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.

Bedtime Blood Pressure Chronotherapy Significantly Improves Hypertension Management.

Consistent evidence of numerous studies substantiates the asleep blood pressure (BP) mean derived from ambulatory BP monitoring (ABPM) is both an independent and a stronger predictor of cardiovascular disease (CVD) risk than are daytime clinic BP measurements or the ABPM-determined awake or 24-hour BP means. Hence, cost-effective adequate control of sleep-time BP is of marked clinical relevance. Ingestion time, according to circadian rhythms, of hypertension medications of 6 different classes and their combinations significantly improves BP control, particularly sleep-time BP, and reduces adverse effects.

Identification of the Alarm Pheromone of Hygia lativentris and Changes in Composition during Development.

Heteropteran insects produce a series of volatile compounds from their scent glands that protect them from predators and parasites. These compounds also play roles in chemical communication that elicit aggregation, dispersal, and mating behaviors. Hygia lativentris (Coreidae) adults frequently aggregate on host plants. When disturbed, they quickly disperse with the release of a sour smell, suggesting that these bugs possess an alarm pheromone in their secretions. This adult secretion-induced dispersal has been examined with a laboratory assay. Hexanal, the predominant component of the adult secretion was identified as a component of the alarm pheromone by evaluation of the adult bug's response time and escape distance from the chemical source. Physicochemical analyses with gas chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy revealed that secretory components differed between nymphs and adults, and also during adult aging. Nymphs produced two unsaturated compounds, (E)-2-hexenal and (E)-4-oxo-2-hexenal, together with hexanal and 1-hexanol, which were found in all developmental stages. In adults, hexyl acetate was the major component of secretions within 3 days of emerging, while the amount of this ester decreased and those of hexanal, hexanoic acid, and hexanal trimer increased with aging. The decomposition of hexyl acetate into hexanal via 1-hexanol was attributed to the presence of esterases and alcohol dehydrogenases specifically found in adult secretory glands. In contrast, the formation of a hexanal trimer may be due to a non-enzymatic reaction under acidic conditions.

Neocucurbitaria chlamydospora sp. nov.: A Novel Species of the Family Cucurbitariaceae Isolated from a Stink Bug in Korea.

The fungal strain KNUF-22-18B, belonging to Cucurbitariaceae, was discovered from a stink bug (Hygia lativentris) during the investigation of insect microbiota in Chungnam Province, South Korea. The colonies of the strain KNUF-22-18B were wooly floccose, white to brown in the center on oatmeal agar (OA), and the colonies were buff, margin even, and colorless, reverse white to yellowish toward the center on malt extract agar (MEA). The strain KNUF-22-18B produced pycnidia after 60 days of culturing on potato dextrose agar, but pycnidia were not observed on OA. On the contrary, N. keratinophila CBS 121759T abundantly formed superficial pycnidia on OA and MEA after a few days. The strain KNUF-22-18B produced chlamydospores subglobose to globose, mainly in the chain, with a small diameter of 4.4-8.8 µm. At the same time, N. keratinophila CBS 121759T displayed a globose terminal with a diameter of 8-10 µm. A multilocus phylogeny using the internal transcribed spacer regions, 28S rDNA large subunit, ß-tubulin, and RNA polymerase II large subunit genes further validated the uniqueness of the strain. The detailed description and illustration of the proposed species as Neocucurbitaria chlamydospora sp. nov. from Korea was strongly supported by molecular phylogeny.

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.

Insufficient reply by Hermida et al. to the critical comments to the MAPEC and HYGIA studies.

The reply of Hermida et al. (2020) to our critical comments on the MAPEC and HYGIA Lemmer and Middeke (2020) studies in this Journal is insufficient and incomplete. Hermida does not address our first and main point on the baseline blood pressure values of 131/77 mmHg over 48 hours comprising 57.4% of the treated hypertensives (according to Table 1 in HYGIA) and consequently 42.6% of the untretated hypertensives! We criticized that in the HYGIA study; both normal and treated patients were included in one group not separated by statistics and without information on the baseline blood pressure values in each subgroup. This basic failure is our key issue of criticism and the basis of unreliability concerning the whole publication. This issue was not picked up in the recent comment of Hermida et al. (2020). They just concentrated on minor points in order to reject our severe criticism.

A commentary on the Spanish hypertension studies MAPEC and HYGIA.

The recently published chronotherapeutic Spanish papers MAPEC and HYGIA proposing that antihypertensive drug treatment should be given at bedtime suffers from obvious deficiencies in study design and are not a valid basis for drug treatment of hypertension.

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.

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.

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.

The Hygia Project and Hygia Chronotherapy Trial: insights of we clinical investigators on the impact of the embedded continuing medical education on primary-care practice and improved patient cardiovascular health.

The participating doctors of the Hygia Chronotherapy Trial (HCT) are aware of the criticisms of its published findings, which have been unjustifiably misrepresented in letters to the editors and commentaries, perhaps because of lack of understanding of the foundations of the Hygia Project, in which the HCT is nested. Thus, our purpose through this communication is to highlight the unique features of the Hygia Project and HCT in terms of: (i) organization, management, and quality control, (ii) physician training/continuing medical education, and (iii) impact on every-day primary-care clinical practice specifically improved patient care through 48 h ambulatory blood pressure monitoring to diagnose and optimally manage by bedtime hypertension chronotherapy true arterial hypertension to markedly improve the cardiovascular health of our patients.

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.

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.

Blood pressure medication should be routinely dosed at bedtime. An internist's critical appraisal of the editorial by Rainhold Kreutz et al. (2020). Blood pressure medication should not be routinely dosed at bedtime. We must disregard the data from the HYGIA project. Blood Pressure. 29 (3):135-136.

The history of hypertension the past hundred years is a successful story of the fall of myths, beliefs, and assumptions under the weight of evidence. The recent editorial by Kreutz et al. (2020),"Blood pressure medication should not be routinely dosed at bedtime. We must disregard the data from the HYGIA project", published in Blood Pressure, conveys unjustified concerns founded on baseless doubts and suspicions about the Hygia Chronotherapy Trial. The physicians of Portugal are beginning to incorporate into routine clinical practice the proven methods of the Hygia Chronotherapy Trial - 48-hour ambulatory blood pressure monitoring and bedtime hypertension chronotherapy - to improve in a cost-effective matter the diagnosis and management of hypertension and to reduce the overwhelming burden of cardiovascular morbidity and mortality in our country.

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.