Effect of aspirin intake at bedtime versus on awakening on circadian rhythm of platelet reactivity

Abstract

The risk of acute cardiovascular events is highest during morning hours, and platelet activity peaks during morning hours. The effect of timing of aspirin intake on circadian rhythm and morning peak of platelet reactivity is not known. It was our objective to evaluate the effect of timing of aspirin intake on circadian rhythm and morning peak of platelet reactivity. A randomised open-label cross-over trial in healthy subjects (n=14) was conducted. Participants used acetylsalicylic acid (80 mg) on awakening or at bedtime for two periods of two weeks, separated by a four-week wash-out period. At the end of both periods blood was drawn every 3 hours to measure COX-1-dependent (VerifyNow-Aspirin; Serum Thromboxane B2 [STxB2]) and COX-1-independent (flow cytometry surface CD62p expression; microaggregation) platelet activity. VerifyNow platelet reactivity over the whole day was similar with intake on awakening and at bedtime (mean difference: -9 [95 % confidence interval (CI) -21 to 4]). However, the morning increase in COX-1-dependent platelet activity was reduced by intake of aspirin at bedtime compared with on awakening (mean difference VerifyNow: -23 Aspirin Reaction Units [CI -50 to 4]; STxB2: -1.7 ng/ml [CI -2.7 to -0.8]). COX-1-independent assays were not affected by aspirin intake or its timing. Low-dose aspirin taken at bedtime compared with intake on awakening reduces COX-1-dependent platelet reactivity during morning hours in healthy subjects. Future clinical trials are required to investigate whether simply switching to aspirin intake at bedtime reduces the risk of cardiovascular events during the high risk morning hours.

Aspirin intake in the morning is associated with suboptimal platelet inhibition, as measured by serum Thromboxane B2, during infarct-prone early-morning hours

“…This study, however, was done in patients with essential thrombocytosis [21]. Furthermore, in line with previous research, we found a better early morning platelet inhibition in OD-evening in comparison with OD-morning [15,18,22]. Since cardiovascular events occur most frequently during late-night and early-morning hours [10], optimum platelet inhibition during these hours seems desirable.…”

“…Prior to storage at −80°C, the serum samples were centrifuged at 3000 x g for 10 minutes. STxB 2 was measured by enzyme immunoassay according to manufacturers' instructions (Thromboxane B2 Express, Cayman Chemicals, Ann Arbor, MI, USA) and previously described by Bonten et al [15]. Samples were analyzed in duplicate in the laboratory in order to measure the intra-assay coefficient of variance (CV), which was < 15% for all measurements.…”

The Influence of Haemoglobin A1c Levels on Platelet Aggregation and Platelet Turnover in Patients with Coronary Artery Disease Treated with Aspirin

“…For now, aspirin remains a cornerstone in secondary prevention of cardiovascular events [ 52 ]. Possible new treatment options include: i) a higher dose of aspirin [ 38 ]; ii) dosing of aspirin twice daily [ 29 , 40 ]; iii) intake of aspirin once daily at bedtime instead of in the morning [ 53 ] or iv) switching to or adding another antiplatelet agent such as the P2Y12-inhibitors clopidogrel, prasugrel or ticagrelor [ 54 ]. Finally, improving glycaemic control may also be a way of reducing platelet aggregation and outcome [ 55 , 56 ].…”

Therapeutic applications of circadian rhythms for the cardiovascular system

“…In an exciting recent chronotherapy study, it was found that evening administration of low-dose aspirin reduces morning platelet reactivity, via COX-1 dependent pathways, as compared with taking aspirin upon awakening ( Bonten et al, 2014 ). This finding is consistent with earlier reports of a circadian rhythm in platelet surface markers ( Scheer et al, 2011 ), and in platelet aggregability ( Andrews et al, 1996 ).…”

“…Collectively these studies are clinically important because acute cardiovascular events (e.g., MI) are most likely to occur in the early morning hours vs. other times of day or night ( Muller et al, 1985 ), and platelet reactivity likely contributes to this early morning peak. Thus it is postulated that aspirin chronotherapy taken at bedtime instead of on awakening, as a preventative measure in healthy subjects and by patients with cardiovascular disease, can reduce the incidence of adverse cardiac events during the high-risk morning hours ( Bonten et al, 2014 ). That daily low-dose aspirin reduces the peak frequency of MIs in the morning and overall risk across the 24-h cycle ( Ridker et al, 1990 ), provides further support for this notion.…”