Vol 26, No 6 (2019)
Original articles — Clinical cardiology
Published online: 2018-11-26

open access

Page views 2924
Article views/downloads 1323
Get Citation

Connect on Social Media

Connect on Social Media

The effect of acetylsalicylic acid dosed at bedtime on the anti-aggregation effect in patients with coronary heart disease and arterial hypertension: A randomized, controlled trial

Beata Krasińska1, Lech Paluszkiewicz2, Ewa Miciak-Lawicka1, Maciej Krasiński3, Piotr Rzymski4, Andrzej Tykarski1, Zbigniew Krasiński5
Pubmed: 30484269
Cardiol J 2019;26(6):727-735.


Background: Acetylsalicylic acid (ASA) is one of the basic drugs used in the secondary prevention of
coronary artery disease (CAD), and in most cases it is taken in the morning in one daily dose. It is suggested
that the morning peak of platelet aggregation is responsible for the occurrence of myocardial infarctions
and strokes. Hence, the aim of the study was to observe the effect of ASA (morning vs. evening)
dosing on the anti-aggregative effect of platelets in patients with CAD and arterial hypertension (AH).
Methods: The study involved 175 patients with CAD and AH. Patients were randomly assigned to
one of two study groups, taking ASA in the morning or in the evening. The patients had two visits, one
baseline and another after 3 months from changing the time of ASA dosage. The platelet aggregation
was determined using the VerifyNow analyzer.
Results: In the ASA evening group, a significant reduction in platelet aggregation was obtained. In
the ASA morning group, a significant difference in response to ASA was observed, depending on sex. In
men, the reactivity of platelets decreased, but in women it increased.
Conclusions: In the group of patients with CAD and AH, bedtime ASA dosing is associated with
a significant reduction in platelet aggregation. The response to ASA may differ between sexes. The benefit
gained by changing the drug administration from the morning to the evening is greater in women.

