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Circadian variations in blood pressure and their implications for the administration of antihypertensive drugs: is dosing in the evening better than in the morning?

Burnier, Michela; Kreutz, Reinholdb; Narkiewicz, Krzysztofc; Kjeldsen, Sverred; Oparil, Suzannee; Mancia, Giuseppef

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doi: 10.1097/HJH.0000000000002532
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Abstract

INTRODUCTION

In most humans, blood pressure (BP) follows a definite and reproducible circadian rhythm, which has been well characterized using intraarterial BP measurements and noninvasive 24-h ambulatory BP monitoring (ABPM) [1–3]. The day starts with an acute morning rise of BP during the transition from sleep to wakefulness, which can reach 15–25 mmHg [4]. Then, BP remains relatively stable, although fluctuating, with highest values at midmorning and in the evening. At bedtime, BP starts to dip progressively to reach the lowest values during night-time, while sleeping. Superimposed on this circadian rhythm, fluctuations in BP occur in response to several external factors that make substantial contributions to the overall 24-h BP variability, with an effective antioscillatory influence of the baroreflex [5,6]. Importantly, BP is higher during active working hours, and the circadian rhythm is reversed in people working during the night such as shift workers [7].

Multiple external and intrinsic factors contribute to the circadian variation in BP [8]. The main external factors are the light cycle (day–night), external temperature, posture (supine vs. standing), physical and mental activities and food intake (meals). The circadian rhythm and 24-h BP variability are also strongly influenced by internal factors that generate or oppose BP variations, such as centrally determined BP oscillations of various frequencies [9], intrinsic 24-h fluctuations of neuroendocrine systems such as cortisol, insulin, melatonin, renin and aldosterone and the antioscillatory effect of the baroreflex [5]. In this context, the sympathetic nervous system plays a fundamental role and its deactivation is the most important determinant of sleep-dependent BP reduction [10,11]. In addition, there is now strong experimental evidence that cells in the brain, heart, vasculature and kidneys have their own intrinsic circadian activity due to tissue-specific clocks, and these activities have an impact on the circadian profile of arterial BP. [12–14] Arterial stiffness, vascular resistance, endothelial function, platelet aggregation and blood viscosity also have diurnal variations [15]. Of note, in 2017, the Nobel Prize in Physiology or Medicine was awarded to Jeffrey Hall, Michael Rosbash and Michael Young for their landmark discoveries of clock genes and their implications for disease [16].

The use of 24-h ABPM in patients with hypertension has revealed several BP patterns which have subsequently been associated with an increased risk of hypertension-mediated organ damage (HMOD) and adverse events [17]. In this context, in addition to mean daytime BP, the components of the diurnal BP profile that have attracted the greatest attention in recent years are BP variability [18], the early morning rise [19] and, above all, the level of nocturnal BP or the nocturnal dip, for which evidence of prognostic significance is especially strong. Currently, in hypertension guidelines [17], neither the morning surge nor the BP variability are considered as having sufficient incremental predictive value to be considered as reliable tools to assess patients’ cardiovascular risk. Therefore, our review will concentrate on night-time BP.

NOCTURNAL BLOOD PRESSURE AND THE DIPPING PATTERN: CLINICAL SIGNIFICANCE

The decrease in BP occurring during night-time may represent an adaptive process due to the changes in the individual's posture, activities and environmental stresses. It may also have a physiological role to protect major organs from damage, for example by reducing the workload on the heart. Thus, in hypertensive rats, a reduction in night-time BP for only a few hours is as effective as a sustained 24-h reduction in BP to prevent the development of left ventricular hypertrophy [20]. In humans, it is not known how many hours of low BP at night are necessary to protect target organs from hypertension-mediated damage.

