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TIME to face the reality about evening dosing of antihypertensive drugs in hypertension

TIME to face the reality about evening dosing of antihypertensive drugs in hypertension BLOOD PRESSURE 2023, VOL. 32, NO. 1, 1–3 https://doi.org/10.1080/08037051.2022.2142512 EDITORIAL TIME to face the reality about evening dosing of antihypertensive drugs in hypertension Should blood pressure (BP) medications be taken in the were gathered from family doctors and hospitals, with an morning or in the evening? The TIME study results independent adjudication by a blinded committee. were presented at the ESC congress 2022 and published The study did find some differences between the two not too long after [1]. TIME was a large prospective, dosing schedules in the BP profiles. When antihyperten- randomised clinical trial that investigated whether taking sive medication was taken in the morning, BP was higher BP medications in the evening improves cardiovascular in the morning and lower in the evening while the outcomes compared to taking the medications in the reverse was true with the evening dosing. The difference morning. A total of 21,104 participants from the United was not large, just 1–2 mmHg, and did not translate into Kingdom were randomised in a 1:1 ratio to take their any difference in outcomes. This indirectly speaks against usual BP medications in the morning or in the evening. a protective effect of a therapeutically-dependent enhance- The average age of participants was 65 years, 58% were ment of the physiological nocturnal BP reduction despite men and 98% were white, 14% had diabetes, 4% were the evidence that attenuation of nocturnal BP fall (from smokers, 13% had prior cardiovascular disease, and dipping to non-dipping and reverse dipping) is accompa- mean BP at entry was 135/79 mmHg. The median fol- nied by a progressive increase of cardiovascular risk [2]. low-up duration was 5.2 years, but some patients were This conclusion, however, may not hold for all patients. followed for over 9 years. The study was funded by the Studies with a limited number of participants have shown British Heart Foundation. The composite primary end- an apparent benefit of night-time dosing (and thus point was hospitalisation for nonfatal myocardial infarc- greater therapeutic BP falls) in certain patient groups, tion (MI) or nonfatal stroke, or vascular death. such as those with sleep apnoea, non-dippers, and Secondary outcomes were non-fatal stroke, non-fatal MI, patients with nocturnal hypertension. If the aim is to look at specific groups of patients then investigators will have cardiovascular death, all-cause mortality, and heart fail- to do larger studies in those particular groups, with a ure hospitalisation. The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group quality level as good as that of the TIME trial in which (0.69 events per 100 patient-years) and 390 (3.7%) in the all events were adjudicated and adherence to treatment morning-dosing group (0.72 events per 100 patient- was measured and good, i.e. at 60%. years), giving an unadjusted hazard ratio of 0.95 (95% The TIME results are in direct contradiction with CIs, 0.83–1.10; p ¼ 0.53). those of the HYGIA Chronotherapy Trial [3] published The results of this large randomised study clearly in 2020, which found an extremely large protective effect show that there was no difference in the primary out- (>50% reduction of cardiovascular outcomes) of evening come between the morning and the evening dosing antihypertensive drug dosing. The study attracted an groups. There were also no differences between groups immediate large media attention, but also much criti- for the secondary outcomes as well as between pre-speci- cism, including an ‘expression of concern’, and is raising fied subgroups. Thus, for the prevention of MI, stroke several important methodological questions and perplex- or vascular death taking BP medications in the evening ities [4,5]. Further, a systematic review from the is no better or worse than taking them in the morning; International Society of Hypertension (ISH) published the key message being that patients can take their BP recently concluded that previous trials of bedtime anti- medications whenever it is convenient to them. hypertensive dosing (Table 1) all had ‘major flaws’ [6] Taking the medication at night does not result in an and that