Should antihypertensive medications be taken at bedtime?

Should antihypertensive medications be taken at bedtime?

Should antihypertensive drugs be taken before going to bed?

Liu Deping

Author Affilications:100730 Department of Cardiology, Beijing Hospital, National Geriatrics Center, Chinese Academy of Medical Sciences, Institute of Geriatrics, Chinese Academy of Medical Sciences

Corresponding author: Liu Deping, e-mail: [email protected]

Based on published prospective studies and meta-analyses, elevated blood pressure at night or non-biased blood pressure changes are independent predictors of cardiovascular events and require special attention in treatment, regardless of daytime office blood pressure levels or average daytime or all-day blood pressure levels at 24 h. However, current guidelines, when based on ambulatory blood pressure, recommend only daytime or all-day average blood pressure levels as a diagnostic criterion for hypertension, but do not recommend specific timing of administration for hypertension treatment [1].

1 Related studies

The MAPEC study [2] is a prospective, randomized, open-label, blind-endpoint trial specifically validating that antihypertensive therapy (at least one antihypertensive agent) before bedtime is better at reducing the risk of cardiovascular events than routine morning antihypertensive medication. A total of 2 156 hypertensive patients were enrolled, with a median follow-up of 5.6 years, compared with morning medications, the average≥ systolic blood pressure and diastolic blood pressure decreased by 6.6 mmHg and 2.7 mmHg at night (both P<0.001), respectively, compared with morning medication, the average systolic blood pressure and diastolic blood pressure were not statistically different, and the proportion of non-biased blood pressure decreased significantly (34% and 62%, respectively, P<0.001), and the risk of cardiovascular events was significantly reduced (RR= 0.39, 95% CI: 0.29 to 0.51).

The Hygia study[3] was a multicenter, prospective randomized controlled study of 19 084 hypertensive patients taking antihypertensive drugs (including ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, β receptor blockers, and diuretics) at bedtime (9 552) or waking up in the morning (9 532), with a median follow-up of 6.3 years and 1 752 patients experiencing cardiovascular events (cardiovascular death, myocardial infarction, coronary artery revascularization, compound endpoint event of heart failure or stroke). After adjusting for age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL, mean sleep systolic blood pressure, relative decrease in systolic blood pressure during sleep, and previous cardiovascular events, bedtime medication significantly reduced the risk of cardiovascular events (HR =0.55, 95% CI: 0.50 to 0.61, P<0.001), cardiovascular death (HR =0.44, 95% CI: 0.34 to 0.56, P<0.001), hemorrhagic stroke (HR = 0.39, 95% CI: 0.23 to 0.65, P) compared with regular morning medication <0.001), heart failure (HR=0.58, 95% CI: 0.49-0.70, P<0.001) and peripheral arterial disease (HR=0.52, 95% CI: 0.41-0.67, P<0.001). The probability of adverse reactions did not differ between the two groups, with only 17 and 39 patients in the morning and bedtime groups developing sleep-time hypotension as defined by ambulatory blood pressure monitoring criteria.

The Hygia study, once published, attracted widespread attention, but it also raised serious questions. (1) With a 45% reduction in the risk of cardiovascular events, the median follow-up time was still as long as 6.3 years, so why not terminate the study early? This is not ethical. (2) About 20,000 patients are followed up for 48 h ambulatory blood pressure monitoring each year, and only 84 patients are followed up for less than 1 year, so the high compliance is significantly different from the monitoring data in general daily clinical practice and clinical research. (3) This study only briefly introduces the generation of random numbers by computer, and does not detail the specific stochastic process. (4) The study doctor selects antihypertensive drugs according to the specific situation of the patient, which may affect the results. (5) Even in clinical studies of antihypertensive therapy controlled with placebo, the decline in cardiovascular events is far from reaching 45%? This is extremely surprising, what is the specific mechanism?

Hermida et al. [4] conducted a systematic review of studies published from 1992 to 2020 comparing the duration of medication, with a total of 62 studies in 6 120 patients, and found that 82.3% of the studies showed that taking the drug before bedtime or in the afternoon compared with morning or morning medication reduced the average systolic blood pressure at night by 5.17 mmHg (95% CI: 4.04 to 6.31 mmHg), did not occur at night hypotension, and improved renal function and reduced left ventricular mass; 17.7% of the studies were neutral results And none of the studies showed that morning or morning medication was preferred to bedtime or afternoon medication.

Hermida et al. [5] also conducted a quality evaluation and systematic review of a total of 155 clinical studies published between 1976 and 2020 comparing taking drugs at different times, with a total of 23 972 patients with hypertension, and found that 83.2% of the study sample size was small, 53.6% of the blood pressure evaluation parameters were improperly selected, and 53.6% required drug administration according to a fixed clock time rather than according to the patient's own work and rest time. In none of the 155 studies, results showed that morning or morning medication was preferred to bedtime or afternoon medication. The results of clinical studies on different medication times are summarized in Table 1.

