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.

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.

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.

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.

Chronotherapy of cardiac and vascular disease: timing medications to circadian rhythms to optimize treatment effects and outcomes.

Circadian rhythms impact cardiac and vascular pathophysiology, resulting in 24-hour patterning of symptoms and life-threatening/ending events (chronopathology), plus kinetics and dynamics of medications (chronopharmacology), resulting in administration-time differences in efficacy and safety. Scheduling medications according to circadian rhythm determinants (chronotherapy) can improve treatment effects, for example, before dinner/bedtime ingestion of cholesterol-lowering medications and acetylsalicylic acid, respectively, exerts enhanced control of hypercholesterolemia and after-awakening peak of platelet aggregation; bedtime ingestion of conventional hypertension medications optimizes normalization of sleep-time blood pressure (BP)-strongest independent BP marker of cardiovascular disease (CVD) risk-and most effectively prevents (chronoprevention) CVD morbidity and mortality. Exploration of chronotherapeutic strategies to improve management of cardiac arrhythmias and vascular pathophysiology is still awaited.

Guidelines for the design and conduct of human clinical trials on ingestion-time differences - chronopharmacology and chronotherapy - of hypertension medications.

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been "time-of-day," i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be the primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the asleep (not "nighttime") BP mean and sleep-time relative BP decline, calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called adjusted calculation procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens.

Ingestion-time - relative to circadian rhythms - differences in the pharmacokinetics and pharmacodynamics of hypertension medications.

INTRODUCTION: Hypertension guidelines do not recommend the time to administer blood pressure (BP)-lowering medications, despite multiple prospective clinical trials reporting both improved normalization of BP 24 h patterning and reduced cardiovascular disease (CVD) events when ingested at bedtime rather than upon awakening. AREAS COVERED: We review: (i) circadian rhythm-dependent influences on the pharmacokinetics (PK) and pharmacodynamics (PD) of hypertension medications; (ii) reports of ingestion-time differences in PK and PD of such therapies; and (iii) (chrono)prevention of CVD morbidity and mortality achieved by the simple and low-cost bedtime hypertension chronotherapy strategy, i.e. scheduling at bedtime ≥1 conventional BP-lowering medications to target asleep BP control of ABPM-diagnosed true arterial hypertension patients. EXPERT OPINION: Proper management of hypertension requires awareness of known ingestion-time differences in both the PK of individual BP-lowering medications and their combinations, which arise from circadian rhythms affecting absorption, distribution, metabolism, and elimination, and their PD, which result from circadian rhythms in mechanisms that regulate the 24 h BP pattern. The vast majority of the multiple published trials document substantially enhanced lowering of asleep BP, increased sleep-time relative BP decline (dipping), and markedly better reduction of CVD morbidity and mortality when hypertension medications and their combinations are ingested at bedtime rather than upon waking.

Ambulatory blood pressure-based inclusion criteria in the Hygia Chronotherapy Trial. Rebuttal to Lemmer and Middeke.

The purpose of this communication is to respond to the continuing invalid criticism by Lemmer and Middeke of the MAPEC and Hygia Chronotherapy Trial by emphasizing the: (i) already unambiguously reported ambulatory blood pressure monitoring (ABPM)-based definition of hypertension utilized as the inclusion criterion of both investigations and (ii) impact of bedtime hypertension chronotherapy on ABPM-assessed parameters and cardiovascular disease (CVD) outcome for participants further categorized by influential markers of CVD risk. In so doing, we call attention to apparent unethical misconduct of Lemmer and Middeke of multiple duplicated publications of the very same unfounded criticisms.

Does Timing of Antihypertensive Medication Dosing Matter?

PURPOSE OF REVIEW: Current hypertension guidelines do not provide recommendation on when-to-treat. Herein, we review the current evidence on ingestion-time differences of hypertension medications in blood pressure (BP)-lowering effects and prevention of cardiovascular disease (CVD) events. RECENT FINDINGS: The vast (81.6%) majority of the 136 published short-term treatment-time trials document benefits, including enhanced reduction of asleep BP and increased sleep-time relative BP decline (dipping), when hypertension medications and their combinations are ingested before sleep rather than upon waking. Long-term outcome trials further document bedtime hypertension therapy markedly reduces risk of major CVD events. The inability of the very small 18.4% of the published trials to substantiate treatment-time difference in effects is mostly explained by deficiencies of study design and conduct. Our comprehensive review of the published literature reveals no single study has reported better benefits of the still conventional, yet scientifically unjustified, morning than bedtime hypertension treatment scheme.

