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The Option of Chronotherapy of Hypertension

March 2024
Cardiology in Review

March 2024

Authors:

University of Oklahoma

The aim of the present paper is to explore the option of chronotherapy of hypertension and its effectiveness in blood pressure (BP) lowering compared with its standard daily treatment. The treatment of BP has gone through many different schemes over the years. From no treatment in the early 1930s, to step care, to multiple drug combinations, or to single daily drug combinations with 2–3 drugs, still BP is not well controlled in a significant number of patients. Recently, the role of the circadian rhythm in the treatment of hypertension has been tested by several studies comparing the evening versus the morning drug administration with no clear evidence of superiority of either mode of drug administration. However, in cases of morning surge of BP, nocturnal hypertension, and renal disease, the evening drug administration has been more effective than the morning drug administration, and thus, more preferable. In order to get a better perspective on this approach of hypertension treatment, a Medline search of the English literature was contacted between 2010 and 2023 using the terms BP control, circadian rhythm, morning drug administration, evening drug administration, and 38 pertinent papers were selected for analysis. Careful review of the selected papers showed that chronotherapy of hypertension is effective. However, the overall effectiveness of evening drug administration compared with the morning administration is not significantly more effective compared to the morning administration and more work is needed in this field.

Beneficial Antihypertensive Effects of Evening Drug Administration

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Higher Diastolic Blood Pressures Associated With the J-Curve Effect

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Cardiology in Review • Volume XXX, Number 00, xxx 2024 www.cardiologyinreview.com | 1

ISSN: 1061-5377/24/XXX00-0000

DOI: 10.1097/CRD.0000000000000644

R A

*From the Department of Cardiology, University of Oklahoma Health Sciences

Center, Oklahoma City, OK.

Disclosure: The authors have no conﬂicts of interest to report.

Correspondence: Steven G. Chrysant, MD, PhD, Department of Cardiology, Uni-

versity of Oklahoma Health Sciences Center, 5700 Mistletoe Court, Oklahoma

City, OK 73142. E-mail: schrysant@yahoo.com.

The Option of Chronotherapy of Hypertension

Steven G. Chrysant, MD, PHD*

Abstract: The aim of the present paper is to explore the option of chrono-

therapy of hypertension and its eectiveness in blood pressure (BP) lowering

compared with its standard daily treatment. The treatment of BP has gone

through many dierent schemes over the years. From no treatment in the early

1930s, to step care, to multiple drug combinations, or to single daily drug

combinations with 2–3 drugs, still BP is not well controlled in a signiﬁcant

number of patients. Recently, the role of the circadian rhythm in the treatment

of hypertension has been tested by several studies comparing the evening ver-

sus the morning drug administration with no clear evidence of superiority of

either mode of drug administration. However, in cases of morning surge of

BP, nocturnal hypertension, and renal disease, the evening drug administra-

tion has been more eective than the morning drug administration, and thus,

more preferable. In order to get a better perspective on this approach of hyper-

tension treatment, a Medline search of the English literature was contacted

between 2010 and 2023 using the terms BP control, circadian rhythm, morn-

ing drug administration, evening drug administration, and 38 pertinent papers

were selected for analysis. Careful review of the selected papers showed that

chronotherapy of hypertension is eective. However, the overall eectiveness

of evening drug administration compared with the morning administration is

not signiﬁcantly more eective compared to the morning administration and

more work is needed in this ﬁeld.

Key Words: hypertension, chronotherapy, morning dose, evening dose,

eectiveness

(Cardiology in Review 2024;XXX: 00–00)

