Chronotherapy with aspirin for reduction of cardiovascular disease

Aspirin is a cornerstone in the secondary prevention of cardiovascular disease
because of its inhibitory effects on platelet aggregation. Although not
supported by evidence, aspirin is usually taken at morning. There is
evidencethat is may be more benificial to take aspirin at bedtime instead of on
awakening. Because it has been shown that platelet reactivity follows a clear
circadian rhythm, with a peak of platelet reactivity during the morning (6-12
AM). Importantly, studies have shown in meta-analyses that high platelet
activity is predictive of adverse cardiovascular outcomes in patients with
stable CVD. Given this knowledge, it is highly likely that the morning peak of
platelet reactivity contributes to the morning peak of CVD and that reduction
of morning platelet activity prevents cardiovascular events during morning
hours. This may be achieved by intake of aspirin at bedtime instead of on
awakening assuming that intake at morning would be too late.

The aim of this comparative effectiveness research is to determine the effect
of intake of aspirin before bedtime in comparison with aspirin on awakening in
patients already using aspirin for secondary prevention of CVD.

Our primary objective will be to assess the major adverse cardiovascular
events, defined as the composite of death from cardiovascular causes, nonfatal
myocardial infarction or nonfatal stroke, transient ischemic attack, need for
repeat revascularization by redo-CABG or repeat percutaneous intervention (the
*cardiovascular endpoints*).

Our secondary objectives are:
* Time of the day of primary outcome: it is expected that bedtime aspirin
reduces the primary outcome more during morning hours (6-12h) compared with the
rest of the day.
* Safety: severe or moderate bleeding events according to established
definitions.
* Side-effects.
* Cost-effectiveness: patients* quality of life (EQ-5D-5L) will be registered
at randomization and after that with a frequency of twice per year during
follow-up to calculate QALYs. Health care utilization data are extracted from
electronic patient records and data from the primary care. Health care use will
be translated into cost using Dutch reference prices.
* Subgroup analyses will be performed for gender and age.

This study follows a parallel double blinded placebo controlled randomized
clinical trial design.

After patient's written informed consent, subjects will be randomised between
aspirin at awakening or at bedtime in treatment periods of 4 years.

Totally, the study will have a duration of max. 4 years. The participants, all
using aspirin, will be randomized to a study arm: (1) aspirin after awakening +
placebo before bedtime, (2) placebo after awakening + aspirin before bedtime.
Participants will continue to use their own aspirin preparation as delivered by
their pharmacy. An identical placebo will be packaged in their multidose drug
dispensing (MDD) by the MDD company.
In addition, the participant will receive 10 questionnaires during the duration
of the study.

Subjects will not be exposed to any experimental drug. Therefore, participation
in the study will not involve any safety risks for subjects. Nevertheless,
subjects will be instructed about the (very small) risk of bleeding associated
with aspirin use.