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The Journal of Clinical Hypertension logoLink to The Journal of Clinical Hypertension
. 2013 Dec 24;16(2):115–121. doi: 10.1111/jch.12238

Efficacy and Safety of Nighttime Dosing of Antihypertensives: Review of the Literature and Design of a Pragmatic Clinical Trial

Barry L Carter 1,2,3,✉, Elizabeth A Chrischilles 1,4, Gary Rosenthal 3,5, Brian M Gryzlak 4, Eric L Eisenstein 6, Mark W Vander Weg 3,5,7
PMCID: PMC4091949  NIHMSID: NIHMS601935  PMID: 24373519

Abstract

Blood pressure exhibits circadian variability, and nighttime blood pressure is one of the best predictors of cardiovascular (CV) events. Adults with hypertension who lack a nighttime dipping pattern are at particularly high risk. Several studies have found that bedtime dosing of antihypertensive agents reduces sleep blood pressure and improves the dipping pattern in nondippers. One small study and 2 substudies of diabetes and chronic kidney disease suggest that bedtime dosing of ≥1 antihypertensives significantly reduced CV events. A Cochrane review of 5 studies found no difference in adverse events between morning and evening dosing. However, several evaluations in ophthalmology have found that nocturnal arterial hypotension precipitated ocular vascular disorders such as ischemic optic neuropathy. Some authors have suggested that additional studies of nighttime dosing of antihypertensive agents that evaluate CV events need to be conducted. The authors describe a randomized controlled pragmatic trial that is being planned at the University of Iowa and Duke University. Patients with hypertension and other comorbid conditions will be randomized to either continue morning dosing of all antihypertensive agents or to switch their nondiuretic medications to bedtime dosing. Patients will be followed for 36 to 42 months. This study will determine whether nighttime dosing reduces CV risk when compared with traditional morning dosing of antihypertensive agents.

A common strategy to improve medication adherence and improve blood pressure (BP) control is to give antihypertensive agents as a single daily dose.1 However, many antihypertensive agents do not adequately control BP throughout the entire 24‐hour dosing interval.2, 3

There is now renewed interest in treating hypertension with divided doses or giving some antihypertensives in the evening.4, 5, 6, 7, 8 The purpose of this paper is to review the literature on nighttime dosing of antihypertensives. We will also describe a pragmatic clinical trial currently being designed to compare cardiovascular (CV) events between conventional dosing and nighttime dosing of BP medications.

Circadian Patterns of BP and CV Events

It has been known for nearly 50 years that BP exhibits circadian variability with a rapid increase on arising in the morning.9 The latter effect is sometimes called early morning BP surge. BP plateaus throughout the afternoon and declines dramatically in most individuals during sleep. The drop during sleep is called nighttime dipping and is defined as a drop in systolic BP ≥10%. Normal nighttime BPs are <120/70 mm Hg, while they are <135/85 mm Hg for daytime pressures and <130/80 mm Hg for the entire 24‐hour period.

Target organ damage and CV events are predicted more reliably by 24‐hour ambulatory BP monitoring (ABPM) than office measurements.10 The most plausible explanation for this observation is that ABPM provides measurements during the critical nighttime period. Studies have demonstrated that sleeptime BP is a better predictor of CV events than daytime pressures or full 24‐hour results.11, 12

The lack of a drop in BP at night (nondippers) increases CV risk.13 Verdecchia and colleagues compared patients with only white‐coat hypertension with those with ambulatory hypertension. Patients with daytime hypertension who had a nocturnal dipping pattern had a relative risk of 3.70 (95% confidence interval [CI], 1.13–12.5) and those with a nondipping pattern had a relative risk of CV events of 6.26 (95% CI, 1.92–20.32) when compared with those with white‐coat hypertension.13 Studies have found that a nondipping pattern may be the best predictor of risk for increased CV events.11, 12 Patients with resistant hypertension,14 diabetes,15 or chronic kidney disease (CKD)16 are much more likely to be nondippers than patients without these conditions. Administration of antihypertensive agents at night has been shown to convert many patients from nondippers to dippers.14

