Has the Sun Set on Nighttime Dosing in Uncomplicated Hypertension?

Abstract

HomeHypertensionVol. 72, No. 4Has the Sun Set on Nighttime Dosing in Uncomplicated Hypertension? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHas the Sun Set on Nighttime Dosing in Uncomplicated Hypertension? Luke J. Laffin and George L. Bakris Luke J. LaffinLuke J. Laffin From the Section of Cardiology (L.J.L.), Department of Medicine, University of Chicago Medicine, IL. The Comprehensive Hypertension Center, Section of Endocrinology, Diabetes and Metabolism (L.J.L., G.L.B.), Department of Medicine, University of Chicago Medicine, IL. Search for more papers by this author and George L. BakrisGeorge L. Bakris Correspondence to George L. Bakris, Department of Medicine, The University of Chicago Medicine, 5841 S Maryland Ave, MC 1027, Chicago, IL 60637. Email E-mail Address: [email protected] The Comprehensive Hypertension Center, Section of Endocrinology, Diabetes and Metabolism (L.J.L., G.L.B.), Department of Medicine, University of Chicago Medicine, IL. Search for more papers by this author Originally published27 Aug 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.11207Hypertension. 2018;72:836–838This article is a commentary on the followingRandomized Crossover Trial of the Impact of Morning or Evening Dosing of Antihypertensive Agents on 24-Hour Ambulatory Blood PressureOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 27, 2018: Ahead of Print See related article, pp 870–873Circadian variation in blood pressure (BP) and heart rate follow highly reproducible patterns. Lower BP levels are normally seen during sleep when compared with daytime values. Increases in BP occur in the early hours of the morning, generally on awakening. These higher values are typically sustained with some variability throughout the day.1 Data from ambulatory BP monitoring (ABPM) studies document a significant association between this circadian variation and the risk of cardiovascular events, as well as predicting prognosis.1 Myocardial infarction, stroke, left ventricular hypertrophy, and the progression of renal disease are among the numerous adverse events seen in patients that lack circadian variation in BP.1Multiple studies using ABPM have identified 2 important deviations in the normal circadian variation of BP that predict a higher risk of cardiovascular events. These factors are nocturnal BP levels and less well established the rate of rise in the early morning BP surge.Nocturnal BPMost normotensive and hypertensive individuals experience a 10% to 30% decline in BP while sleeping compared with their average BP during waking hours (dippers). The absence or dampening of this BP decline during sleep is termed nondipping. Additionally, reverse dipping or the elevation of BP during sleep is considered part of this spectrum as well.O’Brien’s initial use of the terms dipper and nondipper used a difference of 10 mm Hg between mean daytime and nighttime BP to differentiate between the 2 groups. There is no worldwide consensus on a threshold at which to label an individual patient with a nondipping pattern of nocturnal BP, although most sources use 10%.2 However, ABPM diagnoses of nondippers and reverse dippers are less reproducible when using proportional BP decreases, compared with when an absolute threshold is used to define nocturnal hypertension.1,3 The American Heart Association and European Society of Hypertension have previously defined the nocturnal hypertension threshold as >125/75 mm Hg and >120/70 mm Hg, respectively.4Complicating the diagnosis of nocturnal hypertension is the American College of Cardiology/American Heart Association 2017 Hypertension guidelines that attempt to equate office measured BPs to a variety of BP estimates in other settings. For example, a clinic BP of 130/80 mm Hg (stage 1 hypertension) is said to correspond to nighttime ABPM of 110/65 mm Hg. Although the data for these equivalencies are limited to nonexistent, it is unknown if this will, or even should become the new threshold to define nocturnal hypertension. Admittedly, the guidelines acknowledge that additional inquiry into nocturnal hypertension and its relationship to outcomes is needed.5 Nevertheless, all studies and data to date have used the 125/75 or 120/70 mm Hg as the acceptable range with ample data to support this level.It is established that nondippers and reverse dippers have elevated sympathetic tone as well as reduced baroreceptor sensitivity, or poor vascular compliance associated with a myriad of diseases including obesity, sleep apnea or other sleep disorders, stage 3 or higher chronic kidney disease, or Parkinson disease.3,6 Regardless of the associated cause, they uniformly have 2- to 3-fold higher total mortality and cardiovascular events when compared with dippers.1,3 For this reason, there have been many studies examining timing of drug dosing to try and restore dipping status. In this issue of the journal, Poulter et al7 provide further insight into the issue of drug dosing and restoration of nocturnal dipping.Early Morning BP SurgeStudies by Rocco and colleagues in the mid-1980s noted that a higher risk for major cardiovascular events is seen between 6 am to noon compared with other times of the day. The underlying pathophysiology for this validated observation is not well understood but is associated with nonhemodynamic factors such as increased atherosclerotic plaque vulnerability contributing a more prothrombotic state as well as hemodynamic factors related to hormonal increases such as cortisol that generate a rise in BP on awakening. The most recent data to support the concept that early morning BP surge impacts cardiovascular outcomes is seen in a 2020 person cohort with 24-hour ABPM data and ≈20 years of follow-up.8 This study demonstrated that higher slopes of the morning BP surge resulted in higher mortality.Taken together the totality of data strongly supports the concept that re-establishment of nocturnal BP dipping should reduce cardiovascular risk. Nocturnal dosing for BP lowering has been tried with variable outcome results. Commonly cited data to support this hypothesis emanates from the MAPEC trial (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares) published in 2010.9 This trial demonstrated a reduction in cardiovascular morbidity and mortality