thus, bedtime drug dosing should not be rou- increase in nocturnal hypotension that translates into tinely recommended in clinical practice. TIME adds to more dizziness and injurious falls if patients who get up this conclusion, however, that in general bedtime dosing to use the bathroom during the night because the rate of is not associated with any harm, which expands the dos- fractures and hospitalisation for fractures were also iden- ing choice at disposal of the doctor and is preferable by tical between the two groups. the patient. This does not mean that patients can do as TIME was a pragmatic study, with participants they wish or that morning and evening dosing can be recruited from primary and secondary care and register- changed at will. Also to be considered is that the vast ing on the internet, and information on hospitalisations majority of well-conducted outcomes studies that are and deaths obtained from participants by email and used to guide the treatment of hypertension adminis- through record linkage to national databases. Further data tered all drugs in the morning. 2 S. E. KJELDSEN ET AL. Table 1. Studies mentioned in the literature (detailed assessed in reference [6]) with our comments. Study acronym Design and comments HYGIA Non-randomized observational data MAPEC Non-randomized observational data CONVINCE Randomised double-blinded clinical trial aborted by the sponsor HOPE Randomised double-blinded clinical trial; ramipril vs. placebo in high risk patients. Blood pressure collected post-hoc from hospital charts FACET Randomised open label SYST-EUR Randomised double-blinded clinical trial; nitrendipine vs. placebo Sobiczewski et al. Single centre prospective observational study SYST-CHINA Non-randomised prospective study; nitrendipine vs. placebo Before the TIME study, there has never been a properly designed outcome trial investigating the question of morning vs. bedtime dosing of antihypertensive drugs on cardiovascular outcomes. See our comments detailed in references [4,5]. No significant finding. Placebo-controlled and irrelevant for the research question discussed. Morning fosinopril is marginally better than bedtime amlodipine but data unadjusted. Unclear design and results irrelevant to the research question discussed. or morning dosing of usual antihypertensives: a prospect- The TIME study was an important study, far more reli- ive, randomised, open-label, blinded-endpoint clinical able than the observational HYGIA study as we have dis- trial. The TIME study. Lancet. 2022;400(10361): cussed in detail before [4,5]. From a scientific point of 1417–1425. view, patients have a choice as to when to take their medi- [2] Mancia G, Verdecchia P. Clinical value of ambulatory cation, but we strongly recommend taking blood pressure blood pressure: evidence and limits. Circ Res. 2015;116(6): 1034–1045. medication in the morning since adherence to antihyper- [3] Hermida RC, Crespo JJ, Domınguez-Sardina M, et al. tensivemedication is proven to beworse at bedtime[7]. Bedtime hypertension treatment improves cardiovascular However, providers may consider bedtime dosing in risk reduction: the HYGIA chronotherapy trial. Eur Heart patients proven to have high night-time blood pressure. A J. 2020;41(48):4565–4576. [4] Kreutz R, Kjeldsen SE, Burnier M, et al. Blood pressure possible alternative approach for patients taking more than medication should not be routinely dosed at bedtime. We one drug could be to take one in the morning and the must disregard the data from the HYGIA project. Blood remainder in the evening which may give better 24-h Press. 2020;29(3):135–136. coverage similar to a higher smoothness index on combin- [5] Brunstrom M, Kjeldsen SE, Kreutz R, et al. Missing verifi- ation treatment compared to monotherapy [8]. cation of source data in hypertension research: the HYGIA project in perspective. Hypertension. 2021;78(2): 555–558. [6] Stergiou G, Brunstrom € M, MacDonald TM, et al. Bedtime Disclosure statement dosing of antihypertensive medications: systematic review SEK, BME, KN, RK, MB, SO, and GM are editors of Blood and consensus statement. An international society of Pressure and report no relevant conflicts of interest to hypertension position paper. J Hypertens. 