Aspirin in Reduction of Tension II Study

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. Recent studies in healthy subjects with mild hypertension showed that aspirin at bedtime decreases blood pressure (-7/5mmHg), whereas intake of aspirin on awakening does not. Additionally, the investigators found that aspirin at bedtime decreases plasma renin activity, catecholamines and cortisol over 24hrs. Time-dependent effects of aspirin have never been studied in patients with CVD, who may use concomitant antihypertensive drugs. Moreover, platelet reactivity has a circadian rhythm, and intake of aspirin at bedtime may attenuate the morning peak in platelet reactivity. The investigators hypothesize that aspirin intake at bedtime compared with on awakening decreases both blood pressure and platelet reactivity over 24h.

A randomized open-label blinded endpoint crossover trial in which 250 patients, recruited from primary care, will be included who use aspirin for secondary prevention of CVD and have a stable blood pressure of 149/94mmHg or lower. Study subjects will randomly use both aspirin on awakening and at bedtime during two intervention periods of three months. Blood pressure will be recorded for 24hrs at the end of each treatment period in the patients' normal daily situation. To assess effects on platelet inhibition, thromboxane-B2 levels will be measured in a 24h urine sample at the end of both treatment periods. The investigators will asses differential effects according to time of intake on gastrointestinal complaints and potential minor bleeding events, as well as compliance.

The aim of this study is to evaluate the effect of aspirin taken at bedtime compared with on awakening on blood pressure of subjects with stable CVD. In addition, it will generate insights into the effect of aspirin on platelet reactivity over 24hrs, potential side effects and compliance.

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.

Eligibility Criteria:
Inclusion Criteria:

* Use of low-dose aspirin (acetylsalicylic acid or carbasalate calcium 80- 100mg \[brand names: acetylsalicylic acid cardio, aspirin protect, ascal cardio, carbasalate calcium cardio\]) for secondary prevention of cardiovascular events
* Stable blood pressure (with or without therapy) between 120/70 and 159/99
* Age 18-80 year
* Capacity to give informed consent (IC)

Exclusion Criteria:

* Blood pressure lower than 120/70 or higher than 159/99
* Change in blood pressure lowering medication within the last three months
* Regular use of non-steroidal anti-inflammatory drugs (NSAID's)
* Shift workers
* Evidence of secondary arterial hypertension
* Pregnancy