Table 1.
Clinical trials and studies considering time of day in treatment for hypertension.
| DRUG CLASS | DRUG(S) | STUDY DESIGN; POPULATION | STUDY CONCLUSIONS | SUGGESTED TIME OF DAY | CITATION |
|---|---|---|---|---|---|
| Anti-hypertensives | |||||
| Calcium Channel Blockers | Amlodipine | Single center, randomized crossover study; Hypertensive / normotensive subjects. | Highest effect on reducing BP & HR when taken in the morning (0800 h) compared to evening (2000 h). | Morning | Khodadoustan, Nasri Ashrafi et al. 2017 |
| Nifedipine GITS | Multicenter, double-blind, randomized clinical trial; 180 Hypertensive patients (86 males, 94 females) | Bedtime dose was more effective and was associated with decreased negative side effects. | Bedtime | Hermida, Ayala et al. 2008 | |
| Verapamil - COER | 8-wk prospective, multicenter, randomized, double-blind clinical trial; 193 dipper and 64 non-dipper hypertensives | A dose at 2200 h reduced 24h BP on dippers and non-dippers, but had a greater reduction in nocturnal BP on non-dippers. | Night (2200 h) | White, Mehrotra et al. 1997 | |
| Open-label, multiple-dose, four-period, crossover study; 29 healthy men | There were no differences between an 0800 h and a 2200 h dose on BP, however time of administration did affect the rate of absorption (morning dose was slower). | Morning | Gupta, Yih et al. 1995 | ||
| CODAS - verapamil | 8-week, double-blind, placebo-controlled trial; 257 patients:193 dippers & 64 nondippers | Taken between 2100–2300 h produced best effects in the morning (between 0600 – 12000 h). | Night (2100 – 2300 h) | Smith, Neutel et al. 2001; Prisant 2003 | |
| Open-label, multicenter dose-titration study; Elderly (≥65 y/o) 628 patients. | 200 mg/d at bedtime, dosing was titrated to a maximum of 400 mg/d | Night | Weber, Prisant et al. 2004 | ||
| Nitrendipine | 6 hospitalized and drug-free patients with essential hypertension. | More effective at awakening (0600 h) or supper compared to breakfast (0830 h) and supper administration brought a deeper asleep BP decline. | Awakening or Supper | Umeda, Naomi et al. 1994, | |
| Isradipine Sustained Release | Double-blind, randomized, cross-over design; Non-dipping chronic renal failure patients | Both 0800 h and 2000 h effectively reduced 24-h BP, but 2000 h administration showed a more pronounced effect during the night. | Night (2000h) | Portaluppi, Vergnani et al. 1995 | |
| Diltiazem Retard | Open, non-randomized study; 13 dipper, essential hypertension patients | Morning (0800 h, n = 7) dose had the most marked antihypertensive effects during nighttime BP, while evening dose (1900 h, n = 6) dose exerted greatest effects during daytime activity with inhibition of the morning BP rise. | Evening | Kohno, Iwasaki et al. 1997 | |
| Open, non-randomized study; 5 dipper, essential hypertension patients | Dosing 3x a day had the best effect during daytime activity. | 3x daily | |||
| Diltiazem | Open, non-randomized study; 8 non-dipper, essential hypertension patients | Most pronounced antihypertensive effects during nightly rest. Evening dose seems to be more efficacious than the other dosage schedules. | Evening | ||
| Diltiazem Extended Release (ER) | Open-label, randomized, two-way crossover study; 48 healthy volunteers | Administration in the evening (2200 h) exhibited 17% and 22% greater bioavailability compared to morning (0700 or 0800 h) administration under single-dose and steady-state conditions, respectively. The two times of drug administration were bioinequivalent in both studies. Evening schedule provided more than twofold higher plasma diltiazem levels in the critical morning hours. | Evening | Sista, Lai et al. 2003 | |
| NSAIDS | Aspirin | Prospective trial; 328 untreated patients with grade 1 hypertension | 100mg at bedtime reduced ambulatory BP, while a dose upon awakening increased the 24h mean BP | Evening | Hermida et al., 2005 |
| Pregnant women | Bedtime (but not morning) aspirin dosing was best for preventing pregnancy-induced hypertension and preeclampsia. | Bedtime | Smolensky & Haus, 2001 | ||
| Randomized control trial | Low dose aspirin administered in the evening is more effective at reducing morning platelet activity than morning dosing. | Evening | Bonten, Snoep et al. 2015, van Diemen, Fuijkschot et al. 2016, Racca, van Diemen et al. 2019 | ||
| ACE inhibitors | Benazepril | Most effective at controlling nocturnal and early morning BP and consequently, normalizing the circadian BP profile, when dosed at night | Evening | Palatini, Mos et al. 1993 | |
| Enalapril | Randomized, crossover study; 8 hypertensive patients | Witte, Weisser et al. 1993 | |||
| Perindopril | 20 hypertensive patients | Early morning BP rise is reduced more with night (2100 h) administration. However, it does not reduce BP over 24 h as is achieved with the morning (0900 h) dose. | Night (2100 h) | Morgan, Anderson et al. 1997 | |
| Quinapril | Double-blind clinical trial; 18 hypertensive patients | 24-hour BP profiles showed a more sustained antihypertensive action with the evening (2200 h) administration compared with the morning (0800 h) administration. | Evening | Palatini 1992, Palatini, Racioppa et al. 1992 | |
| Ramipril | Open, randomized, crossover trial; 33 patients with mild-to-moderate essential hypertension | A significant decrease from baseline BP was observed with a once-daily dose either at morning (0800 – 1100 h) or evening (2000 – 2300 h), and provided equal or better, BP control when taken in the morning. | Morning (0800 – 1100 h) | Myburgh, Verho et al. 1995 | |
