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Randomized Crossover Trial of the Impact of Morning or Evening Dosing of Antihypertensive Agents on 24-Hour Ambulatory Blood Pressure

The HARMONY Trial
Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.118.11101Hypertension. 2018;72:870–873

Abstract

Some data suggest that nocturnal dosing of antihypertensive agents may reduce cardiovascular outcomes more than daytime dosing. This trial was designed to evaluate whether ambulatory blood pressure monitoring levels differ by timing of drug dosing. Patients aged 18 to 80 years with reasonably controlled hypertension (≤150/≤90 mm Hg) on stable therapy of ≥1 antihypertensive agent were recruited from 2 centers in London and Thessaloniki. Patients were randomized to receive usual therapy either in the morning (6 am–11 am) or evening (6 pm–11 pm) for 12 weeks when participants crossed over to the alternative timing for a further 12 weeks. Clinic blood pressures and a 24-hour recording were taken at baseline, 12, and 24 weeks and routine blood tests were taken at baseline. The study had 80% power to detect 3 mm Hg difference in mean 24-hour systolic blood pressure (α=0.05) by time of dosing. A 2-level hierarchical regression model adjusted for center, period, and sequence was used. Of 103 recruited patients (mean age, 62; 44% female), 95 patients (92%) completed all three 24-hour recordings. Mean 24-hour systolic and diastolic blood pressures did not differ between daytime and evening dosing. Similarly, morning and evening dosing had no differential impact on mean daytime (7 am–10 pm) and nighttime (10 pm–7 am) blood pressure levels nor on clinic levels. Stratification by age (≤65/≥65 years) or sex did not affect results. In summary, among hypertensive patients with reasonably well-controlled blood pressure, the timing of antihypertensive drug administration (morning or evening) did not affect mean 24-hour or clinic blood pressure levels.

Clinical Trial Registration—

URL: http://www.clinicaltrials.gov. Unique identifier: NCT01669928.

Introduction

See Editorial Commentary, pp 836–838

Observational data show a strong linear relationship between clinic blood pressure levels and subsequent major adverse cardiovascular events.1 However, ambulatory blood pressure monitoring has shown that nighttime blood pressure levels are more strongly predictive of major adverse cardiovascular events than 24-hour or daytime levels.2,3 Furthermore, night-to-day blood pressure ratio and dipping status are also significant independent predictors of cardiovascular outcomes.4 These findings may have implications for optimal dosing times for antihypertensive medications.

In the MAPEC study (Monitorización Ambulatoria de la Presión arterial y Eventos Cardiovasculares),5 bedtime dosing of at least 1 blood pressure-lowering agent compared with only morning dosing was associated with better blood pressure control, reduced prevalence of non-dipping patterns, and reduced morbidity and mortality from cardiovascular events. The results of the placebo-controlled HOPE trial (Heart Outcomes Prevention Evaluation)6 in which the protocol specified that the antihypertensive agent (ramipril) should be given at bedtime, showed that active therapy was associated with greater benefits in terms of cardiovascular outcome than would be expected from the small reduction in daytime clinic blood pressure observed.

The TIME study7 (Treatment in the Morning Versus Evening) is designed to compare the impact on major cardiovascular outcomes of evening dosing of antihypertensive agents than morning dosing. In April 2017 after 25 months of recruitment, the TIME study completed randomization of 21 113 patients who are currently being followed up for a mean period of 4 years. Meanwhile, the HARMONY trial (Hellenic-Anglo Research into Morning or Night Antihypertensive Drug Delivery) was designed to evaluate any differential effects of morning versus evening dosing on mean 24-hour ambulatory blood pressure levels.

Methods

The data that support the findings of this study are available from the corresponding author on reasonable request.

This study was a 2-center (London and Thessaloniki), prospective randomized crossover trial of hypertensive men and women who were aged 18 to 80 years. Eligibility was dependent on patients having hypertension diagnosed at least 1 year ago and being on stable antihypertensive medication (at least 1 agent with no change for at least 3 months) with reasonably controlled blood pressure levels (systolic ≤150 mm Hg and ≥115 mm Hg and diastolic ≤90 mm Hg) and the patients’ physician did not feel further antihypertensive therapy was necessary. Patients with atrial fibrillation and night shift workers were excluded. Eligible patients were randomized to receive their usual medications in the morning (6 am–11 am) or in the evening (6 pm–11 pm) for 12 weeks at which point they crossed over to evening and morning dosing, respectively, for a further 12 weeks. Compliance was assessed at 12 and 24 weeks by self-reporting the number of tablets taken and at what time in the previous 2 weeks. Participants were advised to make no changes to their usual diets and lifestyles and other drug therapy, which were in place before entry to the trial unless advised to do so by a physician.