Several biological events exhibit circadian patterns and trigger acute CV events. For example, myocardial infarction and sudden death are known to occur more frequently in the early morning hours (7 am–9 am).2, 17 Platelet aggregation, plasma catecholamines, coronary resistance, and vascular resistance increase in the early morning hours, which, along with the surge in BP, contribute to the greater CV risk in the morning.18

Impact of Timing of Antihypertensive Administration on Treatment Outcomes

Most antihypertensives are taken in the morning at about 6 am to 7 am and achieve peak concentrations in 60 to 90 minutes.2 Therefore, when BP is measured in the usual clinical setting, the antihypertensive effect is at its maximum. However, since the early morning surge in BP occurs before most of the drugs are absorbed, these patients may go unprotected unless the drug has a duration of action of at least 24 hours. Many agents such as hydrochlorothiazide, atenolol, enalapril, labetalol, nadolol, pindolol, sustained‐release propranolol, nifedipine, and others have relatively short half‐lives and often do not reduce BP during the early morning surge in BP when given as a single morning dose.3, 19, 20, 21 In fact, many antihypertensives were given twice daily in the 1980s because of these pharmacokinetic features.2 However, this practice changed largely out of an attempt to facilitate medication adherence but may have jeopardized 24‐hour BP control for many patients. Several authors and recent guidelines from the American Diabetes Association (ADA) suggest that one approach to achieve good 24‐hour control, improve the dipping pattern, and prevent the early morning surge in BP is to give some or all of the antihypertensive agents in the evening.22, 23 The ADA recommendation received an “A” rating, which was somewhat surprising since it was based on one relatively small trial in patients with diabetes (see below).7

It is commonly thought that drug absorption, distribution, and elimination are constant processes in a given individual. However, there are circadian patterns to gastric acid secretion, gastric emptying, gastric transit time, hepatic blood flow, and enzyme activity.24 These changes can influence drug pharmacokinetics in a circadian pattern25 and have been termed chronokinetics.24 β‐Blockers and angiotensin‐converting enzyme inhibitors are known to have time‐dependent pharmacokinetics.24 Therefore, drug pharmacokinetics may change with nighttime dosing.

A bedtime dose will lower BP during the critical nighttime period.5, 6, 7, 26 This strategy should also help protect patients with hypertension during the vulnerable early morning period when BP increases rapidly and has been associated with increased CV events (the early morning surge), but this is not predictable. For example, morning or evening dosing of quinapril had similar effects on daytime BP.27 However, there was a greater reduction in BP during sleep and a greater rise in morning BP when quinapril was given in the evening compared with the morning.

A recent Cochrane review identified 21 studies involving 1993 patients that compared evening dosing with morning dosing of antihypertensive agents.28 There was a small but significantly lower 24‐hour systolic BP with evening dosing by 1.71 mm Hg (95% CI, −2.78 to −0.65). The morning mean systolic BP was 1.62 mm Hg lower with evening dosing than with morning dosing but this did not achieve significance (95% CI, −4.19 to 0.95). The 5 studies reporting adverse events found no difference between evening vs morning dosing (relative risk, 0.78; 95% CI, 0.37–1.65).

Another study compared evening dosing or an add‐on dose to morning dosing of antihypertensive agents in 147 blacks with hypertensive CKD and controlled office BP.29 There was no significant difference in nocturnal, 24‐hour, or daytime systolic BP. This study suggested that bedtime dosing of once‐daily antihypertensive or the addition of drugs taken at bedtime did not significantly reduce nocturnal BP compared with morning dosing.