The treatment of hypertension has gone through several evolu-

tionary stages over the years. In the 1930s high blood pressure

(BP) was considered a benign and evolutionary condition and it was

“essential” for the maintenance of life, and prominent physicians of

the day did not recommend its treatment.1,2 However, later clinical

research studies of US veterans, demonstrated that hypertension was

not a benign condition and was associated with increased incidence

of cardiovascular (CV) and renal complications if left untreated.3,4

The results of the Veterans Administration studies resulted in the ini-

tiation of the Joint National Commission (JNC) guidelines for the

treatment of hypertension. The JNCs 1–3 focused on the treatment

of diastolic blood pressure (DBP) to <90 mm Hg recommending

the step-care approach starting with a diuretic and progressively

adding other drugs as necessary, stating that the beneﬁts of treat-

ing the systolic BP (SBP) were not clear at the time.5–8 The subse-

quent JNC reports (JNC 4–7) recommended the treatment of SBP

as well as the DBP to <140/80 mm Hg since clinical evidence had

shown the beneﬁts of lowering the SBP and recommended combina-

tion drug treatments.9–11 The JNC 7 report recommended even lower

BP < 130/80 mm Hg if tolerated.11 Later, the emphasis was focused

on treating the SBP, stating that SBP is all that matters especially in

older patients.12 Subsequent studies showed that more aggressive BP

control to <120/80 mm Hg was associated with a decrease in CVD,

stroke, and renal complications of hypertension.13,14 Based on the

results of these studies, new BP treatment guidelines were issued

by the American College of Cardiology/American Heart Associa-

tion (ACC/AHA) recommending BP reduction to <130/80 mm Hg15

and by the European Society of Cardiology/European Society of

Hypertension recommending BP reduction to <140/90 mm Hg for

adults ≥65 years of age and <130/80 mm Hg for patients <65 years

of age and in those with type 2 diabetes mellitus, coronary artery

disease, or chronic kidney disease (CKD).16 However, despite the

multidrug treatment of hypertension a signiﬁcant number of patients

continue to have uncontrolled or resistant to treatment hypertension

in the United States and other countries.17–19 For better BP control,

a new approach to treatment of hypertension should be tried. Such

an approach could be the use of chronotherapy of hypertension. In

order to get a better perspective on this approach, a Medline search

of the English literature was contacted between 2010 and 2023 using

the terms BP control, circadian rhythms, chronotherapy, evening

drug administration, morning drug administration, and 38 pertinent

papers were selected. The ﬁndings from these papers in combination

with collateral literature will be discussed in this concise review.

THE PATHOPHYSIOLOGY OF CHRONOTHERAPY OF

HYPERTENSION

In 2023 the National Institutes of Health convened a workshop

on precision medicine involving circadian rhythm and chronother-

apy of hypertension.20 The workshop demonstrated that a promising

emerging area of BP treatment is the translation of circadian biol-

ogy into the treatment of hypertension. The goal of this of circadian

medicine is to leverage the power of circadian biology for the better

control of BP and for the improvement of human health.21–23 The

circadian rhythm is the biological process that occurs on a 24-hour

basis, is coordinated by the light-dark cycle, is present in all ani-

mal species, and controlled by the circadian clock located in the

suprachiasmatic nucleus (SCN) of the hypothalamus.24 The circa-

dian rhythm has a very important function, since it controls almost

all the mammalian physiological functions in all animal species,24

and has helped in the design of chronopharmacology, and the time-

depending drug dosing.21–23 It also aects the drug pharmacokinet-

ics regarding absorption, distribution, metabolism, and excretion,

which bear on the duration and level of activity of certain drugs.

Several studies have shown the importance of circadian rhythm and

the evening drug administration being more ecacious in normal-

izing the BP and in reducing the early morning surge of BP and

CV events.25–27 These beneﬁcial antihypertensive and CV eects

of chronotherapy have been demonstrated with several antihyper-

tensive drugs that include calcium channel blockers, angiotensin

converting enzyme inhibitors, angiotensin receptor blockers, and

diuretics as well as other classes of drugs and depend on the chro-

notherapeutic drug delivery systems.28–32 Other studies have shown

that chronotherapy improves resistant hypertension by reversing the

nondipper status to dipper.27 The BP regulation follows a circadian

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rhythm increasing during the active hours of the day, decreasing

postprandially and during sleep at night and increasing in the morn-

ing upon awakening.33 The subjects that show a 10–20% decrease

in the evening BP relative to daytime are considered dippers and

those that show less than 10% decrease in evening BP are called

nondippers. The best way to measure the circadian variations of BP

is through telemetry in experimental animals by placing catheters

in the common carotid arteries and monitoring the BP continuously

in real time and assessing the eects of antihypertensive drugs.20

In man, this can be done only through ambulatory blood pressure

monitoring (ABPM), but this method is not very useful because

it is cumbersome and does not allow continuous BP monitoring.

