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 : Journal of Hypertension

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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

Stergiou, Georgea; Brunström, Mattiasb; MacDonald, Thomasc; Kyriakoulis, Konstantinos G.a; Bursztyn, Michaeld; Khan, Nadiae; Bakris, Georgef; Kollias, Anastasiosa; Menti, Ariadnia; Muntner, Paulg; Orias, Marceloh; Poulter, Neili; Shimbo, Daichij; Williams, Bryank; Adeoye, Abiodun Moshoodl; Damasceno, Albertinom; Korostovtseva, Lyudmilan; Li, Yano; Muxfeldt, Elizabethp; Zhang, Yuqingq; Mancia, Giusepper; Kreutz, Reinholds; Tomaszewski, Maciejt,u

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Journal of Hypertension 40(10):p 1847-1858, October 2022. | DOI: 10.1097/HJH.0000000000003240
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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.

Video Abstract


Accumulating evidence suggests an adverse prognosis associated with night-time hypertension, nondipping profile and morning blood pressure (BP) surge, and increased incidence of cardiovascular events during the first few morning hours [1]. These observations provide justification for complete 24-h BP control as the primary goal of antihypertensive treatment. To achieve 24-h BP control, evening or bedtime administration of antihypertensive drugs has been proposed as a potentially more effective strategy to control night-time hypertension, normalize the night-time BP dip, and dampen or eliminate the morning BP surge (Fig. 1) [1–3]. However, most of the available evidence on the outcome benefit of the antihypertensive treatment has been derived from clinical trials adopting morning dosing of medications [4]. In addition, a bedtime dosing strategy would seem less necessary with modern antihypertensive therapies, which have a duration of action of 24 h or longer, especially at a steady state. Moreover, bedtime dosing could potentially be accompanied by significant risks, such as an extreme BP fall during night-time sleep might result in cardiovascular complications [4–9] and lower adherence to treatment [1,4,10,11]. It might be argued that bedtime dosing is a reasonable ‘tailored’ approach to be applied specifically to nondippers, or patients with isolated night-time hypertension, or with exaggerated morning BP surge (Fig. 1) [1,12,13]. To date, the supporting evidence, clinical relevance and indications for bedtime dosing remain debatable.

Graphical presentation of clinical research question (?) on whether bedtime administration of antihypertensive medication aiming to treat nocturnal hypertension and nondipping might be superior to standard morning administration in reducing cardiovascular events risk.

Two recent studies led by the same research group suggest that bedtime administration of antihypertensive drugs is much more protective of cardiovascular outcomes than the conventional morning dosing [14,15]. These findings have not been confirmed by other investigators and the methodology, results and conclusions of these studies have been questioned [4,16–19]. However, these data have gained much attention in the media and have influenced some experts, practicing physicians and patients [20]. For example, in 2017, the American Diabetes Association recommended bedtime administration of one or more antihypertensive medications [21]. This recommendation was not endorsed by other organizations, or by successive diabetes guidelines, possibly due to the criticism it received [22,23].

The International Society of Hypertension (ISH) decided to dedicate an official Position Paper to address controversies surrounding the diurnal BP variation in relation to the management of hypertension and offer guidance to researchers, practicing clinicians and patients, given concerns about widespread promotion of night-time dosing in the absence of sufficiently robust evidence. An international panel of 23 academic experts in BP monitoring and clinical hypertension appointed by the ISH College of Experts have reviewed the published evidence on the clinical relevance of diurnal BP variation and the timing of antihypertensive drug treatment. Topics that were considered included: (i) methodologic issues in the assessment of diurnal BP variation, (ii) its clinical and prognostic relevance, (iii) effects of antihypertensive drug treatment in terms of duration of BP-lowering effect, dosing time and adherence, (iv) effects of bedtime dosing of antihypertensive treatment on outcomes, and (v) ongoing outcome studies investigating morning versus bedtime dosing. Finally, consensus recommendations are provided, based on the evaluation of the available evidence.



