TIME ASPIRIN: Chronotherapy With Aspirin for Reduction of Cardiovascular Disease (TImE ASPIRIN)

Chronotherapy With Aspirin for Reduction of Cardiovascular Disease

This study will be a comparative effectiveness research to determine the difference in major adverse cardiovascular events between the group with aspirin after awakening and placebo before bedtime and the group with placebo after awakening and aspirin before bedtime.

Study Overview

• Status: Terminated
• Conditions: Cardiovascular Diseases
• Intervention / Treatment: Other: aspirin after awakening + placebo before bedtime; Other: placebo after awakening + aspirin before bedtime

Detailed Description

Aspirin is the cornerstone of preventive cardiovascular disease (CVD) treatment and bedtime intake of aspirin (chronotherapy) has been shown to reduce morning activity of platelets. It has been shown that platelet reactivity follows a clear circadian rhythm, with a peak of platelet reactivity during the morning (6-12 AM). Importantly, studies have shown in meta-analyses that high platelet activity is predictive of adverse cardiovascular outcomes in patients with stable CVD. Given this knowledge, it is highly likely that the morning peak of platelet reactivity contributes to the morning peak of cardiovascular events and that reduction of morning platelet activity prevents cardiovascular events during morning hours. This may be achieved by intake of aspirin at bedtime instead of on awakening. This study will be a comparative effectiveness research to determine the difference in major adverse cardiovascular events between the group with aspirin after awakening and placebo before bedtime and the group with placebo after awakening and aspirin before bedtime.

• Study Type: Interventional
• Enrollment (Actual): 328
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Zuid-Holland
    • Leiden, Zuid-Holland, Netherlands, 2333 ZA
      • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Use of low-dose aspirin (acetylsalicylic acid 80mg [brand name: acetylsalicylic acid cardio TEVA]~)
• Patients using aspirin from an MDD ('Baxter')
• Capacity to give informed consent (IC)

Exclusion Criteria:

• Pregnancy
• Mental or physical disability to fulfil study requirements
• Insufficient knowledge of the Dutch language
• Patients currently participating in another (clinical) trial or study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: aspirin after awakening + placebo before bedtime; Acetylsalicylic acid 80 mg once daily, orally. Intake in de morning after awakening. Participants already use acetylsalicylic acid 80 mg once daily due to secondary prevention of cardiovascular disease. Placebo tablet once daily will be added to their medication. The placebo tablet will be taken before bedtime, orally. The placebo is given throughout the study.	Other: aspirin after awakening + placebo before bedtime; determine the difference in major adverse cardiovascular events between the group with aspirin after awakening and placebo before bedtime and the group with placebo after wakening and aspirin before bedtime.; Other Names: Acetylsalicylic acid Cardio Teva 80 mg, intake after awakening
Experimental: placebo after awakening +aspirin before bedtime; Acetylsalicylic acid 80 mg once daily, orally. The time will be changed form morning to bedtime. Participants already use acetylsalicylic acid 80 mg once daily due to secondary prevention of cardiovascular disease. Placebo tablet once daily will be added to their medication. The placebo tablet will be taken after awakening, orally. The placebo is given throughout the study.	Other: placebo after awakening + aspirin before bedtime; determine the difference in major adverse cardiovascular events between the group with aspirin after awakening and placebo before bedtime and the group with placebo after wakening and aspirin before bedtime.; Other Names: Acetylsalicylic acid Cardio Teva 80 mg, intake before bedtime

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence rate of major adverse cardiovascular events	the difference in number of participants with a major adverse cardiovascular events, defined as the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, transient ischemic attack, need for repeat revascularízation by redo-CABG or repeat percutaneous intervention.	maximum of 4 years follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparing the incidence rate of major cardiovascular events between the two groups in the morning (6-12), evening (12-21) and night (21-6).	It is expected that bedtime aspirin reduces the number of participants with primary outcome (major cardiovascular events) more during morning hours (6-12h) compared with the rest of the day. So we will compare the mornig events, afternoon/evening and night events between the two groups and compare the difference.	maximum of 4 years follow up
Incidence rate of side-effects between the 2 groups	the difference between the 2 groups of the number of participants that experience side-effects (e.g. bleeding, gastrointestinal symptoms)	maximum of 4 years follow up
cost-effectiveness of the intervention	Comparing the relative costs and outcomes (effects) between the 2 groups. Data from questionnaire (use of health care) and data from the primary and secondary health care systems. We can compare the use of health care between the two groups en we can calculate the difference in cost between the two groups. So we can estimate if our intervention is cost-effective.	maximum of 4 years follow up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
difference in quality of life	Health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Rated level per dimensions can be coded as a number 1-5, which indicates having no problems for 1 and having extreme problems for 5. We can define 3,125 (=55) different health states. We compare the average health status of the groups at the beginning and at the end of the study. See if there is a difference in health status/ quaulity of life between the two groups.	maximum of 4 years follow up

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Tobias Bonten, Leiden University

Study record dates

Study Major Dates

• Study Start (Actual): October 7, 2019
• Primary Completion (Actual): March 31, 2022
• Study Completion (Actual): March 31, 2022

Study Registration Dates

• First Submitted: June 7, 2019
• First Submitted That Met QC Criteria: October 16, 2019
• First Posted (Actual): October 21, 2019

Study Record Updates

• Last Update Posted (Actual): June 24, 2022
• Last Update Submitted That Met QC Criteria: June 20, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Aspirin; Chronotherapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: P18.127

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Will be decided in our data management plan

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No