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

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ClinicalTrials.gov Identifier: NCT01900639
Recruitment Status : Completed
First Posted : July 16, 2013
Last Update Posted : February 20, 2014
Sponsor:
Information provided by (Responsible Party):
Leiden University Medical Center

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.


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Study Type : Interventional  (Clinical Trial)
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 : July 2013
Actual Primary Completion Date : January 2014
Actual Study Completion Date : January 2014

Resource links provided by the National Library of Medicine

Drug Information available for: 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



Primary Outcome Measures :
  1. Circadian rhythm of platelet reactivity [ Time Frame: 24hour rhythm of platelet reactivity ]
    Platelet reactivity will be measured by VerifyNow-aspirin assay, serum thromboxane B2, and flow-cytometry.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01900639


Locations
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Netherlands
Leiden University Medical Center
Leiden, Netherlands, 2300RC
Sponsors and Collaborators
Leiden University Medical Center

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT01900639     History of Changes
Other Study ID Numbers: NL.44378.058.13
2013-001410-16 ( EudraCT Number )
P13.092 ( Other Identifier: Leiden University Medical Center )
First Posted: July 16, 2013    Key Record Dates
Last Update Posted: February 20, 2014
Last Verified: February 2014
Keywords provided by Leiden University Medical Center:
aspirin
circadian rhythm
platelet reactivity
platelet activation
time dependent
Additional relevant MeSH terms:
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Cardiovascular Diseases
Aspirin
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics