Cardiovascular chronotherapy (primary papers)

What is chronotherapy?

Chronotherapy aims to match timing of therapy administration to patient’s endogenous circadian rhythms. The regimen can be applied to new or long-standing treatments where the schedule corresponds to the patient’s rhythms to maximize efficacy while decreasing side effects. Chronotherapeutics is used for treatment of various diseases, including cardiovascular, cancer, asthma, depression, seasonal affective disorders, and others.

Academic Articles
Keywords used: “cardiovascular chronotherapy,” “hypertension chronotherapy,” “chronotherapy heart,” – original papers (reviews omitted in this list).

Cardiovascular chronotherapy studies

Evening administration of non-diuretic antihypertensive drug improved BP control in non-dipper and riser refractory arterial hypertension patients (n=27).

Beta1 receptor blocker, nebivolol, reduced 24 hr BP parameters when administered in the morning or evening, however, the evening dose reduced prewaking SBP in a study of 38 hypertensive patients.

Early morning ambulatory SBP and 24h BP was better controlled with morning metoprolol vs. atenolol in 26 hypertensive patients.

Propranolol controlled release formulation significantly reduced morning DBP after 8 wks of treatment (7mmHg from baseline) as well as well controlled evening BP in 434 total patients with mild-to-moderate hypertension.

Trichlormethiazide evening vs. morning administration affected blood glucose levels in the evening with serum electrolyte and lipid levels unchanged in an 8 week trial in 12 hypertensive patients.

Olmesartan evening, but not morning, administration improved the diurnal BP profile towards a dipper pattern while maintaining 24 h control over BP with both treatment times in 123 hypertensive patients over 3 months.

Evening telmisartan administration partially restores the nighttime dipper profile while maintaining 24h BP control in 215 hypertension patients over 12 weeks of treatment.

Sleeptime blood pressure nocturnal dip was improved with bedtime zofenopril than morning administration, both times of day effectively controlled diurnal BP reductions.

Bedtime spirapril administration improved nighttime BP and improved control of ambulatory BP from 23% to 59% of essential hypertension patients.
Hermida, R.C., D. E. Ayala, M. J. Fontao, A. Mojon, I. Alonso and J. R. Fernandez (2010)."Administration-time-dependent effects of spirapril on ambulatory blood pressure in uncomplicated essential hypertension." Chronobiol Int 27(3):560-574. 

Bedtime ramipril improved nocturnal BP regulation as well as maintained 24 h BP. The proportion of patients increased significantly that have better controlled ambulatory BP. 

Kohno, I., H. Ijiri, M. Takusagawa, D. F. Yin, S. Sano, T. Ishihara, T. Sawanobori, S. Komori and K. Tamura (2000). "Effect of imidapril in dipper and nondipper hypertensive patients: comparison between morning and evening administration." Chronobiol Int 17(2): 209-219.

Morning perindopril administration reduced BP over 24 hrs, while evening perindorpil reduced BP for only 18 hrs. Evening perindopril exerted better control of morning BP. this study was conducted in 20 male patients with 4 weeks of treatment.

Morgan, T.,A. Anderson and E. Jones (1997). "The effect on 24 h blood pressure control of an angiotensin converting enzyme inhibitor (perindopril) administered in the morning or at night." J Hypertens 15(2): 205-211.

Enalapril administrated 07:00 better controlled daytime BP vs 19:00 which better controlled nighttime BP, but not afternoon BP in 8 patients with AMBP monitoring.

Quinapril administered in the evening better controlled 24h BP and reduced nighttime BP compared to morning administration in 18 patients after 2 weeks of treatment with each timing regimen.

Palatini,P. (1992). "Can an angiotensin-converting enzyme inhibitor with a shorthalf-life effectively lower blood pressure for 24 hours?" Am Heart J123(5): 1421-1425.

The nifedipine gastrointestinal therapeutic system bedtime administration improved dose dependent efficacy, significantly reduced the number of adverse events, including edema in an 8 week study of 80 patients.
Hermida RC,Calvo C, Ayala DE, López JE, Rodríguez M, Chayán L, Mojón A, Fontao MJ,Fernández JR. Dose- and administration time-dependent effects of nifedipinegits on ambulatory blood pressure in hypertensive subjects. Chronobiol Int.2007;24(3):471-93.

Bedtime doxazosin GITS significantly reduced 24 hr BP (SBP and DBP) including nocturnal BP in 91 subjects over 3 months of therapy. These effects were not seen with wake time treatment.
Hermida RC,Calvo C, Ayala DE, Domínguez MJ, Covelo M, Fernández JR, Fontao MJ, López JE. Administration-time-dependent effects of doxazosin GITS on ambulatory blood pressure of hypertensive subjects. Chronobiol Int. 2004 Mar;21(2):277-96.

Bedtime administration of amlodipine and hydrochlorothiazide resulted in patients with lower BP over 24, lower BP at night, normalize the nocturnal dip, and reduce the morning BP surge compared to morning administration in 80 patients.
Zeng J, JiaM, Ran H, Tang H, Zhang Y, Zhang J, Wang X, Wang H, Yang C, Zeng C. Fixed-combination of amlodipine and diuretic chronotherapy in the treatment of essential hypertension: improved blood pressure control with bedtime dosing-amulticenter, open-label randomized study. Hypertens Res. 2011 Jun;34(6):767-72.