Current evidence on the circadian-time-dependent effects of hypertension medications and their combinations in relation to findings of MAPEC and Hygia Chronotherapy Trial.

The main purpose of this commentary is to update, based on our extensive review of the published literature of the past 45 yrs, the differential therapeutic effects of hypertension medications of various classes and their combinations when ingested in the evening/at-bedtime versus in the morning/upon-awakening. Interestingly, revision of the currently available evidence on the differential circadian-time-dependent effects of hypertension medications of six different classes and their combinations indicates among the 137 published hypertension medication trials that evaluated blood pressure (BP)-lowering efficacy according to treatment-time, 112 (81.75%) documented significant better benefits by evening/bedtime compared to morning/awakening-scheduled therapy. The remaining 25 published trials found no treatment-time difference in effects; indeed, no single study has reported better benefits of the still conventional, but scientifically unjustified, morning than evening/at-bedtime treatment scheme.

Chronotherapy of hypertension: advantages of 48-h ambulatory blood pressure monitoring assessments in MAPEC and Hygia Chronotherapy Trial.

The specific purpose of this communication is to summarize the relevant details of the methods utilized to conduct, analyze, and interpret the ambulatory blood pressure (BP) monitoring (ABPM)-obtained patient data in both MAPEC and Hygia Chronotherapy Trial, including details of the sampling requirements in terms of duration and frequency, proper calculation of ABPM-derived mean values, prognostic and therapeutic implications of BP dipping, and limitations of the 24 h BP mean as diagnostic/prognostic parameter still mistakenly recommended by some hypertension guidelines.

Bedtime hypertension chronotherapy best reduces cardiovascular disease risk as documented by MAPEC and Hygia Chronotherapy outcomes trials.

The purpose of this communication is to describe the unique features of the investigative protocols of both MAPEC and Hygia Chronotherapy Trial and to discuss in detail the advantages, limitations, and potential implications of their findings, both for the diagnosis and management of true arterial hypertension that we propose must be defined according to ambulatory blood pressure monitoring (ABPM)-based criteria. In particular, the recommended approach for diagnosis and follow-up of hypertension derived from the findings of MAPEC and Hygia Chronotherapy Trial entails baseline 48-h ABPM assessment for both proper diagnosis of true arterial hypertension and establishment of the eventual need of therapeutic intervention, plus follow-up by periodic 48-h ABPM assessment, specifically for evaluation of timed treatment efficacy and safety.

Bedtime hypertension chronotherapy best reduces cardiovascular disease risk as corroborated by the Hygia Chronotherapy Trial. Rebuttal to European Society of Hypertension officials.

Reinhold Kreutz and colleagues in a recent editorial claim the Hygia Chronotherapy Trial lacks credibility because of deficient methods, thereby dismissing both the plausibility and clinical significance of its reported findings. They misstate and misrepresent crucial information, findings and conclusions unambiguously detailed in the published report of the Hygia Chronotherapy Trial. The purpose of this communication is to provide a complete rebuttal to each and every one of the misleading and scientifically unsupported claims by Kreutz et al. that calls into question their expertise to decry the merits, advantages, limitations and validity of correctly designed and conducted ambulatory blood pressure monitoring-based chronotherapy trials.

New perspectives on the definition, diagnosis, and treatment of true arterial hypertension.

INTRODUCTION: Office blood pressure measurements (OBPM), still used today for diagnosis and management of hypertension, fail to reveal clinically important features of the mostly predictable blood pressure (BP) 24 h pattern, and lead to >45% of individuals being misclassified. Current hypertension guidelines do not provide recommendation on when-to-treat, despite multiple prospective clinical trials documenting improved normalization of 24 h BP pattern and significant reduction in cardiovascular disease (CVD) events when hypertension medications are ingested at bedtime rather than upon waking. AREAS COVERED: In this review, the authors discuss current evidence on the: (i) most relevant attributes of the 24 h BP pattern deterministic of CVD risk; (ii) asleep systolic BP (SBP) mean as the most significant therapeutic target for CVD risk reduction; (iii) ingestion-time differences in pharmacodynamics of BP-lowering medications as reported with high consistency in multiple clinical trials; and (iv) enhanced prevention of CVD events achieved by bedtime hypertension chronotherapy. EXPERT OPINION: Several prospective trials consistently document asleep SBP mean and sleep-time relative SBP decline (dipping) constitute highly significant CVD risk factors, independent of OBPM. Bedtime, compared to customary upon-waking, hypertension chronotherapy reduces risk of major CVD events. Collectively, these findings call for new definition of true hypertension and, accordingly, its proper diagnosis and management.