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

ESC 2024 – In a systematic review and meta-analysis of 5 large RCTs, there was no difference in evening versus morning dosing of antihypertensives with regard to MACE risk and safety outcomes.

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 –