Valsartan/hydrochlorothiazide combination bedtime therapy improved the 24 hr BP in 15% more patients than morning therapy. Additionally, bedtime therapy improved nocturnal SBP towards a dipper profile, and pulse pressure. This study was conducted in 204 subjects with 12 weeks of treatment.
Hermida RC,Ayala DE, Mojón A, Fontao MJ, Fernández JR. Chronotherapy with valsartan/hydrochlorothiazide combination in essential hypertension: improved sleep-time blood pressure control with bedtime dosing. Chronobiol Int. 2011 Aug;28(7):601-10.

Amlodipine/valsartan combination in the morning and evening controlled 24 hr BP, evening administration further improved the nocturnal BP.
Asmar R,Gosse P, Queré S, Achouba A. Efficacy of morning and evening dosing ofamlodipine/valsartan combination in hypertensive patients uncontrolled by 5 mg of amlodipine. Blood Press Monit. 2011 Apr;16(2):80-6.

Valsartan/amlodipine combination therapy controlled hypertension significantly better with bedtime administration over 48 hrs as well as a shift toward nocturnal dipper profile in 203 hypertensive patients. 
Hermida RC,Ayala DE, Fontao MJ, Mojón A, Fernández JR. Chronotherapy with valsartan/amlodipine fixed combination: improved blood pressure control of essential hypertension with bedtime dosing. Chronobiol Int. 2010Jul;27(6):1287-303.

Meng Y,Zhang Z, Liang X, Wu C, Qi G. Effects of combination therapy with amlodipine and fosinopril administered at different times on blood pressure and circadian blood pressure pattern in patients with essential hypertension. Acta Cardiol.2010 Jun;65(3):309-14.

Amlodipine-olmesartan bedtime therapy significantly reduced the morning BP surge, improved the nocturnal BP dip in non-dippers, and increased the urinary albumin excretion in 31 hypertensive patients. 
Bedtime dosing of ACEIs and CCBs significantly reduced 24-h MBP, DBP, and shifted towards a dipper profile and increased the number of patients with controlled ABP. Morning administration did not reduce nighttime BP.  This study was conducted in 60 patients with hypertension. 
Farah R, Makhoul N, Arraf Z, Khamisy-Farah R. Switching therapy to bedtime for uncontrolled hypertension with a nondipping pattern: a prospective randomized-controlled study. Blood Press Monit. 2013 Aug;18(4):227-31.

Resistant hypertension patients with bedtime regimen (n=1436) vs. upon-awakening and split doses (n=1463) of hypertension medications had significantly decreased ABPM, sleep SBP and DBP. Patients in upon-awakening and split dosing groups were more likely to have a non-dipping profile and a riser BP pattern, increasing CVD risk.
Hermida RC,Ríos MT, Crespo JJ, Moyá A, Domínguez-Sardiña M, Otero A, Sánchez JJ, Mojón A,Fernández JR, Ayala DE; Hygia Project Investigators. Treatment-time regimen of hypertension medications significantly affects ambulatory blood pressure and clinical characteristics of patients with resistant hypertension. ChronobiolInt. 2013 Mar;30(1-2):192-206.

Bedtime dosing of hypertension medication significantly improved mean sleep BP and ABPM, and decreased risk for cardiovascular events in 661 patients with chronic kidney disease over a 5.4-year follow-up.
Hermida RC,Ayala DE, Mojón A, Fernández JR. Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J Am Soc Nephrol. 2011 Dec;22(12):2313-21.

Bedtime vs. awakening administration of >1 hypertension medication significantly decreased cardiovascular risk, lower sleeptime BP, and better controlled ABPM in 448 hypertensive patients with type II diabetes over a 5.4-year follow-up.
Hermida RC, Ayala DE, Mojón A, Fernández JR. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care. 2011 Jun;34(6):1270-6.

The Ambulatory Blood Pressure Monitoring and Cardiovascular Events (MAPEC) clinical trial demonstrated that bedtime dosing of anti-hypertensive resulted in a nocturnal dipping profile with lower sleeptime BP, and better controlled ABPM in 2156 hypertensive patients. At 5.6-year follow up, the bedtime-treatment decreased CVD morbidity and mortality.
Hermida RC,Ayala DE, Mojón A, Fernández JR. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int.2010 Sep;27(8):1629-51.

Hypertensive patients taking 1 of 3 anti-hypertension drugs at bedtime vs 3 upon awakening had significantly improved ABPM, decreased nocturnal BP mean, and increased the percentage of dipping patients. 


Aspirin therapy vs placebo significantly reduced the morning peak of myocardial infarctions (MI) by 59%, and in the rest of the day by 34%. Overall, aspirin therapy reduced MI by 44% over 24 h. This study was conducted in 22,071 US male physicians with a 5year follow-up.

Bedtime administration of diltiazem (extended release) vs. ramipril significantly decreased SBP, DBP, and HR in a study of 261 hypertensive subjects after a 10 week treatment period. White WB,Lacourciere Y, Gana T, Pascual MG, Smith DH, Albert KS. Effects ofgraded-release diltiazem versus ramipril, dosed at bedtime, on early morning blood pressure, heart rate, and the rate-pressure product. Am Heart J. 2004Oct;148(4):628-34.