Aspirin in Reduction of Tension II Study
Condition: Hypertension; Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Acetylsalicylic acid; Acetylsalicylic acid lysinate
Intervention type(s): Drug; Drug
Intervention description(s): aspirin intake at bedtime; aspirin intake on awakening
Other intervention name(s): Ascal, Ascal Cardio/Neuro, Carbasalate Calcium; Ascal, Ascal Cardio/Neuro, Carbasalate Calcium
Intervention MeSH terms: Aspirin; Calcium, Dietary; Acetylsalicylic acid lysinate; Carbaspirin calcium; Calcium
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment