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

Summary

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.

Keywords

Aspirin - chronotherapy - circadian rhythm - platelet aggregation - randomised controlled trial

• References

• 1 Vandvik PO, Lincoff AM, Gore JM. et al. Primary and Secondary Prevention of Cardiovascular Disease. Chest 2012; 141: e637S-e668S.
• 2 Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
• 3 Davi G, Patrono C. Platelet Activation and Atherothrombosis. N Engl J Med 2007; 357: 2482-2494.
• 4 Patrono C, Garcia Rodriguez LA, Landolfi R. et al. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353: 2373-2383.
• 5 Tofler GH, Brezinski D, Schafer AI. et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987; 316: 1514-1518.
• 6 Scheer FAJL, Michelson AD, Frelinger AL. et al. The Human Endogenous Circa-dian System Causes Greatest Platelet Activation during the Biological Morning Independent of Behaviors. PLoS ONE 2011; 06: e24549.
• 7 Mogabgab O, Wiviott SD, Antman EM. et al. Relation Between Time of Symptom Onset of ST-Segment Elevation Myocardial Infarction and Patient Baseline Characteristics: From the National Cardiovascular Data Registry. Clin Cardiol 2013; 36: 222-227.
• 8 Cohen MD, Rohtla BS, Lavery BS. et al. Meta-Analysis of the Morning Excess of Acute Myocardial Infarction and Sudden Cardiac Death. Am J Cardiol 1997; 79: 1512-1516.
• 9 Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis. Stroke 1998; 29: 992-996.
• 10 Willich SN, Kulig M, Muller-Nordhorn J. European Survey on Circadian Variation of Angina Pectoris (ESCVA) in Treated Patients. Herz 2004; 29: 665-672.
• 11 Kelle S, Roes SD, Klein C. et al. Prognostic value of myocardial infarct size and contractile reserve using magnetic resonance imaging. J Am Coll Cardiol 2009; 54: 1770-1777.
• 12 Suarez-Barrientos A, Lopez-Romero P, Vivas D. et al. Circadian variations of infarct size in acute myocardial infarction. Heart 2011; 97: 970-976.
• 13 Di Minno G, Silver MJ, Murphy S. Monitoring the entry of new platelets into the circulation after ingestion of aspirin. Blood 1983; 61: 1081-1085.
• 14 Patrono C, Ciabattoni G, Patrignani P. et al. Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation 1985; 72: 1177-1184.
• 15 Grove EL, Hvas AM, Mortensen SB. et al. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost 2011; 09: 185-191.
• 16 Perneby C, Wallen NH, Rooney C. et al. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost 2006; 95: 652-658.
• 17 Grove EL, Hvas AM, Kristensen SD. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009; 101: 151-156.
• 18 Guthikonda S, Lev EI, Patel R. et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Hae-most 2007; 05: 490-496.
• 19 Rocca B, Santilli F, Pitocco D. et al. The Recovery of Platelet Cyclooxygenase Activity Explains Interindividual Variability in Responsiveness to Low-Dose Aspirin in Patients With and Without Diabetes. J Thromb Haemost 2012; 10: 1220-1230.
• 20 Wurtz M, Hvas AM, Jensen LO. et al. 24-hour antiplatelet effect of aspirin in patients with previous definite stent thrombosis. Int J Cardiol. 2014 Epub ahead of print.
• 21 Henry P, Vermillet A, Boval B. et al. 24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost 2010; 105: 336-344.
• 22 Kriszbacher I, Ajtay Z, Koppan M. et al. Can the time of taking aspirin influence the frequency of cardiovascular events?. Am J Cardiol 2005; 96: 608-610.
• 23 Cornelissen G, Halberg F, Prikryl P. et al. Prophylactic Aspirin Treatment: The Merits of Timing. J Am Med Assoc 1991; 266: 3128-3129.
• 24 Hansson L, Hedner T, Dahlof B. Prospective randomized open blinded endpoint (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point. Blood Press 1992; 01: 113-119.
• 25 Koch PA, Schultz CA, Wills RJ. et al. Influence of food and fluid ingestion on aspirin bioavailability. J Pharm Sci 1978; 67: 1533-1535.
• 26 Coleman JL, Wang JC, Simon DI. Determination of Individual Response to Aspirin Therapy Using the Accumetrics Ultegra RPFA-ASA System. Point of Care 2004; 03: 77-82.
• 27 Accumetrics. VerifyNow Aspirin Package Insert. 2011.