Observational studies have demonstrated that nocturnal BP has significant prognostic importance for mortality and the occurrence of cardiovascular events in humans [21–29]. Studies consistently reported that night-time BP is a better predictor of mortality and adverse cardiovascular outcomes than daytime BP, even after adjustment for daytime BP. Conversely, the predictive value of daytime BP decreases when corrected for night-time BP. The prognostic importance of nocturnal BP has been documented in men and women [25], in persons with or without hypertension [23], in elderly patients with hypertension [28] and in patients with diabetes [30–32], chronic kidney disease (CKD) [33–35] and sleep disorders [36]. In patients with diabetes, CKD and sleep disorders, nocturnal hypertension is particular frequent and represents a major cause of masked hypertension and target organ damage in both treated and untreated patients [37–39].

Why nocturnal BP is a better biomarker of cardiovascular risk than daytime BP is not well understood. BP measurements during the night are obtained in better-standardized conditions and are less affected by external factors that are known to increase BP variability. However, the determination of night-time BP also has several pitfalls. Night-time BP is strongly influenced by the quality of sleep, which may vary from one night to another. The number of measurements performed is generally limited to 2 rather than 3 or 4 values per hour, as during the daytime. In addition, the definition of sleep vs. awake periods during ABPM is often imprecise, unless a strict protocol is used. Finally, although observed in an old study, automatic cuff inflations did not affect night-time intraarterial BP [40,41], many patients complain of sleep disturbances during ABPM. Today, new devices enable to acquire BP values during the night using cuffless methods [42] or home BP monitoring devices [43]. These devices have less interference with sleep and are better tolerated than ABPM performed with traditional devices [44]. Early clinical experiences suggest that night-time systolic BPs obtained using home devices are predictive of incident cardiovascular disease (CVD) events, independent of in-office and morning in-home measurements [43].

A clinically important pattern revealed by 24-h ABPM is the dipping of BP during night-time [45]. Whereas BP decreases physiologically by 10–20% during the night, some patients with hypertension have either no decrease or a blunted dip (<10%) and others have a more profound fall in BP exceeding 20%. The former are described as nondippers and the latter as extreme dippers [45]. Some hypertensive patients exhibit an increase in BP during the night and are labelled as reverse dippers. Currently, the night-time dip is a recognized measure of cardiovascular risk with a strong predictive value for adverse cardiovascular events [46]. In 1988, O’Brien et al.[45] reported for the first time that hypertensive patients with a blunted nocturnal BP fall had a greater prevalence of stroke. Since then, numerous studies have demonstrated the prognostic importance of a blunted dip or reverse dipping for hypertension-mediated cardiovascular outcomes such as coronary events, stroke, cardiovascular and total mortality [47]. Patients with no overnight decrease in BP are also at higher risk of developing HMOD, such as microalbuminuria, left ventricular hypertrophy and cerebrovascular disease.

A meta-analysis by Salles et al.[48] performed on data from 17 312 patients with hypertension from three continents confirmed the major clinical impact of the dipping pattern on cardiovascular events and mortality, independently of the 24-h BP level. The predictive value of the absence of fall in night-time BP has also been demonstrated in large population studies [49–51]. Importantly, the nondipping pattern is highly prevalent in patients at high or very high cardiovascular risk, such as the elderly, African-Americans and patients with diabetes, CKD, secondary forms of hypertension, malignant hypertension, heart failure or organ transplantation (Table 1).

TABLE 1
TABLE 1:
Clinical conditions and risk factors associated with nocturnal hypertension and/or a nondipping pattern

The evaluation of nocturnal BP and the dipping pattern shares the limitations described above for ABPM. In addition, the classification of patients into dippers and nondippers has been criticized for its lack of reproducibility in treated and untreated patients. Omboni et al.[52] reported that when 24-h ABPM was repeated twice in the absence of treatment, or during a treatment that had achieved a stable antihypertensive effect, 40% of patients changed their dipping status. A similar observation was made in hypertensive and normotensive patients that underwent three separate 24-h ABPM sessions in a 1-year period: 44% of patients had variable dipping status [53]. Reproducibility might be better among patients groups with a high prevalence of nondippers, such as those with diabetes or CKD. The poor reproducibility of the dipping pattern in almost 50% of patients is not yet well explained, but may be, at least in part, due to changes in dietary sodium intake. The ability to eliminate sodium during the day is a key determinant of the circadian rhythm of BP, and the nondipping pattern contributes to the pressure-natriuresis mechanism [54].