A diurnal rhythm of BP usually manifests as higher values during daytime and lower during night-time [24], leading researchers to hypothesize that there is an intrinsic mechanism of short-term BP variability regulation [25–28]. Indeed, BP oscillations are under the control of several endogenous factors with centrally generated rhythmic influences [29] and the suprachiasmatic nucleus of the hypothalamus acting as the master periodic molecular clock in all mammals [27,30]. Other important mechanisms modulating these oscillations are genetic factors, circadian rhythm of the renin-angiotensin-aldosterone system, changes in sympathetic drive, plasma adrenergic neurotransmitters, diurnal fluctuations in renal volume and sodium excretion, rhythmicity in atrial natriuretic peptide secretion, circadian melatonin excretion and thyroid hormones [27,30–33]. Antioscillatory influences by the baroreflex during the day and night may also play a role [34]. These mechanisms may be further influenced by conditions such as diabetes, obesity, obstructive sleep apnoea (OSA), chronic kidney disease (CKD), and by extrinsic factors such as daylight exposure and melatonin excretion [27,33,35–38]. Moreover, extrinsic behavioural factors and especially individuals’ activities and arousal status play a major role in the 24-h BP variation pattern [3,25,26,39–41]. In studies wherein physical activity was eliminated (e.g. in immobilized patients in orthopaedic wards), the diurnal variation in BP was less prominent. Nevertheless, a higher BP level whilst awake and a lower level during sleep remained, but sinusoidal changes that would fit a typical circadian model were not observed [25,26]. Moreover, studies among shift workers showed that BP rhythm was directly reversed following individuals’ activities when people worked during night-time and slept during the day [25,26,42,43]. Further to awake/asleep status, other extrinsic factors affecting BP fluctuations include physical and mental activities, ambient temperature and noise, dietary patterns (salt, coffee, tea, alcohol) and drugs affecting BP [2,3,39].

Collectively, these data suggest that the diurnal BP variation is influenced by both endogenous and exogenous factors. Thus, the term ‘diurnal variation’ might not be entirely appropriate, as it implies a variation mostly governed by day/night periods, while the awake/asleep status (and thus the level of the individual's activity) appears to be the strongest determinant [25,26]. However, for most people following a consistent pattern of daily activities and night-time sleep, it could be indeed stated that BP presents a diurnal pattern. To what extent and under which circumstances intrinsic or extrinsic factors are more important for BP oscillations remain debatable [2,3,25–27,30].


Nocturnal hypertension has been defined as night-time (asleep) systolic ambulatory BP (ABP) 120 mmHg or higher and/or diastolic 70 mmHg or higher [44,45]. The term ‘nondippers’ was introduced in 1988 by Eoin O’Brien to define individuals with attenuated BP fall during night-time sleep assessed by 24-h ABP monitoring [46]. Normal night-time ABP dip is considered as a fall of 10–20% compared with daytime (awake) ABP, nondipping 0–10%, extreme dipping more than 20% and reverse dipping as a higher asleep than awake ABP. Reverse dipping is often included in the broad term of ‘nondipping’ [47].

Clinical relevance of nocturnal hypertension and nondipping

Nocturnal hypertension and a nondipping BP pattern are common in older adults and individuals who are salt-sensitive, obese, with CKD, OSA, diabetes, African ancestry, insomnia, nocturia, neurodegenerative diseases (e.g. Parkinson's disease), treatment with short-acting antihypertensive medications, and with resistant and some types of secondary hypertension [36,37,48–59]. Both nocturnal hypertension and a nondipping BP pattern have been associated with an increased risk of target organ damage and adverse cardiovascular and kidney outcomes in individuals with hypertension and in general populations [60–63]. Night-time SBP has been associated with an increased risk of adverse outcomes, even after adjustment for office, and daytime BP or the dipping ratio or status [61]. Nocturnal hypertension has often been masked by normal office BP, and therefore may not be detected [60].

Diabetes is associated with higher nocturnal SBP and a nondipping BP pattern [35]. Autonomic nervous dysfunction appears to be responsible for the higher prevalence of these phenotypes among patients with diabetes when compared with nondiabetic individuals, and microvascular disease, reduced baroreflex sensitivity and hyperglycaemia have been also proposed as potential contributors [64,65]. Furthermore, higher nocturnal BP is associated with a higher risk of diabetic nephropathy [66] and the progression of albuminuria in type-1 [67] and type-2 diabetes [68].

In CKD, nondipping is common [38] as a result of sympathetic overactivity [69] and salt sensitivity [52]. In CKD patients, nocturnal SBP less than 115 mmHg is associated with a lower risk of cardiovascular and renal damage, even in the absence of hypertension [70].