• 28 Cattaneo M. Laboratory detection of ’aspirin resistance’: what test should we use (if any)?. Eur Heart J 2007; 28: 1673-1675.
• 29 Roest M, van Holten TC, Fleurke GJ. et al. Platelet Activation Test in Unprocessed Blood (Pac-t-UB) to Monitor Platelet Concentrates and Whole Blood of Thrombocytopenic Patients. Transfus Med Hemother 2013; 40: 117-125.
• 30 Jin J, Quinton TM, Zhang J. et al. Adenosine diphosphate (ADP)-induced thromboxane A(2) generation in human platelets requires coordinated signaling through integrin alpha(IIb)beta(3) and ADP receptors. Blood 2002; 99: 193-198.
• 31 Kashiwagi H, Shiraga M, Honda S. et al. Activation of integrin alpha IIb beta 3 in the glycoprotein Ib-high population of a megakaryocytic cell line, CMK, by inside-out signaling. J Thromb Haemost 2004; 02: 177-186.
• 32 De Cuyper IM, Meinders M, van de Vijver E. et al. A novel flow cytometry-based platelet aggregation assay. Blood 2013; 121: e70-e80.
• 33 Middelburg RA, Roest M, Ham J. et al. Flow cytometric assessment of agonist-induced P-selectin expression as a measure of platelet quality in stored platelet concentrates. Transfusion 2013; 53: 1780-1787.
• 34 Chow SC, Wang H, Shao J. Sample size calculations in clinical research. CRC Press; 2007
• 35 Madsen EH, Saw J, Kristensen SR. et al. Long-term aspirin and clopidogrel response evaluated by light transmission aggregometry, VerifyNow, and thrombelastography in patients undergoing percutaneous coronary intervention. Clin Chem 2010; 56: 839-847.
• 36 O’Brien JR. Shear-induced platelet aggregation. Lancet 1990; 335: 711-713.
• 37 Kriszbacher I, Koppan M, Bodis J. Aspirin for stroke prevention taken in the evening?. Stroke 2004; 35: 2760-2761.
• 38 Ridker PM, Manson JE, Buring JE. et al. Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation 1990; 82: 897-902.
• 39 McCall NT, Tofler GH, Schafer AI. et al. The effect of enteric-coated aspirin on the morning increase in platelet activity. Am Heart J 1991; 121: 1382-1388.
• 40 Eikelboom JW, Hirsh J, Spencer FA. et al. Antiplatelet Drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e89S-e119S.
• 41 Rocca B, Petrucci G. Variability in the responsiveness to low-dose aspirin: pharmacological and disease-related mechanisms. Thrombosis 2012; 2012: 376721.
• 42 Brezinski DA, Tofler GH, Muller JE. et al. Morning increase in platelet aggregability. Association with assumption of the upright posture. Circulation 1988; 78: 35-40.
• 43 Grove EL, Hvas AM, Johnsen HL. et al. A comparison of platelet function tests and thromboxane metabolites to evaluate aspirin response in healthy individuals and patients with coronary artery disease. Thromb Haemost 2010; 103: 1245-1253.
• 44 Capodanno D, Patel A, Dharmashankar K. et al. Pharmacodynamic Effects of Different Aspirin Dosing Regimens in Type 2 Diabetes Mellitus Patients With Coronary Artery Disease. Circulation Cardiovasc Interv 2011; 04: 180-187.
• 45 Dillinger JG, Drissa A, Sideris G. et al. Biological efficacy of twice daily aspirin in type 2 diabetic patients with coronary artery disease (Abstract). Am Heart J 2012; 164: 600-606.
• 46 Choudhry NK, Fischer MA, Avorn J. The implications of therapeutic complexity on adherence to cardiovascular medications. Arch Intern Med 2011; 171: 814-822.
• 47 Huang ES, Strate LL, Ho WW. et al. A Prospective Study of Aspirin Use and the Risk of Gastrointestinal Bleeding in Men. PLoS ONE 2010; 05: e15721.
• 48 Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989; 79: 733-743.
• 49 Frelinger AL, Li Y, Linden MD. et al. Association of Cyclooxygenase-1-Dependent and -Independent Platelet Function Assays With Adverse Clinical Outcomes in Aspirin-Treated Patients Presenting for Cardiac Catheterization. Circulation 2009; 120: 2586-2596.
• 50 Breet NJ, van Werkum JW, Bouman HJ. et al. High on-aspirin platelet reactivity as measured with aggregation-based, cyclooxygenase-1 inhibition sensitive platelet function tests is associated with the occurrence of atherothrombotic events. J Thromb Haemost 2010; 08: 2140-2148.
• 51 Chen WH, Cheng X, Lee PY. et al. Aspirin resistance and adverse clinical events in patients with coronary artery disease. Am J Med 2007; 120: 631-635.