Written informed consent was obtained from all participants and at baseline 3 sitting blood pressure recordings were taken in the clinic (mean of the last 2 were used for analyses) using standardized methods and machines.8,9 In addition, a 24-hour ambulatory blood pressure recording was taken before baseline using the Spacelabs 90207 and 90217 machines in London and the TM-2430 (A&D Company Limited) or the BPOne 2.03a (H and C Medical Devices Spa) machines in Thessaloniki. Cuff sizes for ambulatory and clinic blood pressure recordings were adjusted according to current UK recommendations10 and manufacturer’s instructions. Routine blood samples were taken and an electrocardiogram recorded during screening to ensure eligibility and at baseline, a quality of life questionnaire (EQ-5D-5L)11 was administered. At 12 weeks and at the end of the trial any changes in lifestyle, medical procedures, visits to a doctor and self-reported serious adverse events were recorded. In addition, at the same time points, the quality of life questionnaire was completed and clinic blood pressures plus a 24-hour ambulatory blood pressure recording were taken and body weight measured.

The primary end point was change in 24-hour mean systolic blood pressure, and secondary end points were change in mean daytime and nighttime systolic and diastolic pressures and mean sitting clinic systolic and diastolic pressures. Change in self-reported quality of life was also prespecified as a secondary end point.

Statistical Methods

The study was designed to include 100 patients (≈50 at each site) in order that it would have 80% power (2-sided) at the 5% α-level, to detect a 3 mm Hg difference in mean 24-hour systolic blood pressure between those taking medication in the morning compared with the evening. Assumptions included a drop-out rate of 10% and an estimated SD (standard deviation) in mean 24-hour systolic blood pressure of 10 mm Hg.

Patient characteristics were summarized as means with SDs for continuous variables and frequencies and percentages for categorical variables and data on all patients completing both limbs of the trial were included in an intention to treat analyses.

A 2-level hierarchical regression adjusted for center, carry over, and period effect was used to compare the impact of drug dosing time on blood pressure.

Prespecified subgroup analyses were performed by center (London and Thessaloniki) and also post hoc sensitivity analyses were performed stratifying by sex, age (<65 years/≥65 years), alternate daytime and nighttime windows (9 am–9 pm and midnight to 6 am), and excluding non-white participants and extreme outliers in terms of differences in 24-hour systolic blood pressure (those which were >20 mm Hg when medications were taken in the morning compared with the evening).

Results

Between July 2013 and January 2015, 103 eligible patients (mean age, 62 years; 56% male) were randomized (53 in London, 50 in Thessaloniki) in the trial. At baseline, those randomized were taking a mean of 1.9 antihypertensive agents per day (range 1–4). All patients were receiving at least 1 agent which is recommended for once-daily dosing, and 80% were receiving at least 1 agent which provides good 24-hour blood pressure control. Only 8 patients were receiving an agent which should ideally be prescribed on a twice-daily basis. One patient reported any significant lack of compliance before their 12-week assessment and 3 patients reported incorrect timing of drug dosing on >15% of days, 1 before their 12-week visit, and 2 at their 24-week visit. Baseline mean clinic blood pressure readings of participants showed good control (systolic 128.0 mm Hg, SD=8.8; diastolic 76.4 mm Hg, SD=6.1) with a mean body mass index of 29.1 kg/m2, SD=5.2, fasting plasma glucose of 5.6 mmol/L, SD=0.9, and a non-HDL (high-density lipoprotein) cholesterol of 3.5 mmol/L, SD=1.0 (Table 1). There were no important or significant differences in baseline variables between the 2 randomized groups (Table 1). Of those randomized, 95 (92%) completed all three 24-hour ambulatory blood pressure recordings.

