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

• Published in: Chronobiology international 2021, Vol.38 (1), p.1-26
• Main Authors: Hermida, Ramón C, Smolensky, Michael H, Balan, Horia, Castriotta, Richard J, Crespo, Juan J, Dagan, Yaron, El-Toukhy, Sherine, Fernández, José R, FitzGerald, Garret A, Fujimura, Akio, Geng, Yong-Jian, Hermida-Ayala, Ramón G, Machado, Antonio P, Menna-Barreto, Luiz, Mojón, Artemio, Otero, Alfonso, Rudic, R Daniel, Schernhammer, Eva, Skarke, Carsten, Steen, Tomoko Y, Young, Martin E, Zhao, Xiaoyun
• Format: Article
• Language: English
• Subjects: Antihypertensive Agents - therapeutic use; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Chronotherapy; Circadian Rhythm; Eating; Humans; Hypertension - drug therapy; Reproducibility of Results; Risk Factors; Time Factors
• ISSN: 0742-0528; 1525-6073; 1525-6073
• DOI: 10.1080/07420528.2020.1850468

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 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 (not "nighttime") and , calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called 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 dipp