Risk of heart failure in ambulatory resistant hypertension: a meta-analysis of observational studies.

The impact of ambulatory resistant hypertension (ARH) on the occurrence of heart failure (HF) is not yet completely known. We performed for the first time a meta-analysis, by using published data or available data from published databases, on the risk of HF in ARH. Patients with ARH (24-h BP ≥ 130/80 mmHg during treatment with ≥3 drugs) were compared with those with controlled hypertension (CH, clinic BP < 140/90 mmHg and 24-h BP < 130/80 mmHg regardless of the number of drugs used), white coat uncontrolled resistant hypertension (WCURH, clinic BP ≥ 140/90 mmHg and 24-h BP < 130/80 mmHg in treated patients) and ambulatory nonresistant hypertension (ANRH, 24-h BP ≥ 130/80 mmHg during therapy with ≤2 drugs). We identified six studies/databases including 21,365 patients who experienced 692 HF events. When ARH was compared with CH, WCURH, or ANRH, the overall adjusted hazard ratio for HF was 2.32 (95% confidence interval (CI) 1.45-3.72), 1.72 (95% CI 1.36-2.17), and 2.11 (95% CI 1.40-3.17), respectively, (all P < 0.001). For some comparisons a moderate heterogeneity was found. Though we did not find variables that could explain the heterogeneity, sensitivity analyses demonstrated that none of the studies had a significant influential effect on the overall estimate. When we evaluated the potential presence of publication bias and small-study effect and adjusted for missing studies identified by Duval and Tweedie's method the estimates were slightly lower but remained significant. This meta-analysis shows that treated hypertensive patients with ARH are at approximately twice the risk of developing HF than other ambulatory BP phenotypes.

Clinical trial design for assessing hypertension medications: are critical circadian chronopharmacological principles being taking into account?

INTRODUCTION: Clinical hypertension trials typically rely on homeostatic principles, including single time-of-day office blood pressure (BP) measurements (OBPM), rather than circadian chronopharmacological principles, including ambulatory monitoring (ABPM) done around-the-clock to derive the asleep systolic BP (SBP) mean and sleep-time relative SBP decline - jointly the strongest prognosticators of cardiovascular disease (CVD) risk and true definition of hypertension - to qualify participants and assess outcomes. AREAS COVERED: Eight chronopharmacological elements are indispensable for design and conduct of hypertension medication trials, mainly those on ingestion-time differences in effects, and also a means of rating quality of investigations. Accordingly, we highlight the findings and shortcomings of: (i) 155 such ingestion-time trials, 83.9% finding at-bedtime/evening treatment more beneficial than conventional upon-awakening/morning treatment; (ii) HOPE and ONTARGET CVD outcomes investigations assessing in the former add-on ramipril at-bedtime and in the latter telmisartan, ramipril, or both in combination in the morning; and (iii) pragmatic TIME CVD outcomes trial. EXPERT OPINION: Failure to incorporate chronopharmacological principals - including ABPM to derive asleep SBP and SBP dipping to qualify subjects as hypertensive and assess CVD risk - results in deficient study design, dubious findings, and unnecessary medical controversy at the expense of advances in patient care.

Critical appraisal of recent translational chronopharmacology and chronotherapeutic reviews, meta-analyses, and pragmatic patient trials discloses significant deficiencies of design and conduct and suspect findings.