Table 1. Baseline Characteristics by Order of Dosing Schedule

Variable*Evening/MorningMorning/EveningTotal
Number, N5251103
Age62.8 (9.7)61.8 (11.0)61.8 (10.3)
Female, N (%)21 (40)24 (47)45 (44)
BMI29.1 (5.6)29.1 (4.7)29.1 (5.2)
Heart rate72.8 (10.3)72.7 (9.6)72.7 (9.9)
Systolic BP127.1 (8.7)129.0 (8.8)128.0 (8.8)
Diastolic BP76.6 (6.1)76.3 (6.2)76.4 (6.1)
Current smoker, N (%)4 (8)8 (16)12 (12)
Alcohol units per week16.7 (17.2)11.8 (11.9)14.6 (15.2)
Fasting plasma glucose5.6 (0.9)5.5 (1.0)5.6 (0.9)
Non-HDL cholesterol3.4 (1.0)3.5 (1.0)3.5 (1.0)

BMI indicates body mass index; BP, clinic blood pressure; and HDL, high-density lipoprotein.

*Mean (SD) except where specified.

Mean 24-hour ambulatory systolic blood pressure did not differ after taking tablets in the morning or evening compared with baseline (Table 2). Similarly, there were no significant differences between the 2 groups in mean 24-hour diastolic blood pressure, mean daytime or nighttime systolic or diastolic blood pressure, nor in clinic systolic or diastolic blood pressure (Table 2).

Table 2. BP Levels (mm Hg) by Timing of Dosing Schedules

OutcomeBaseline (n=95)Drug takenObserved differenceAdjusted* Difference (95% CI)
Morning (n=95)Evening (n=97)
24h Systolic BP128.64 (9.18)129.65 (10.66)129.75 (12.75)0.100.11 (−3.20, 3.42)
24h Diastolic BP76.92 (6.50)77.24 (7.22)77.99 (8.20)0.750.77 (−1.38, 2.91)
Day time SBP131.16 (9.98)132.24 (10.86)132.77 (12.87)0.530.54 (−2.82, 3.89)
Day time DBP79.14 (7.03)79.27 (7.73)80.55 (8.51)1.281.30 (−0.96, 3.56)
Night time SBP120.89 (10.79)122.76 (12.18)121.08 (14.92)−1.68−1.62 (−5.38, 2.15)
Night time DBP69.83 (7.52)70.92 (9.68)70.57 (9.67)−0.35−0.32 (−2.81, 2.17)
Clinic SBP128.07 (8.97)129.37 (11.21)129.81 (12.53)0.440.39 (−2.91, 3.69)
Clinic DBP76.54 (5.88)77.26 (7.12)77.41 (8.36)0.150.14 (−2.03, 2.32)
Quality of Life Score82.80 (11.89)84.14 (11.45)84.04 (10.25)−0.10−0.12 (−3.12, 2.89)

BP indicates blood pressure; DBP, diastolic BP; QoL, quality of life; and SBP, systolic BP.

*Site, period (visit), and sequence (group).

There were no changes in quality of life score recorded, body weight, or heart rates between groups and no changes with baseline (data not shown).

Results were unaffected in sensitivity analyses when data were stratified by center, age, sex and using restricted time windows for day and nighttime blood pressures, and excluding 1 South Asian and 1 black patient or 7 extreme outliers (>20 mm Hg difference in mean 24-hour systolic blood pressure recorded after daytime compared with nighttime dosing).

Discussion

Results of the HARMONY trial suggest that the dosing of routine antihypertensive medication in the morning or evening does not affect ambulatory blood pressure levels—whether 24-hour, daytime or nighttime, nor clinic blood pressure levels. This is, as far as we are aware, the only trial to have evaluated a comparison of the timing of all antihypertensive agents currently in use, on 24-hour ABPM levels and conflicts with results of the MAPEC study.5 The MAPEC study included patients whose blood pressures were uncontrolled while receiving 3 antihypertensive agents taken in the morning. They were randomized to continue to receive all 3 drugs in the morning or to take one of the agents in the evening and 2 in the morning. After 3 months, the latter regimen produced significantly lower 24-hour mean systolic and diastolic pressures and reduced major cardiovascular events.

The large beneficial effects on cardiovascular outcomes observed in the HOPE6 and SYST-EUR (Systolic Hypertension in Europe)12 trials have been considered by some to be attributable to the nocturnal dosing used preferentially in these trials but no randomized evaluation of day versus night dosing was incorporated into these trials. In a trial of 41 patients with obstructive sleep apnea and newly diagnosed hypertension, patients received 1 or 2 agents as a morning dose for 8 weeks, followed by the same treatment as an evening dose, for a further 8 weeks.13 The second 8-week period was associated with significantly lower clinic and 24-hour blood pressures but the non-randomized design precludes the definitive conclusion that the benefits accrued from the dosing time, rather than an order effect.