OSA, especially moderate-severe OSA, is associated with blunted BP dipping [71] and is influenced by the degree of desaturation and sleep fragmentation with increased nocturnal sympathetic activity [72]. Continuous positive airway pressure therapy seems to lower nocturnal systolic BP, improve nocturnal BP dipping [73] and overall 24-h BP control [74], as well as improve the quality of sleep and reduce nocturia [75,76].

In patients with resistant hypertension, nocturnal BP dipping is often attenuated and up to 65% of them appear to be nondippers [77]. Resistant hypertension is associated with sympathetic overactivity, visceral obesity, salt retention and hyperaldosteronism [54,77,78]. It often coexists with several comorbidities, including obesity, OSA, diabetes and CKD, all related to a blunted BP dip, which is an important adverse prognostic marker in resistant hypertension [49,62].

Adults of Black African ancestry have higher nocturnal BP and a smaller night-time BP dip than white adults in both high-income countries and in Africa [54–56]. Social deprivation, obesity, diabetes, vulnerability to CKD, salt-sensitivity, resistant hypertension, as well as a different sleep architecture [57] are likely the main contributors to different dipping pattern across racial groups.

Methodologic issues

The diagnosis of nocturnal hypertension and nondipping BP depends on whether BP levels are defined using arbitrary clock time or the individual's awake and asleep time. The former is easy to define, which has made it preferred in epidemiologic studies. The latter avoids misclassification of daytime asleep periods (naps) [79] or awake periods during the night [80]. Using arbitrary day/night intervals, the asleep BP decline is underestimated with an overestimation of nondippers, particularly in individuals with daytime sleep [81]. Sleep is objectively defined by electroencephalogram, which is impractical in large studies and clinical practice; electronic activity monitoring is more feasible but not widely available, and an individual's self-report is subjective. Also, compared with day/awake BP, the lower number of night-time/asleep BP measurements makes it vulnerable to the influence of a few deviant values that may occur when sleep periods are not accurately obtained.

Individuals’ self-reported awake/asleep times is probably the most pragmatic method and has been found to approximate reasonably to both electroencephalogram and electronic activity monitoring [55,82]. Whereas night-time BP seems to be reasonably reproducible [83,84], the dipper/nondipper BP status is reproducible in repeated ABP recordings in 60–70% of individuals, which undermines its feasibility for implementation in clinical practice [55,83,85,86]. Thus, current guidelines recommend the assessment of average daytime and night-time BP values to be based on the individuals’ sleeping times and the diagnosis of nondippers to be confirmed with repeat ABP monitoring [47].

The nocturnal BP dip quantification and the dipper/nondipper classification are also affected by the seasonal BP variation in ambient temperature. Daytime BP is reduced in hot compared with cold season, but it is not during night-time sleep, resulting in a reduced night-time BP dip and an increased prevalence of nondippers [87,88].

Despite the above-mentioned limitations, 24-h ABP monitoring is regarded as the standard method for assessing the diurnal BP profile and the dipping pattern. Novel low-cost home BP monitors allowing automated BP measurements during sleep may provide a useful alternative to ABP monitoring for the assessment of night-time BP and dipping status [89–93]. Moreover, recently developed cuffless wearable BP monitors providing frequent or continuous BP monitoring for days, weeks, or months, may allow complete and convenient evaluation of the individuals’ diurnal BP profile. However, at present, cuffless BP technologies require further validation on accuracy and clinical utility and they are not recommended for clinical use [94,95].


Antihypertensive medication action

The efficacy of any antihypertensive agent on 24-h BP control depends on its pharmacodynamics, pharmacokinetics, as well as individual patient factors such as diurnal changes in physiological systems relevant for uptake, elimination and target action (e.g. gastrointestinal motility, autonomic nervous activity, renin-angiotensin system activity and adrenocortical secretion) [4,96].

Factors such as drug half-life, irreversible target (e.g. receptor) binding and dosing also have an impact on 24-h BP control. First, several antihypertensive agents have half-lives less than 12 h [96–98], and thus, their effective use requires either extended-release formulations or repeated dosing to achieve 24-h BP control. However, most modern antihypertensive agents exhibit longer half-lives or duration of action, resulting in fairly stable BP-lowering effects when dosed once daily, even in the last hours before the next dose [99,100]. Second, some drugs with relatively short half-lives may have long duration of action due to irreversible target (e.g. receptor) modification [101]. Last, drug dosage also has a major influence on the duration of action. Thus, by selecting a sufficiently high dose, 24-h BP control can be achieved even with relatively short-acting drugs, but with considerably BP drop at the time of peak effect. Most angiotensin-converting enzyme inhibitors [102] and some angiotensin-receptor blockers [103] at a steady state exhibit flat or shallow dose--response curves. Drug potency and BP-lowering effect are therefore similar at low doses and high doses, yet the duration of action is shorter at low doses. This often requires the use of full doses to achieve 24-h coverage [102].

