ABSTRACT

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.

摘要

目前的高血压指南未能提供关于何时治疗的建议，因此忽略了调节血压 (BP) 水平和 24 小时模式以及药物药代动力学和药效学的相关昼夜节律。摄入时间（时间药理学，即对药物动力学和动力学的生物节律依赖性影响，以及时间疗法，即药物和其他治疗的时机，以优化疗效和安全性）试验的理想目的应该是探索潜在的影响内源性昼夜节律对药物作用的影响。此类调查和结果试验要求遵守人类时间生物学研究的基本标准。对自 1974 年以来发表的 150 多项人类高血压药理学和治疗试验进行了深入审查，这些试验解决了醒来/早上与睡前/晚上治疗方案的不同影响，揭示了有时设计和行为不理想或有缺陷的各种方案。许多都是“一天中的时间”，即早上与晚上，而不是基于昼夜节律时间，有些依赖于醒时办公室血压，而不是全天候动态血压测量 (ABPM)。此外，过去的大多数研究样本量都太小，因此统计数据不足。迄今为止，尚未就此类试验的适当设计、方法和实施达成共识。本立场声明建议摄入时间高血压试验遵循最低准则：(i) 招募参与者应仅限于根据 ABPM 诊断阈值和类似活动/睡眠程序诊断的高血压个体。(ii) 应根据内部生物时间选择测试的治疗时间，以睡眠/觉醒周期的觉醒和就寝时间表示。(iii) ABPM 应该是血压评估的主要或唯一方法。(iv) 分析 ABPM 确定的 24 小时 BP 模式的最低要求特征应该是睡眠（而不是“夜间”）BP 平均值和睡眠时间相对 BP 下降，参考每个活动/休息周期计算个人。(v) ABPM 获得的 BP 均值应通过所谓的调整计算得出程序，而不是通过不准确的算术平均值。(vi) ABPM 应在两个或多个连续 24 小时期间（总共 48 小时）至少每小时使用经过验证和校准的设备进行一次，以实现平均清醒时间、睡眠时间和 48 小时 BP 值以及可靠的浸渍状态分类。(vii) 必须按照适当的统计方法计算所需的最小样本量。(viii) 高血压时间药理学和时间治疗试验最好是随机双盲、随机开放标签、盲端点或交叉设计，后者在测试的治疗时间方案之间有足够的清除期。