Table 1 Summary of clinical study results of different medication taking times[5]

Note: a proteinuria decreased or/and estimated increased glomerular filtration rate; b left ventricular mass decreased or left ventricular posterior wall thinning; AEI: ACE inhibitor; ARB: angiotensin II receptor antagonist; CCB: calcium channel antagonist

Hermida et al. [4,5] also summarized the clinical situation of taking antihypertensive drugs before bedtime or in the morning for different clinical conditions, such as non-oleetile blood pressure, diabetes, chronic kidney disease, refractory hypertension, and people with previous cardiovascular events, in which almost all studies showed that taking antihypertensive drugs at bedtime was better than taking antihypertensive drugs in the morning. The five commonly used antihypertensive drugs can be taken before going to bed, and the antihypertensive efficacy is not inferior to taking drugs in the morning.

2 Guidelines recommended

Due to the shortcomings of the current relevant research, in 2021, the International Society for Chronobiology (ISC) and the American Association for Medical Chronobiology and Chronotherapy published a position paper on hypertension guidelines[6], and the design and implementation of clinical studies on the time-based treatment of hypertension must follow the following principles:

(1) Hypertension cannot be diagnosed or used as a basis for hypertension control by self-testing in the clinic or home at the time of waking, and the selected patients should include uncontrolled hypertension patients who meet the ambulatory blood pressure diagnostic criteria, and the patient's activity and sleep time should be confirmed according to their activity log or watch-type activity monitor.

(2) The patient's treatment time must be determined according to the patient's specific wakefulness or sleep, etc., rather than only based on "morning", "evening" or specified clock time.

(3) Hypertensive time pharmacology and time therapy must take ambulatory blood pressure as the only blood pressure measurement method. It cannot be diagnosed and evaluated by self-testing of blood pressure in the clinic or home during waking hours, and the characteristics of 24-hour blood pressure changes in hypertensive patients cannot be evaluated, nor is it recommended to evaluate the difference in efficacy of the medication time.

(4) It is not recommended to use the average blood pressure of ambulatory blood pressure throughout the day or during the day as a criterion for evaluating efficacy. Blood pressure monitoring measures must include average blood pressure during sleep, and the effect of blood pressure changes on target organs should also be evaluated.

(5) Ambulatory blood pressure monitoring must be continuously monitored for 48 h, and blood pressure must be monitored at least once an hour to ensure the reproducibility of average blood pressure and the judgment of whether blood pressure is in a biathic shape.

(6) Since the time interval of ambulatory blood pressure monitoring blood pressure measurement is not the same, it is not recommended to use a simple blood pressure arithmetic average as the blood pressure evaluation standard, and it must be corrected according to the different time intervals of blood pressure measurement.

(7) The minimum sample size must be determined according to the specific design and objectives of different studies.

(8) The study design must be a randomized double-blind prospective study, or a cross-double-blind design with an elution period of at least 2 weeks.

3

summary

Based on the current research, patients with hypertension who have the following clinical conditions clinically, such as non-oleurotic blood pressure, diabetes, chronic kidney disease, refractory hypertension and people with previous cardiovascular events, can take one or more antihypertensive drugs before going to bed and be closely observed.

bibliography

[1] China Cardiovascular Health and Disease Report 2020. Interpretation of key points of China Cardiovascular Health and Disease Report 2020[J]. Chinese Journal of Cardiovascular Diseases, 2021, 26(3): 209-218.

[2] Hermida RC, Ayala DE, Mojon A, et al. Influence of circadian time of hypertension treatment on cardiovascular risk：Results of the MAPEC study[J]. Chronobiol Int, 2010, 27(8): 1629-1651.

[3] Hermida RC, Crespo JJ, Dominguez-Sardina M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the hygia chronotherapy trial[J]. Eur Heart J, 2020, 41(48): 4565-4576.

[4] Hermida RC, Mojon A, Hermida-Ayala RC, et al. Extent of asleep blood pressure reduction by hypertension medications is ingestion-time dependent: Systematic review and meta-analysis of published human trials[J]. Sleep Med Rev, 2021, 59: 101454.

[5] Hermida RC, Hermida-ayala RG, Mojon A, et al. Systematic review and quality evaluation of published human ingestion-time trials of blood pressure-lowering medications and their combinations[J]. Chronobiol Int, 2021, 38(10): 1460-1476.

[6] Hermida RC, Smolensky MH, Balan H, et al. Guidelines for the design and conduct of human clinical trials on ingestion-time differences-chronopharmacology and chronotherapy of hypertension medications[J]. Chronobiol Int, 2021, 38(1): 1-26.

Source of this article

LIU Deping. Should antihypertensive medications be taken at bedtime? [J]. Chinese Journal of Cardiovascular Medicine, 2021, 26(6): 513-515.