Article available in PDF format

View PDF Download PDF file


  1. Smolensky MH, Portaluppi F. Chronopharmacology and chronotherapy of cardiovascular medications: relevance to prevention and treatment of coronary heart disease. Am Heart J. 1999; 137(4 Pt 2): S14–S24.
  2. Reinberg A. Human chronobiology and chronopharmacology. Isr J Med Sci. 1976; 12(8): 770–779.
  3. Cohen DL, Townsend RR. Is it morning blood pressure surge or extreme nocturnal dipping that accounts for the increased stroke risk in the morning waking hours? J Clin Hypertens (Greenwich). 2014; 16(12): 847.
  4. Sumiyoshi M, Kojima S, Arima M, et al. Circadian, weekly, and seasonal variation at the onset of acute aortic dissection. Am J Cardiol. 2002; 89(5): 619–623.
  5. Behar S, Reicher-Reiss H, Goldbourt U, et al. Circadian variation in pain onset in unstable angina pectoris. Am J Cardiol. 1991; 67(1): 91–93.
  6. Cohen MC, Rohtla KM, Lavery CE, et al. Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol. 1997; 79(11): 1512–1516.
  7. Willich S, Levy D, Rocco M, et al. Circadian variation in the incidence of sudden cardiac death in the framingham heart study population. Am J Cardiol. 1987; 60(10): 801–806.
  8. Willich SN, Linderer T, Wegscheider K, et al. Increased morning incidence of myocardial infarction in the ISAM Study: absence with prior beta-adrenergic blockade. ISAM Study Group. Circulation. 1989; 80(4): 853–858.
  9. Guerci AD, Ross RS. TIMI II and the role of angioplasty in acute myocardial infarction. N Engl J Med. 1989; 320(10): 663–665.
  10. 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(4): 222–227.
  11. Kapiotis S. Morning hypercoagulability and hypofibrinolysis. Diurnal variations in circulating activated factor VII, prothrombin fragment F1+2, and plasmin-plasmin inhibitor complex. Circulation. 1997; 96(1): 19–21.
  12. Ehrly AM, Jung G. Circadian rhythm of human blood viscosity. Biorheology. 1973; 10(4): 577–583.
  13. Haus E. Chronobiology of hemostasis and inferences for the chronotherapy of coagulation disorders and thrombosis prevention. Adv Drug Deliv Rev. 2007; 59(9-10): 966–984.
  14. Ündar L, Türkay C, Korkmaz L. Circadian variation in circulating platelet aggregates. Annals of Medicine. 2009; 21(6): 429–433.
  15. Noel H, Saunders E, Smolensky M. Hypertension, chronotherapy, and patient management. Nurse Pract. 2000; 25(Supplement): 2–10.
  16. Andrys-Wawrzyniak I, Jabłecka A. Chronobiologia, chronofarmakologia i ich miejsce w medycynie. Farmacja Współczesna. 2008; 1: 156–168.
  17. Chapman AR, Rushworth GF, Leslie SJ. Aspirin desensitization in patients undergoing percutaneous coronary intervention: a survey of current practice. Cardiol J. 2013; 20(2): 134–138.
  18. Würtz M. Aspirin in coronary artery disease: an appraisal of functions and limitations. Dan Med J. 2015; 62(4): B5011.
  19. Suárez-Barrientos A, López-Romero P, Vivas D, et al. Circadian variations of infarct size in acute myocardial infarction. Heart. 2011; 97(12): 970–976.
  20. Richards AM, Nicholls MG, Espiner EA, et al. Diurnal patterns of blood pressure, heart rate and vasoactive hormones in normal man. Clin Exp Hypertens A. 1986; 8(2): 153–166.
  21. Morning peak in the incidence of myocardial infarction: experience in the ISIS-2 trial. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Eur Heart J. 1992; 13(5): 594–598.
  22. Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis. Stroke. 1998; 29(5): 992–996.
  23. Englund A, Behrens S, Wegscheider K, et al. Circadian variation of malignant ventricular arrhythmias in patients with ischemic and nonischemic heart disease after cardioverter defibrillator implantation. European 7219 Jewel Investigators. J Am Coll Cardiol. 1999; 34(5): 1560–1568.
  24. Manfredini R, Boari B, Gallerani M, et al. Chronobiology of rupture and dissection of aortic aneurysms. J Vasc Surg. 2004; 40(2): 382–388.
  25. Franco E, Núñez-Gil IJ, Vivas D, et al. Heart failure and non-ST-segment elevation myocardial infarction: a review for a widespread situation. Eur J Intern Med. 2011; 22(6): 533–540.
  26. 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(24): 1514–1518.
  27. Scheer FA, Michelson AD, Frelinger AL, et al. The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors. PLoS One. 2011; 6(9): e24549.
  28. Mogabgab O, Wiviott SD, Cannon CP, et al. Circadian variation of stent thrombosis and the effect of more robust platelet inhibition: a post hoc analysis of the TRITON-TIMI 38 trial. J Cardiovasc Pharmacol Ther. 2013; 18(6): 555–559.
  29. Perk J. [European Guidelines on Cardiovascular Disease Prevention in Clinical Practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts)]. G Ital Cardiol (Rome). 2013; 14(5): 328–392.
  30. Mancia G. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013; 31(7): 1281–357.
  31. Tykarski A, Narkiewicz K, Gaciong Z, et al. 2015 guidelines for the management of hypertension. Recommendations of the Polish Society of Hypertension - short version. Kardiol Pol. 2015; 73(8): 676–700.
  32. Bonten TN, Snoep JD, Assendelft WJJ, et al. Time-dependent effects of aspirin on blood pressure and morning platelet reactivity: a randomized cross-over trial. Hypertension. 2015; 65(4): 743–750.
  33. Bonten TN, Saris A, van Oostrom MJ, et al. Effect of aspirin intake at bedtime versus on awakening on circadian rhythm of platelet reactivity. A randomised cross-over trial. Thromb Haemost. 2014; 112(6): 1209–1218.
  34. 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; 9(1): 185–191.
  35. Postula M, Janicki PK, Rosiak M, et al. Association of plasma concentrations of salicylic acid and high on ASA platelet reactivity in type 2 diabetes patients. Cardiol J. 2013; 20(2): 170–177.
  36. Perneby C, Wallén NH, Rooney C, et al. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost. 2006; 95(4): 652–658.
  37. 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(7): 1220–1230.
  38. Kriszbacher I, Ajtay Z, Koppán M, et al. Can the time of taking aspirin influence the frequency of cardiovascular events? Am J Cardiol. 2005; 96(4): 608–610.
  39. Cornélissen G, Halberg F, Prikryl P, et al. Prophylactic aspirin treatment: the merits of timing. International Womb-to-Tomb Chronome Study Group. JAMA. 1991; 266(22): 3128–3129.
  40. Kriszbacher, I., M. Koppan, and J. Bodis, Aspirin for stroke prevention taken in the evening? Stroke, 2004. 35(12): p. 2760-1; author reply 2761-2.
  41. Henry P, Vermillet A, Boval B, et al. 24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost. 2011; 105(2): 336–344.
  42. Breet NJ, Sluman MA, van Berkel MA, et al. Effect of gender difference on platelet reactivity. Neth Heart J. 2011; 19(11): 451–457.