These diculties will eventually be overcome by the development

of accurate wearable cuess BP monitoring devices, which at pres-

ent are not accurate and not recommended for clinical use.34

ANTIHYPERTENSIVE AND CARDIOVASCULAR

EFFECTS OF CHRONOTHERAPY OF HYPERTENSION

Chronotherapy of hypertension is scarcely used today and

the reason for this is that most clinical trials for the treatment of

hypertension were conducted with the daily administration of anti-

hypertensive drugs. However, there are several trials with the night

administration of antihypertensive drugs based on the circadian

variation of BP with very good antihypertensive and CV protec-

tive eects.35–44 These studies are listed in Table 1 and they will be,

brieﬂy, discussed here. The prospective study by Kasiakoglas et al,35

included 41 patients with hypertension and obstructive sleep apnea

mean age of 52 ± 9 years. The patients were treated with a single

dose of valsartan or a combination of valsartan with amlodipine in

the morning for 8 weeks and then given the same drug regimen in

the evening for 8 weeks. Compared with the morning administration

of the drugs, the 24-hour SBP and DBP were greater decreased by

the evening administration of the drugs by 4.4 ± 8.6 mm Hg in SBP

and by 2.9 ± 5.6 mm Hg in DBP, P = 0.007 and P = 0.006, respec-

tively. Jiang et al36 examined the eect of evening versus morning

administration of antihypertensive drugs on BP control in a review

and meta-analysis of 9 studies involving 10,157 patients. The results

demonstrated that bedtime administration of antihypertensive drugs

resulted in SBP reduction by 1.37 mm Hg [95% conﬁdence interval

(CI), −2.49–0.14, P = 0.08] comparing with the morning admin-

istration Similarly, the review and meta-analysis by Sun et al,37

included 1566 hypertensive patients on the eects of evening admin-

istration of drugs on 24-hour ABPM, ages 54–60 years followed

from 8 weeks to 4.4 years. Bedtime administration of drugs resulted

in reduction of 24-hour SBP/DBP by 2.7/0.36 mm Hg and in the

evening SBP/DBP reduction by 6.32/3.17 mm Hg, P = 0.03/0.007,

compared with the morning drug administration. There was no sig-

niﬁcant dierence in the diurnal mean SBP/DBP control from the

baseline with the evening and morning drug administration, but a

signiﬁcant decrease in nocturnal SBP/DBP by 4.72/3.57 mm Hg,

(P = 0.01/0.05) with the bedtime drug administration. There was no

evidence of publication bias by a funnel plot. The study by Hjork-

jaer et al38 is a randomized, placebo-controlled, crossover study of

24 patients with T1DM and CV autonomic neuropathy with non-

dipping BP mean age 60 ± 7 years, on the eects of evening drug

administration on BP dipping. These patients were randomized to

20 mg enalapril in the morning and placebo in the evening and fol-

lowed for 12 weeks. Then the treatment was reversed for another

12 weeks. Treatment of BP with evening administration of enalapril

resulted in increase of SBP dipping by 2.4% compared to morning

administration of enalapril. There were no changes in left ventricu-

lar function. The reduction in dipping of SBP could result in long-

term CV beneﬁcial eects. The eect of evening administration of

antihypertensive drugs on BP and renal function was examined by

Wang et al,39 in 3752 patients with hypertension and CKD. They

found that evening administration of antihypertensive drugs was

associated with a signiﬁcant reduction of nondipper hypertension

in 40% of patients, risk ratio (RR) (95% CI, 0.43–0.84) compared

to morning administration. It also resulted in a signiﬁcant reduction

in nocturnal SBP, MD −3.17 mm Hg (95% CI, −5.41 to −0.94) and

nocturnal DBP, MD −1.37 mm Hg (95% CI, −2.05 to −0.69), and

a signiﬁcant decrease in awake SBP, MD −1.15 mm Hg (95% CI,

0.10−2.19). In addition, evening drug administration improved renal

function by signiﬁcantly increasing the eGFR (P = 0.042). However,

there was no signiﬁcant dierence in all-cause and CV mortality

between the evening and morning drug administration. The study

by Luo et al,40 is a review and meta-analysis of 19 RCTs involving

1215 hypertensive patients on the eects of time administration of

amlodipine on BP. Amlodipine given in the evening compared to

the morning administration, signiﬁcantly decreased the night BP,

RR 2.04 (95% CI, 1.27–2.81, P < 0.00001), and also, decreased

the nondipping BP, RR 0.51 (95% CI, 0.41–0.63, P < 0.00001).

Hermida et al41 investigated the eects of evening drug adminis-

tration compared to morning administration in 2156 hypertensive

subjects mean age 56 ± 14 years, in the Monitarizacion Ambulato-

ria para Prediction de Eventos Cardiovasculares (MAPEC) study.

These patients were taken most of their medications in the morning

TABLE 1. Beneﬁcial Antihypertensive Effects of Evening Drug Administration

Study Patients Age F-U Results

Author (Type) (No) (Years) (Weeks) Δ SBP mm Hg E/M

Kasiakoglas et al35 Prosp 41 52 16 −4.4 P < 0.007

Jiang et al36 Rev-Meta 10,157 NA NA −1.17 P = 0.08

Sun et al37 Rev-Meta 1566 54–60 8–238 −6.32 P = 0.03

Hjorkjaer et al38 Prosp 24 60 24 +2.4% dipping P = 0.03

Wang et al39 Prosp 3732 NA NA −3.17 nocturnal P = NA

Luo et al40 Rev-Meta 1215 NA NA −SBP RR 2.04 P < 0.001

Hermida et al41 Prosp 2156 56 5.6 years −SBP 62% vs 34% am

Hermida et al42 Prosp 19,084 61 6.3 years −SBP/CVE P < 0.001

MacKenzie et al43 Prosp 21,104 65 5.2 years −1.8 P < 0.0001

Zhao et al44 Rev-Meta 5433 39–67 NA −3.39, Nocturnal–6.70

CVE indicates cardiovascular events; E/M, evening vs morning; F-U, follow-up; NA, not available; Prosp, prospective; Rev-Meta, review and meta-analysis.

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Cardiology in Review • Volume XXX, Number 00, xxx 2024 Chronotherapy of Hypertension

and ≥1 of them in the evening. Their BP was monitored by ABPM

and their activity by actigraphy. After 5.6 years of follow-up, eve-

ning administration of medications resulted in a decrease of ABP

by 62% compared to 53% with the morning drug administration

and decreased the nondipping status by 62% compared to 34% for

the morning drug administration. In addition, evening drug admin-

istration decreased signiﬁcantly the CVD events, HR 0.39 (95% CI,

0.20–0.51, P < 0.001) compared to morning drug administration.