Nocturnal BP and the dipping pattern are two closely linked features that provide similar clinical information [55]. Patients with nocturnal hypertension may be dippers or nondippers. According to available data, one would expect that patients exhibiting both nocturnal hypertension and a lack of the nocturnal BP dip would have the worst cardiovascular risk profile [55]. Therefore, information obtained from the level of night-time BP and the dipping profiles are complementary for assessing the cardiovascular risk of patients with hypertension.

CIRCADIAN RHYTHM OF BLOOD PRESSURE AND ANTIHYPERTENSIVE THERAPY

For decades, the main objective of antihypertensive therapy was to lower daytime office BP to recommended targets. Accordingly, the prescription of BP-lowering drugs once per day taken in the morning was and still is the conventional therapeutic approach for the management of hypertension. However, with the wider use of 24-h ABPM, current guidelines recognize the importance of controlling BP around the clock and to normalize the circadian BP pattern [17]. To this purpose, prescribing part of the antihypertensive drug treatment in the evening may seem a reasonable approach, at least in some groups of patients. This strategy may have the theoretical advantage of lowering BP during the critical night-time period, transforming nondippers into dippers and protecting patients during the vulnerable early morning period. However, there is little evidence from prospective randomized controlled trials that restoring a normal dipping pattern or specifically reducing the morning surge of BP is associated with significant decreases in morbidity and mortality in hypertensive patients.

The ability to normalize BP during the entire 24 h period depends on the pharmacodynamic and pharmacokinetic properties of antihypertensive agents. The absorption, distribution, metabolism and elimination of these drugs after oral intake are also influenced by circadian variations of gastrointestinal function, transport systems and enzymatic processes involved in drug metabolism. In contrast to long-acting agents, short-acting drugs are unlikely to cover the 24-h period and must be administered more than once a day. Importantly, many antihypertensive drugs promoted as once-a-day agents do not cover the entire 24-h day, and lose efficacy during final hours of the dosing interval. There may also be a dissociation between the ability of a drug to lower BP for 24 h and its ability to provide organ protection for the same period, as observed with blockers of the renin-angiotensin system [56].

Many true long-acting agents that effectively lower BP during the last 4–6 h of the dosing interval are available in almost all classes of antihypertensive drugs. Long-acting calcium channel antagonists, such as amlodipine or nifedipine GITS (gastrointestinal therapeutic system), decrease BP without affecting the circadian rhythm of BP, regardless of their time of administration (morning or evening) [57]. In contrast, the efficacy of blockers of the renin-angiotensin system appears to be influenced by the circadian activities of renin and aldosterone. For example the duration of the BP-lowering effect of perindopril 4 mg was found to be 24 h when ingested regularly in the morning, and only 12–14 h when ingested in the evening [58]. This suggests that the pharmacokinetics and/or pharmacodynamics of perindopril is modulated by the time of administration. This was not the case for another angiotensin converting enzyme-inhibitor, that is quinapril [59]. Regarding angiotensin receptor blockers (ARB), in a randomized controlled study, the effects of valsartan 320 mg given in the morning or in the evening were compared with lisinopril 20 mg given in the morning in mild hypertension [60]. The effects of valsartan on the circadian rhythm, on night-time and early morning BP and on the BP surge were comparable regardless the dosing time (morning or evening) of valsartan [60]. A similar effect was observed with a dose of 160 mg of valsartan [61]. Another study, in which olmesartan 20 mg was administered to patients with hypertension for 12 weeks in the morning and for another 12-week period in the evening according to a cross-over design [62] showed that dosing time did not exert any statistically significant difference on the efficacy of olmesartan. The reductions in the 24-h mean systolic and DBPs were comparable during the two treatment periods. If anything, olmesartan appeared to be more effective when given in the morning.

