Effects of low-dose aspirin taken at bedtime vs. on awakening on circadian rhythm of platelet function in healthy subjects

Low-dose aspirin is a cornerstone in the secondary prevention of cardiovascular
disease (CVD) and is usually taken on awakening, although evidence regarding
optimal time of intake is lacking. Platelets play a crucial role in the
development of acute thrombotic events and it has been convincingly shown that
platelet activity follows a circadian rhythm, with a peak of platelet
reactivity in the morning. This might in part explain the peak of
cardiovascular events in the morning between 6 and 12 AM1. Due to its short
half life, aspirin only inhibits platelets which are present at the time of
intake. Thus, the timing of aspirin intake may influence its inhibitory effect
on platelets and intake of aspirin at bedtime may attenuate the morning peak of
platelet reactivity. The time-dependent effect of aspirin on circadian rhythm
of platelet function has never been studied before.

To study the effect of 80 mg aspirin intake at bedtime compared with 80 mg
aspirin intake on awakening on circadian rhythm of platelet function in healthy
subjects.

The design of our study is a randomized, open-label, blinded endpoint (PROBE)
crossover trial. Benefits of the PROBE design and its validity as compared to
double-blind, placebo-controlled trials have been previously documented. 12
healthy volunteers, as calculated below, will randomly use aspirin on awakening
and aspirin at bedtime during two intervention periods of two weeks. The two
intervention periods are separated by a wash-out period of 4 weeks, which is
approximately 4 times the duration of action of aspirin (7-10 days), and long
enough to guarantee washout of the effect of two weeks of aspirin intake in the
preceding period. At the end of both treatment periods, subjects will be
admitted for 24 hours to the LUMC to assess the effect of aspirin intake on
awakening or at bedtime on the circadian rhythm of platelet function.

aspirin 80mg on awakening (2 weeks)
aspirin 80mg at bedtime (2 weeks)

Extensive knowledge is available about AEs associated with use of aspirin.
Related to its effect on platelet aggregation is impairment of primary
haemostasis. Unless it is given to patients with an underlying haemostatic
defect, it does not cause a generalized bleeding abnormality. The most
well-known effect is the gastrointestinal toxicity. By dose-related inhibition
of prostaglandin synthesis, erosions in the gastric mucosa may occur. In
several reviews, the use of low dose aspirin (30-300mg a day) was associated
with a relative risk of severe upper gastrointestinal bleeding or perforation
of 1.6 - 2.2 versus placebo. A recent meta-analysis reported a total of 0.53
major gastrointestinal and other extracranial bleeds per 10.000 person-years.
Given the short duration of exposure to the study drug in a healthy population,
we consider the bleeding- and gastrointestinal risk very low for this study.
Additionally, medical and hematological screening before entry into the study
excludes entry of subjects with an increased risk of side effects or platelet
dysfunction. In our opinion, there is a tolerable risk for healthy study
subjects during the study period, regarding the minimal risk of side effects
with the short term use of low-dose aspirin.