In another prospective endpoint multicenter study Hermida et al,42

investigated the eects of chronotherapy on CVD risk reduction in

19,084 hypertensive patients mean age of 61 ± 14 years. The patients

were instructed to take ≥1 medication at bedtime, or all of their

medications in the morning. The BP was measured by ABPM for

48 hours at every visit. After 6.3 years of follow-up, the SBP and

the primary CVD outcomes were signiﬁcantly decreased, HR 0.55

(95% CI, 0.50–0.61, P < 0.001). Also, all the single components of

the primary outcomes (CVD death, MI, coronary revascularization,

HF, or stroke) were signiﬁcantly decreased (P < 0.001) compared

to the morning drug administration. There were no signiﬁcant dif-

ferences in the incidence of adverse eects between the treatments.

Also, in a prospective, randomized, open-label, blind-endpoint trial,

MacKenzie et al43 investigated the timing of drug administration and

their eects on BP and CV events in 21,104 hypertensive patients

mean age 65 years. The primary composite endpoint was besides

BP, the incidence of vascular death, hospitalization from nonfatal

MI, or nonfatal stroke. After a median follow-up of 5.2 years, the

primary endpoint occurred in 362 of 10,503 (3.4%) patients receiv-

ing their medications in the evening, 0.69 events (95% CI, 0.62–

0.76) per 100 person-years and in 390 (3.7%), 0.72 events (95%

CI, 0.65–0.79) per 100 person-years in those receiving their medi-

cations in the morning. The mean morning SBP assessed by home

BP measurement was lower by 1.8 mm Hg (P < 0.0001) and the

mean DBP was lower by 0.4 mm Hg (P = 0.23) with the evening vs

the morning drug administration. Also, there were no statistically

signiﬁcant dierences for the individual outcomes between the eve-

ning and morning doses. Drug-induced side eects such as dizziness

or lightheadedness were more common with the morning dose of

drugs. The study by Zhao et al,44 is a review and meta-analysis of

36 randomizes clinical trials involving 5433 hypertensive patients

ages 39–67 years. This study showed that evening administration of

antihypertensive drugs resulted in a reduction of 24-hour mean SBP

by 3.39 mm Hg (95% CI, −4.57 to −2.32 and mean DBP by 1.12 mm

Hg (95% CI, −1.70 to −0.53). It also reduced the nocturnal mean

SBP by 6.70 mm Hg (95% CI, −8.35 to −5.05) and the nocturnal

mean DBP by 3.54 mm Hg (95% CI, −4.46 to −2.63). In addition, it

reduced the CV events, RR 0.39 (95% CI, 0.25–0.60).

NO DIFFERENCE IN BLOOD PRESSURE AND

CARDIOVASCULAR EFFECTS OF CHRONOTHERAPY

Besides the beneﬁcial antihypertensive and CV eects of eve-

ning administration of antihypertensive drugs, there are several stud-

ies that show no dierence in these eects between the evening and

daytime administration of antihypertensive drugs.45–50 These studies

are summarized in Table 2 and they will be, brieﬂy, discussed here.

The study by Lafeber et al,45 was a randomized 3-period crossover

trial of 78 patients with established CVD mean age 67 ± 8 years, on

the CV and BP eects in patients treated randomly with a polypill

containing aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg, and

HCTZ 12.5 mg given in the morning or evening. The polypill given

in the evening decreased the LDL-C by 0.2 mmol (7.7 mg) compared

with the morning administration. However, it resulted in no signiﬁ-

cant dierence in the 24-hour BP reduction of 0.7 mm Hg (95% CI,

−2.1–3.4) by the polypill or the individual agents. Also, the adher-

ence to taking the polypill was similar between the morning and eve-

ning administration. The study by Zappe et al,46 was a multicenter,

randomized, double-blind study of 1093 hypertensive patients mean

age 62 years on the BP eects of valsartan and lisinopril. The patients

were randomized to valsartan 320 mg given in the morning or eve-

ning and lisinopril 40 mg given in the morning and HCTZ 12.5 mg

given as needed. After 26 weeks of treatment, the 24-hour ASBP

was decreased by 10.6 and 13.3 mm Hg at weeks 12 and 26 weeks,

respectively with the morning administration of valsartan and by 9.8

and 12.3 mm Hg, respectively with the evening administration of val-

sartan, which was not signiﬁcant. Also, the 24-hour ASBP decrease

with lisinopril given in the morning was 10.7 and 13.7 mm Hg at

weeks 12 and 26, respectively, and was not dierent from valsartan.