2022;40(10): 1847–1858. disclose related to this editorial. [7] Vrijens B, Vincze G, Kristanto P, et al. Adherence to pre- scribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. Funding 2008;336(7653):1114–1117. [8] Parati G, Schumacher H, Bilo G, et al. Evaluating 24-h The author(s) reported there is no funding associated with antihypertensive efficacy by the smoothness index: a meta- the work featured in this article. analysis of an ambulatory blood pressure monitoring data- base. J Hypertens. 2010;28(11):2177–2183. ORCID Sverre E. Kjeldsen Sverre E. Kjeldsen http://orcid.org/0000-0003-2389-0272 Departments of Cardiology and Nephrology, Ullevaal Brent M. Egan http://orcid.org/0000-0002-1470-5875 Hospital, University of Oslo, Oslo, Norway Krzysztof Narkiewicz http://orcid.org/0000-0001- s.e.kjeldsen@medisin.uio.no 5949-5018 Reinhold Kreutz http://orcid.org/0000-0002-4818-211X Brent M. Egan Michel Burnier http://orcid.org/0000-0003-1283-8487 American Medical Association, University of South Suzanne Oparil http://orcid.org/0000-0002-7505-2599 Giuseppe Mancia http://orcid.org/0000-0003-0942-3176 Carolina, Greenville, SC, USA Krzysztof Narkiewicz References Department of Hypertension and Diabetology, Krzysztof Narkiewicz, Medical University of Gdansk, Gdansk, [1] Mackenzie IS, Rogers A, Poulter NR, et al. Cardiovascular outcomes in adults with hypertension allocated to evening Poland BLOOD PRESSURE 3 Reinhold Kreutz Giuseppe Mancia Charite – Universitatsmedizin Berlin, Institute of Clinical University of Milan-Bicocca, Milan, Italy Pharmacology and Toxicology, Berlin, Germany Received 24 October 2022; Accepted 27 October 2022 Michel Burnier 2022 The Author(s). Published by Informa UK Limited, trading University of Lausanne, Lausanne, Switzerland as Taylor & Francis Group This is an Open Access article distributed under the terms of the Suzanne Oparil Creative Commons Attribution License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted Vascular Biology and Hypertension Program, Department use, distribution, and reproduction in any medium, provided the of Medicine, University of Alabama at Birmingham, original work is properly cited. Birmingham, AL, USA http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Blood Pressure Taylor & Francis

TIME to face the reality about evening dosing of antihypertensive drugs in hypertension

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Blood Pressure , Volume 32 (1): 3 – Jan 1, 2
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© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
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0803-7051
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10.1080/08037051.2022.2142512
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Abstract

BLOOD PRESSURE 2023, VOL. 32, NO. 1, 1–3 https://doi.org/10.1080/08037051.2022.2142512 EDITORIAL TIME to face the reality about evening dosing of antihypertensive drugs in hypertension Should blood pressure (BP) medications be taken in the were gathered from family doctors and hospitals, with an morning or in the evening? The TIME study results independent adjudication by a blinded committee. were presented at the ESC congress 2022 and published The study did find some differences between the two not too long after [1]. TIME was a large prospective, dosing schedules in the BP profiles. When antihyperten- randomised clinical trial that investigated whether taking sive medication was taken in the morning, BP was higher BP medications in the evening improves cardiovascular in the morning and lower in the evening while the outcomes compared to taking the medications in the reverse was true with the evening dosing. The difference morning. A total of 21,104 participants from the United was not large, just 1–2 mmHg, and did not translate into Kingdom were randomised in a 1:1 ratio to take their any difference in outcomes. This indirectly speaks against usual BP medications in the morning or in the evening. a protective effect of a therapeutically-dependent enhance- The average age of participants was 65 years, 58% were ment of the physiological nocturnal BP reduction despite men and 98% were white, 14% had diabetes, 4% were the evidence that attenuation of nocturnal BP fall (from smokers, 13% had prior cardiovascular disease, and dipping to non-dipping and reverse dipping) is accompa- mean BP at entry was 135/79 mmHg. The median fol- nied by a progressive increase of cardiovascular risk [2]. low-up duration was 5.2 years, but some patients were This conclusion, however, may not hold for all patients. followed for