Introduction
Adequately controlling blood pressure reduces the risk of major cardiovascular events, including stroke, ischaemic heart disease, and cardiovascular death.
Clinical trials supporting the cardiovascular benefits of antihypertensive therapy primarily use conventional morning dosing. When measured using 24 h ambulatory monitoring, normal blood pressure exhibits a diurnal rhythm, with lower pressures during night-time sleep (referred to as dipping), followed by a morning increase or surge in blood pressure. The risk of adverse cardiovascular outcomes is increased in people whose blood pressure does not have the typical diurnal variation, such as reduced, reversed, or extreme dipping patterns, and high night-to-day blood pressure ratios.
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Additionally, cardiovascular events are temporally associated with the morning blood pressure surge.
Evening dosing of antihypertensive medication has been suggested to potentially be more effective at normalising the diurnal rhythm, lowering 24 h blood pressure, and preventing the long-term cardiovascular sequelae of hypertension than morning dosing.
Evidence before this study
A 2022 systematic review for the International Society of Hypertension identified eight studies testing the effect of bedtime dosing of antihypertensive drugs on outcomes. All eight studies were determined to have a high risk of bias and only two were completed randomised studies that compared morning and bedtime dosing of antihypertensive medication for cardiovascular outcomes. The MAPEC study and the Hygia Chronotherapy studies were both prospective, randomised, open-label, blinded-endpoint design studies done by a single research group in Spain. The 2010 MAPEC study (2156 participants) reported a substantial reduction in major cardiovascular events (cardiovascular deaths, myocardial infarction, ischaemic stroke, and haemorrhagic stroke) in the bedtime treatment group compared with the morning treatment group (adjusted relative risk 0·33 [95% CI 0·19–0·55]). The subsequent and larger Hygia Chronotherapy study (19 084 participants) also reported a substantial reduction in cardiovascular events (cardiovascular death, myocardial infarction, coronary revascularisation, heart failure, and stroke) in the bedtime treatment group compared with the morning treatment group (adjusted hazard ratio 0·55 [95% CI 0·50–0·61]). Several expert commentators have questioned the methods and plausibility of the effect sizes reported in both of these studies. There was a clear need for an independent, large, randomised trial testing the hypothesis that bedtime, or evening, dosing of antihypertensives would be better than morning dosing in terms of major cardiovascular outcomes.
Added value of this study
The Treatment in Morning versus Evening (TIME) study was a large, pragmatic, decentralised, prospective, randomised, open-label, blinded-endpoint, superiority trial conducted in the UK, comparing cardiovascular outcomes in adults with hypertension randomly assigned to evening versus morning dosing of their usual antihypertensive medications. We found no difference between the evening and morning dosing groups for the primary composite outcome of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke over a median follow-up time of 5·2 years (IQR 4·9–5·7). Additionally, we found no difference in all-cause mortality between the evening and morning dosing groups.
Implications of all the available evidence
These findings are an important addition to the hitherto limited and controversial randomised clinical trial evidence available comparing the effects of dosing times of antihypertensive medication with regard to cardiovascular outcomes. Given the continued controversy around MAPEC and the Hygia Chronotherapy trial, the evidence from the TIME trial suggests that dosing time should not be a significant consideration when advising most patients on managing their blood pressure. Instead, clinicians should focus on selecting appropriate medications and supporting adherence to agreed treatment plans.
However, the HARMONY trial reported no difference of morning versus evening dosing time, on either 24 h ambulatory blood pressure or clinic-measured blood pressure.
A recent systematic review
identified only two completed randomised studies that have compared cardiovascular outcomes with morning and bedtime dosing of antihypertensive medication in adults with hypertension: the MAPEC study
and the subsequent larger study from the same research group, the Hygia Chronotherapy Trial.
Both studies reported a reduction in all major cardiovascular events with bedtime treatment compared with morning treatment. The effect size in each of these studies was considered by many to be implausibly large.