In another randomized. double-blind, placebo-controlled trial, Seri-

nel et al,47 investigated the morning and evening administration of

perindopril in 79 hypertensive patients with obstructive sleep apnea

mean age 52 ± 9 tears, on BP reduction. After 6 weeks of treatment,

the sleep SBP was reduced by 6.9 and 8.0 mm Hg, respectively with

the evening and morning administration of the drug, a dierence of

1.1 mm Hg (95% CI, −0.3–2.5). In contrast, morning drug admin-

istration resulted in a greater reduction of awake SBP by 9.8 ver-

sus 8.0 mm Hg with the evening drug administration, a dierence of

1.8 mm Hg (95% CI, 1.1–2.5). The prospective study by Fujiwara et

al,48 investigated the eects of morning and evening administration

TABLE 2. Higher Diastolic Blood Pressures Associated With the J-Curve Effect

Study Patients Age F-U DBP CAD J-C Event

Author (Type) (No) (Years) (Years) (mm Hg) (Existing) (Kind)

Klerman et al22 PC 902 55 6.1 80–90 Ye s MI

Cederroth et a23 PC 169 44 6.3 100–109 No MI

Douma and Gumz24 PC 2574 59 7.4 84 No MI

Kario25 PC 2145 51 4.0 86–91 Yes MI

Hermida et al26 PC 1765 51 4.2 84–88 Ye s MI

Bowls et al27 PC 686 52 12.0 81 Ye s MI

Schillaci et al28 PC 912 30–79 3-21 84 Ye s MI

White29 DB 4695 70 1-8 60–65 Ye s CVM

Sajan et al30 PC 10,355 52 30 <80 NO PCO

ACM, all-cause mortality; CAD, cardiovascular disease; CVM, cardiovascular mortality; DB, double-blind study; F-U, follow-up; J-C Event, J-curve event; MI, myocardial infarction;

PC, prospective cohort study; PCO, primary composite outcome (MI, CV death, stroke, hospitalization).

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Chrysant

of combination of valsartan/amlodipine 80/5 mg on the brachial and

central BP in 23 patients aged 68 years. After 16 weeks of treatment,

the dierence in the 24-hour brachial ASBP between the morning

and evening administration of drugs was −3.2 mm Hg (95% CI,

−6.8–0.4). Also, the dierence in the nocturnal central SBP was

−4.0 mm Hg (95% CI, −7.6 to −0.4). The upper limit of the 95%

CI was below the margin of 3.0 mm Hg for both the nocturnal bra-

chial and central SBP conﬁrming the noninferiority of morning

and evening drug administration. The study by Poulter et al,49 was

a prospective crossover trial of 95 hypertensive patients mean age

of 62 years. The patients were randomized to take their customary

medications either in the morning or evening for 12 weeks and then

were crossed over to the opposite drug administration for another

12 weeks. The BP was monitored by 24-hour ABPM at baseline and

at weeks 12 and 24. Drug administration either in the morning or

evening resulted in similar reductions of 24-hour ASBP 129.65 mm

Hg and 129.75 mm Hg for morning or evening drug administration,

adjusted mean dierence 0.11 mm Hg (95% CI, −3.20–3.42) and

ADBP 7.7.24 mm Hg for morning and 7.7.99 mm Hg for evening

drug administration, adjusted mean dierence 0.77 (95% CI, −1.38–

2.91) regardless of age ≤65 or ≥65 years. Similarly, there were no

dierences in the daytime and nighttime BP between the morning

and evening drug administration. In another prospective study, Kuate

et al,50 investigated the morning and evening administration of 10 mg

of perindopril on BP and mean albumin/creatinine ratio in 20 type 2

diabetes mellitus subjects mean age of 57.5 years. The patients were

randomized to morning administration of perindopril for 28 days and

then were crossover to the evening administration of the drug for

another 28 days. The BP was monitored by 24-hour ABPM at base-

line and at days 28 and 56. In this study, there was no dierence in the

24-hour ABP lowering (P = 0.61), but the albumin/creatinine ratio

was reduced by both the morning and evening drug administration,

−41.7 (95% CI, −92.6–9.2) mg/g.

DISCUSSION

Circadian rhythms control all the functions of our body

including BP, HR, and CV variability through the circadian clock

located in the SCN in the hypothalamus.24,51,52 The circadian variation

of BP is associated with a lower BP in the evening (BP dipping)