in those taking at least 1 antihypertensive agent in the evening. However, the methods used in the trial have been challenged by numerous authorities, especially because of major methodological issues including how randomization was performed. Moreover, independent adjudication of cardiovascular events did not occur, and thus, the primary outcomes are not easily evaluated compared with other cardiovascular outcome trials.Poulter et al7 performed the HARMONY (Hellenic-Anglo Research into Morning or Night Antihypertensive Drug Delivery), a 2-center, prospective randomized crossover trial of hypertensive individuals. Trial participants were randomized to receive all their usual BP medications in the morning, or the evening, for 12 weeks. They subsequently crossed over to the alternative dosing strategy for another 12 weeks. At baseline, 12-week, and 24-week time-points, clinic BP and 24-hour ABPM were measured. The primary end point was a change in 24-hour mean systolic BP. Secondary end points included changes in mean daytime and nighttime BPs and mean clinic BPs. Of the 103 participants randomized, 95 completed all three 24-hour ABPM recordings, with a mean number of 1.9 antihypertensive medications being taken daily. The baseline mean clinic BP was 128/76 mm Hg. In HARMONY, mean 24-hour ambulatory systolic and diastolic BP did not differ after taking medications in the morning, or evening, compared with baseline levels. There were also no significant differences between the 2 groups in the mean daytime or nighttime systolic or diastolic BP, or in clinic systolic or diastolic BP. Thus, the trial supports the concept that nighttime dosing of all antihypertensive medication does not lower BP more than morning administration.Undoubtedly, the greatest limitation of HARMONY is the composition of the cohort studied, that is, relatively healthy, and clearly racially homogeneous. Given the burden of nondipping and nocturnal hypertension is much greater in sicker, higher risk patients, the trial participants are not necessarily the cohort one would expect to derive the most benefit from nocturnal versus morning dosing.One key difference between HARMONY and MAPEC is that in HARMONY antihypertensive agents were either taken all in the morning or all in the evening. For certain classes of antihypertensive agents, this makes little difference as they have very long half-lives, for example, amlodipine. However, taking a diuretic at night clearly has the potential to produce disrupted, poor sleep quality and increase BP, ultimately confounding or negating the beneficial effects of nighttime dosing. Unfortunately, the HARMONY trial does not provide information on classes of antihypertensive agents used. Although this is a potential confounder, as most medications do not have half-lives of >18 hours, it should have helped lower nocturnal BP if dosed at night, and it did not.In keeping with these results, a cohort from the black study of kidney disease randomized BP lowering therapy to day versus night; it also failed to show a benefit for conversion to dipping status in a large group of nondippers.10 Thus, while the HARMONY trial does provide some valuable information in a well-controlled hypertensive white cohort, similar findings were observed in blacks with advanced kidney disease. However, in contrast to the timing of medication, improvement of sleep quality and subsequent reduction in sympathetic tone has consistently shown improvement of nocturnal BP.11The authors of HARMONY acknowledge that we may gain more insight about antihypertensive agent dose timing from the ongoing TIME trial (Treatment in the Morning Versus Evening).12 TIME is designed to test whether evening or morning dosing of all antihypertensive agents results in differences in cardiovascular outcomes. More than 20 000 participants were randomized and will be followed for an average of 4 years. TIME, however, will have similar limitations to HARMONY in that it is a homogenous cohort and the all-or-none timing approach to taking antihypertensive agents is used. Additionally, given TIME’s pragmatic and novel design using predominantly an online portal for enrollment and self-reporting, the study does not incorporate ABPM data.In total >25 years of data consistently indicate that lack of nocturnal dipping is associated with higher cardiovascular and total mortality risk, especially in the early morning hours. Data are also consistent that reducing sympathetic tone either with renal denervation, improving sleep quality, or to a lesser extent use of α-blocking agents at night, improves the likelihood of dipping restoration. Thus, given this data, it seems that dose timing of antihypertensive medications, apart from α-blockers and in those patients with baroreceptor dysfunction, does not matter. Dosing at night should then focus on improving adherence by minimizing common side effects such as lethargy from certain medication classes. Although there has been significant inquiry into obstructive sleep apnea and BP-related issues, more work is needed to understand how to improve sleep quality in those with insomnia, reduce sympathetic tone at night, and ultimately translate these findings into conversion of nondippers to dippers. This will be possible with new technology using portable devices without tubing to assess BP throughout day. These technologies will require further validation and correlation with the traditional brachial noninvasive BP cuffs. Thus, a soon to come data influx will help clinicians and patients undertake more personalized BP management strategies, particularly in the current era of precision medicine.Sources of FundingL.J. Laffin is supported by the National Heart, Lung, and Blood Institute T32 postdoctoral training grant (T32 HL007381). G.L. Bakris is the Principal Investigator of the FIDELIO trial (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease; Bayer), Steering Committee-CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy; Janssen), and CALM-2 (Controlling and Lowering Blood Pressure With the MobiusHD™; Vascular Dynamics) and served as a consultant for Merck and KBP.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to George L. Bakris, Department of Medicine, The University of Chicago Medicine, 5841 S Maryland Ave, MC 1027, Chicago, IL 60637. Email [email protected]edu