*For medical professionals only for reference
As we all know, insisting on taking antihypertensive drugs is the key to reducing the risk of cardiovascular and cerebrovascular diseases in patients with [1].
However, there have been many different opinions on whether the best time for is in the morning or evening, and there is a lack of credible answers. Even the choices about morning and evening often make doctors get confused.
With the release of the latest clinical research results, whether it is better to reduce blood pressure in the morning or "lower blood pressure in the evening", there is finally an accurate answer.
Recently, Thomas M MacDonald team from the Department of Molecular and Clinical Medicine, School of Medicine, Dundee University, UK, published an important randomized controlled research result in the journal "The Lancet" [2].
MacDonald team designed a decentralized effective randomized controlled trial . 21,104 patients with hypertensive from the UK were randomly assigned to the morning medication group (6:00-10:00) and the night medication group (20:00-00:00) , and followed up and database comparison analysis of primary outcome events such as vascular-related death, non-fatal myocardial infarction/ stroke . The results of the
study showed that during the follow-up period of with a median time of 5.2 years, the incidence of primary outcome events in the night medication group was 3.4% (362/10503), while in the morning medication group, it was 3.7% (390/10601) . After evaluating the risk of primary outcome events, it was found that 0.69 events occurred in the night medication group every 100 people-year follow-up, while 0.72 cases were found in the morning medication group. There was no significant difference between compared with .
This study uses large samples, long-term follow-up and randomized control design, strongly proves that taking antihypertensive drugs in the morning or night has no correlation with the risk of cardiovascular and cerebrovascular events. This study also reminds patients with hypertension and doctors: what is more important to lowering blood pressure is the rationality of drug selection and compliance with medication. As for whether to take it in the morning or in the evening, you might as well make a decision as you like. Anyway, as long as you insist on taking it, it will be beneficial.
Article title
Hypertension is the main risk factor for cardiovascular disease [3]. Well-controlled blood pressure can effectively reduce the risk of cardiovascular and cerebrovascular diseases. Previous randomized controlled trials of antihypertensive therapy were mostly given in the morning, but changes in the daytime high and night low rhythms of blood pressure, the heterogeneity of individual blood pressure patterns, and the association between sudden morning blood pressure and cardiovascular events [4] cast a layer of doubt on the optimal time for taking blood pressure drugs.
In previous studies, the comparison of the pros and cons of taking antihypertensive drugs in the morning or at night has different conclusions. Two randomized controlled trials suggested that the risk of major cardiovascular events in the bedtime group was lower than that in the morning medication group [5-6], but some researchers questioned the rationality of the methodology and conclusions of these two trials.
Considering the high prevalence of hypertension and the pros and cons of taking medication in the morning or night, whether taking medication at night can reduce the incidence of major cardiovascular events compared to morning has become an important question that the MacDonald team wants to answer.
MacDonald's team designed a prospective, open-label, blinded outcome assessment, and decentralized randomized controlled trial of , using the UK National Health Service Database, to send trial registration invitations to adult British hypertensive patients who are taking antihypertensive drugs. Patients who regularly work night shifts and take antihypertensive drugs more than once a day will be excluded. The researchers randomized the eligible patients using an algorithm and informed the patients by email about the assigned medication time (6:00-10:00 or 20:00-00:00). The subsequent screening and follow-up of
were completed through registration websites and emails. The patients filled out the online access volume one month after randomization and every 3 months, and counted the time, compliance, outcome, and occurrence of of antihypertensive drugs. The primary outcome of the
study was defined as a compound cardiovascular endpoint event such as vascular-related death, non-fatal myocardial infarction/stroke, and other hospitalization. Secondary outcomes include hospitalization caused by non-fatal myocardial infarction, hospitalization caused by non-fatal stroke, vascular-related death, all-cause mortality, and compliance with random medication regimens.Safety outcomes include falls, fractures, predefined dizziness, head-heavy symptoms, etc. The endpoints of the study were blindly assessed by an independent assessment committee and verified in combination with multiple national databases.
From December 17, 2011 to June 5, 2018, a total of 24,610 patients participated in the screening, and 21,104 cases completed randomization. The average age of participants was 65.1 years old, with women accounting for 42.5%, and whites accounting for 90.5%. During the follow-up period with a median time of 5.2 years, the incidence of primary outcome events in the night-treated group was 3.4% (362/10503), compared with 3.7% (390/10601) in the morning-treated group.
night medication group had 0.69 events in the follow-up of 100 person-years, while in the morning medication group, there was no significant difference between the two (hazard ratio 0.95, 95% CI: 0.83-1.10, P=0.53). Comparison of cumulative risks of primary outcome events in the night and morning medication groups
researchers conducted intentional analysis and comparison of other preset secondary outcomes, and no significant differences were found.
Comparison of primary and secondary outcomes of night medication group and morning medication group
During the entire experimental stage, 69.3% of patients fully followed the randomly assigned medication regimen. The non-compliance rate in the night-treated group was significantly higher than that in the morning-treated group (39.0% vs 22.5%, P0.0001). However, when the status of the last follow-up report was reported, the overall non-compliance rate was only 13.4%, and the proportion of the night-treated group who was forced to adjust the medication time due to diuretics was also significantly higher (5.2% vs 0.7%, P0.0001).