To date, more than 20 similar studies, often with small numbers of patients, have been published using different classes of antihypertensive drugs, including beta blockers and alpha blockers. These studies were reviewed in a Cochrane meta-analysis by Zhao et al.[63] in 2001 that examined the administration-time-related-effects of evening vs. morning dosing regimens of antihypertensive drugs. Among a total of 21 studies that fulfilled the selection criteria, more than half (11) originated from one research group led by Hermida et al.[63]. In the meta-analysis, there was a slightly but significantly lower 24-h BP in patients who received the evening dose vs. the morning dose. However, the difference was very modest for both systolic [−1.71 mmHg, 95% confidence interval (CI): −2.78 to −0.65] and diastolic (−1.38 mmHg, 95% CI: −2.13 to −0.62) BP. As none of these randomized controlled trials reported clinically relevant outcome measures, that is all cause mortality, cardiovascular morbidity or mortality, the clinical significance of this BP difference is unclear. In patients with CKD or sleep apnoea, administration of one antihypertensive drug in the evening induced a greater fall in night-time BP, but without evidence that the risk of cardiovascular morbidity and mortality was reduced [64,65]. Further, in Black patients with hypertension and CKD, neither bedtime dosing of a once-daily antihypertensive nor the addition of drugs taken at bedtime significantly reduced nocturnal BP compared with morning dosing of antihypertensive medications [66]. Results of a recent double-blind randomized placebo-controlled crossover trial in patients with moderate-to-severe obstructive sleep apnoea and hypertension showed that nocturnal BP decreased similarly with perindopril taken in the morning or in the evening over a 6-week treatment period [67]. There is clearly a need for more data before the intake of antihypertensive drugs in the evening can be recommended for patients with CKD or sleep apnoea.

Data are scarce and often inconsistent on the impact of morning vs. evening dosing of antihypertensive drugs on intermediate endpoints such as albuminuria, left ventricular hypertrophy or vascular function, as reviewed by Stergiou et al.[68]. Some studies reported a lower urinary albumin/creatinine ratio with bedtime administration of a single antihypertensive drug. How much of the reduction in albuminuria was due to the decrease in BP associated with the peak effect of the drugs is not known [69–71]. Moreover, the pharmacokinetic characteristics of BP-lowering drugs may play an important role. Nevertheless, in a randomized study of 218 patients with primary hypertension randomly assigned to receive olmesartan once daily in the morning or evening, urinary albumin excretion decreased significantly and similarly regardless of whether olmesartan was taken in the morning or in the evening [72].

European Society of Cardiology/European Society of Hypertension (ESC/ESH) and American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of arterial hypertension recommend the use of single pill combinations, possibly of two long-acting antihypertensive agents, as first-line therapy [17,73]. These combinations both increase the likelihood of reaching the recommended target BPs and also induce sustained BP reductions throughout the 24-h period when administered in the morning. Among the most popular single pill combinations are those that contain a calcium channel blocker and a blocker of the renin–angiotensin system. A small 16-week, prospective, randomized, open-label, crossover study showed that morning administration of a valsartan/amlodipine combination was noninferior to bedtime administration in its ability to reduce nocturnal BP [74]. Another study of 232 hypertensive patients uncontrolled on 5 mg amlodipine showed that morning and evening dosing with amlodipine/valsartan had equivalent effects on mean 24-h, daytime, night-time and 24–30-h BP [75]. In another study, a polypill containing aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and hydrochlorothiazide 12.5 mg was administered either in the morning or in the evening to 78 patients according to a randomized triple cross-over design [76]. There was no difference in 24 h mean systolic BP between morning and evening dosing of the polypill, but adherence was better with morning dosing.