Effects of bedtime versus morning treatment on blood pressure levels and dipping status

Several short-term studies investigating the antihypertensive effect of bedtime versus morning treatment have been published, over 50 reporting ABP monitoring data [4,104]. They vary in study design (crossover/parallel; observational/interventional), treatment allocation procedure (many lacking detailed information on blinding/randomization procedure), group characteristics (sample size, treated versus untreated hypertension, concomitant diseases) and comparators (baseline/placebo/between-arm; specific drug/any antihypertensive medication). Furthermore, most studies excluded patients with recent cardiovascular events, making generalizability to a secondary prevention setting limited.

Available meta-analyses suggest that bedtime versus morning administration may provide a modest reduction in 24-h SBP/DBP in the range of about 2/1 mmHg [104,105]. However, the meta-analysis by Schillaci et al.[105] showed that these results were driven by studies performed in a single centre, and, if data from that centre were excluded, the effect on 24-h SBP was negligible [105]. Some studies suggest that evening dosing is predominantly associated with a decrease in SBP during sleep resulting in a larger nocturnal BP dip without a significant change in awake values [4]. Factors such as nondipping pattern, fixed combination treatment, high cardiovascular risk and concomitant CKD and sleep disorders have been associated with a greater reduction in nocturnal (asleep) BP upon evening dosing [4,106]. However, the randomized crossover Hellenic-Anglo Research into Morning or Night Antihypertensive Drug Delivery (HARMONY) trial showed no difference in 24-h, night-time or daytime ambulatory BP in controlled hypertensive patients, using long-acting medications [107].

Data for specific antihypertensive agents are conflicting and limited mostly to small studies [104,108]. On the basis of the available data, the impact of dosing time is not consistent and depends on drug-related factors listed above, but timing is unlikely to play an important role on BP lowering when using long-acting drugs. The data for single-pill combination or polypill bedtime treatment are scarce.

Adherence and time of taking the medication

Nonadherence or suboptimal adherence are common problems to all chronic diseases, including hypertension [109]. Accurate assessment of adherence is challenging and ideally involves either the measurement of drugs and/or their metabolites in urine [110] or blood [111], or the use of expensive electronic devices that register the time the patient opens the device to take his medication [112].

There are few studies that compared the adherence to a morning or evening dosed antihypertensive medication. In an analysis of large database of patients with hypertension taking their medication once a day, determined with electronic monitoring, patients taking their medication in the morning were significantly more adherent to medication, on a long-term basis, than those taking the medication at night [10]. The same was found in another study that assessed the adherence to amlodipine (5 mg once daily) administered either in the morning or at night assessed with the Medication-event Monitoring System (MEMS) [113]. In this study, 24-h ABP was not different between the two regimens, but adherence was better with morning than night administration.

Given that an increased number of prescribed antihypertensive medications [114] and more than once-daily dosing consistently show strong associations with reduced adherence to BP-lowering therapy, choosing single-pill combinations, reduction in polypharmacy, long-acting medications and once-daily administrations are amongst the most important strategies for achieving optimal BP control [44,112]. More high-quality prospective investigations are necessary to clarify whether the morning/evening dosing of antihypertensive medications influences long-term adherence.


The benefits of drug-induced BP lowering in terms of cardiovascular outcome and total mortality have been demonstrated in several long-term randomized controlled trials, most of which implemented morning drug administration protocols [4,115–117]. However, a prognostic advantage of bedtime drug dosing, through improved management of night-time hypertension, nondipping and the morning BP surge may theoretically be possible. To address the research question whether bedtime dosing of antihypertensive drugs improves prognosis compared with standard morning dosing, a systematic review of published outcome studies involving bedtime dosing of BP-lowering drugs and its association with major adverse cardiovascular events (MACE) and/or all-cause mortality was conducted.

