Aspirin AM or PM: Effect on Circadian Rhythm of Platelet Reactivity

Sponsor

Leiden University Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT01900639

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

2.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Low-dose 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. Platelet reactivity follows a circadian rhythm, with a peak in the morning, contributing to the morning peak of cardiovascular disease. Due to its short half life, aspirin only inhibits platelets which are present at the time of intake. Thus, the timing of aspirin intake may influence its inhibitory effect on platelets and intake of aspirin at bedtime may attenuate the morning peak of platelet reactivity. The time-dependent effect of aspirin on circadian rhythm of platelet function has never been studied before. We hypothesize that aspirin intake at bedtime compared with intake on awakening results in a reduction of the morning peak in platelet reactivity.

Condition or Disease	Intervention/Treatment	Phase
Aspirin Circadian Rhythm Platelet Activation Cardiovascular Diseases	Behavioral: change time of intake of aspirin	Phase 4

Detailed Description

Cardiovascular events are a leading cause of mortality and morbidity in western countries. In the European Union, 47% of total mortality is caused by cardiovascular disease2. 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 quarter3. Although not supported by evidence, aspirin is usually taken in the morning, but it may be more beneficial to take aspirin at bedtime instead of on awakening. It has been convincingly shown that platelet activity follows a circadian rhythm, with a peak of platelet reactivity in the morning4-8. This might in part explain the increase in cardiovascular events in the early morning, with the highest incidence between 6 and 12 AM1.

Since platelet reactivity follows a circadian rhythm, the timing of aspirin intake may influence its inhibitory effect on platelets. Due to its short half-life, aspirin only inhibits platelets which are present at the time of intake. New platelets are released at a rate of 10%/day, predominantly during the night9. Because they are more reactive and not inhibited by aspirin taken in the preceding morning, these young platelets contribute to the morning peak of platelet reactivity10, 11. It has been argued that intake of aspirin at bedtime could better prevent the early morning increase in platelet reactivity than intake on awakening, assuming that intake on awakening would be too late to prevent this morning peak in platelet reactivity12. Additionally, a recent study showed significant recovery of platelet aggregation after 24 hours in patients using low-dose aspirin on a daily basis13. This supports the hypothesis that aspirin intake at bedtime could be beneficial in reducing the morning peak of platelet reactivity, thereby possibly also reducing the incidence of arterial thrombotic events in the morning. However, this has never been studied before.

Study Design

Study Type:

Interventional

Actual Enrollment :

14 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Effect of Aspirin Intake on Awakening Versus at Bedtime on Circadian Rhythm of Platelet Reactivity in Healthy Subjects

Study Start Date :

Jul 1, 2013

Actual Primary Completion Date :

Jan 1, 2014

Actual Study Completion Date :

Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: aspirin on awakening intake of 80 acetylsalicylic acid on awakening for 2 weeks	Behavioral: change time of intake of aspirin
Experimental: aspirin at bedtime intake of 80mg acetylsalicylic acis at bedtime	Behavioral: change time of intake of aspirin

Arm

Intervention/Treatment

Active Comparator: aspirin on awakening

intake of 80 acetylsalicylic acid on awakening for 2 weeks

Behavioral: change time of intake of aspirin

Experimental: aspirin at bedtime

intake of 80mg acetylsalicylic acis at bedtime

Behavioral: change time of intake of aspirin

Outcome Measures

Primary Outcome Measures

Circadian rhythm of platelet reactivity [24hour rhythm of platelet reactivity]
Platelet reactivity will be measured by VerifyNow-aspirin assay, serum thromboxane B2, and flow-cytometry.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Healthy subject
Age >18yrs
Capacity to give informed consent (IC)

Exclusion Criteria:

Active chronic disease
Use of any other medication
History of: major bleeding events, known bleeding diathesis or disorder, cardiovascular disease, malignancy
Known allergy to salicylates
Platelet count < 150 * 109/L
VerifyNow Aspirin Reaction Units <550 Aspirin Reaction Units (ARU)
Smoking
Shift work in preceding 2 months
Extreme chronotypes, defined as regular (>2 days/week) bedtime <22:00h or >24:00h and/or awakening <6:00h or >9:00h
Pregnancy