Effects of low-dose aspirin taken at bedtime on blood pressure of subjects with who use aspirin for prevention of recurrent cardiovascular events: the Aspirin In Reduction of Tension II (ASPIRETENSION II) Study

Aspirin is a cornerstone in the secondary prevention of cardiovascular disease
because of its inhibitory effects on platelet aggregation. It reduces the risk
of recurrent cardiovascular events with about a quarter. Although not supported
by evidence, aspirin is usually taken at morning. There are several reasons why
it may be more beneficial to take aspirin at bedtime instead of on awakening.

First, one of the most important modifiable risk factors for cardiovascular
disease is arterial hypertension. Aspirin is usually assumed to have no effects
on blood pressure. However, in two randomized clinical trials of Hermida et al.
among (otherwise healthy) grade I hypertensive subjects (140/90-159/99 mmHg),
aspirin intake at bedtime decreased 24h blood pressure with 6.8/4.6 and 7.2/4.9
mmHg, whereas use of aspirin at morning slightly increased blood pressure
(2.6/1.6 and 1.3/0.8 mmHg). We have demonstrated that aspirin at bedtime
decreases both plasma renin activity over 24h and excretion of catecholamines
and cortisol in 24h urine compared to morning intake. Decreased activity of
these pressor systems forms a biologically plausible explanation for the
finding that aspirin at bedtime may reduce blood pressure whereas aspirin at
morning does not.
The effect of aspirin at bedtime versus on awakening on blood pressure has
never been studied in a clinically relevant group of patients, i.e. patients
already using aspirin for the secondary prevention of recurrent
atherothrombotic events who mostly use also a wide variety of concomitant
(antihypertensive) drugs. If time of intake has an effect, this could lead to a
very simple improvement of therapy at no extra cost.

Second, it has been convincingly shown that there is a morning peak in platelet
reactivity, which might partly explain the increase in cardiovascular events in
the early morning (highest incidence between 6 and 12 AM). Coming in an upright
posture can lead to increased platelet activity and platelets can also be
stimulated by the early morning increase of sympathetic activity (which starts
few hours before awakening).
Since platelet reactivity has a circadian rhythm, time of intake of aspirin may
influence its inhibitory effect on platelets. It has been argued that intake of
aspirin at bedtime could better prevent the early morning increase in platelet
reactivity than intake at morning assuming that intake at morning would be too
late.

The aim of our project is to study whether treatment with aspirin at bedtime
compared with intake at morning has additional benefits in patients using
aspirin to prevent recurrent cardiovascular events.
1. Our primary objective is to study the effect of 100 mg aspirin intake at
bedtime compared with 100 mg aspirin intake at morning on blood pressure (24h
ambulatory blood pressure measurements (ABPM)) in patients who use aspirin for
secondary prevention of recurrent atherothrombotic events.
2. As a secondary objective, we will study the effect of aspirin intake at
bedtime compared with at morning on platelet function. Furthermore, we will
address differential effects on potential side effects and compliance, as well
as potential effect modification of the effect on blood pressure by genes
involved in blood pressure regulation.

The design of our study is a prospective, randomized, open-label, blinded
endpoint, (PROBE) crossover trial.

After patient's written informed consent and screening, subjects will be
randomised between aspirin at awakening and at bedtime in two treatment periods
of 3 months. Before the start of the study period there will be a screening
visit during which a blood sample and questionnaire is taken. After both
treatment periods there will be a short visit of half an hour to complete
questionnaires and take a blood sample. After both periods blood pressure will
be measured for 24 hours and urine will be collected for 24 hours.

Totally, the study will have a duration of 6 months. Patients will take pills
during the whole study period: 3 months aspirine in the morning and 3 months
aspirine in the evening, the order depending on the randomisation of the
subject. Subjects will not be exposed to any experimental drug. The study drug
is aspirin, but only subjects that were already using aspirin before the study
will be included. 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. They will be
informed about signs and symptoms and will receive emergency contact numbers in
order to guarantee a low threshold for clinical presentation if necessary.