Twenty-four-hour time dependency of clopidogrel effects in patients with acute coronary syndromes: The CiCAD-Study
Susanne Claudia Gruber1, Matthias Karl Freynhofer1, Martin Willheim2
1a 3rd Medical Department, Cardiology and Intensive Care Medicine , Wilhelminenhospital , Vienna , Austria.
Insights
Platelet function significantly varies over 24 hours in patients taking clopidogrel and aspirin, with reduced effectiveness at the end of the dosing interval. Enhanced platelet turnover does not explain this diurnal variability.
Area of Science:
- Cardiology
- Pharmacology
- Hematology
Background:
- Cardiovascular events exhibit diurnal variation, often peaking in the morning.
- Aspirin therapy is linked to increased morning platelet reactivity.
- Limited data exists on the pharmacodynamic variability of adenosine-diphosphate (ADP) receptor inhibitors like clopidogrel.
Purpose of the Study:
- To investigate diurnal changes in clopidogrel-mediated platelet function and activation over 24 hours.
- To determine if increased platelet turnover contributes to the diurnal variability of platelet function.
- To assess clopidogrel's effectiveness at the end of its dosing interval in patients with acute coronary syndromes (ACS).
Main Methods:
- Twenty-one ACS patients on daily clopidogrel (75 mg) and aspirin (100 mg) were studied.
- Blood samples were collected at five time points within 24 hours.
- Platelet function and activation were measured using vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P), Verify Now, multiple electrode aggregometry (MEA), PAC-1, and P-selectin expression. Platelet count, mean platelet volume (MPV), and reticulated platelet fraction (RPF) were also analyzed.
Main Results:
- Significant diurnal variability in clopidogrel's effects was observed via VASP-P, Verify Now, PAC-1, and P-selectin assays (p < 0.05).
- Multiple electrode aggregometry (MEA) showed no significant diurnal variation.
- Neither MPV nor RPF varied significantly over 24 hours, but higher RPF correlated with increased platelet function and activation (p < 0.05).
Conclusions:
- ADP-dependent platelet function and activation significantly recover by the end of the 24-hour dosing interval in ACS patients on clopidogrel and aspirin.
- While higher reticulated platelet fraction is associated with increased platelet activity, it may not be the primary driver of diurnal variability.
- These findings highlight the importance of considering the timing of antiplatelet medication in relation to diurnal variations in cardiovascular risk.
Abstract:
Long-term evidence shows an increased risk of cardiovascular events in the morning hours and recent studies in aspirin-treated patients have shown increased platelet reactivity at the end of the dosing interval. Similar pharmacodynamic analyses of adenosine-diphosphate (ADP) receptor inhibitors are scarce. We therefore investigated changes in clopidogrel-dependent platelet function and activation over 24 h and whether enhanced platelet turnover might explain diurnal variability of platelet function and activation. Twenty-one patients after acute coronary syndromes (ACS) on maintenance doses of clopidogrel (75 mg) and aspirin (100 mg) Once per day (OD) were included. Blood was collected at five time points in 24 h. Platelet function and activation was analyzed by vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P), Verify Now, multiple electrode aggregometry (MEA), and platelet PAC-1 and P-selectin (P-sel) expression. Additionally, platelet count, mean platelet volume (MPV), and reticulated platelet fraction (RPF) were analyzed. There was significant diurnal variability of clopidogrel effects as documented with VASP-P, Verify Now, and PAC-1 and P-sel (all p < 0.05), whereas MEA did not differ over 24 h. Neither MPV nor RPF varied significantly over 24 h. In patients with high RPF, platelet function and activation was significantly higher in all assays, compared to patients with low RPF (all p < 0.05). However, the changes over time in low versus high RPF groups were similar. ADP-dependent platelet function and activation recovers significantly at the end of the 24-h dosing interval in patients with ACS on a maintenance dose of clopidogrel and aspirin. Although platelet function and activation is increased in patients with higher RPF, platelet turnover might not explain the observed diurnal variability.
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