BEDTIME ADMINISTRATION OF ANTIHYPERTENSIVE DRUGS IN CLINICAL TRIALS

A large number of randomized controlled trials have demonstrated the clinical benefit of lowering BP, and all classes of BP-lowering drugs have a comparable effect in reducing coronary events and stroke for a given reduction in BP [77,78]. In more than 90% of these trials, the antihypertensive drugs were administered in the morning, as recommended at the time. Few outcome trials of antihypertensive treatment have administered any or all of the drugs in the evening (Table 2). Heart Outcomes Prevention Evaluation Study (HOPE) [79], Systolic Hypertension in Europe (SYST-EUR) [80], Systolic Hypertension in China (SYST-CHINA) [81], CONVINCEControlled Onset Verapamil Investigation of Cardiovascular End Points trial (CONVINCE) [82] and Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) [83] did administer some antihypertensive drugs in the evening. The reasons why some treatments were administered in the evening rather than in the morning in these trials were not always explicit. However, it is clear that their main objective was not to demonstrate the superiority of drug dosing at bedtime, except perhaps for the CONVINCE trial [82]. In HOPE [84], SYST-EUR [80] and SYST-CHINA [81], drug treatment was superior to placebo. In CONVINCE [82], the extended release form of verapamil given in the evening was not superior to atenolol or hydrochlorothiazide taken in the morning in preventing cardiovascular events despite comparable decreases in BP. The sponsor terminated this trial prematurely, thus limiting our ability to interpret the results In the FACET trial, patients randomized to fosinopril, taken in the morning, had a significantly lower risk of major cardiovascular events, when compared with patients randomized to amlodipine given in the evening [83].

TABLE 2
TABLE 2:
Clinical trials with at least one drug administered in the evening or at bedtime and hard cardiovascular endpoints measurements before the HYGIA study

Recently, Poulter et al.[85] published the results of an Anglo-Hellenic randomized crossover trial of the impact of morning or evening dosing of antihypertensive agents on 24-h ambulatory BP (the HARMONY trial). Hypertensive patients controlled on treatment were randomized to receive their usual therapy either in the morning or in the evening for 12 weeks. Thereafter, participants crossed over to the alternative timing for a further 12 weeks. Results demonstrated that the timing of antihypertensive drug administration had no effect on mean 24-h or clinic BP levels. This study differs from studies reported by Hermida et al. in that all antihypertensive drugs were given either in the morning or in the evening, whereas in Hermida's studies the entire daily dose of at least one medication was taken at bedtime.

CLINICAL BENEFITS OF BEDTIME DRUG ADMINISTRATION IN HYPERTENSION: THE MAPEC STUDY AND THE HYGIA PROJECT

The major source of evidence that a bedtime hypertension treatment strategy may reduce the incidence of cardiovascular events and mortality has come from the work of Hermida et al.[47]. This research group has published a large number of articles on the effects of drugs administered in the morning or evening on sleep BP and conducted the first ‘outcome’ study in hypertension, the Ambulatory Blood Pressure Monitoring in the Prediction of Cardiovascular Events and Effects of Chronotherapy (MAPEC) study. The design of the trial was reported in ClinicalTrials.gov (Identifier: NCT00295542) in 2006. This was a single centre, prospective randomized, open-label, blinded endpoint (PROBE) study, designed to demonstrate that bedtime administration of at least one hypertension medication exerts better BP control and CVD risk reduction than conventional therapy [86].

The authors enrolled 2156 hypertensive patients that presented to the single recruiting centre to perform ABPM (mainly in untreated patients) or for being evaluated for uncontrolled hypertension. Patients were randomized to ingest all of their prescribed hypertension medications upon awakening or at least one drug of their regimen at bedtime. A 48-h ABPM was performed on each participant at baseline and yearly during the follow-up. All participants wore a wrist activity monitor to determine their daily activity and when they were asleep. The fact that only 45 patients (2%) were lost during the 5.6 years of mean follow-up appears particularly surprising against the background that yearly ABPM sessions were performed for 48 h. The primary endpoint included: death from all causes, myocardial infarction (MI), angina pectoris, heart failure, coronary revascularization, acute arterial occlusion of the lower extremities, rupture of aortic aneurysms, thrombotic occlusion of the retinal artery, hemorrhagic stroke, ischemic stroke and transient ischemic attack.

