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REFLECTIONS
Hypertension
Hypertension Global Newsletter #4 2023

Cardiovascular outcomes in adults with hypertension with evening versus Hypertension

morning dosing of usual antihypertensives in the UK (TIME study): A prospective,
randomised, open-label, blinded-endpoint clinical trial.
Mackenzie IS, et al. Lancet. 2022 Oct 22;400(10361):1417-1425.

Adequately controlling BP reduces the risk of major CV events, including stroke, ischemic heart disease, and CV death. When
measured using 24h ambulatory monitoring, normal BP exhibits a diurnal rhythm, with lower pressure at night followed by a
morning increase or surge in BP. Evening dosing of antihypertensive medications has been suggested to potentially be more
effective at normalising the diurnal rhythm and preventing long-term CV outcomes of hypertension than morning dosing.

Previous studies (MAPEC study and the Hygia Chronotherapy study) have suggested a reduction in CV outcomes with a
bedtime dosing compared to a morning dosing. Still, several expert commentators have questioned the methods and plausibility
of the effect size reported in those studies.

The Treatment in Morning versus Evening (TIME) study was a large, pragmatic, decentralized, prospective, randomized, open-
label, blinded-endpoint, superiority trial conducted in the UK. It compared CV outcomes in adults with hypertension randomly
assigned to evening vs. morning dosing of their usual antihypertensive medications. The study included 21,104 individuals
randomly assigned to evening (n=10,503) or morning (n=10,601) dosing groups. The mean age at study entry was 65.1 (SD
9.3) years; 57.5% were men; and 90.5% were White; 0.5% Black, African, Caribbean, or Black British; and 7.8% had no
ethnicity reported.

With a median follow-up of 5.2 years, there was no difference between the evening and morning dosing groups for the primary
composite outcome of vascular death or hospitalization for non-fatal MI or non-fatal stroke. There was also no difference in all-
cause mortality between the two groups.

For the secondary endpoints, the evening dosing group participants were slightly less likely to report falls than those in the
morning dose (21.1% vs. 22.2% respectively; p=0.048). There were no differences in reported non-hospitalized or fractures that
required a hospital stay. Fewer participants in the evening dosing group reported one or more prespecified symptom adverse
events during the study than participants in the morning dosing group (69.2% vs. 70.5%, respectively; p=0.041). Dizziness or
light-headedness, upset stomach or indigestion, diarrhea, and
muscle aches were all reported more commonly with morning
dosing than evening dosing. However, excessive visits to the Key points
toilet during the day or night and other non-specified adverse • Evening dosing of usual antihypertensive
events were more commonly reported with evening dosing.
medication did not improve the primary
With regards to adherence, 69.3% of patients reported composite endpoint of vascular death or
adherence to their assigned dosing time throughout the trial. hospitalization for non-fatal MI or non-fatal
Reported non-adherence was more common in the evening stroke compared with morning dosing.
treatment than the morning treatment (39.0% vs. 22.5%; • Patients may be advised that they need not
p<0.0001); however, the last known status was reported change their antihypertensive medication
non-adherence with allocated dosing time for only 13.4% of dosing time but might choose to take their
participants overall (19.8% evening and 7.1% morning dose).
Some patients may have changed to an evening dosing in medication at a time that suits them best.
response to the high-profile media coverage of the results • Clinicians should focus on selecting appropriate
from the Hygia Chronotherapy Trial in the UK in October medications and emphasize adherence to
2019. These participants reverted to morning dosing shortly assented treatment plans rather than timing
afterwards (data not shown), after being informed that the of doses.
TIME study independent data monitoring committee had

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