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Additionally, there is a paucity of evidence on the potential harms of bedtime dosing related to excessive night-time blood pressure lowering (eg, potential increased risk of falls, glaucoma, and cerebrovascular events).
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Dosing time might also affect medication adherence. Although previous research has found that evening dosing is generally associated with worse medication adherence,
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the convenience of evening dosing might enhance adherence in some patients.
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In the Treatment in Morning versus Evening (TIME) study, we aimed to investigate whether evening dosing of antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension treated with their usual antihypertensive medications.
Methods
Study design and participants
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Patients were eligible if they were UK residents, aged at least 18 years, with diagnosed hypertension, and taking at least one antihypertensive medication daily. Participants were required to have an email address and be registered with a UK general practitioner. People undertaking regular overnight shift work or taking antihypertensive medications at more than one dosing time daily were excluded. Recruitment took place in a rolling pilot, which then continued into the main trial. Participants who had registered on the study website after the time that registration closed were able to complete their enrolment at a later date. All participants provided written informed consent.
and is in the appendix (pp 19–46). The study was approved by the East of Scotland Research Ethics Committee (11/AL/0309). The University of Dundee (Dundee, zUK) was the study sponsor and study data were managed by the University of Dundee and analysed by statisticians based at the Robertson Centre for Biostatistics, University of Glasgow (Glasgow, UK).
Randomisation and masking
Enrolled and consenting participants were randomly assigned (1:1), with no restriction, stratification, or minimisation, using a computer algorithm, to take their usual prescribed antihypertensive therapy either in the morning (0600–1000 h) or the evening (2000–0000 h) and were advised of their dosing time allocation via email. The randomisation algorithm used randomly generated bits (0s and 1s, where 0 = morning and 1 = evening), which were allocated to participants as they completed enrolment. Patients and investigators were not masked to group allocation due to the nature of the intervention, but endpoint assessors were masked to group allocation.
Procedures
All screening, consent, randomisation, and follow-up were done through an online study portal and by email.
Participants randomly assigned to evening dosing and taking diuretics as one of their medications were instructed to attempt evening dosing of diuretic along with other medication, with instructions to move their dosing time of only the diuretic to early evening (1800 h), then morning, if troubled by persistent nocturia. All participants were asked to remain on their randomised dosing time for the duration of the study.
Participants were invited to complete online follow-up questionnaires at regular intervals (1 month after randomisation and every 3 months thereafter). The follow-up questionnaires asked if the participant was currently taking their blood pressure lowering medication at their assigned time and if they had experienced any events of interest since their last follow-up submission (ie, potential endpoint events and prespecified side-effects). Any participants who indicated that they were not currently taking their medication at their study-assigned time were asked to indicate whether this was due to experiencing side-effects, medical advice, or inconvenience, and they were continued in the study. Participants who reported non-adherence to assigned dosing time were free to return to their assigned dosing time at a later date.
Participant-nominated alternative contacts were approached if participants did not respond as expected to consecutive follow-up invitations. Potential endpoint events were identified, and packages of de-identified clinical information were created by interrogating medical records.
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Those willing to do this were invited to provide sets of home blood pressure measurements in the morning and evening at 3-monthly intervals via an online portal throughout the study.
Safety was assessed by participant reporting via the online follow-up questionnaires (hospitalised and non-hospitalised falls and fractures, and other prespecified symptoms [ie, dizziness or light-headedness, upset stomach or indigestion, diarrhoea, muscle aches, excessive visits to the toilet during the day or night, sleep problems, feeling generally less well, and other]) and linked hospitalisation data (glaucoma events).
cognitive function, mood, and chronotype, which will be reported elsewhere.
Outcomes
An independent clinical endpoint committee, based at the University of Dundee and comprising specialist cardiology and stroke physicians who were masked to dosing time allocation, adjudicated all components of the primary composite outcome and selected secondary outcomes (all-cause mortality, and hospitalisations or death due to heart failure).