Search strategy – Study selection – Data extraction

A systematic PubMed search was performed independently by two investigators (K.G.K. and A.M.) following the 2020 Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA 2020) statement [118,119]. Research questions of interest included: (i) What is the available evidence regarding bedtime dosing of antihypertensive drugs and outcome in general? and (ii) What is the evidence on the comparison of bedtime versus morning dosing (randomized trials) in terms of hard endpoints such as MACE and total mortality? Studies were subsequently deemed eligible if they reported bedtime dosing of BP-lowering drugs, and had MACE (myocardial infarction, stroke, heart failure, cardiovascular death) and/or mortality endpoints. The literature search was conducted using the algorithm (night-time OR bedtime OR chronotherap∗ OR nocturnal) AND (dosing OR dose∗ OR administration) AND (antihypertensive OR treatment OR drug OR medication) AND (hypertension OR ‘blood pressure’) AND (prognos∗ OR outcome OR mortality OR death OR ‘myocardial infarction’ OR stroke OR ‘heart failure’ OR MACE) until 19 September 2021. Articles were also selected from references of relevant articles and websites through the snowball procedure. The two investigators independently extracted and tabulated data regarding study design, main characteristics of included populations and data regarding the outcome of interest. Disagreements between them were resolved by consensus with a third investigator (G.S.S.).

Endpoints of interest and risk of bias

For the endpoint of interest regarding the comparison of bedtime versus morning dosing on the outcome, the optimal components of study design used as reference were inclusion of patients with hypertension; randomized double-blind; comparison of bedtime versus morning dosing of the same drugs; and primary outcome with cardiovascular events and/or mortality endpoints.

Four key design characteristics were evaluated, namely randomized to morning versus bedtime dosing; same drugs morning and bedtime; double-blind design; and hard primary outcome (MACE or mortality). Because the research question was the net impact of bedtime versus morning dosing of antihypertensive treatment, the fulfilment of the first two study characteristics was deemed as of primary relevance, before considering the other two.

The Cochrane revised tool for assessing the risk of bias in randomized trials (RoB 2) [120] was used to evaluate the methodological quality and adequacy of the included studies.


The initial literature search identified 752 potentially relevant articles. Six additional articles were assessed after hand-searching articles’ references. No published systematic review or meta-analysis of outcome data was identified. The flowchart of the selection of articles is presented in Supplemental Digital Content, Suppl. Figure 1, Eight studies fulfilled the criteria to be included in this review [14,15,121–126]. A description of these studies is presented in Table 1. Three studies were multinational [121,124,125], two were conducted in Spain [14,15], and the remaining three in Poland [126], Italy [123] and China [122]. Six of the eight studies specified hypertension as an inclusion criterion. Follow-up ranged from 2 to 6.6 years. There was considerable heterogeneity among studies regarding various aspects of study design, including the primary objective and endpoint, the intervention protocols, statistical analyses and reporting of main findings, which precluded any pooled analysis (Table 1). Eventually, as presented below, all eight studies had a high risk of bias in testing the impact of bedtime treatment (Table 2).