The conduct of molecular and laboratory animal circadian rhythm research has increased exponentially in the past few decades, such that today investigations are being performed by scientists of many diverse disciplines. Knowledge gained from past works is now being explored for translational applications to clinical medicine, often termed "circadian medicine," through the implementation of patient trials. However, these trials are being led, more often than not, by investigators who have little or no formal training and in-depth expertise in the methods of human circadian rhythm research, causing them to be deficient in design and produce dubious findings that have already led to unnecessary medical controversy at the expense of advances in patient care. Evidence of the very significant shortcomings of today's translational circadian medicine research is exemplified in two recent publications in well-read reputable medical journals concerning the chronotherapy of blood pressure (BP) medications: one a review and meta-analysis by Maqsood et al. published in the journal Hypertension in 2023 that pertains to ingestion-time differences in the extent of BP reduction exerted by hypertensive medications and the other a report by Mackenzie et al. in the journal Lancet in 2022 that details the results of the pragmatic TIME study that assessed ingestion-time differences in cardiovascular disease outcomes. Herein, we appraise the inaccurate trial selection, lack of quality assessment, and the numerous other shortcomings that culminated in suspect findings and faulty conclusions of the former, as well as the deficiencies in design and conduct of the latter using as reference the eight items identified in 2021 by a working committee of the International Society for Chronobiology and American Association for Medical Chronobiology and Chronotherapeutics as being necessary for high-quality research of circadian rhythm-dependencies of the therapeutic effects of BP-lowering medications. The TIME study when rated for its quality according to the extent to which its investigational methods satisfy all of the eight recommended items attains a very low overall score of + 1 out of a possible range of -1 to + 7. Moreover, our review of the methods of the currently ongoing pragmatic BedMed trial discloses major deficiencies of the same sort rending a poor quality score of + 0.5. Although the focus of this article is the appraisal of the quality of contemporary circadian medicine hypertension chronotherapy research, it additionally exposes the inadequacies and dubious quality of the critique of such manuscripts submitted for publication to influential journals, in that some peer reviewers might also be deficient in the knowledge required to properly rate their merit.

Twenty-four hour pattern of childhood febrile seizures substantiated by time series meta-analysis: Circadian medicine perspectives.

Major objectives of this work were to: (1) substantiate the 24-hour pattern in the occurrence of childhood febrile seizures (CFSs) by a novel time series meta-analysis of past reported time-of-day data and (2) discuss its potential circadian rhythm-dependencies. Comprehensive search of the published literature retrieved eight articles that met inclusion criteria. Three investigations were conducted in Iran, two in Japan, and one each in Finland, Italy, and South Korea, representing a total of 2461 mostly simple febrile seizures of children who were on average about 2 years of age. Population-mean cosinor analysis validated (p < .001) a 24-hour pattern in the onset of CFSs, with an approximate four-fold difference in the proportion of children expressing seizures at its peak at 18:04 h (95% confidence interval: 16:40-19:07 h) vs trough at 06:00 h, in the absence of meaningful time-of-day differences in mean body temeprarure. The CFS time-of-day pattern likely derives from the actions of multiple circadian rhythms, particularly the cytokines that comprise the pyrogenic inflammatory pathway and melatonin that influences the excitation level of central neurons and helps regulate body temperature. Past laboratory animal and patient investigations document that the vulnerability to a seizure by a provoking trigger of the same intensity is not the same but different in a predictable-in-time manner during the 24 h as a circadian susceptibility/resistance rhythm. Knowledge of the marked disparity in the time-of-day risk of CFSs can be translated into improved prevention, particularly during the late afternoon and early evening when highest, through proper timing of prophylactic interventions.

Recommended timing of medications that impact sleep and wakefulness: A review of the American Prescribers' Digital Reference.

An appreciable number of medicines have a recommended unique single time-of-day or asymmetrical or unequal-interval multiple-daily administration schedule. Many prescription and over-the-counter (OTC) products, according to administration time, can exert positive or negative impact on nighttime sleep and daytime wakefulness. Intuitively, medicines used to manage nighttime sleep and daytime wake disorders should be taken, respectively, at night before bedtime and morning after arising. However, some utilized for other medical conditions, if improperly timed, may compromise nocturnal sleep and diurnal attentiveness. We conducted a comprehensive review of the American Prescribers' Digital Reference, internet version of the Physician's Desk Reference, for the recommended scheduling of medications and OTC remedies that can impact sleep and wakefulness. The search revealed several hundred therapies of various classes -- α2-receptor agonists, antidepressants, barbiturates, central nervous system stimulants, benzodiazepines, dopamine agonists, dopamine norepinephrine reuptake inhibitors, selective norepinephrine reuptake inhibitors, eugeroics, γ-aminobutyric acid modulators, H1 and H3-receptor antagonists, melatonin analogues, OTC melatonin-containing products, non-benzodiazepine benzodiazepine-receptor agonists, dual orexin-receptor antagonists, and serotonin modulators -- that have a recommended unique dosing schedule. The tables and text of this article are intended to guide the proper scheduling of these medicines to optimize desired and/or minimize undesired effects.

Elevated asleep blood pressure and non-dipper 24h patterning best predict risk for heart failure that can be averted by bedtime hypertension chronotherapy: A review of the published literature.