Statistical analysis
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the sample size was increased to at least 20 000 to ensure the study would be powered to report reliable results. The primary endpoint, and secondary cardiovascular and mortality endpoints, were assessed in the intention-to-treat population, which comprised all participants randomly assigned to treatment. Safety was assessed in all participants who submitted at least one follow-up questionnaire, except for glaucoma, which was assessed in the intention-to-treat population.
We assessed the primary endpoint as the time to the occurrence of the first primary endpoint event on an intention-to-treat basis using an unadjusted Cox proportional-hazards model. We also assessed the secondary cardiovascular and mortality outcomes using this approach. We present time-to-event curves for the primary composite outcome as a cumulative incidence function, censoring for the competing risk of deaths not included in the endpoint, and we present a Kaplan-Meier curve for all-cause mortality. We calculated event rates for the cardiovascular and mortality endpoints using Poisson tests. To compare differences between groups for the remaining secondary outcomes, we used Yates’ χ2 test for categorical outcomes and the independent samples t test for continuous outcomes; p values of less than 0·05 were considered to be significant. We calculated between-group differences with 95% confidence intervals for prespecified symptoms using Yates’ χ2 test.
We did prespecified subgroup analyses of the primary outcome by age (≤median vs >median age), sex (female vs male), BMI (≤median vs >median BMI), smoking (never vs former vs current), previous heart attack (yes vs no), previous stroke (yes vs no), previous cardiovascular disease (yes vs no), diabetes (yes vs no), taking angiotensin-converting enzyme inhibitor (ACE; yes vs no), taking angiotensin II receptor blocker (ARB; yes vs no), taking ACE or ARB (yes vs no), taking beta blocker (yes vs no), taking calcium channel blocker (yes vs no), number of antihypertensives (≤three vs >three), taking alpha blocker (yes vs no), and taking diuretics (yes vs no).
The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641).
Role of the funding source
The funder and sponsor had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit for publication.
Results
Figure 1Study profile
Table 1Baseline demographic and clinical characteristics
Data are mean (SD), n, or n (%).
Study follow-up ended on March 31, 2021 (data cutoff), by which time we estimated that at least 631 participants had experienced a first primary outcome event. 437 (4·2%) of 10 503 participants assigned to the evening dosing group and 434 (4·1%) of 10 601 assigned to the morning dosing group had died before the end of the study. Median follow-up was 5·2 years (IQR 4·9–5·7) and the maximum follow-up was 9·3 years. Of 11 314 (53·6%) participants who retrospectively reported their pre-study dosing time, 9961 (85·4%) had previously taken all their antihypertensive medications in the morning.
Figure 2Cumulative hazard of the first primary composite endpoint event, accounting for the competing risk of deaths not included in the endpoint (intention-to-treat population; n=21 104)
The primary composite endpoint was vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke.
Table 2Primary composite outcome and secondary cardiovascular and mortality outcomes (intention-to-treat population; n=21 104)
14 629 (69·3%) participants reported adherence to their assigned dosing time throughout the trial. Non-adherence to randomised dosing time at any time occurred in 6475 (30·7%) participants overall, with a mean time to first reported non-adherence to dosing time of 1·7 years (SD 1·6). Reported non-adherence to allocated dose timing at any point in the study was more common in those assigned to evening treatment than to morning treatment (4091 [39·0%] vs 2384 [22·5%]; p<0·0001). However, the last known status was reported non-adherence with allocated dosing time for only 2834 (13·4%) participants overall, 2084 (19·8%) in the evening dosing group and 750 (7·1%) in the morning dosing group. 617 (3·2%) participants reported that they had to change the time of day that a diuretic was administered (546 [5·2%] in the evening group vs 71 [0·7%] in the morning group; p<0·0001).
Table 3Prespecified adverse events (symptoms) in safety analysis population (n=19 628)
Numbers reported are the number of participants who indicated that they had experienced each prespecified symptom.
