Aspirin AM or PM in Reduction of Tension: a Randomized Cross-over Trial

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). The investigators 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. 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. As a secondary objective, the investigators will study the effect of aspirin intake at bedtime compared with at morning on platelet function. Furthermore, the investigators 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.