1; 6 months # of antihypertensive drugs 1.4 including ACEI, CCB, β-blockers, diuretics and spironolactone. Group 2: none | Group1: none Group 2: Baseline dose of ARB, 14 ± 5 mg; 6 month dose, 21 ± 12 mg. Baseline # number of antihypertensive drugs, 1.2; 6 months # of antihypertensive drugs 1.4 including ACEI, CCB, β-blockers, diuretics and spironolactone. | Office BP and morning home BP obtained after 2 minutes of sitting rest within 1h of waking from nighttime sleep. | Renal function: glomerular filtration rate, sCR, albumin-to-creatinine ratio; C-reactive protein; pulse rate; cardiothoracic ratio; total voltage of the S wave of V1 + R wave of V5 (SV1 + RV5); dose amount. | Compared to baseline, group 1 and 2 ↓ office and morning SBP and DBP, SV1 + RV5, and albumin-to-creatinine ratio with no difference between dose time. Office and morning pulse rate ↓ in group 1 but not group 2. Compared to baseline, group 1↓ glomerular filtration rate, and group 2 ↓ cardiothoracic ratio. There was no significant difference in dose of ARB between groups or number of drugs administered. |
| Santiago et al. 2014 (84). | Portugal. | Cross-sectional; observational study; random sampling with replacement; patients with controlled (group 1) vs. uncontrolled (group 2) HTN. | 52% male; 86% aged <65 y; 65% controlled HTN; n=201. | ICPC-2 classification of HTN based on the mean of the last 3 measurements over a minimum of 9 months. | N/A. | N/A. | N/A. | Number and type of antihypertensive medications, time of day of medication ingestion, use of NSAIDs. | Age, gender, previous CV events, comorbidity. | ↑Target organ damage and nighttime dosing of antihypertensive medications in group 1; ↑NSAIDs use in group 2. |
| Soumela et al. 2015 (237). | Finland. | Prospective; morning vs. evening aspirin administration; unclear blinding. | 59% male; aged 65±8 y; regular antihypertensive therapy ≥ 1 year; n=34. | N/A. | 3. | Before intervention: aspirin taken on awakening. | Aspirin taken at bedtime. | 24 h ABPM, office BP, home morning and evening BP | Arterial pulse wave velocity (PWV), stiffness index, and reflection index. | Evening administration ↓office SBP and ↑carotid-femoral PWV, and plasma TG compared to morning administration. |
| Szauder et al. 2015 (103). | Hungary. | Prospective; once daily (evening-group 1) vs. twice-daily (morning and evening-group 2); unclear blinding. | 40% male; aged 56 ± 14 y; newly diagnosed primary HTN; BMI 24 ±2 men, 21 ±3 women; 100% non-dipperb; 100% Caucasian; sedentary occupation; non-smokers; no other comorbidity; no other regular medication (prescribed or illicit); no cardiologic complains; normal sleep quality; and clinically free of any sleep-related disorder. (n=164; group 1, n=41). | Office SBP ≥160 mmHg, DBP ≥100 mmHg and confirmed by 24 h ABPM with mean SBP/DBP >130/80 mmHg and diurnal mean >135/85 mm Hg or nocturnal mean >120/80 mmHg untreated. | ~0.5. | Group 1: none. Group 2: Split-dose of long-acting ACEI at 8 AM OR Split-dose of long-acting ARB at 8 AM. | Group1: Complete dose of long-acting ACEI OR long-acting ARB at 8 PM. Group 2: Split-dose of long-acting ACEI at 8PM OR Split-dose of long-acting ARB at 8 PM | 24 h ABPM-SBP/DBP mean, hypertensive time index (proportion of timing BP values are above normal), diurnal index (difference between day-time and night-time BP), hyperbaric impact/pressure load: in mmHg x h | N/A. | Mean BP, % time elevation index, and the hyperbaric impact ↓ in all groups. Diurnal index (i.e. reducing # of non-dippers) ↑ with group 2 (either drug) compared to group 1. |