There were only 2 non-white patients (1 black and 1 South Asian) among the HARMONY participants and particularly in view of the known lower rates of nocturnal dipping among black patients,14 the results of this trial may not be generalizable to ethnic groups other than white.

This trial was relatively small, with 80% power to detect a 3 mm Hg difference in 24-hour systolic blood pressure between morning and evening dosing. Furthermore, it is possible that if the 1.62 mm Hg lower nighttime systolic blood pressure associated with evening dosing (Table 2) reflects a real difference, this could translate into lower rates of cardiovascular outcomes, as suggested by epidemiological observations.2,3 However, all analyses with or without adjustment and among subgroups were consistent in suggesting limited, if any, differences in blood pressures related to dosing time.

This apparently neutral effect could reflect the small average number of agents being used (<2) by the HARMONY patients and their good blood pressure control at baseline. Furthermore, because participants were recruited from 2 specialist hypertension centers, the drugs routinely prescribed were, in keeping with currently recommended best practice,8,9,15 very largely long-acting agents providing good 24-hour control. This, in turn, might minimize any 24-hour blood pressure difference based on dosing times. By contrast, in settings in which agents with shorter durations of action are more commonly used, dosing times may more likely affect 24-hour blood pressure control (assuming differential effects of such agents when given at day or night time).

It remains to be seen whether these possible limitations of the HARMONY trial will be reflected in the results of the TIME trial7 in which large numbers of patients recruited from more population-based settings throughout the United Kingdom have been randomized.

Meanwhile, it seems reasonable to conclude that the timing of dosing of antihypertensive medications should be primarily based on whichever time suits the patient best while using as simple a regimen as possible, and long-acting agents.

Perspectives

The results of the HARMONY trial suggest that the impact of antihypertensive medications on 24-hour ambulatory blood pressure levels is unaffected by whether medications are taken in the morning or evening. In light of the trial inclusion criteria and demography of participants these findings may be only applicable to white patients with reasonably well-controlled blood pressure levels.

These results may be in part dependent on the predominant use of long-acting formulations of agents. Nevertheless, these findings seem reasonably robust given the trial had 80% power to detect a 3 mm Hg difference in 24-hour systolic blood pressure between randomized groups, high rates of adherence (albeit self-reported) and 92% of participants completing all three 24-hour blood pressure recordings. Furthermore, the lack of impact of morning versus evening dosing was consistent across all types of blood pressure measurements and in all sensitivity analyses.

By contrast, extensive epidemiological data suggest that nighttime blood pressure levels predict cardiovascular outcomes better than daytime or 24-hour levels and therefore a link between nighttime drug dosing levels and preferential cardiovascular outcomes has been made. The results of the large TIME trial which is evaluating the impact of daytime versus nighttime dosing on major cardiovascular events are required to see definitively whether nighttime dosing does impart important benefits. Meanwhile, there is no reason to expect specific drug timing to improve blood pressure control, except presumably if the timing adversely affects drug compliance at the individual level.

Therefore, pending further evidence patients should be advised to take their antihypertensive medications when it best suits them.

Acknowledgments

N.R. Poulter, C. Savopoulos, and A. I. Hatzitolios designed the study. A. Anjum, M. Apostolopoulou, and M. Cross administered the study. E. Falaschetti and M. Szigeti performed the statistical analyses. All authors provided advice during the design and conduct of the trial. N.R. Poulter wrote the first draft of the article and all other authors commented and developed the text as required. N.R. Poulter and P. Sever are recipients of National Institute for Health Research Senior Investigator Awards and are supported by the Biomedical Research Centre Award to Imperial College Healthcare NHS Trust.

Footnotes

Correspondence to Neil R. Poulter, Imperial Clinical Trials Unit, Imperial College London, 1st Floor Stadium House, 68 Wood Ln, London W12 7TA, United Kingdom. Email

References

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Novelty and Significance

What Is New?

  • This is the first randomized trial to evaluate and to show that taking usual blood pressure-lowering medications either all in the evening or in the morning did not impact on 24-hour ambulatory blood pressure levels or clinic blood pressure levels.

What Is Relevant?

  • Epidemiological data suggest that nocturnal blood pressure levels predict adverse cardiovascular outcomes better than daytime levels and hence the possible preferential use of nighttime drug dosing has been suggested.

Summary

Pending further definitive evidence (particularly the results of the TIME [Treatment in the Morning Versus Evening] trial) patients should take their antihypertensive medications at a time which optimizes adherence.

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