Meta-analysis concludes: MACE risk not affected by timing of antihypertensive medication

This summary is based on the presentation of Ricky Turgeon (Vancouver, BC, Canada) at the ESC Congress 2024 - Meta-analysis of trials of antihypertensive medication bedtime dosing including individual-patient data from BedMed and BedMed-Frail.

Introduction and methods

In 2010, the results of the Spanish MAPEC trial were published, which showed a 61%-reduction in the risk of CVD morbidity and mortality when patients took ≥1 of their once-daily antihypertensive medications in the evening instead of all of them in the morning. The same research group demonstrated 9 years later that this approach reduced the risk of CV death, MI, coronary revascularization, HF, or stroke by 45% in the Hygia trial. Other investigators tried to validate these findings, but neither the TIME trial (UK, 2022) nor the BedMed and BedMed-Frail trials (Canada, 2024) could confirm them. Of note, these latter 3 trials made the participants take all their antihypertensives either in the evening or morning.

Hence, a systematic review and meta-analysis was performed of all parallel-group RCTs that compared taking ≥1 antihypertensive medications in the evening or at bedtime with taking all of them in the morning and assessed ≥1 CV outcomes of interest. 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 aforementioned 5 trials (MAPEC, Hygia, TIME, BedMed, and BedMed-Frail), which enrolled a total of 46,606 patients. They also conducted a systematic assessment of potential sources of bias in each trial.

The primary endpoint was MACE, defined as a composite outcome of all-cause mortality, nonfatal MI, nonfatal stroke, or HF exacerbation. Secondary endpoints included the individual components of the primary endpoint, hospitalization for any reason, and specific safety events (fractures, glaucoma-related events, and cognitive decline).

Main results

• Across the 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 by risk of bias showed that in the 3 trials judged to have low risk of bias (TIME, BedMed, and BedMed-Frail), the risk of MACE did not differ between the evening- and morning-dosing groups (HR: 0.94; 95%CI: 0.85–1.04), with a negligible degree of heterogeneity (I²=0%; τ²=0). In the 2 trials with bias concerns (particularly regarding the randomization process),the HR was 0.43 (95%CI: 0.26–0.72).
• There was no difference in the rate of all-cause mortality between the dosing groups (HR: 0.77; 95%CI: 0.51–1.16), nor in the frequency of any of the other secondary endpoints.

Conclusion

This systematic review and meta-analysis of 5 large RCTs demonstrated there was no difference in taking some or all antihypertensives in the evening versus all in the morning with regard to MACE risk and safety outcomes.

- Our reporting is based on the information provided at the ESC Congress 2024 –