Recent Studies That Evaluated Hard Endpoints

A Cochrane review published in 2011 found no papers that evaluated hard endpoints for nighttime dosing compared with morning dosing of antihypertensives.28 Since that review, 3 papers from Spain have been published including subsets of patients with diabetes7 and CKD (Table).5 The Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares (Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events [MAPEC]) study was designed to investigate whether bedtime treatment with ≥1 antihypertensive reduced BP and CV disease risk significantly better than conventional therapy, in which all medications were taken upon waking.22 The study was a prospective, randomized, open‐label, blinded endpoint trial in 2156 individuals with hypertension from one center in Spain. Patients were randomized to take all of their antihypertensive agents on awakening or ≥1 agent at bedtime. The investigators used actigraphy to ensure medications were being taken at the prescribed times. CV disease events included death from all causes, myocardial infarction, angina pectoris, coronary revascularization, heart failure, acute arterial occlusion of lower extremities, thrombotic occlusion of the retinal artery, hemorrhagic stroke, ischemic stroke, and transient ischemic attack. Patients were followed for a median of 5.6 years. The sleeptime systolic BP was significantly lower with bedtime dosing (110.9±13.9 mm Hg vs 116.1±17.9 mm Hg, P<.001). Ambulatory BP was controlled (<135/85 mm Hg for systolic BP/diastolic BP) in 62.2% of patients with dosing at bedtime vs 52.8% with dosing on awakening (P<.001). There were significantly fewer major events (CV disease deaths, acute myocardial infarction, and stroke) with bedtime dosing than in those who took all medications on awakening (hazard ratio, 0.33; 95% CI, 0.19–0.55; P<.001).

Table 1.

Studies Evaluating Nighttime Dosing on CV Outcomesa

References Sample Size, No. Follow‐Up, y Nighttime vs Morning Dosing on Sleeptime SBP, mean±SD, mm Hg Hazard Ratio (95% CI)
22 2156 5.6 110.9±13.9 vs 116.1±17.9b 0.33 (0.19–0.55)b
7 Subset of 448 patients with diabetes 5.4 115.0±17.1 vs 122.4±21.8b 0.25 (0.10–0.61)c
5 Subset of 661 patients with CKD 5.4 116.7±16.8 vs 122.6±21.3b 0.28 (0.13–0.61)b
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Abbreviations: CI, confidence interval; CKD, chronic kidney disease; SD, standard deviation; SBP, systolic blood pressure.

a

Cardiovascular (CV) disease events included death from all causes, myocardial infarction, angina pectoris, coronary revascularization, heart failure, acute arterial occlusion of lower extremities, thrombotic occlusion of the retinal artery, hemorrhagic stroke, ischemic stroke, and transient ischemic attack.

b

P<.001.

c

P<.003.

Hermida reported a subgroup analysis from the MAPEC study in 448 patients with diabetes.7 Patients were followed for a median of 5.4 years. The sleeptime systolic BP was significantly lower with nighttime dosing (115.0±17.1 mm Hg vs 122.4±21.8 mm Hg, P<.001). Ambulatory BP was controlled (<135/85 mm Hg for systolic BP/diastolic BP) in 62.5% of patients with dosing at bedtime vs 50.9% with dosing on awakening (P=.013). BP was controlled during sleep (<120/70 mm Hg) in 70.8% of patients with bedtime dosing and 54.7% with dosing on awakening (P<.001). Importantly, there were significantly fewer major events with bedtime dosing (5.16/1000 patient‐years) compared with dosing on awakening (17.55/1000 patient‐years, P<.001). Patients who took ≥1 medication at bedtime had significantly lower risk of major events than those who took all medications on awakening (hazard ratio, 0.25; 95% CI, 0.10–0.61; P<.003). Interestingly, there was a J curve with greater risk when clinic systolic BP was below 134 mm Hg but a J curve was not observed even with sleep systolic BP below 106 mm Hg.

In a second MAPEC substudy, Hermida evaluated 661 patients with CKD who were randomized to ingest all of their BP medications on awakening or to take ≥1 at bedtime.5 Patients were followed for a median of 5.4 years. The sleeptime systolic BP was significantly lower with nighttime dosing (116.7±16.8 vs 122.6±21.3 mm Hg, P<.001). Ambulatory BP was controlled in 56.5% of patients with dosing at bedtime vs 45.2% with dosing on awakening (P=.003). BP was controlled during sleep in 67.2% with bedtime dosing and 54.8% with dosing on awakening (P<.001). Of importance, 41.0% were nondippers with bedtime dosing compared with 71.1% with dosing on awaking (P<.001). There were significantly fewer major events with bedtime dosing (5.1/1000 patient‐years) compared with dosing on awakening (14.5/1000 patient‐years, P<.001). Patients who took ≥1 medication at bedtime had significantly lower risk of major events than those who took all medications on awakening (hazard ratio, 0.28; 95% CI, 0.13–0.61; P<.001). Again, there was a J curve with greater risk when clinic systolic BP was below 131 mm Hg but this was not observed with sleep systolic BP below 106 mm Hg.

