Hypertension is the main cause of cardiovascular disease and death, with more than 1 billion hypertensive patients around the world. The high prevalence of hypertension puts a huge burden on the global health care system and economy.
At present, the most common way to treat hypertensive patients in clinical practice is to take antihypertensive drugs. However, the best time to take antihypertensive medications: morning or evening?
Previous studies
Neurohormone changes lead to day-night changes in blood pressure . The peak blood pressure is usually recorded after awakening, and the blood pressure is the lowest at night. This phenomenon is usually called decline.
No changes in diurnal blood pressure are usually associated with adverse cardiovascular outcomes. This association leads to a suggestion that nighttime administration of antihypertensive drugs to mimic the physiological decline of blood pressure can improve cardiovascular outcomes.
Spanish MAPEC study is the first prospective study to test this hypothesis. In the MAPEC study, 2156 hypertensive patients were randomly assigned to take medication before bed or in the morning. After
follow-up for 5·6 years, it was observed that taking medication before bedtime reduced the total number of cardiovascular events (cardiovascular death, myocardial infarction, ischemic stroke and hemorrhagic stroke), with a relative risk of 0·39 (95% CI 0·29–0·51).
Subsequently, another prospective Spanish study, the Hygia Chronotherapy trial, included 19,084 patients with hypertension.
follow-up time was 6 years, and the results were similar. The cardiovascular outcomes (cardiovascular death, myocardial infarction, coronary revascularization, heart failure or stroke ) in patients assigned to bedtime were reduced by 45%.
" Lancet " Latest study
In "Lancet , Mackenzie Island and colleagues reported the results of morning and evening treatment (TIME) studies.
This is a practical, prospective, randomized, open, open label, blind endpoint clinical trial, including 21,104 adults with hypertension.
They were randomly assigned to give all antihypertensive medications to morning (06:00-10:00) or evening (20:00-00:00). The average age of the
trial was 65 years old. In terms of gender, 12136 subjects were male (57·5%) and 8968 were female (42·5%). In terms of
ancestry, 19,101 of the trial participants were white (90·5%), 98 were black (0·5%), 155 were Asian (0·7%), 113 were mixed-race (0·5%), and 1,637 were missing data (7·8%).
test uses symptoms such as myocardial infarction, vascular death, and non-fatal stroke hospitalization as the criteria for judgment. study found that there was no statistical difference in the experimental group taking antihypertensive drugs in the morning and the experimental group taking antihypertensive drugs in the evening.
study lacks
Although there are many participants, the design is stable and pragmatic, and the follow-up time is relatively long, the study still has some shortcomings.
First, most of the included patients were white, limiting the generalizability of the results to other races.
Secondly, among the patients randomly assigned to the night treatment group, the failure to comply with the predetermined time at any time was significantly higher than those assigned to the morning treatment group (4091 [39·0%] vs 2384 [22·5%]; p0·0001). This differential adherence to the time of administration may attenuate the benefits observed in the night group.
Third, the rate of withdrawal from questionnaire follow-up in the evening group was much higher (929 [8·8%] in the evening group, of which 10 503 cases were , , and 10 601 cases were 547 [5·2%] in the morning group, which may lead to the underestimation of the incidence of adverse events in this group.
Fourth, this study did not conduct a class-based sub-analysis; given the different neurohormonal pathways affected by different classes of antihypertensive drugs, the cardiovascular outcomes of different antihypertensive drugs may have some degree of chronological changes, although not easily obvious.
Nevertheless, the TIME study, based on a well-designed and well-produced trial, provides considerable evidence that demonstrates that the time of administration of antihypertensive drugs is unlikely to affect cardiovascular outcomes .
Looking forward to the future
What direction will the next step in research?
Although the meta-analysis of methods are generally reasonable when dealing with conflicting studies to produce more reliable evidence, this approach may not be appropriate in this case due to concerns surrounding the results and progress of Hygia and MAPEC studies.
Therefore, before any such further analysis is performed, researchers should await the results of ongoing BedMed (NCT02990663) and BedMed-Frail (NCT04054648) trials designed to address the changing effects of antihypertensive drugs on cardiovascular outcomes.
In addition, trials are needed to evaluate the changing effects of different classes of antihypertensive drugs on cardiovascular outcomes.
In summary, the TIME study demonstrated that the effects of taking antihypertensive drugs on cardiovascular outcomes are consistent, contrary to the results of the Hygia and MAPEC trials.
TIME studies show that the time of administration of antihypertensive drugs should be a common decision-making process between patients and clinicians, which considers each patient's lifestyle and situation to maximize compliance while awaiting further trials to confirm that antihypertensive drugs have no preferred chronological effects on cardiovascular outcomes.
References
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2. Gheorghe A, Griffiths U, Murphy A, Legido-Quigley H, Lamptey P, Perel P. The economic burden of cardiovascular disease and hypertension in low[1] and middle-income countries: a systematic review. BMC Public Health 2018; 18: 975.
3. Sharma T, Mathur P, Mehta JL. Daytime or nighttime administration of antihypertensive medications? Am J Hypertens 2020; 33: 987–89.
4. Kario K. Nocturnal hypertension: new technology and evidence. Hypertension 2018; 71: 997–1009.
5. Hermida RC, Ayala DE, Mojón A, Fernández JR. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int 2010; 27: 1629–51.
6. Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J 2020; 41: 4565–76.
7. Turgeon RD, Althouse AD, Cohen JB, et al. Lowering nighttime blood pressure with bedtime dosing of antihypertensive medications: controversies in hypertension - con side of the argument. Hypertension 2021; 78: 871–78.
8. Lemmer B, Middeke M. A commentary on the Spanish hypertension studies MAPEC and HYGIA. Chronobiol Int 2020; 37: 728–30.
9. Mackenzie IS, Rogers A, Poulter NR, et al. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet 2022; published online Oct 11. https://doi.org/ S0140-6736(22)01786-X
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