Several prospective studies consistently report elevated asleep blood pressure (BP) and blunted sleep-time relative systolic BP (SBP) decline (non-dipping) are jointly the most significant prognostic markers of cardiovascular disease (CVD) risk, including heart failure (HF); therefore, they, rather than office BP measurements (OBPM) and ambulatory awake and 24 h BP means, seemingly are the most worthy therapeutic targets for prevention. Published studies of the 24 h BP pattern in HF are sparse in number and of limited sample size. They report high prevalence of the abnormal non-dipper/riser 24 h SBP patterning. Despite the established clinical relevance of the asleep BP, past as do present hypertension guidelines recommend the diagnosis of hypertension rely on OBPM and, when around-the-clock ambulatory BP monitoring (ABPM) is conducted to confirm the elevated OBPM, either on the derived 24 h or "daytime" BP means. Additionally, hypertension guidelines do not advise the time-of-day when BP-lowering medications should be ingested, in spite of known ingestion-time differences in their pharmacokinetics and pharmacodynamics. Between 1976 and 2020, 155 unique trials of ingestion-time differences in the effects of 37 different single and 14 dual-combination hypertension medications, collectively involving 23,972 patients, were published. The vast majority (83.9%) of them found the at-bedtime/evening in comparison to upon-waking/morning treatment schedule resulted in more greatly enhanced: (i) reduction of asleep BP mean without induced sleep-time hypotension; (ii) reduction of the prevalence of the higher CVD risk non-dipper/riser 24 h BP phenotypes; (iii) improvement of kidney function, reduction of cardiac pathology, and with lower incidence of adverse effects. Most notably, no single published randomized trial found significantly better BP-lowering, particularly during sleep, or medical benefits of the most popular upon-waking/morning hypertension treatment-time scheme. Additionally, prospective outcome trials have substantiated that the bedtime relative to the upon-waking, ingestion of BP-lowering medications not only significantly reduces risk of HF but also improves overall CVD event-free survival time.

Dosing time optimization of antihypertensive medications by including the circadian rhythm in pharmacokinetic-pharmacodynamic models.

Blood pressure (BP) follows a circadian variation, increasing during active hours, showing a small postprandial valley and a deeper decrease during sleep. Nighttime reduction of 10-20% relative to daytime BP is defined as a dipper pattern, and a reduction of less than 10%, as a non-dipper pattern. Despite this BP variability, hypertension's diagnostic criteria and therapeutic objectives are usually based on BP average values. Indeed, studies have shown that chrono-pharmacological optimization significantly reduces long-term cardiovascular risk if a BP dipper pattern is maintained. Changes in the effect of antihypertensive medications can be explained by circadian variations in their pharmacokinetics (PK) and pharmacodynamics (PD). Nevertheless, BP circadian variation has been scarcely included in PK-PD models of antihypertensive medications to date. In this work, we developed PK-PD models that include circadian rhythm to find the optimal dosing time (Ta) of first-line antihypertensive medications for dipper and non-dipper patterns. The parameters of the PK-PD models were estimated using global optimization, and models were selected according to the lowest corrected Akaike information criterion value. Simultaneously, sensitivity and identifiability analysis were performed to determine the relevance of the parameters and establish those that can be estimated. Subsequently, Ta parameters were optimized to maximize the effect on BP average, BP peaks, and sleep-time dip. As a result, all selected models included at least one circadian PK component, and circadian parameters had the highest sensitivity. Furthermore, Ta with which BP>130/80 mmHg and a dip of 10-20% are achieved were proposed when possible. We show that the optimal Ta depends on the therapeutic objective, the medication, and the BP profile. Therefore, our results suggest making chrono-pharmacological recommendations in a personalized way.

Does Patient-Applied Testosterone Replacement Therapy Pose Risk for Blood Pressure Elevation? Circadian Medicine Perspectives.