TABLE 1 - Description of outcome studies involving bedtime dosing of antihypertensive drugs
Study Year Country/Centres Design Primary endpoint Population N Age (years ± SD) Males (%) BP measurement Follow-up (years) Main findings Ratios with (95% CIs)
Hermida et al. (HYGIA) [14] 2019 Spain Multicentre Randomized PROBE Composite CVD Hypertension 19 084 61 ± 14 10 611 (56) OBP 48-h ABP 6.3 (median) CVD: Adjusteda HR 0.55 (0.50–0.61) with ≥1 bedtime drug versus morning dosing and Total mortality: Adjusteda HR 0.55 (0.48–0.63) with ≥1 bedtime drug versus morning dosing
Hermida et al. (MAPEC) [15] 2010 Spain Single-centre Randomized PROBE Composite CVD and total mortality Hypertension (untreated or treated uncontrolled) 2156 56 ± 14 1044 (48) OBP 48-h ABP 5.6 (median) CVD + Total Mortality: Adjustedb RR 0.39 (0.29–0.51) with ≥1 bedtime drug versus morning dosing
Black et al. (CONVINCE) [125] 2003 15 countries worldwide Multicentre Randomized Double-blind Composite CVD ≥55 years, hypertension + ≥1 CVD risk factor 16 476 66 ± 7 7252 (44) OBP 3 (median) CVD: Unadjusted HR 1.02 (0.88–1.18) andTotal mortality: Unadjusted HR 1.08 (0.93–1.26) with bedtime verapamil COER versus morning atenolol or hydrochlorothiazide
HOPE Study Investigators (HOPE) [124] 2000 19 countries worldwide Multicentre Randomized Double-blind Composite CVD ≥55 years, CVD, or diabetes + ≥1 CVD risk factor 9297 66 ± 7 6817 (73) OBP 5 (mean) CVD: Unadjusted RR 0.78 (0.70–0.86) with bedtime ramipril versus bedtime placebo and Total mortality: Unadjusted RR 0.84 (0.75–0.95) with bedtime ramipril versus bedtime placebo
Tatti et al. (FACET) [123] 1998 Italy Single-centre Randomized Open-label Serum lipids and diabetes control Hypertension and diabetes 380 63 ± 1 226 (59) OBP 2.5 (mean) CVD: Unadjusted HR 0.49 (0.26–0.95) with morning fosinopril versus bedtime amlodipine
Staessen et al. (Syst-Eur) [121] 1997 23 countries Europe Multicentre Randomized Double-blind Stroke ≥60 yearsSBP 160–219 mmHg 4695 70 ± 7 1557 (33) OBP 2 (median) Stroke: 42% (P < 0.01) decrease and Total mortality: 14% (P = NS) decrease with bedtime nitrendipine versus bedtime placebo
Sobiczewski et al.[126] 2014 Poland Single-centre Not randomised Prospective Observational Total mortality Coronary heart disease 1345 63 ± 9 820 (61) OBP 24-h ABP 6.6 (median) Total mortality: HRc 1.13 (1.01–1.45) with exclusively morning dosing versus mixed dosing strategies
Liu et al. (Syst-China) [122] 1998 China Multicentre Not randomized Prospective Stroke ≥60 yearsSBP 160–219 mmHg 2394 67 ± 6 1541 (64) OBP 3 (median) Stroke: 38% (P = 0.01) decrease and Total mortality: 39% (p<0.01) decrease with bedtime nitrendipine versus bedtime placebo
ABP, ambulatory blood pressure; b.i.d., twice a day; BP, blood pressure; CI, confidence intervals; COER, controlled-onset extended-release; CONVINCE, Controlled Onset Verapamil Investigation of Cardiovascular End Points; CVD, cardiovascular disease; FACET, Fosinopril Amlodipine Cardiovascular Events Trial; HOPE, Heart Outcomes Prevention Evaluation; HR, hazard ratio; MAPEC, Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares; NR, not reported; OBP, office blood pressure; PROBE, prospective, randomized, open-label, blinded endpoint; RR, relative risk; Syst-China, Systolic Hypertension in China; Syst-Eur, Systolic Hypertension in Europe; tid, three times a day.
aAdjusted for age, sex, diabetes type-2, chronic kidney disease, smoking, high-density lipoprotein, previous CVD, asleep SBP, sleep SBP decline.
bAdjusted for sex, age, diabetes type-2.
cUnclear whether unadjusted or adjusted.

