Evidence Against Using a Chronotropic Strategy for Blood Pressure Control
Michael J. Bloch, MD
Associate Professor, University of Nevada School of Medicine
Medical Director, Vascular Care, Renown Institute for Heart and Vascular Health
President, Blue Spruce Medical Consultants, PLLC
Bloch MJ. Evidence against using a chronotropic strategy for blood pressure control. Consultant360. December 7, 2022.
The results of two studies suggested that bedtime dosing of at least one antihypertensive agent not only led to improved blood pressure (BP) control but also reduced subsequent cardiovascular (CV) events. In the 2156 participant Monitorización Ambulatoria de la Presión arterial y Eventos Cardiovasculares (MAPEC) study, published in 2010, participants who were randomly assigned to a group who took at least one of their prescribed antihypertensive medications in the evening had a 61% reduction in major CV events after a mean of 5.6 years, compared with those taking all of their medications in the morning.1 Similarly, in The Hygia Chronotherapy Trial, with 19,084 participants and published in 2020, participants who were randomly assigned to a group who took at least one of their prescribed antihypertensive medications at night had a 45% reduction in major CV events after a mean of 6.3 years compared with those taking all of their medications in the morning.2 Given the unexpectedly large magnitude of this treatment benefit, many commentators have questioned the validity of these results, both of which came from a single center in Spain.
Based on the controversy following the publication of these Spanish trials, several protocols were initiated around the world to attempt to replicate or refute these findings. The first of these large prospective randomized trials to be published is the Treatment in Morning Versus Evening (TIME) Study.3 This study employed a prospective pragmatic parallel-group study that recruited adults with hypertension who were taking at least one prescribed antihypertensive medication in the United Kingdom. Individuals who worked night shifts or were taking antihypertensive medications that required multiple doses in a 24-hour period were excluded. Eligible participants were randomly assigned in 1:1 fashion to take all their usually prescribed antihypertensive medications in the morning (6am-10am) or in the evening (8pm-midnight). No changes were made to the previously prescribed antihypertensive medications, aside from the timing of administration. Participants were not blinded to treatment allocation. However, the outcome assessment was blinded. Outcomes were identified by patient questionnaire and by linkage to the National Hospital System electronic medical record. The primary outcome was defined as the composite CV endpoint of vascular death or hospitalization for non-fatal myocardial infarction or non-fatal stroke, analyzed as time to first event. Secondary outcomes included the individual components of the primary outcome as well as all-cause mortality and hospitalization or death from heart failure. Participant-reported adherence data and adverse events (falls, fractures, etc) were also collected.
Overall, 21,104 participants met the inclusion criteria and were randomly assigned. The mean age at study entry was 65.1 years, 57.5% of participants were men, and 13% had a history of CV disease. After a median follow-up of 5.2 years, there was no significant difference in CV outcome rates between those assigned to evening administration (3.4%) and to morning administration (3.7%). There was also no significant difference in all-cause mortality or in other secondary events. There was perhaps a slight decrease in reported falls in those assigned to evening dosing, but self-reported, adverse-event rates were low.
Like all clinical trials, the TIME study was subject to certain limitations but certainly fewer than the previously reported studies on this topic. Pending results of future planned trials in other countries, particularly the Canadian Bedtime Versus Morning Use of Antihypertensives for Cardiovascular Risk Reduction (BedMed) Trial, these results should “put to bed” a great deal of the controversy surrounding chronotropic dosing of antihypertensive medications.4 While the dipping pattern certainly impacts CV events, a chronotropic strategy to improve dipping status has not been demonstrated to improve CV events in well-designed clinical trials. When confronted with non-dipping status, providers should identify and treat underlying causes, such as sleep disturbance or chronic kidney disease and promote beneficial lifestyle changes, like exercise and weight loss. To increase adherence, providers should prescribe long-acting, once-daily medications as fixed-dose combinations whenever possible. Patients should be encouraged to take these medications at the same time each day, whenever best fits their schedule and preference.
- Hermida RC, Ayala DE, Mojon A, Fernandez HR. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010;27(8):1629-51. https://doi.org/10.3109/07420528.2010.510230
- Hermida RC, Crespo JJ, Dominguez-Sandina M, et al; Hygia Project Investigators. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. 2020;41(48):4565-4576. https://doi.org/10.1093/eurheartj/ehz754
- Mackenzie IS, Rogers A, Poulter NR, et al; TIME Study Group. Cardiovascular outcomes in adults with hypertension with evening versus morning doses of usual antihypertensives in the UK (TIME study): a prospective, randomized, open-label, blinded-endpoint clinical trial. Lancet. 2022;400(10361):1417-1425. https://doi.org/10.1016/s0140-6736(22)01786-x
- Garrison SR, Kolber MR, Allan GM, et al. Bedtime versus morning use of antihypertensives for cardiovascular risk reduction (BedMed): protocol for a prospective, randomized, open-label, blinded end-point pragmatic trial. BMJ Open. 2022;12(2):e059711. https://doi.org/10.1136/bmjopen-2021-059711