and higher BP in the morning with occasional BP surges that are

responsible for the increased CV complications with the morning

surge after arising from sleep.53–56 Also, no-dipping of BP or reverse

nighttime dipping of BP is associated with increased incidence of CV

complications, stroke, and death.57–61 Therefore, chronotherapy of

hypertension with evening administration of antihypertensive drugs

to avoid these complications makes perfect physiologic sense. Also,

the best time to administer a drug is at a time when the activity of the

target of the event is at its highest, such as is the case with enzyme

3-hydroxy-3-methylglutaril coenzyme A reductase (HMG co A) with

the production of cholesterol at night. Therefore, the administra-

tion of statins at night produces the best results, especially for the

short-acting statins.61–63 In contrast, the long-acting statins produce

similar cholesterol-lowering eects regardless of the time of admin-

istration. Similarly, aspirin administered at night, prevents the CV

complications that occur early in the morning when the aggregability

of platelets is the highest.64,65 Thus, the translation of circadian biol-

ogy in the treatment of hypertension and the prevention of CVDs

is gaining increasing interest and the development of a new ﬁeld of

medicine, the “circadian medicine” with the leverage of the power

of circadian biology to improve human health.66–68 However, despite

the potential beneﬁts of chronotherapy of hypertension, the current

United States15 and European16 BP treatment guidelines recommend

morning administration of antihypertensive drugs. The main reason

for this recommendation is based on the current available data from

the treatment of hypertension with the morning administration of

antihypertensive drugs. Data from the evening administration of anti-

hypertensive drugs are limited and based on small studies with short

duration of treatment. There are only 2 large long-term prospective

studies on the eects of chronotherapy on the reduction of BP and

cardiovascular diseases.41,42 However, these studies have been criti-

cized for several problems, regarding design and data reporting.69–72

These authors also, argue that the antihypertensive and CV beneﬁts

of bedtime drug administration were very small and nonsigniﬁcant

compared to daytime administration. On a con side of this argument,

Hermida et al,73 state that many studies have shown better antihyper-

tensive and CV beneﬁts with the bedtime administration of drugs.

However, our analysis of studies showed no signiﬁcant dierence in

the reduction of BP between the bedtime and daytime administra-

tion of medications (Tables 1 and 2). The reason for this dierence

could be the availability of long-acting antihypertensive drugs, which

makes the time of drug administration not very important. Based

on these ﬁndings, the ACC/AHA guideline, the International Soci-

ety of Hypertension, and the European Society of Hypertension do

not emphasize the bedtime administration of antihypertensive drugs

and leave this decision up to the treating physician to decide when

is the appropriate time to administer the antihypertensive medica-

tions.74 However, conditions such as a nondipping pattern of noc-

turnal BP, increased CV risk, CKD, morning surge of BP, and sleep

disorders have shown better results with the bedtime administration

of antihypertensive drugs.75,76 Although bedtime drug administration

of antihypertensive drugs makes a physiologic sense, there are no

long-term randomized, controlled trials so far, to demonstrate the

superior beneﬁts of bedtime drug administration. There are only 2

long-term studies available, the MAPEC and the HYGIA, but both

studies suer from several shortcomings and have been criticized

by some investigators.69–72 Also, the Hellenic-Anglo Research into

Morning or Night Antihypertensive Drug Delivery trial did not show

any dierence in the decrease of 24-hour nighttime or daytime ABP

in hypertensive patients using long-acting medications.49 Similarly,

the recently published Morning versus Evening (TIME) study did

not show any dierence in CV events and BP reduction between the

evening and morning drug administration.43 Hopefully, the ongoing,

randomized studies UK (TIME study),77 the BedMed78 and BedMed

Frail79 will provide the needed information regarding the best time of

drug administration.

CONCLUSION

The circadian rhythms control all the functions in our body

including BP, HR variability, and CVD through the circadian clock

located in the SCN of the hypothalamus. Interest in circadian rhythms

has increased lately and could introduce a new phase of medicine, cir-

cadian medicine. However, the experimental evidence so far is equiv-

ocal regarding the chronotherapy of hypertension, since evening and

morning administration of antihypertensive drugs does not show a

signiﬁcant dierence in their antihypertensive eects. This could

possibly, be due to the small studies and short duration of treatment

and also, to the availability of long-acting antihypertensive drugs.

In addition, the unavailability of long-term, randomized controlled

studies is another reason. Two large outcomes studies (MAPEC and

HYGIA) have shown promising results despite some shortcomings.

Based on the current evidence, the ACC/AHA guidelines, Interna-

tional Society of Hypertension, and the European Society of Hyper-

tension do not emphasize the use of evening drug administration

for the treatment of hypertension, except in certain conditions such

as, nocturnal hypertension, nondipping hypertension, high CV risk,

CKD, and morning surge of BP. Hopefully, the currently ongoing,

randomized, long-term outcome studies BedMed78 and BedMed

Frail79 will provide the needed information when completed.

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Cardiology in Review • Volume XXX, Number 00, xxx 2024 Chronotherapy of Hypertension

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Bedtime versus morning use of antihypertensives in frail continuing care residents (BedMed-Frail): protocol for a prospective, randomised, open-label, blinded end-point pragmatic trial