TABLE 2 - Methodology of outcome studies involving bedtime dosing of antihypertensive drugs regarding testing of their primary endpoint and testing the impact of bedtime dosing on outcome
Methodology for testing primary study endpoint Methodology for testing the impact of bedtime dosing on outcome
Study Year Study design Study arms Risk of biasa Randomized to bedtime versus morning dosing Same drugs bedtime and morning Double-blind design Hard primary outcome Study design issues Risk of biasa Interpretation
Hermida et al. (HYGIA) [14] 2019 Randomized PROBE 2 arms: ≥1 bedtime drug versus morning treatment High + + Not fixed drug choices same in the 2 arms High Partially adequate
Hermida et al. (MAPEC) [15] 2010 Randomized PROBE 2 arms: ≥1 bedtime drug versus morning treatment High + + Not fixed drug choices same in the 2 arms High Partially adequate
Black et al. (CONVINCE) [125] 2003 Randomized Double-blind 2 arms: bedtime verapamil COER versus morning atenolol or hydrochlorothiazide Highb + + + Bedtime versus morning dosing but with different drugs High Partially adequate
HOPE Study Investigators (HOPE) [124] 2000 Randomized Double-blind Two arms: (ramipril versus placebo) both given at bedtime Low + + Both arms with bedtime dosing High Inadequate
Tatti et al. (FACET) [123] 1998 Randomized Open label Two arms: bedtime amlodipine versus morning fosinopril High + Bedtime versus morning dosing but with different drugs High Inadequate
Staessen et al. (Syst-Eur) [121] 1997 Randomized Double-blind Two arms: (nitrendipine versus placebo) both given at bedtime Some concerns + + Both arms with bedtime dosing High Inadequate
Sobiczewski et al.[126] 2014 Not randomised Prospective Observational Four arms: different timing of treatment (morning, bedtime, bid, tid or more) High + Not randomized. Not fixed drug choices same in each arm. Morning dosing versus all other arms High Inadequate
Liu et al. (Syst-China) [122] 1998 Not randomized Prospective Two arms: (nitrendipine versus placebo) both given at bedtime High + Both arms with bedtime dosing High Inadequate
bid, twice daily; COER, controlled-onset extended-release; CONVINCE, Controlled Onset Verapamil Investigation of Cardiovascular End Points; FACET, Fosinopril Amlodipine Cardiovascular Events Trial; HOPE, Heart Outcomes Prevention Evaluation; MAPEC, Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares; Syst-China, Systolic Hypertension in China; Syst-Eur, Systolic Hypertension in Europe; t.i.d., three times daily.
aAssessed using the Cochrane revised tool for assessing risk of bias in randomized trials (RoB 2) [120].
bCONVINCE was prematurely terminated for commercial reasons.

Four studies [121,122,124,126] had major design flaws that impaired their ability to test the impact of bedtime drug dosing on outcome versus any other time of drug dosing, as they only administered bedtime antihypertensive dosing [121,122,124] or used multiple timings with variable medications [126].

Four studies [14,15,123,125] randomized participants to bedtime or morning drug dosing (Table 2). Of these studies, two randomized patients to morning versus bedtime dosing in an unblinded fashion and with different drug classes in each arm (bedtime verapamil versus morning atenolol or hydrochlorothiazide [125] and bedtime amlodipine versus morning fosinopril [123]). As each of these classes is known to have different antihypertensive effects and cardiovascular benefits, differences attributed to bedtime versus morning dosing time may reflect unequal effects of different drug classes on outcome [125]. Therefore, these two studies had a high risk of confounding in investigating the impact of bedtime dosing on the outcome. The Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial, although double-blinded, also compared different drug classes at morning and bedtime (Table 2). Further, the negative CVD results reported in the CONVINCE trial may have resulted from insufficient power, as the study was stopped prematurely because of funding issues resulting in a considerably reduced and inadequate sample size [125].

The remaining two studies [14,15] also had a high risk of bias, as patients were randomized to bedtime versus morning dosing, but about half in the bedtime dosing arm received both bedtime and morning treatment, and treatment choices were not fixed in the two groups potentially resulting in treatment differences. These studies were deemed partially adequate to answer the research question of interest (Table 2). Of note, in the HYGIA study [14], an implausibly large 50% decline in cardiovascular events and total mortality was observed with bedtime dosing, whereas the difference between the two study arms in the 48-h ABP change between baseline and follow-up was only 1.6/1.2 mmHg (systolic/diastolic). Similarly, in the MAPEC study [15], an implausible 60% decline in cardiovascular events and total mortality was observed between the study arms, with only 1.1/0.2 mmHg difference between the two study arms in the change in 48-h systolic/diastolic ABP between baseline and follow-up. The magnitude of the differences in cardiovascular events and total mortality [14,15] is unexpected, given the existing evidence indicating the strength of the relationship between BP changes and outcome and on the differential effects of antihypertensive drug classes on the outcome. Several experts have expressed concern regarding the rigor and reproducibility of the HYGIA and MAPEC studies, questioned the internal validity of the findings and conclusions and called for further research that has sufficiently addressed the limitations of these studies [4,16–19,22]. These two studies, which were conducted by the same group of principal investigators, implemented an unblinded protocol and drug choices were not fixed in the randomized treatment arms. The drop-out rate was implausibly low (MAPEC 2%, HYGIA 0.4%) and there were various reporting issues [16]. Another concern is whether the MAPEC registry is not a single randomized clinical trial but is based on data of several smaller trials [127]. Finally, the reported large effect size of bedtime dosing on outcome raises substantial concerns as early discontinuation of the study would be expected due to the marked superiority of bedtime versus morning drug dosing [4,16–18,22].