The distribution of pre-set adverse reaction events between the two groups was roughly similar, but the frequent toilet problems and other adverse events in the night-time medication group were significantly higher than those in the morning medication group. After analyzing some patients who completed blood pressure measurement and reported data, the blood pressure measurement value in the morning was significantly lower when taking medicine at night. Similarly, the blood pressure measurement value at night is also significantly lower when taking medication in the morning, but the difference between systolic blood pressure and diastolic blood pressure is less than 2mmHg.
The pre-set incidence of adverse events in the night-time medication group and morning medication in
Overall, this large-scale randomized controlled study led by Professor MacDonald proved that the hypothesis that taking antihypertensive drugs at night was better than taking morning medication was not valid, because there was no difference in the risk of cardiovascular events in different medication time groups, and strongly answered the question that has long troubled the academic community. This also means that patients with hypertension do not have to worry about taking medicine in the morning or at night. According to personal habits, they can do whatever they want, just keep taking it. The focus of academic circles in the future should also be on the rational selection of drugs and the improvement of compliance, thereby generating greater social benefits.
In addition, while answering past questions, this study also reveals some new and interesting details. Patients with hypertension who take medication at night, especially diuretics, may need to consider issues related to getting up at night. The comparison results of the morning and evening blood pressure measurements of the two groups of patients suggest that most antihypertensive drugs taken by patients may have a stable effect time of less than 24 hours. Therefore, the development of long-term stable antihypertensive drugs is still a difficult problem to be solved.
Of course, this study also has some shortcomings, such as patients knowing group information, which may have a certain impact on behavior and report results; self-reported adverse events may not be accurate enough, and regular collection also means that there may be recall bias; the proportion of questionnaire follow-up in the night group is higher than that in the morning group, which may have an impact on the comparison between groups; the accuracy and representation of individual blood pressure measurements, etc. are possible problems; the race of participants is mainly white, and they should be extra cautious when promoting the conclusions, but the flaws do not conceal the merits.
As one of the basic vital signs, blood pressure plays an important role in various physiological and pathological processes. I hope one day humans can fully illustrate the mystery behind these numbers that are going up and down. But before this goal is achieved, "regardless of morning and evening, insist on taking medicine" is worthy of attention for every patient with hypertension.
References
[1] Blood Pressure Lowering Treatment Trialists' Collaboration. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. Lancet. 2021 May 1;397(10285):1625-1636. doi: 10.1016/S0140-6736(21)00590-0. Erratum in: Lancet. 2021 May 22;397(10288):1884. PMID: 33933205; PMCID: PMC8102467.
[2] Mackenzie IS, Rogers A, Poulter NR, Williams B, Brown MJ, Webb DJ, Ford I, Rorie DA, Guthrie G, Grieve JWK, Pigazzani F, Rothwell PM, Young R, McConnachie A, Struthers AD, Lang CC, MacDonald TM; TIME Study Group. 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 Oct 11:S0140-6736(22)01786-X. doi: 10.1016/S0140-6736(22)01786-X. Epub ahead of print. PMID: 36240838.
[3] GBD 2019 Risk Factors Collaborators. Global burden of 87 risk factors in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020 Oct 17;396(10258):1223-1249. doi: 10.1016/S0140-6736(20)30752-2. PMID: 33069327; PMCID: PMC7566194.
[4] Kario K. Morning surge in blood pressure and cardiovascular risk: evidence and perspectives. Hypertension. 2010 Nov;56(5):765-73. doi: 10.1161/HYPERTENSIONAHA.110.157149. Epub 2010 Oct 11. PMID: 20937968.
[5] Stergiou G, Brunström M, MacDonald T, Kyriakoulis KG, Bursztyn M, Khan N, Bakris G, Kollias A, Menti A, Muntner P, Orias M, Poulter N, Shimbo D, Williams B, Adeoye AM, Damasceno A, Korostovtseva L, Li Y, Muxfeldt E, Zhang Y, Mancia G, Kreutz R, Tomaszewski M. Bedtime dosing of antihypertensive medications: systematic review and consensus statement: International Society of Hypertension position paper endorsed by World Hypertension League and European Society of Hypertension. J Hypertens. 2022 Oct 1;40(10):1847-1858. doi: 10.1097/HJH.00000000000000003240. Epub 2022 Aug 12. PMID: 35983870.
[6] Turgeon RD, Althouse AD, Cohen JB, Enache B, Hogenesch JB, Johansen ME, Mehta R, Meyerowitz-Katz G, Ziaeian B, Hiremath S. Lowering Nighttime Blood Pressure With Bedtime Dosing of Antihypertensive Medications: Controversies in Hypertension - Con Side of the Argument. Hypertension. 2021 Sep;78(3):871-878. doi: 10.1161/HYPERTENSIONAHA.121.16501. Epub 2021 Aug 11. PMID: 34379435; PMCID: PMC8363122.
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