INFLUENCE OF CIRCADIAN TIME OF HYPERTENSION TREATMENT ON CARDIOVASCULAR RISK: RESULTS OF THE MAPEC STUDY
Open accessAbstract
Clinical studies have documented morning-evening, administration-time differences of several different classes of hypertension medications in blood pressure (BP)-lowering efficacy, duration of action, safety profile, and/or effects on the circadian BP pattern. In spite of these published findings, most hypertensive subjects, including those under combination therapy, are instructed by their physicians and pharmacists to ingest all of their BP-lowering medications in the morning. The potential differential reduction of cardiovascular (CVD) morbidity and mortality risk by a bedtime versus upon-awakening treatment schedule has never been evaluated prospectively. The prospective MAPEC study was specifically designed to test the hypothesis that bedtime chronotherapy with ≥1 hypertension medications exerts better BP control and CVD risk reduction than conventional therapy, i.e., all medications ingested in the morning. A total of 2156 hypertensive subjects, 1044 men/1112 women, 55.6 ± 13.6 (mean ± SD) yrs of age, were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48 h. Physical activity was simultaneously monitored every min by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Despite lack of differences in ambulatory BP between groups at baseline, subjects ingesting medication at bedtime showed at their last available evaluation significantly lower mean sleep-time BP, higher sleep-time relative BP decline, reduced prevalence of non-dipping (34% versus 62%; p < .001), and higher prevalence of controlled ambulatory BP (62% versus 53%; p < .001). After a median follow-up of 5.6 yrs, subjects ingesting ≥1 BP-lowering medications at bedtime exhibited a significantly lower relative risk of total CVD events than those ingesting all medications upon awakening (0.39 [0.29-0.51]; number of events 187 versus 68; p < .001). The difference between the treatment-time groups in the relative risk of major events (including CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also highly statistically significant (0.33 [0.19-0.55]; number of events: 55 versus 18; p < .001). The progressive decrease in asleep BP and increase in sleep-time relative BP decline towards a more normal dipping pattern, two novel therapeutic targets requiring proper patient evaluation by ambulatory BP, were best achieved with bedtime therapy, and they were the most significant predictors of event-free survival. Bedtime chronotherapy with ≥1 BP-lowering medications, compared to conventional upon-waking treatment with all medications, more effectively improved BP control, better decreased the prevalence of non-dipping, and, most importantly, significantly reduced CVD morbidity and mortality.
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Evening dosing of antihypertensive medication reduced the incidence of all cardiovascular events and cardiovascular mortality over 5.6 years of follow-up in the MAPEC study.
“Evening dosing reduced incidence of all CV events and CV mortality during 5.6 years of follow-up.”
From Role of the circadian system in cardiovascular disease (2018) · cites this paper as [180]
In the MAPEC study, patients with resistant hypertension were randomized to either change the timing of at least one antihypertensive medication to bedtime or maintain their usual practice of taking all antihypertensive medications in the morning.
“Patients in the MAPEC study were randomized to either change the timing of the dose of at least one antihypertensive medication to bedtime, or to maintain their usual practice of taking all hypertensive medications in the morning (180).”
From Role of the circadian system in cardiovascular disease (2018) · cites this paper as [180]
The MAPEC study is one of the few chronotherapeutic trials with long-term cardiovascular outcomes in humans.
“The MAPEC study of over 2,000 individuals with resistant hypertension is one of the few chronotherapeutic trials with longterm CV outcomes in humans (180).”
From Role of the circadian system in cardiovascular disease (2018) · cites this paper as [180]
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- Authors
- Hermida, R. C., Ayala, D. E., Mojón, A., & Fernández, J. R.
- Affiliations
- Universidade de Vigo (ES)
- Corresponding author
- Hermida, Ramón C.
- Venue
- Chronobiology International
- Publisher
- Informa UK Limited
- Published
- 2010-09-20
- Volume
- 27
- Issue
- 8
- Pages
- 1629-1651
- ISSN
- 0742-0528 (ISSN-L)
- 1525-6073
- OpenAlex
- W2167915551
- Cited by
- 608
- References
- 53
- Citations by year
- 2026: 22 · 2025: 40 · 2024: 21 · 2023: 61 · 2022: 32 · 2021: 30 · 2020: 72 · 2019: 24 · 2018: 38 · 2017: 31 · 2016: 36 · 2015: 46 · 2014: 30 · 2013: 21 · 2012: 68
- FWCI
- 27.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Chronobiology International (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Universidade de Vigo
- Xunta de Galicia (PGIDIT03-PXIB-32201PR, INCITE-08-E1R-322063ES, INCITE09-E2R-322099ES, INCITE07-PXI-322003ES)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Nursing › Nutrition and Dietetics › Sodium Intake and Health
- Keywords
- hypertension, chronotherapy, circadian rhythm, ambulatory blood pressure, non-dipping blood pressure, cardiovascular risk reduction, cardiovascular events, antihypertensive drugs, nocturnal blood pressure, combination antihypertensive therapy, nocturnal blood pressure dipping, myocardial infarction, cardiovascular mortality, physical activity monitoring, actigraphy
- MeSH terms
- Adult, Aged, Antihypertensive Agents, Biological Clocks, Blood Pressure, Cardiovascular Diseases, Circadian Rhythm, Female, Humans, Hypertension, Male, Middle Aged, Prospective Studies, Risk Factors, Treatment Outcome, Blood Pressure Monitoring, Ambulatory, Kaplan-Meier Estimate, Actigraphy
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