The question of whether night-time dosing of antihypertensive medications is likely to be more beneficial than morning dosing for patients is far from settled. At present, there are three major ongoing trials of antihypertensive dosing time, which together should shed considerable light on this issue: Treatment in Morning vs Evening (TIME) study [128], BedMed [127] and BedMed-Frail [129]. All three of these trials use a pragmatic clinical endpoint-driven Prospective Open-label Blinded-endpoint (PROBE) design.

The first of these trials, which is expected to report its results within 2022, is the UK-based TIME study [128]. TIME completed active participant follow-up of 21 104 people with treated hypertension randomized to either morning or evening dosing of their usual antihypertensive medication. The study will use an intention-to-treat analysis to test the hypothesis that night-time dosing of antihypertensive medication reduces hospitalization or death from cardiovascular events compared with conventional morning dosing. Secondary questions will examine whether night-time dosing is acceptable to patients. Other potential concerns, such as nocturnal hypotension causing falls and fractures, will also be explored. TIME has been conducted using a secure study web portal, eConsent, E-Mail-prompted online participant-reported outcomes and record-linkage to national health and administrative databases [128]. Final record linked data are awaited at the time of writing.

BedMed, part of the Canadian Pragmatic Trials Collaborative, uses a similar trial design to randomize 3400 people with treated hypertension in primary care to either bedtime or morning dosing [127]. The primary outcome of BedMed will be the first occurrence of either death (all-cause) or hospitalization or emergency department visit for acute coronary syndrome/myocardial infarction, congestive heart failure or stroke. The results of BedMed are expected in early-2023. BedMed-Frail, run by the same investigative team as BedMed, randomizes long-term care residents to the medication timing intervention with outcomes determined using routinely collected electronic healthcare claims and long-term care datasets [129]. Results are expected in late-2022.

The results from these three pragmatic trials will provide much-needed clarity on whether night-time dosing of antihypertensive treatment is a safe and more effective intervention than morning dosing to improve cardiovascular outcomes.


In this ISH Position Paper, the published data on the clinical relevance of diurnal BP variation and antihypertensive drug treatment chronotherapy were reviewed, aiming to provide recommendations for treating hypertension in clinical practice based on the best available evidence. The main conclusions and consensus recommendations are the following:

  • (1) It is reasonable to recommend that a key aim of BP-lowering treatment should be to achieve complete 24-h control of BP by using long-acting antihypertensive medications.
  • (2) The current evidence on the comparative impact of bedtime versus other times of antihypertensive drug dosing on 24-h BP profile and on cardiovascular morbidity and mortality is limited by insufficient design and/or rigor of the available studies. The available studies have methodological limitations and therefore uncertainty remains about whether there is added value or harm of bedtime versus morning dosing of antihypertensive drugs. To date, most data favouring bedtime dosing were derived from a single research group and are subject of extensive controversy.
  • (3) At the present time, bedtime drug dosing should not be routinely recommended in clinical practice. This recommendation takes into consideration the unproven benefits, as well as possible harmful effects, such as the risk of excessive asleep BP drop or worsening daytime BP control.
  • (4) Until high-quality data become available, treatment of hypertension in clinical practice should follow protocols as used in the vast majority of long-term outcome hypertension trials. Thus, treatment of hypertension should be based on long-acting agents in monotherapy or in combinations administered in a single morning dose, aiming at optimal and consistent BP control.
  • (5) Prospective randomized outcome studies with appropriate design and sufficient power are needed to reach robust conclusions and guide clinical practice. Three relevant outcome studies are ongoing, and their results are expected to shed light on the impact of bedtime versus morning drug dosing on outcome. Once these results are available, more definitive advice can be given.
  • (6) Ongoing studies may confirm or exclude a considerable benefit or harm of bedtime dosing of antihypertensive drugs. Whatever the outcome of these studies, questions will remain whether for selected patients with confirmed nocturnal hypertension and concomitant disease (e.g. cardiovascular disease, CKD, OSA or diabetes), there might be a benefit from tailoring treatment to control nocturnal BP, but this will need further investigation.



Conflicts of interest

T.M. is a Chief Investigator of TIME study. N.P. is Steering Committee Chairman of TIME study. No conflicts of interest were declared for other authors.


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ambulatory blood pressure monitoring; antihypertensive drugs; bedtime administration; chronotherapy; dipper; nocturnal blood pressure; systematic review

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