| Prospective, randomized, open-label, parallel-group, blinded end point multicenter clinical trial; 115 untreated hypertensive patients | Diurnal BP reduction was similar with awakening or bedtime treatment. However, Bedtime administration was significantly more efficient at reducing asleep BP. | Bedtime | Hermida and Ayala 2009 | ||
| Spirapril | 165 previously untreated subjects | The BP reduction during diurnal activity was similar for both treatment times. However, bedtime administration was more efficient than morning administration in reducing asleep BP. The awake/asleep BP ratio was decreased with the upon-awakening schedule but significantly increased toward a more dipping pattern with the bedtime treatment schedule. | Bedtime | Hermida, Ayala et al. 2010 | |
| Lisinopril | 40 subjects with primary mild to moderate hypertension | Greater reduction of systolic BP and diastolic BP from 0600 h to 1100 h after 2100 PM dosing. | Night (2100 h) | Macchiarulo, Pieri et al. 1999 | |
| Zofenopril | 33 untreated patients with grade 1 or 2 uncomplicated essential hypertension | Nocturnal BP regulation is better achieved at bedtime administration as compared to at awakening, without any loss in efficacy during diurnal active hours. | Bedtime | Balan, Popescu et al. 2011 | |
| Trandolapril | 37 hypertensive patients | The 24-h systolic BP was reduced with both morning and bedtime regimes, but bedtime dosing had a greater decrease in pre-waking and morning systolic BP. | Bedtime | Kuroda, Kario et al. 2004 | |
| Captopril + Hydrochlorothiazide | 20 hypertensive patients | Morning dose resulted in reduced daytime BP, and an evening dose reduced evening BP. | Morning intake controls morning BP; Evening intake controls evening BP | Middeke et al., 1991 | |
| α-Adrenoceptor Antagonists | Doxazosin | Clinical trial; 111 patients with mild hypertension | Slightly reduced the 24-h systolic BP and diastolic BP ratio, having no significant effect in asleep BP; evening, dose of these drugs had a significant 24-h SBP and DBP-lowering effect throughout the entire day, with the greatest effects on early morning BP. | Evening | Pickering, Levenstein et al. 1994 |
| Doxazosin GITS | 91 subjects: 49 men and 42 women with grade 1–2 essential hypertension | 24 h mean BP reduction was larger and statistically significant (6.9 and 5.9 mm for systolic and diastolic BP, respectively, in monotherapy; 5.3 and 4.5 mm Hg in polytherapy) when doxazosin GITS was scheduled at bedtime. This BP-lowering effect was similar during both the day and nighttime hours. Doxazosin GITS ingested daily on awakening failed to provide full 24h therapeutic coverage | Evening | Hermida, Calvo et al. 2004 | |
| β-adrenoceptor antagonists | Propranolol | 4 subjects | No circadian variation in the maximum decrease in HR, but the time to peak effect dependended on time intake. Circadian variation in sympathetic tone and vascular reactivity is mainly responsible for the circadian changes in the effects of propranolol. | No difference | Langner and Lemmer 1988 |
| Nebivolol | Hypertensive patients with a non-dipper BP profile | Either morning or evening administration, had significant BP-lowering effects throughout the day, with more marked effects on the awake BP mean. However, morning administration had a greater attenuation of the nocturnal BP decline, which effectively increased the number of non-dipper patients. | Morning | Hermida, Calvo et al. 2006 | |
| 19–76 y/o with mild to moderate hypertension | Morning and evening were equally effective but evening administration had greater anti-hypertensive effects on prewaking BP. | Equaly effective; evening had added benefits | Acelejado et al., 2012 | ||
| Angiotensin II Receptor Blockers | Valsartan | Patients with essential hypertension | 1600mg at night was more effective at reducing nocturnal BP than when taken during the morning. | Night | Hermida, Calvo et al. 2003, Hermida, Calvo et al. 2005, Hermida, Calvo et al. 2005 |
| Non-sleepy (at nighttime) hypertensives w/obstructive sleep apnea | Evening dose better controls BP; there are differential BP patterns between am and pm | Evening | Kasiakogias, Tsioufis et al. 2015; Reviewed in Bowles, Thosar et al. 2018 | ||
| Olmesartan | 40 Patients: 23 Females 17 Males | Night-time to create dipper phenotype | Evening | Hermida, Ayala et al. 2009, Tofe Povedano and Garcia De La Villa 2009 | |
| Candesartan | Evening doses were more effective at reducing the risk of microalbuminuria compared to morning dosing. | Evening | Kario, Hoshide et al. 2010 | ||
| Diuretics | Torsemide | Randomized control study; 113 grade 1 and 2 hypertensive patients, 51.7+/−10.6 yrs of age | A 5 mg dose at bedtime, but not upon awakening, was effective at reducing the 24h-SBP:DBP, and providing complete 24-h BP coverage. | Bedtime | (Hermida et al., 2008) |
| Combination Therapies | Hydrochlothiazide + Valsartan | Greatest ambulatory BP control when taken in the evening, compared to the morning. | Evening | Hermida, Ayala et al. 2011 | |
| Hydrochlothiazide + Amlodipine | Greater control of BP across the day when taken in the evening compared to the morning. | Evening | Hermida, Ayala et al. 2010, Zeng, Jia et al. 2011 | ||
| Hypertensives with chronic kidney disease | Evening anti-hypertensive dosing was more effective than morning dosing for controlling nocturnal BP and lowering the percentage of non-dipper BP patterns. | Evening | Crespo, Pineiro et al. 2013, Wang, Ye et al. 2017 | ||
| Hypertensive African Americans | No beneficial effects of evening dosing over morning dosing were reported. | No difference | Rahman, Greene et al. 2013 | ||