Participants ingesting at least one medication at bedtime showed significantly lower mean sleep-time BP than the control group. Moreover, taking medications at bedtime was associated with a significantly lower relative risk (RR) of the primary endpoint, with a RR of 0.39 (95% CI: 0.29–0.51; P < 0.001). The RR of major CVD events, that is CVD deaths, MI, ischemic stroke and hemorrhagic stroke was 0.33 (CI: 0.19–0.55, P < 0.001) [86]. Analyses were adjusted initially for age, sex and diabetes but not for 24-h BP. Hence, it is not clear whether bedtime administration was beneficial due to a higher rate of ‘dipping’ physiology or simply because of better BP control. In addition, the study had several important limits: it was not prospectively powered; the process of randomization was not reported; and the endpoints included some unusual cardiovascular events, and were not independently adjudicated. Clinicians were surprised by the amazing reduction in RR associated with a relatively easy manoeuver, and they asked for a confirmatory study in the form of a well designed multiinstitutional randomized controlled trial (RCT). The authors acknowledged that 48-h ABPM is unusual and would be difficult to implement in many countries.

After the initial publication of the MAPEC study, additional articles were published using the same database in subgroups of patients with diabetes [87] and CKD [88], with similar incredible adjusted RR reductions (hazard ratios of 0.25 and 0.31, respectively) for the endpoints mentioned above, despite inclusion of a much smaller number of patients. Two additional publications of the same data included patients with resistant hypertension [86] and the general hypertension population [89].

The MAPEC started in 2000 and ended in 2009 and was considered afterwards as a proof of concept study by the authors. In 2016, the same group published the protocol of the HYGIA project defined as ‘a research network primarily designed to extend the use of ABPM in primary care as a requirement for the diagnosis of hypertension, evaluation of response to treatment and individualized assessment of CVD and other risks’ [90]. The project used the same protocol and study design as MAPEC. However, the number of study endpoints was even higher and included: first, new-onset hypertension, diabetes and CKD; second, total events, defined as the composite of death from all causes, MI, angina pectoris, heart failure, coronary revascularization, acute arterial occlusion of the lower extremities, thrombotic occlusion of the retinal artery, hemorrhagic stroke, ischemic stroke and transient ischemic attack; and third, the composite of CVD death, MI, heart failure, coronary revascularization, ischemic stroke and hemorrhagic stroke.

The results of this project were reported a first time in 2018 in the European Heart Journal [91] and a second time in the same journal in 2019 [92]. Conclusions were identical to those of the MAPEC study that is ‘Routine ingestion by hypertensive patients of at least one prescribed BP-lowering medications at bedtime, results in improved ambulatory BP control (mainly asleep BP and BP dipping) and markedly diminished occurrence of major cardiovascular events events’. The latter publication has generated a number of concerns regarding the way the trial was carried out ([93] and Carlberg B and Brunström M, ISH Newsletter 2018, doi: 10.30824/2003-9). The most critical questions are summarized in Table 3.

TABLE 3
TABLE 3:
Questions and comments regarding inconsistencies in the HYGIA Study

Hermida et al. published the HYGIA study protocol on ClinicalTrials.gov in 2008 (NCT00741585) and planned initially on a recruitment of 5000 patients. However, as indicated on the site, actual recruitment began in 2007, that is before the end of the MAPEC study. Without clear justification, the planned enrolment increased from 5000 to 15 000 in 2014 and 18 000 in 2016. This marked increase is difficult to understand, as in the published protocol [90], 10 700 individuals with uncomplicated hypertension would have been sufficient for the detection of the postulated reduction in morbidity/mortality of more than 20% after a median follow-up of 5 years. The database appears to be a summary database of multiple smaller studies that had already been completed and published, including perhaps the MAPEC study [86], which enrolled more than 3000 persons in an identical protocol. The randomization described for HYGIA is an unclear process, as it was in MAPEC. There is no evidence that the strict rules that apply to randomized clinical trials were implemented. There is no indication on how the progress of the study was monitored and no documentation of who participated in the event adjudication committee or in the study audit by independent investigators. How many endpoints were actually rejected by the endpoint committee is not mentioned. In large clinical trials, this may range between 15 and 30%, depending on the endpoint. It is odd that the number of patients with composite outcomes are the same as the sum of the individual outcomes included in each composite outcome, as raised by Carlberg and Brunström (ISH Newsletter 2018, doi: 10.30824/2003-9). Further, it is unclear how reliable the reporting of adverse events by physicians was and how they were assessed and dealt with by investigators, particularly those occurring during the night. Finally, according to the publication, the authors engaged 40 centres and 292 physicians to enrol patients and to perform yearly 48 h ABPM sessions on over 19 000 patients. It was reported that only 800 patients dropped out because of inappropriate 48-h measurements and only 0.4% of patients were lost to follow-up. These figures seem amazingly low if one takes into account the known problems that investigators encounter when using ABPM devices for even 24 h, let alone the 48 h used in MAPEC and HYGIA.