Article

Full-text available

Aug 2023

Introduction BedMed-Frail explores risks and benefits of switching antihypertensives from morning to bedtime in a frail population at greater risk of hypotensive adverse effects. Methods and analysis Design : Prospective parallel randomised, open-label, blinded end-point trial. Participants : Hypertensive continuing care residents, in either long-term care or supportive living, who are free from glaucoma, and using ≥1 once daily antihypertensive. Setting : 16 volunteer continuing care facilities in Alberta, Canada, with eligible residents identified using electronic health claims data. Intervention : All non-opted out eligible residents are randomised centrally by the provincial health data steward to bedtime versus usual care (typically morning) administration of once daily antihypertensives. Timing changes are made (maximum one change per week) by usual care facility pharmacists. Follow-up : Via linked governmental healthcare databases tracking hospital, continuing care and community medical services. Primary outcome : Composite of all-cause death, or hospitalisation for myocardial infarction/acute-coronary syndrome, stroke, or congestive heart failure. Secondary outcomes : Each primary outcome element on its own, all-cause unplanned hospitalisation or emergency department visit, non-vertebral fracture and, as assessed roughly 135 days postrandomisation, fall in the last 30 days, deteriorated cognition, urinary incontinence, decubitus skin ulceration, inappropriate or disruptive behaviour a minimum of 4 days per week, and receipt of antipsychotic medication or physical restraints in the last 7 days. Process outcome : Proportion of blood pressure medication doses taken at bedtime (broken down monthly). Primary outcome analysis : Cox-Proportional Hazards Survival Analysis. Sample size : The trial will continue until a projected 368 primary outcome events have occurred. Current status : Enrolment is ongoing with 642 randomisations to date (75% female, mean age 88 years). Ethics and dissemination BedMed-Frail has ethical approval from the University of Alberta Health Ethics Review Board (Pro00086129) and will publish results in a peer-reviewed journal. Trial registration number NCT04054648 .

Keeping an eye on circadian time in clinical research and medicine

Article

Full-text available

Dec 2022

Background: Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms. Content: The goal of this manuscript is to provide guidance on best practices in measuring metrics of endogenous circadian rhythms in humans and promote the inclusion of circadian rhythms assessments in studies of health and disease. Circadian rhythms affect all aspects of physiology. By specifying minimal experimental conditions for studies, we aim to improve the quality, reliability and interpretability of research into circadian and daily (i.e., time-of-day) rhythms and facilitate the interpretation of clinical and translational findings within the context of human circadian rhythms. We describe protocols, variables and analyses commonly used for studying human daily rhythms, including how to assess the relative contributions of the endogenous circadian system and other daily patterns in behaviours or the environment. We conclude with recommendations for protocols, variables, analyses, definitions and examples of circadian terminology. Conclusion: Although circadian rhythms and daily effects on health outcomes can be challenging to distinguish in practice, this distinction may be important in many clinical settings. Identifying and targeting the appropriate underlying (patho)physiology is a medical goal. This review provides methods for identifying circadian effects to aid in the interpretation of published work and the inclusion of circadian factors in clinical research and practice.

Dosing time optimization of antihypertensive medications by including the circadian rhythm in pharmacokinetic-pharmacodynamic models

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Nov 2022
PLOS COMPUT BIOL

Blood pressure (BP) follows a circadian variation, increasing during active hours, showing a small postprandial valley and a deeper decrease during sleep. Nighttime reduction of 10–20% relative to daytime BP is defined as a dipper pattern, and a reduction of less than 10%, as a non-dipper pattern. Despite this BP variability, hypertension’s diagnostic criteria and therapeutic objectives are usually based on BP average values. Indeed, studies have shown that chrono-pharmacological optimization significantly reduces long-term cardiovascular risk if a BP dipper pattern is maintained. Changes in the effect of antihypertensive medications can be explained by circadian variations in their pharmacokinetics (PK) and pharmacodynamics (PD). Nevertheless, BP circadian variation has been scarcely included in PK-PD models of antihypertensive medications to date. In this work, we developed PK-PD models that include circadian rhythm to find the optimal dosing time ( Ta ) of first-line antihypertensive medications for dipper and non-dipper patterns. The parameters of the PK-PD models were estimated using global optimization, and models were selected according to the lowest corrected Akaike information criterion value. Simultaneously, sensitivity and identifiability analysis were performed to determine the relevance of the parameters and establish those that can be estimated. Subsequently, Ta parameters were optimized to maximize the effect on BP average, BP peaks, and sleep-time dip. As a result, all selected models included at least one circadian PK component, and circadian parameters had the highest sensitivity. Furthermore, Ta with which BP>130/80 mmHg and a dip of 10–20% are achieved were proposed when possible. We show that the optimal Ta depends on the therapeutic objective, the medication, and the BP profile. Therefore, our results suggest making chrono-pharmacological recommendations in a personalized way.

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

Article

Full-text available

Oct 2022
LANCET

Background: Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension. Methods: The TIME study is a prospective, pragmatic, decentralised, parallel-group study in the UK, that recruited adults (aged ≥18 years) with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned (1:1), without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning (0600-1000 h) or in the evening (2000-0000 h). Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete. Findings: Between Dec 17, 2011, and June 5, 2018, 24 610 individuals were screened and 21 104 were randomly assigned to evening (n=10 503) or morning (n=10 601) dosing groups. Mean age at study entry was 65·1 years (SD 9·3); 12 136 (57·5%) participants were men; 8968 (42·5%) were women; 19 101 (90·5%) were White; 98 (0·5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 4·9-5·7), and 529 (5·0%) of 10 503 participants assigned to evening treatment and 318 (3·0%) of 10 601 assigned to morning treatment had withdrawn from all follow-up. A primary endpoint event occurred in 362 (3·4%) participants assigned to evening treatment (0·69 events [95% CI 0·62-0·76] per 100 patient-years) and 390 (3·7%) assigned to morning treatment (0·72 events [95% CI 0·65-0·79] per 100 patient-years; unadjusted hazard ratio 0·95 [95% CI 0·83-1·10]; p=0·53). No safety concerns were identified. Interpretation: Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects. Funding: British Heart Foundation.