over 9 years. The study was funded by the Studies with a limited number of participants have shown British Heart Foundation. The composite primary end- an apparent benefit of night-time dosing (and thus point was hospitalisation for nonfatal myocardial infarc- greater therapeutic BP falls) in certain patient groups, tion (MI) or nonfatal stroke, or vascular death. such as those with sleep apnoea, non-dippers, and Secondary outcomes were non-fatal stroke, non-fatal MI, patients with nocturnal hypertension. If the aim is to look at specific groups of patients then investigators will have cardiovascular death, all-cause mortality, and heart fail- to do larger studies in those particular groups, with a ure hospitalisation. The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group quality level as good as that of the TIME trial in which (0.69 events per 100 patient-years) and 390 (3.7%) in the all events were adjudicated and adherence to treatment morning-dosing group (0.72 events per 100 patient- was measured and good, i.e. at 60%. years), giving an unadjusted hazard ratio of 0.95 (95% The TIME results are in direct contradiction with CIs, 0.83–1.10; p ¼ 0.53). those of the HYGIA Chronotherapy Trial [3] published The results of this large randomised study clearly in 2020, which found an extremely large protective effect show that there was no difference in the primary out- (>50% reduction of cardiovascular outcomes) of evening come between the morning and the evening dosing antihypertensive drug dosing. The study attracted an groups. There were also no differences between groups immediate large media attention, but also much criti- for the secondary outcomes as well as between pre-speci- cism, including an ‘expression of concern’, and is raising fied subgroups. Thus, for the prevention of MI, stroke several important methodological questions and perplex- or vascular death taking BP medications in the evening ities [4,5]. Further, a systematic review from the is no better or worse than taking them in the morning; International Society of Hypertension (ISH) published the key message being that patients can take their BP recently concluded that previous trials of bedtime anti- medications whenever it is convenient to them. hypertensive dosing (Table 1) all had ‘major flaws’ [6] Taking the medication at night does not result in an and that thus, bedtime drug dosing should not be rou- increase in nocturnal hypotension that translates into tinely recommended in clinical practice. TIME adds to more dizziness and injurious falls if patients who get up this conclusion, however, that in general bedtime dosing to use the bathroom during the night because the rate of is not associated with any harm, which expands the dos- fractures and hospitalisation for fractures were also iden- ing choice at disposal of the doctor and is preferable by tical between the two groups. the patient. This does not mean that patients can do as TIME was a pragmatic study, with participants they wish or that morning and evening dosing can be recruited from primary and secondary care and register- changed at will. Also to be considered is that the vast ing on the internet, and information on hospitalisations majority of well-conducted outcomes studies that are and deaths obtained from participants by email and used to guide the treatment of hypertension adminis- through record linkage to national databases. Further data tered all drugs in the morning. 2 S. E. KJELDSEN ET AL. Table 1. Studies mentioned in the literature (detailed assessed in reference [6]) with our comments. Study acronym Design and comments HYGIA Non-randomized observational data MAPEC Non-randomized observational data CONVINCE Randomised double-blinded clinical trial aborted by the sponsor HOPE Randomised double-blinded clinical trial; ramipril vs. placebo in high risk patients. Blood pressure collected post-hoc from hospital charts FACET Randomised open label SYST-EUR Randomised double-blinded clinical trial; nitrendipine vs. placebo Sobiczewski et al. Single centre prospective observational study SYST-CHINA Non-randomised prospective study; nitrendipine vs. placebo Before the TIME study, there has never been a properly designed outcome trial investigating the question of morning vs. bedtime dosing of antihypertensive drugs on cardiovascular outcomes. See our comments detailed in references [4,5]. No significant finding. Placebo-controlled and irrelevant for the research question discussed. Morning fosinopril is marginally better than bedtime amlodipine but data unadjusted. Unclear design and results irrelevant to the research question discussed. or morning dosing of usual antihypertensives: a prospect- The TIME study was an important study, far more reli- ive, randomised, open-label, blinded-endpoint clinical able than the observational HYGIA study as we have dis- trial. The TIME study. Lancet. 