Dr. Berkant Öztürk  -  Dr. Mustafa Yenerçağ

Meta-analysis of trials of antihypertensive medication bedtime dosing including individual-patient data from BedMed and BedMed-Frail.

This summary is based on the presentation of Ricky Turgeon (Vancouver, BC, Canada) at the ESC Congress 2024 

Objective:
Meta-analysis of studies designed to test the effects of doses of antihypertensives when taken in the evening or in the morning.

Introduction and methods:
The results of the Spanish MAPEC study conducted in 2010 showed that if patients took ?1 of their antihypertensive drugs in the evening instead of taking all of them once a day in the morning, there was a 61% reduction in the risk of cardiovascular disease morbidity and mortality. The same research group showed 9 years later that this approach reduced the risk of cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke by 45% in the Hygia trial. However, neither the TIME study (UK, 2022) nor the BedMed and BedMed-Frail studies (Canada, 2024) could confirm these in subsequent studies. Of note, in the last 3 studies, participants took all their antihypertensive medications in the evening or in the morning.

Therefore, a systematic review and meta-analysis of all parallel group RCTs comparing taking ?1 antihypertensive drug in the evening or at bedtime with taking all in the morning was performed.  Studies also had to have follow-up of ?500 patient-years per group and a median follow-up duration of ?12 months. The researchers included the five aforementioned studies (MAPEC, Hygia, TIME, BedMed, and BedMed-Frail) encompassing a total of 46,606 patients. They also conducted a systematic assessment of possible sources of bias in each trial.

The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite outcome of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or heart failure exacerbation. Secondary endpoints included individual components of the primary endpoint, hospitalization for any cause, and select safety events (fractures, glaucoma-related events, and cognitive decline).

Results:
            In 5 trials, evening dosing had no effect on the incidence of the primary endpoint of MACE compared with morning dosing (HR: 0.71; 95% CI: 0.43-1.16).

A sensitivity analysis of risk of bias showed that in the 3 studies considered to have low risk of bias (TIME, BedMed and BedMed-Frail), the risk of MACE did not differ between the evening and morning dose groups (HR: 0.94; 95%CI: 0.85-1.04) and there was negligible heterogeneity (I²=0%; ?²=0). In the 2 studies (MAPEC, Hygia) where there was a concern for bias (especially regarding the randomization process), the HR was found to be 0.43 (95% CI: 0.26-0.72).

There was no difference in the rate of all-cause death (HR: 0.77; 95% CI: 0.51-1.16) or the frequency of other secondary endpoints between dose groups.

Conclusion:
A systematic review and meta-analysis of five large RCTs showed no difference in the risk of MACE or safety outcomes between taking some or all antihypertensives in the evening and taking all in the morning.

Interpretations:
This meta-analysis concludes that the risk of MACE is not affected by the timing of antihypertensive medication. Using antihypertensive drugs in the morning or evening does not make a difference in terms of MACE risk, based on available data.

As an effect of this study on daily practice; blood pressure lowering drugs can be applied once a day at the most appropriate time for the patient.