WHAT ARE THE RISKS OF BEDTIME ANTIHYPERTENSIVE DRUG ADMINISTRATION?

Most clinical studies consider the administration of antihypertensive drugs at bedtime to be well tolerated. However, lowering of BP at night can be hazardous for many patients if they experience an excessive BP fall in the middle of the night. Over-dipping or extreme-dipping (>20% fall in night-time BP) has been associated with increased risk of myocardial ischemia in patients with coronary heart disease [94] and with silent cerebral infarcts [95]. These risks are especially high in elderly patients [28,96]. A low BP during the night may also increase the risk of falls in elderly patients with nocturia [97]. Nocturnal BP fall is also a risk factor for progressive visual field loss in patients with glaucoma [98]. No information on glaucoma is provided in MAPEC or in the HYGIA project. Further, using the Medication Event Monitoring System it has been shown that drug adherence is significantly lower when drugs are taken in the evening compared with morning [99]. In a double-blind placebo controlled study, adherence was up to 20% lower at bedtime than in the morning with AT1 blockers [100].

SUMMARY AND CONCLUSION

There is no convincing evidence that the administration of BP-lowering drugs at bedtime provides any significant advantage in terms of quality of BP control, prevention of target organ damage or reduction of cardiovascular events. The outcome data reported from the MAPEC and HYGIA projects, due to several important limitations, do not provide convincing evidence for benefit of taking BP medication at bedtime. Long-acting compounds and available single pill combinations taken in the morning lower night-time BP as effectively as daytime BP. If anything, the prescription of antihypertensive drugs at bedtime should be limited to short acting drugs, which do not cover the 24 h of the day. There is no reliable evidence that BP-lowering medications should be routinely dosed at bedtime, unless there is a specific evidence-based indication.

Before changing practice for unproven benefit it is wise to wait for the results of the three ongoing RCTs that are addressing this issue. The first is the Treatment In Morning versus Evening (TIME) study conducted in the United Kingdom, a study with PROBE design (trial registration number: UKCRN17071) [101]. The aim of TIME is to establish whether evening dosing is more cardioprotective than morning. Participants randomized to morning dosing are advised to take all of their usual BP-lowering medications between 0600 and 1000 h and those allocated to evening dosing are instructed to take all their BP-lowering medications between 2000 h and midnight. The trial should run for 5 years, randomizing 10 269 participants, with average participant follow-up of 4 years. The primary endpoint is hospitalization for the composite endpoint of nonfatal MI, nonfatal stroke (cerebrovascular accident; CVA) or any vascular death determined by record-linkage. The BedMed trial, now actively recruiting, is a pragmatic randomized controlled trial (target N = 8750) facilitated by over 300 Canadian family physician members of the Pragmatic Trials Collaborative (NCT02990663). Patients will be randomized to take their medications either in the morning or in the evening. In this latter group, BP-lowering medications will be switched (one at a time as tolerated) to bedtime, or maintained at bedtime if already taken at that time. All decisions related to which, and how many, medications to switch are at the discretion of the care provider. The primary endpoint is the first occurrence of either death (all-cause), or hospitalization or emergency department visit for acute coronary syndrome/MI, congestive heart failure or stroke. Data should be available in 2022. A trial similar to BedMed is being conducted in nursing homes with 1200 frail elderly patients (‘BedMed-Frail’ – NCT04054648) to determine whether the risks and benefits of bedtime prescribing differ in this understudied population.

ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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Keywords:

bedtime; clinical trials; dipping; drug administration; nocturnal blood pressure

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