We reviewed medication package inserts, US Food and Drug Administration (FDA) reports, and journal publications concerning the 10 nonbiosimilar patient-applied (PA) testosterone (T) replacement therapies (TRTs) for intraday serum T patterning and blood pressure (BP) effects. Blood T concentration is circadian rhythmic in young adult eugonadal males, being highest around awakening and lowest before bedtime. T level and 24 h variation are blunted in primary and secondary hypogonadism. Utilized as recommended, most PA-TRTs achieve nonphysiologic T 24 h patterning. Only Androderm® , an evening PA transdermal patch, closely replicates the normal T circadian rhythmicity. Accurate determination of risk for BP elevation and hypertension (HTN) by PA-TRTs is difficult due to limitations of office BP measurements (OBPM) and suboptimal methods and endpoints of ambulatory BP monitoring (ABPM). OBPM is subject to "White Coat" pressor effect resulting in unrepresentative BP values plus masked normotension and masked HTN, causing misclassification of approximately 45% of trial participants, both before and during treatment. Change in guideline-recommended diagnostic thresholds over time causes misclassification of an additional approximately 15% of participants. ABPM is improperly incorporated into TRT safety trials. It is done for 24 h rather than preferred 48 h; BP is oversampled during wakefulness, biasing derived 24 h mean values; 24 h mean systolic and diastolic BP (SBP, DBP) are inappropriate primary outcomes, because of not being best predictors of risk for major acute cardiovascular events (MACE); "daytime" and "nighttime" BP means referenced to clock time are reported rather than biologically relevant wake-time and sleep-time BP means; most importantly, asleep SBP mean and dipping, strongest predictors of MACE, are disregarded. © 2022 American Physiological Society. Compr Physiol 12: 1-20, 2022.

Novel temperature-controlled sleep system to improve sleep: a proof-of-concept study.

The sleep-wake cycle is regulated by circadian Process C and homeostatic Process S. Selective thermal stimulation (STS) of the cervical spine region enhances glabrous skin blood flow (GSBF) and augments body heat dissipation to increase distal-to-proximal skin gradient (DPG) causing decrease of core body temperature (CBT), which can shorten sleep onset latency (SOL) and improve sleep quality. A total of 11 young healthy/normal sleeper males challenged to go to bed (lights-off) 2 h earlier than usual were subjected in a randomised order to non-consecutive treatment and control night-time sleep sessions. The treatment night entailed activation of a dual-temperature zone mattress with a cooler centre and warmer periphery plus STS pillow that applied mild heating to the cervical spinal skin for 30 min after lights-off for sleep. During the first 30 min after lights-off, GSBF (mean [standard error (SE)] Δ = 49.77 [19.13] perfusion units, p = 0.013) and DPG (mean [SE] Δ = 2.05 [0.62] °C, p = 0.005) were significantly higher and CBT (mean [SE] Δ = -0.15 [0.07] °C, p = 0.029) was significantly lower in the treatment than control night, while there was no significant difference in these variables during the 45 min prior to lights-off (baseline). Moreover, SOL was significantly reduced (mean [SE] Δ = -48.6 [23.4] min, p = 0.032) and subjective sleep quality significantly better (p < 0.001) in the treatment than control night. In conclusion, the novel sleep facilitating system comprised of the STS pillow plus dual-temperature zone mattress induced earlier increase in GSBF and DPG and earlier decline in CBT. This resulted in statistically significant shortened SOL and improved overall sleep quality, thereby reducing sleep pressure of Process S, even under the challenging investigative protocol requiring participants to go to sleep 2 h earlier than customary.

Ingestion-time differences in the pharmacodynamics of dual-combination hypertension therapies: Systematic review and meta-analysis of published human trials.

The pharmacodynamics of hypertension medications can be significantly affected by circadian rhythms in the biological mechanisms of the 24 h blood pressure (BP) pattern. Hypertension guidelines fail to recommend the time of day when patients, including those who require treatment with multiple medications, are to ingest BP-lowering therapy. We conducted a systematic review of published prospective trials that investigated hypertension medications for ingestion-time differences in BP-lowering, safety, patient adherence, and markers of target organ pathology. Among the search-retried 155 trials, 17 published between 1991 and 2020 totaling 1,508 hypertensive participants concerned the differential ingestion-time dependent effects of 14 unique dual-combination therapies. All but one (94.1%) of the trials, involving 98.5% of the total number of investigated individuals, reported clinically and statistically significant benefits - including enhanced reduction of asleep BP without induction of sleep-time hypotension, reduced prevalence of BP non-dipping, decreased adverse effects, improved kidney function, and reduced cardiac pathology - when dual-combination hypertension medications were ingested at-bedtime/evening rather than upon-waking/morning. A systematic and comprehensive review of the literature published in the past three decades reveals no single dual-combination hypertension trial reported significantly better benefit of the still conventional, yet unjustified by medical evidence, upon-waking/morning hypertension treatment scheme.