Foundations of circadian medicine

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Mar 2022
PLOS BIOL

The circadian clock is an evolutionarily highly conserved endogenous timing program that structures physiology and behavior according to the time of day. Disruption of circadian rhythms is associated with many common pathologies. The emerging field of circadian medicine aims to exploit the mechanisms of circadian physiology and clock–disease interaction for clinical diagnosis, treatment, and prevention. In this Essay, we outline the principle approaches of circadian medicine, highlight the development of the field in selected areas, and point out open questions and challenges. Circadian medicine has unambiguous health benefits over standard care but is rarely utilized. It is time for clock biology to become an integrated part of translational research.

Pathophysiology of the Nondipping Blood Pressure Pattern

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Jan 2023

The nondipping blood pressure (BP) pattern corresponds to a disruption in the circadian BP rhythm with an insufficient decrease in BP levels during night-time sleep as observed using 24-hour ambulatory BP monitoring. Patients with nondipping BP pattern have poorer renal and cardiovascular outcomes, independent of their average 24-hour BP levels. The pathophysiology of nondipping BP is complex and involves numerous mechanisms: perturbations of (1) the circadian rhythm, (2) the autonomic nervous system, and (3) water and sodium regulation. This review provides an outline of the pathways potentially involved in the nondipping BP profile in different conditions. A recent hypothesis is also discussed involving the role of gut microbiota in the dipping/nondipping patterns, via the fecal diet-derived short chain fatty acids.

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Toward Precision Medicine: Circadian Rhythm of Blood Pressure and Chronotherapy for Hypertension - 2021 NHLBI Workshop Report

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Nov 2022
Hypertension

Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.

Bedtime dosing of antihypertensive medications: systematic review and consensus statement: International Society of Hypertension position paper endorsed by World Hypertension League and European Society of Hypertension

Article

Aug 2022

Antihypertensive drug therapy is one of the most efficient medical interventions for preventing disability and death globally. Most of the evidence supporting its benefits has been derived from outcome trials with morning dosing of medications. Accumulating evidence suggests an adverse prognosis associated with night-time hypertension, nondipping blood pressure (BP) profile and morning BP surge, with increased incidence of cardiovascular events during the first few morning hours. These observations provide justification for complete 24-h BP control as being the primary goal of antihypertensive treatment. Bedtime administration of antihypertensive drugs has also been proposed as a potentially more effective treatment strategy than morning administration. This Position Paper by the International Society of Hypertension reviewed the published evidence on the clinical relevance of the diurnal variation in BP and the timing of antihypertensive drug treatment, aiming to provide consensus recommendations for clinical practice. Eight published outcome hypertension studies involved bedtime dosing of antihypertensive drugs, and all had major methodological and/or other flaws and a high risk of bias in testing the impact of bedtime compared to morning treatment. Three ongoing, well designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing. Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose.

Evening versus morning administration of drug therapy for hypertension: A meta-analysis of randomized controlled trials

Article

Feb 2022

Introduction Studies have suggested that different administration times may lead to different antihypertensive effects. This systematic review was designed to evaluate the effectiveness of evening versus morning drug administration for hypertension. Methods Eight databases were searched to identify randomized controlled trials (RCTs) from database inception to August 2021. The RCTs compared the effects of evening and morning dosing on cardiovascular disease events, adverse events and reduction of blood pressure (BP) in hypertensive. Two reviewers independently extracted data and assessed trial quality. Meta-analysis was performed using Stata 12.0 software. Results A total of 36 RCTs were included and analysed. The results showed that, compared with the morning administration, evening administration of hypertensives could decrease cardiovascular disease events (risk ratio=0.39, 95% confidence interval (CI)=0.25 to 0.60), 24h/48h mean systolic BP (SBP) (mean differences (MD) =-3.39, 95% CI=-4.57 to -2.22), 24h/48h mean diastolic BP (DBP) (MD=-1.12, 95% CI=-1.70 to -0.53), nocturnal mean SBP (MD=-6.70, 95% CI=-8.35 to -5.05) and nocturnal mean DBP (MD=-3.54, 95% CI= -4.46 to -2.63), while diurnal mean SBP (MD=-0.53, 95% CI=-1.72 to 0.65) and diurnal mean DBP (MD=-0.31, 95% CI=-1.04– 0.42) showed no difference between two groups. Conclusion This meta-analysis indicated that evening administration was superior to morning administration in reducing asleep BP and the risk of cardiovascular disease events, especially for patients with essential hypertension, patients with renal hypertension and the non-dipper hypertensive patients. More evidence is needed to support this conclusion.