The findings of these two MAPEC substudies are provocative in that the samples sizes were small for an outcome trial yet major differences in events were observed in 5.4 years of follow‐up. These publications included approximately 2100 patients. Even so, based on these limited findings, the ADA recommended that at least 1 antihypertensive be given at bedtime.23 Some have suggested that these findings should be replicated in well‐designed, multicenter trials conducted in the United States and we agree.30

Potential Risks From Evening Dosing

There are theoretical risks for dosing anithypertensives at bedtime, especially for patients who display a typical dipping pattern. In these individuals, it is not unusual for BP to reach a nadir of 90/60 mm Hg during sleep. Most antihypertensives will achieve peak effects in 1 to 2 hours after a dose. Depending on the agent, bedtime dosing would result in the most substantial effects in the middle of the night and early morning hours.2 While these effects would minimize the early morning surge in BP, there could be an excessive drop in BP from midnight to 4 am. However, the Cochrane review found no significant difference in adverse events between morning dosing compared with dosing in the evening or at bedtime.28

Hayreh and colleagues31 were the first to demonstrate that nocturnal arterial hypotension precipitated ocular vascular disorders such as ischemic optic neuropathy, which patients often discovered on awakening.31 These investigators used 24‐hour ABPM in 166 patients with anterior ischemic optic neuropathy, glaucoma, and other optic nerve head disorders. There was a 26% reduction in systolic BP and 33% reduction in diastolic BP at night (P<.0001). Patients with a progressive visual field deterioration had a significantly lower systolic BP (114.4±2.5 mm Hg) compared with those without deterioration (123.6±3.2 mm Hg, P=.0262). Patients with a progressive visual field deterioration had significantly greater mean decreases in systolic BP from daytime readings (46.8±2.5 mm Hg) compared with those without deterioration (35.0±3.1 mm Hg, P=.0035). Of interest, the authors anecdotally noted that on repeated ABPM, some patients with marked nocturnal hypotension who had been taking their antihypertensives at bedtime, showed much less nocturnal hypotension when the bedtime dose was discontinued. These investigators also evaluated another 544 episodes of anterior ischemic optic neuropathy and found that 399 (73.3%) were discovered on awakening in the morning, from a nap or at the first opportunity to use vision critically.32 Interestingly, the occurrence was much more common in the summer and fall than in the winter or spring. From these and other studies,33 the authors have concluded that nocturnal hypotension (or with napping) reduces optic nerve head blood flow below a crucial level in certain vulnerable patients and becomes the final insult in anterior ischemic optic neuropathy.

Finally, another group of investigators from Poland evaluated 88 patients with primary open‐angle glaucoma.34 Patients were divided into two groups: those whose BP medications were dosed only in the morning (n=43) and those whose antihypertensives were given in the evening (n=45). There was a significantly lower mean perfusion pressure and greater visual field loss in patients whose medications were given at bedtime. The authors concluded that evening dosing of antihypertensives may cause significant pressure drops at night that can lead to degenerative changes within the optic nerve of patients with open‐angle glaucoma. The findings from these studies in ophthalmology suggest that excessive reductions in nighttime BP may have significant adverse effects in patients with certain visual conditions.

Design of a Pragmatic Clinical Trial to Evaluate Nighttime Dosing

The ADA suggestion that at least 1 antihypertensive be given at nighttime surprised some experts.30 The recommendation was considered level A evidence even though it was based on the substudies in diabetes and in CKD, with only 1109 patients making it difficult to extrapolate these findings to broader populations.5, 7

Recently, the National Heart Lung and Blood Institute (NHLBI) issued a request for proposals for Pragmatic Clinical Trials. The call had two phases: the UH2 phase was a 1‐year planning phase for the eventual UH3 clinical trial. The authors were recently awarded a UH2 grant (Rosenthal, principal investigator) to plan a pragmatic trail of nighttime dosing of antihypertensive medications. We will briefly describe the potential design for this study even though the actual design may be modified during the ongoing planning phase and the National Institutes of Health review process.