Pharmacogenomics and circadian rhythms as mediators of cardiovascular drug-drug interactions.

This article summarizes the current literature and documents new evidence concerning drug-drug interactions (DDI) stemming from pharmacogenomic and circadian rhythm determinants of therapies used to treat common cardiovascular diseases (CVD), such as atherosclerosis and hypertension. Patients with CVD often have more than one pathophysiologic condition, namely metabolic syndromes, hypertension, hyperlipidemia, and hyperglycemia, among others, which necessitate polytherapeutic or polypharmaceutic management. Interactions between drugs, drugs and food/food supplements, or drugs and genetic/epigenetic factors may have adverse impacts on the cardiovascular and other systems of the body. The mechanisms underlying cardiovascular DDI may involve the formation of a complex pharmacointeractome, including the absorption, distribution, metabolism, and elimination of drugs, which affect their respective bioavailability, efficacy, and/or harmful metabolites. The pharmacointeractome of cardiovascular drugs is likely operated with endogenous rhythms controlled by circadian clock genes. Basic and clinical investigations have improved the knowledge and understanding of cardiovascular pharmacogenomics and pharmacointeractomes, and additionally they have presented new evidence that the staging of deterministic circadian rhythms, according to the dosing time of drugs, e.g., upon awakening vs. at bedtime, cannot only differentially impact their pharmacokinetics and pharmacodynamics but also mediate agonistic/synergetic or antagonistic DDI. To properly manage CVD patients and avoid DDI, it is important that clinicians have sufficient knowledge of their multiple risk factors, i.e., age, gender, and life style elements (like diet, smoking, psychological stress, and alcohol consumption), and comorbidities, such as diabetes, hypertension, dyslipidemia, and depression, and the potential interactions between genetic or epigenetic background of their prescribed therapeutics.

The Circadian Rhythm of Thermoregulation Modulates both the Sleep/Wake Cycle and 24 h Pattern of Arterial Blood Pressure.

Borbély proposed an interacting two-component model of sleep regulation comprising a homeostatic Process S and a circadian Process C. The model has provided understanding of the association between core body temperature (CBT) as a key element of Process C that is deterministic of sleep onset and offset. However, it additionally provides a new perspective of the importance of the thermoregulatory mechanisms of Process C in modulating the circadian rhythm of arterial blood pressure (ABP). Herein, we examine the circadian physiology of thermoregulation, including at the end of the activity span the profound redistribution of cardiac output from the systemic circulation to the arteriovenous anastomoses of the glabrous skin that markedly enhances convective transfer of heat from the body to the environment to cause (i) decrease of the CBT as a pathway to sleep onset and (ii) attenuation of the asleep ABP mean and augmentation of the ABP decline (dipping) from the wake-time mean, in combination the strongest predictors of the risk for blood vessel and organ pathology and morbid and mortal cardiovascular disease events. We additionally review the means by which blood perfusion to the glabrous skin can be manipulated on demand by selective thermal stimulation, that is, mild warming, on the skin of the cervical spinal cord to intensify Process C as a way to facilitate sleep induction and promote healthy asleep ABP. © 2021 American Physiological Society. Compr Physiol 11:1-14, 2021.

Systematic review and quality evaluation of published human ingestion-time trials of blood pressure-lowering medications and their combinations.