Discussion
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The present study was sufficiently well powered to show a clinically important cardiovascular benefit with evening dosing compared with morning dosing; however, we found no such benefit. We found no advantage of evening versus morning dosing of antihypertensive medication with regard to major cardiovascular outcomes or mortality.
Our overall primary event rate was lower than expected, which might be due to the healthy-participant effect but might also reflect decreasing rates of cardiovascular events in the general population.
Blood pressure measurements by home blood pressure machines showed significant but small differences between the randomised dosing groups. Antihypertensive treatment regimens were prescribed for participants by their usual treating clinician, and we have no reason to believe that the choice of treatment was affected by participation in the trial. Therefore, these findings show that most antihypertensive agents prescribed in UK usual care do not lower blood pressure evenly over 24 h.
Because event accrual was non-linear, due to the receipt of linked data in batches, predicting the date of achieving our target number of participants with primary outcome events was not simple. This fact, combined with delays in accessing linked data from NHS Digital and difficulty accessing NHS clinical records during periods of strain on the NHS due to the COVID-19 pandemic, meant that the number of accrued endpoints exceeded the minimum required for statistical purposes. The resulting 95% CI for the primary outcome excludes a benefit of more than 17%. Additionally, we calculated the endpoint target for the primary outcome only; therefore, comparisons in subgroups and secondary outcomes might be insufficiently powered to detect clinically meaningful differences between dosing times.
This trial design has some limitations that should be considered when interpreting our findings. First, the study used a prospective, randomised, open-label, blinded-endpoint design. All participants were aware of their allocated dosing time, which might have influenced behaviour and reporting. Moreover, participant-reported adverse events might be incomplete and subject to recall and reporting bias. Linked data and clinical source documentation corroborated participant-reported endpoint events. However, because prespecified adverse events were participant-reported only, they might be more subject to bias. In particular, higher rates of withdrawal from questionnaire follow-up in the evening dosing group than in the morning dosing group might have resulted in an underestimation of actual adverse event rates in between-group comparisons. Therefore, we believe that these self-reported prespecified adverse event data should be interpreted with caution. Additionally, home blood pressure measurements submitted manually to the study website might have been susceptible to recall bias and data entry errors.
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Older participants, those with a positive family history of hypertension, those taking a higher number of antihypertensive medications, and those with less social deprivation were more likely to participate in providing home blood pressure measurements, whereas those with a higher BMI and who were smokers were less likely to provide home blood pressure measurements. Therefore, the home blood pressure data are not necessarily fully representative of the randomised population in the TIME study.
However, the study team were aware that many of these participants reverted to morning dosing shortly afterwards (data not shown), after being informed that the TIME study independent data monitoring committee had recommended that the TIME study should continue after reviewing the study safety data.
which is assessing whether bedtime antihypertensive administration reduces major adverse cardiovascular events compared with conventional morning use, and the associated BedMed-frail trial, which includes several secondary safety outcomes of relevance to a frail older population, are both continuing (NCT04054648).
Finally, the TIME study was not a study of nocturnal hypertension or other disorders of diurnal blood pressure variation, and further research is needed to advise on dosing time in those populations.
In this pragmatic study, reflecting usual care, allocation to evening dosing of usual antihypertensive medication did not improve the primary composite endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke compared with morning dosing. Taking medication in the evening was not harmful but provided no additional benefit versus morning dosing. Therefore, patients should be advised that they need not change their antihypertensive medication dosing time but might choose to take their medication at a time that suits them best, because the timing makes no difference to cardiovascular outcomes.
TMM and ISM conceived the idea for the study with support from BW and MJB. TMM and ISM designed the study. DAR programmed the study software. TMM, ISM, AR, DAR, RY, and AM had full access to data in the study. RY and AM did the statistical analysis and directly accessed and verified the underlying data reported in the manuscript. TMM, ISM, and AR wrote, reviewed, and edited the manuscript with input from RY. All authors participated in the interpretation of the data and critical review of the manuscript. All authors have read and approved the final version. TMM and ISM had final responsibility for the decision to submit for publication.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01786-X/fulltext
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