The major goal of the UH2 component of this application is to implement and test the validity and reliability of methodological approaches that will be used in a 2‐site randomized pragmatic trial to determine the impact of nighttime dosing of antihypertensive medications on reducing the risk of CV events in patients with hypertension and >1 other significant comorbid condition that increase CV risk. The pragmatic nature of the trial will: (1) develop an electronic medical record (EMR)–based patient recruitment strategy; (2) build interactive Web‐based platforms for obtaining informed consent; (3) extract research data from EMRs and Medicare claims data; and (4) collect patient‐centered and patient‐reported outcomes information from secure Web‐based personal heath records. The primary objective of this study is to compare the likelihood of major CV events (CV death; hospitalization for acute myocardial infarction, stroke, or acute ischemic heart disease or congestive heart failure; and operative or percutaneous procedures for coronary, cerebral, or peripheral revascularization) among patients taking nighttime doses of ≥1 antihypertensive medication with patients taking morning doses of all antihypertensive medications. Secondary objectives will be to: (1) compare outpatient BPs, patient‐reported medication adherence, health‐related quality of life, healthcare utilization, and all‐cause mortality in intervention and control patients, and (2) compare the individual components of the composite adverse CV event endpoints in intervention and control patients.

The proposed trial will capitalize on the informatics, data management, and regulatory support infrastructures that exist in the two collaborating health care systems (University of Iowa Healthcare [UIHC] and Duke University Health System [DUHS]) and through their Clinical and Translational Science Awards (CTSA) programs. The study will involve a 2‐site randomized pragmatic trial to examine the impact of nighttime dosing of antihypertensive medications among patients with hypertension and ≥1 other significant comorbid condition that increase CV risk. Patients will be enrolled and followed for a period of 36 to 42 months. The Figure displays the current study design being planned.

Figure 1.

Figure 1

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Timeline for the recruitment and follow‐up of patients. EMR indicates electronic medical record.

Once participants have provided informed consent, they will be asked to complete a questionnaire that collects baseline data used to confirm eligibility and questions to assess understanding of the informed consent document.

Eligible patients will be randomized in a 1:1 ratio to either nighttime dosing or morning dosing. Randomization will be stratified by study site (UIHC or DUHS) and whether the patient has diabetes (because diabetic patients have lower target BPs and tend to have lower nighttime BP). The nighttime dosing group will receive mailed instructions to begin taking all once‐daily nondiuretic medications at night, and the morning dosing group will receive instructions to continue taking these medications in the morning.

Consistent with the pragmatic nature of the trial, endpoints will be ascertained in UIHC and DUHS EMRs and billing databases by applying algorithms validated for use with healthcare administrative data. To ascertain endpoints that occur outside the UIHC and DUHS systems, these algorithms will be applied to insurance claims and death indices. Out‐of‐system events will also be identified by patient self‐report and retrieval of hospital face sheets and discharge summaries to confirm the self‐reports. Endpoint assessment procedures will be blinded to the study aims to prevent differential ascertainment bias.35 The primary endpoint includes adverse CV events. Secondary endpoints include health‐related quality of life (HRQL), healthcare utilization, and self‐reported medication adherence.

We will capture all EMR BPs routinely obtained in outpatient settings. Both baseline and follow‐up BP values will be evaluated. However, we do not expect office pressures to differ between intervention and control groups. In fact, in two preliminary studies that led to this pragmatic trial, there were no differences in daytime BPs with nighttime medication dosing.5, 7 However, sleeptime BPs were significantly lower in one study in nighttime dosing patients and somewhat lower (borderline statistical significance) in the other study. These findings were confirmed in the Cochrane review.28 While it would be desirable to obtain 24‐hour ABPM in at least a sample of the patients, such an approach would diminish the pragmatic nature of the trial. Therefore, we are not planning such an evaluation at this time.