| Ushijima et al. 2015 (101). | Japan. | Multicenter, open-label, RCT, parallel-group; comparison of morning valsartan ARB vs. evening of valsartan ARB (group 1), morning olmesartan ARB (group 2) and evening olmesartan ARB (group 3), no blinding. | 65% male; aged 65 ±9; 5% T2D; 100% non-dipperb. (n=40; group 1, n=12; group 2, n=13; group 3, n=15; 88% completed study-results not presented in an intention to treat format). | Office SBP ≥140 mmHg, DBP ≥90 mmHg; controlled BP: Office BP <140/90 mm Hg in non-diabetic patients and <130/80 mmHg in diabetic patients. | 4. | All groups-valsartan ARB at randomization. Group 2: Switched to olmesartan ARB. Group 3: none. | Group 1: Switched to valsartan ARB. Group 2: none. Group 3: Switched to olmesartan ARB. | 24h ABPM-SBP reduction at night, SBP/DBP during waking hours, during sleep, and average 24 h. | Renal function: serum creatinine, eGFR. | Compared to baseline SBP ↓during sleep and ↑during waking hours in group 1, SBP ↓during sleep and waking hours for group 2 and 3. % Reduction in SBP at night compared to SBP at waking ↑in all dosing groups compared to valsartan AM. Serum creatinine ↓in groups 2 and 3; ↑ eGFR in group 2. |
| Zappe et al. 2015 (102). | Germany, Spain, France, Italy, and the Netherlands. | Multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group; morning administration of long acting ACEI (group 1) vs. ARB administered in the morning (group 2) or evening (group 3). | 56% male; aged 62 ± 11; BMI 29 ± 4; 55% non-dipperb; 27% controlled T2D; 12% metabolic syndrome; 4% MI/PTCA/CABS/stroke. (Group 1, n= 359; group 2, n=367; group 3, n=356). | 24h ABMP >130/80 mmHg + 1 additional CV risk factor; BP did not exceed 160/95 mmHg. | 6.5. | Group 1: ACEI. Group 2: ARB + possible addition of diuretic if BP not controlled following 12 weeks of treatment. Group 3: none. | Group 1: none. Group 2: none. Group 3: ARB + possible addition of diuretic if BP not controlled following 12 weeks of treatment. | BP control rate (24h ABPM average <130/80 mmHg) and change from baseline to week 12 mean 24h ABPM-before addition of diuretic; office BP (sitting mean of 3 measures), daytime BP, nighttime BP, daytime/nighttime BP ratio, early morning BP, morning BP surge, BP variability. | N/A. | Mean 24h ABPM similar between groups. |
| Meta-analysis | ||||||||||
| Roush et al. 2014 (104). | Meta-analysis of randomized trials using evening dosing or usual dosing of antihypertensives to reduce cardiovascular events. | 5 evening dosing trials: 33–73% male; mean age 63–77 years, (evening dosing, n=35,075; usual dosing, n=312,057). | Varied. | 24-64. | 3 studies had a morning dosing arm using ACEI. | 4 studies used CCB, 1 used ACEI. | Office BP. | Coronary artery disease, CV events, stroke. | Evening dosing ↓risk of coronary artery disease and stroke versus usual dosing. | |
Inclusive of original studies reviewed from January 2013 to December 2017.
a
Mean number of medications taken in total.
b
Non-dipping BP defined as average nocturnal SBP reduction compared to average awake SBP (measured using ABPM) ≥0% but <10%; extreme dipper nocturnal SBP reduction ≥20%; and riser or reverse dipper when reduction <0%. ABPM, ambulatory blood pressure monitoring; ACEI, angiotensin-converting enzyme inhibitors; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; BP, blood pressure; CABS, coronary artery bypass surgery; CCB, calcium channel blockers; CKD, chronic kidney disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; HF, heart failure; HTN, hypertension; ICPC-2, International Classification of Primary Care second edition; MI, myocardial infarction; OSA, obstructive sleep apnea; PTCA, percutaneous transluminal coronary angioplasty; RCT, randomized controlled trial; SBP, systolic blood pressure; sCr, serum creatinine; T2D, type 2 diabetes mellitus.