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

Abstract

Antihypertensive drug therapy is one of the most efficient medical interventions for preventing disability and death globally. Most of the evidence supporting its benefits has been derived from outcome trials with morning dosing of medications. Accumulating evidence suggests an adverse prognosis associated with night-time hypertension, nondipping blood pressure (BP) profile and morning BP surge, with increased incidence of cardiovascular events during the first few morning hours. These observations provide justification for complete 24-h BP control as being the primary goal of antihypertensive treatment. Bedtime administration of antihypertensive drugs has also been proposed as a potentially more effective treatment strategy than morning administration. This Position Paper by the International Society of Hypertension reviewed the published evidence on the clinical relevance of the diurnal variation in BP and the timing of antihypertensive drug treatment, aiming to provide consensus recommendations for clinical practice. Eight published outcome hypertension studies involved bedtime dosing of antihypertensive drugs, and all had major methodological and/or other flaws and a high risk of bias in testing the impact of bedtime compared to morning treatment. Three ongoing, well designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing. Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose.

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

“…However, this subject is not without controversy and has resulted in heated discussions. 8 , 30 The present study was sufficiently well powered to show a clinically important cardiovascular benefit with evening dosing compared with morning dosing; however, we found no such benefit. We found no advantage of evening versus morning dosing of antihypertensive medication with regard to major cardiovascular outcomes or mortality.…”

“… 6 However, the HARMONY trial reported no difference of morning versus evening dosing time, on either 24 h ambulatory blood pressure or clinic-measured blood pressure. 7 A recent systematic review 8 identified only two completed randomised studies that have compared cardiovascular outcomes with morning and bedtime dosing of antihypertensive medication in adults with hypertension: the MAPEC study 9 and the subsequent larger study from the same research group, the Hygia Chronotherapy Trial. 10 Both studies reported a reduction in all major cardiovascular events with bedtime treatment compared with morning treatment.…”

“…The effect size in each of these studies was considered by many to be implausibly large. 8 , 11 Additionally, there is a paucity of evidence on the potential harms of bedtime dosing related to excessive night-time blood pressure lowering (eg, potential increased risk of falls, glaucoma, and cerebrovascular events). 12 , 13 , 14 Dosing time might also affect medication adherence.…”

“…The relative pros and cons of evening dosing have been debated, and controversy persists, with some researchers suggesting that the Hygia Chronotherapy Trial might not have been a true randomised controlled trial. 8 , 17 , 18 In the Treatment in Morning versus Evening (TIME) study, we aimed to investigate whether evening dosing of antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension treated with their usual antihypertensive medications.…”

Evening or morning dosing of antihypertensive medications: valid epidemiological findings for consensus statement

“…Tomoyuki Kawada I read the article by Stergiou et al [1] with great interest. They reviewed summarized validities of eight published articles regarding the advantage of bedtime dosing of antihypertensive medications.…”