Medication Adherence, Quality of Life and CV Endpoints

Patients at both UIHC and DUHS will obtain medications from potentially hundreds of community pharmacies making refill history measurements, a common approach to measuring adherence, impractical and unreliable. Therefore, self‐report will be used in surveys at baseline and every 6 months. First, participants will be asked to complete two items from the Medication Adherence Subscale of the Hill‐Bone Blood Pressure Therapy Compliance Scale36 to assess how frequently they: (1) forget to take their high BP medication, and (2) decide not to take their high BP medication. Second, participants will also be asked to characterize their antihypertensive medication‐taking pattern over the previous 7 days by selecting from among the following options: (a) I took all doses of my BP medication; (b) I missed or skipped 1 dose of my BP medication; (c) I missed or skipped 2 doses of my BP medication; or (d) I missed or skipped ≥3 doses of my BP medication.

HRQoL will be collected at baseline and every 6 months thereafter. Two brief measures of health‐related quality of life will be collected: a single‐item visual analogue scale (VAS)37 and the Centers for Disease Control and Prevention's Healthy Days Core Module (HRQoL‐4).38 The VAS asks participants to rate their global quality of life on a horizontal line ranging from 0 (worst imaginable quality of life) to 100 (perfect quality of life). The single‐item VAS has demonstrated excellent test‐retest reliability and good convergent validity based on correlations with other accepted measures of quality of life.37 The CDC HRQoL‐4 is a 4‐item measure assessing self‐perceived health, recent physical and mental health, and activity limitations. The HRQoL‐4 has been shown to possess moderate to excellent test‐retest reliability, good construct validity, and predictive validity among older adults, as evidenced by associations with both short‐ and long‐term hospitalization.39

Healthcare utilization will be based on numbers of clinic visits, emergency department visits, and admissions for acute medical and surgical conditions and will be based on EMR data and Medicare claims data, as well as on self‐reported utilization using items we have tested in 2 previous studies that were modified from items in the Medical Expenditure Panel Study.40 These descriptive data will be important to inform future expectations about the impact of nighttime dosing on healthcare and other service utilization. These measures may decrease with better BP control and a reduction in CV events.

Individual components of the composite adverse CV event will be measured by CV death; hospitalization for acute myocardial infarction, stroke, acute ischemic heart disease, and congestive heart failure; and operative or percutaneous procedures for coronary, cerebral, and peripheral revascularization. All‐cause mortality will be assessed through review of the EMR and from state death certificates and/or national death indices.

It is possible that nighttime dosing may induce symptomatic hypotensive events. Therefore, falls and fall‐related injuries, along with episodes of vision loss, will be directly queried in the surveys every 6 months.

Conclusions

Nighttime BP is one of the best predictors of CV events. A Cochrane review found that bedtime dosing of antihypertensive agents reduced sleep BP. One study conducted in Spain found that bedtime dosing of ≥1 antihypertensive significantly reduced CV events. While it does not appear that adverse events are different between morning and bedtime dosing, nocturnal hypotension has precipitated ischemic optic neuropathy and blindness. We are planning a randomized controlled pragmatic trial to determine whether nighttime dosing reduces CV risk when compared with traditional morning dosing of antihypertensive agents. The results of this trial should be available in 2018.

Funding

Supported by the National Heart, Lung, and Blood Institute, 1‐ UH2AT007784‐01. Drs Carter, Chrischilles, and Vander Weg are also supported by RO1 HL09184. Drs Carter and Chrischilles are supported by the Agency for Healthcare Research and Quality (AHRQ) Centers for Education and Research on Therapeutics Cooperative Agreement #5U18HSO16094. Drs Carter, Rosenthal, and Vander Weg are also supported by the Comprehensive Access and Delivery Research and Evaluation (CADRE), Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (HFP 04‐149). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. All of the authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Disclosures

The authors have no conflicts of interest to report.

J Clin Hypertens (Greenwich). 2014;16:115–121. DOI: 10.1111/jch.12238. ©2013 Wiley Periodicals, Inc.

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