2022;400(10361): cussed in detail before [4,5]. From a scientific point of 1417–1425. view, patients have a choice as to when to take their medi- [2] Mancia G, Verdecchia P. Clinical value of ambulatory cation, but we strongly recommend taking blood pressure blood pressure: evidence and limits. Circ Res. 2015;116(6): 1034–1045. medication in the morning since adherence to antihyper- [3] Hermida RC, Crespo JJ, Domınguez-Sardina M, et al. tensivemedication is proven to beworse at bedtime[7]. Bedtime hypertension treatment improves cardiovascular However, providers may consider bedtime dosing in risk reduction: the HYGIA chronotherapy trial. Eur Heart patients proven to have high night-time blood pressure. A J. 2020;41(48):4565–4576. [4] Kreutz R, Kjeldsen SE, Burnier M, et al. Blood pressure possible alternative approach for patients taking more than medication should not be routinely dosed at bedtime. We one drug could be to take one in the morning and the must disregard the data from the HYGIA project. Blood remainder in the evening which may give better 24-h Press. 2020;29(3):135–136. coverage similar to a higher smoothness index on combin- [5] Brunstrom M, Kjeldsen SE, Kreutz R, et al. Missing verifi- ation treatment compared to monotherapy [8]. cation of source data in hypertension research: the HYGIA project in perspective. Hypertension. 2021;78(2): 555–558. [6] Stergiou G, Brunstrom € M, MacDonald TM, et al. Bedtime Disclosure statement dosing of antihypertensive medications: systematic review SEK, BME, KN, RK, MB, SO, and GM are editors of Blood and consensus statement. An international society of Pressure and report no relevant conflicts of interest to hypertension position paper. J Hypertens. 2022;40(10): 1847–1858. disclose related to this editorial. [7] Vrijens B, Vincze G, Kristanto P, et al. Adherence to pre- scribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. Funding 2008;336(7653):1114–1117. [8] Parati G, Schumacher H, Bilo G, et al. Evaluating 24-h The author(s) reported there is no funding associated with antihypertensive efficacy by the smoothness index: a meta- the work featured in this article. analysis of an ambulatory blood pressure monitoring data- base. J Hypertens. 2010;28(11):2177–2183. ORCID Sverre E. Kjeldsen Sverre E. Kjeldsen http://orcid.org/0000-0003-2389-0272 Departments of Cardiology and Nephrology, Ullevaal Brent M. Egan http://orcid.org/0000-0002-1470-5875 Hospital, University of Oslo, Oslo, Norway Krzysztof Narkiewicz http://orcid.org/0000-0001- s.e.kjeldsen@medisin.uio.no 5949-5018 Reinhold Kreutz http://orcid.org/0000-0002-4818-211X Brent M. Egan Michel Burnier http://orcid.org/0000-0003-1283-8487 American Medical Association, University of South Suzanne Oparil http://orcid.org/0000-0002-7505-2599 Giuseppe Mancia http://orcid.org/0000-0003-0942-3176 Carolina, Greenville, SC, USA Krzysztof Narkiewicz References Department of Hypertension and Diabetology, Krzysztof Narkiewicz, Medical University of Gdansk, Gdansk, [1] Mackenzie IS, Rogers A, Poulter NR, et al. Cardiovascular outcomes in adults with hypertension allocated to evening Poland BLOOD PRESSURE 3 Reinhold Kreutz Giuseppe Mancia Charite – Universitatsmedizin Berlin, Institute of Clinical University of Milan-Bicocca, Milan, Italy Pharmacology and Toxicology, Berlin, Germany Received 24 October 2022; Accepted 27 October 2022 Michel Burnier 2022 The Author(s). Published by Informa UK Limited, trading University of Lausanne, Lausanne, Switzerland as Taylor & Francis Group This is an Open Access article distributed under the terms of the Suzanne Oparil Creative Commons Attribution License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted Vascular Biology and Hypertension Program, Department use, distribution, and reproduction in any medium, provided the of Medicine, University of Alabama at Birmingham, original work is properly cited. Birmingham, AL, USA

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