The pharmacokinetics (PK) - absorption, distribution, metabolism, and elimination - and pharmacodynamics (PD) of hypertension medications can be significantly affected by circadian rhythms. As a consequence, the time when blood pressure (BP) lowering medications are ingested, with reference to the staging of all involved circadian rhythms modulating PK and PD, can affect their duration of action, magnitude of effect on features of the 24 h BP profile, and safety. We conducted a systematic and comprehensive review of published prospective human trials that investigated individual hypertension medications of all classes and their combinations for ingestion-time differences in BP-lowering, safety, patient adherence, and markers of hypertension-associated target organ pathology of the kidney and heart. The systematic review yielded 155 trials published between 1976 and 2020 - totaling 23,972 hypertensive individuals - that evaluated 37 different single and 14 dual-combination therapies. The vast (83.9%) majority of them reported clinically and statistically significant benefits - including enhanced reduction of asleep BP mean without induced sleep-time hypotension, reduced prevalence of the higher cardiovascular risk non-dipper 24 h BP profile, decreased incidence of adverse effects, improved kidney function, and reduced cardiac pathology - when hypertension medications are ingested at-bedtime/evening rather than upon-waking/morning. Nonetheless, the findings and conclusions of some past conducted trials are inconsistent, often due to disparities and deficiencies of the investigative protocols. Accordingly, we developed a quality assessment method based upon the eight items identified as crucial according to the recently published guidelines of the International Society for Chronobiology and the American Association for Medical Chronobiology and Chronotherapeutics for the design and conduct of human clinical trials on ingestion-time differences of hypertension medications. Among the most frequent deficiencies are: absence or miscalculation of minimum required sample size (83.2%), incorrect choice of primary BP endpoint (53.6%), and inappropriate arbitrary and unrepresentative clock hours chosen for tested treatment times (53.6%). The inability of the very small proportion (16.1%) of trials to verify the advantages of the at-bedtime/evening treatment strategy is likely explained by deficiencies of their study design and conduct. Nonetheless, regardless of the quality score of the 155 trials retrieved by our systematic review, it is most noteworthy that no single published prospective randomized trial reported significantly enhanced BP-lowering, safety, compliance, or other benefits of the unjustified by medical evidence, yet still most recommended, upon-waking/morning hypertension treatment-time scheme.

Extent of asleep blood pressure reduction by hypertension medications is ingestion-time dependent: Systematic review and meta-analysis of published human trials.

Combined evidence of published prospective outcome trials and meta-analyses substantiate elevated asleep blood pressure (BP) and blunted sleep-time relative BP decline (non-dipping), regardless of wake-time office BP and awake or 24 h BP means, are jointly the most highly significant independent prognostic markers of cardiovascular disease (CVD) risk and worthy therapeutic targets for prevention. Nonetheless, current guidelines continue to recommend the diagnosis of hypertension, when based on ambulatory BP monitoring (ABPM), rely, solely, on either the 24 h or "daytime" BP means. They also fail to recommend the time to treat patients. We conducted a systematic review of published human trials regarding ingestion-time differences in the effects of hypertension medications on asleep BP and sleep-time relative BP decline. Some 62 such trials published between 1992 and 2020, totaling 6120 hypertensive persons, evaluated 21 different single and 8 dual-fixed combination therapies. The vast (82.3%) majority of the trials substantiate the bedtime/evening vs. upon-waking/morning treatment schedule produces statistically significant better clinical benefits, including enhanced reduction of asleep systolic BP by an average 5.17 mmHg (95%CI [4.04, 6.31], P < 0.001 between treatment-time groups) without inducing sleep-time hypotension, reduced prevalence of the high CVD risk non-dipper 24 h BP pattern, improved kidney function, and reduced cardiac pathology. Furthermore, systematic and comprehensive review of the ABPM-based literature published the past 29 years reveals no single study that reported significantly better benefits of the most recommended, yet unjustified by medical evidence, morning hypertension treatment-time scheme.

Ingestion-time differences in the pharmacodynamics of hypertension medications: Systematic review of human chronopharmacology trials.

Pharmacokinetics of hypertension medications is significantly affected by circadian rhythms that influence absorption, distribution, metabolism and elimination. Furthermore, their pharmacodynamics is affected by ingestion-time differences in kinetics and circadian rhythms comprising the biological mechanism of the 24 h blood pressure (BP) pattern. However, hypertension guidelines do not recommend the time to treat patients with medications. We conducted a systematic review of published evidence regarding ingestion-time differences of hypertension medications and their combinations on ambulatory BP-lowering, safety, and markers of target organ pathology. Some 153 trials published between 1976 and 2020, totaling 23,869 hypertensive individuals, evaluated 37 different single and 14 dual-fixed combination therapies. The vast (83.7%) majority of the trials report clinically and statistically significant benefits - including enhanced reduction of asleep BP without inducing sleep-time hypotension, reduced prevalence of the higher cardiovascular disease risk BP non-dipping 24 h profile, decreased incidence of adverse effects, improved renal function, and reduced cardiac pathology - when hypertension medications are ingested at-bedtime/evening rather than upon-waking/morning. Non-substantiated treatment-time difference in effects by the small proportion (16.3%) of published trials is likely explained by deficiencies of study design and conduct. Systematic and comprehensive review of the literature published the past 45 years reveals no single study reported significantly better benefit of the still conventional, yet unjustified by medical evidence, upon-waking/morning hypertension treatment schedule.