Drugs & Aging

, Volume 23, Issue 7, pp 559–567 | Cite as

Aspirin Resistance

Possible Roles of Cardiovascular Risk Factors, Previous Disease History, Concomitant Medications and Haemorrheological Variables
  • Gergely Feher
  • Katalin Koltai
  • Elod Papp
  • Balint Alkonyi
  • Alexander Solyom
  • Peter Kenyeres
  • Gabor Kesmarky
  • Laszlo Czopf
  • Kaiman Toth
Original Research Article


Background and objective

Recent studies have described the incidence (approximately one in eight high-risk patients will experience a further atherothrombotic event over a 2-year period) of aspirin (acetylsalicylic acid) resistance and its possible background. The aim of this study was to compare the characteristics (risk profile, previous diseases, medications and haemorrheological variables) of patients in whom aspirin provided effective platelet inhibition with those in whom aspirin was not effective in providing platelet inhibition.


599 patients with chronic cardio- and cerebrovascular diseases (355 men, mean age 64 ±11 years; 244 women, mean age 63 ± 10 years) taking aspirin 100–325 mg/day were included in the study. Blood was collected between 8:00am and 9:00am from these patients after an overnight fast. The cardiovascular risk profiles, history of previous diseases, medication history and haemorrheological parameters of patients who responded to aspirin and those who did not were compared. Platelet and red blood cell (RBC) aggregation were measured by aggregometry, haematocrit by a microhaematocrit centrifuge, and plasma fibrinogen by Clauss’ method. Plasma and whole blood viscosities were measured using a capillary viscosimeter.


Compared with aspirin-resistant patients, patients who demonstrated effective aspirin inhibition had a significantly lower plasma fibrinogen level (3.3 g/L vs 3.8 g/L; p < 0.05) and significantly lower RBC aggregation values (24.3 vs 28.2; p < 0.01). In addition, significantly more patients with effective aspirin inhibition were hypertensive (80% vs 62%; p < 0.05). Patients who had effective platelet aggregation were significantly more likely to be taking β-adrenoceptor antagonists (75% vs 55%; p < 0.05) and ACE inhibitors (70% vs 50%; p < 0.05), whereas patients with ineffective platelet aggregation were significantly more likely to be taking HMG-CoA reducíase inhibitors (statins) [52% vs 38%; p < 0.05]. Use of statins remained an independent predictor of aspirin resistance even after adjustment for risk factors and medication use (odds ratio 5.92; 95% CI 1.83, 16.9; p < 0.001).


The mechanisms underlying aspirin resistance are multifactorial. Higher fibrinogen concentrations increase RBC aggregation and can also result in increased platelet aggregation. The higher rate of hypertension in patients with effective platelet aggregation on aspirin could explain the differences in β-adrenoceptor antagonist and ACE inhibitor use between these patients and aspirin-resistant patients. Furthermore, an additive effect of these drugs may contribute to effective antiplatelet therapy. It is also possible that drug interactions with statins might reduce aspirin bioavailability and/or activity, thereby reducing platelet inhibition in aspirin-resistant patients.


Aspirin Platelet Aggregation Platelet Inhibition Trimetazidine Aggregation Index 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by OTKA (Hungarian National Research Programme) Grant T 047152. The authors have no conflicts of interest that are directly relevant to the contents of this review.


  1. 1.
    Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86CrossRefGoogle Scholar
  2. 2.
    Patrono Coller, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 2001; 119: 39–63CrossRefGoogle Scholar
  3. 3.
    Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345: 1809–17PubMedCrossRefGoogle Scholar
  4. 4.
    Helgason CM, Bolin KM, Hoff JA, et al. Development of aspirin resistance in persons with previous ischaemic stroke. Stroke 1994; 25: 2331–6PubMedCrossRefGoogle Scholar
  5. 5.
    Gum PA, Kottke-Marchant K, Poggio ED, et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001; 88: 230–5PubMedCrossRefGoogle Scholar
  6. 6.
    Grotemeyer KH, Scharafinski HW, Husstedt IW. Two-year follow-up of aspirin responder and aspirin non-responder: a pilot study including 180 post-stroke patients. Thromb Res 1993; 71: 397–403PubMedCrossRefGoogle Scholar
  7. 7.
    Mueller MR, Salat A, Stangl P, et al. Variable platelet response to low-dose aspirin and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost 1997; 78: 1003–7PubMedGoogle Scholar
  8. 8.
    Eikelboom JW, Hirsh J, Weitz JI, et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105: 1650–5PubMedCrossRefGoogle Scholar
  9. 9.
    Gum PA, Kottke-Marchant K, Welsh PA, et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961–5PubMedCrossRefGoogle Scholar
  10. 10.
    Chen WH, Lee PY, Ng W, et al. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol 2004; 43: 1122–6PubMedCrossRefGoogle Scholar
  11. 11.
    Born GVR, Cross M. The aggregation of blood platelets. J Physiol 1963; 168: 178–95PubMedGoogle Scholar
  12. 12.
    Papp E, Havasi V, Bene J, et al. Glycoprotein IIIA gene (PIA) polymorphism and aspirin resistance: is there any correlation? Ann Pharmacother 2005; 39: 1013–8PubMedCrossRefGoogle Scholar
  13. 13.
    Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237–46PubMedCrossRefGoogle Scholar
  14. 14.
    Toth K, Ernst E, Habon T, et al. Hemorheological and hemodynamical effects of fish oil (Ameu) in patients with ischemic heart disease and hyperlipoproteinemia. Clin Hemorheol 1995; 15: 867–75Google Scholar
  15. 15.
    Klose HJ, Volger E, Brechtelsbauer H, et al. Microrheology and light transmission of blood. Pflugers Arch 1972; 333: 126–39PubMedCrossRefGoogle Scholar
  16. 16.
    Toth K, Wenby RB, Meiselman HJ. Inhibition of polymer-induced red blood cell aggregation by poloxamer 188. Biorheology 2000; 37: 301–12PubMedGoogle Scholar
  17. 17.
    Patrono C. Aspirin resistance: definition, mechanisms and clinical read-outs. J Thromb Haemost 2003; 8: 1710–3CrossRefGoogle Scholar
  18. 18.
    Eikelboom JW, Hankey GJ. Aspirin resistance: a new independent predictor of vascular events? J Am Coll Cardiol 2003; 41: 966–8PubMedCrossRefGoogle Scholar
  19. 19.
    Alexy T, Marton Z, Horvath B, et al. Resistance to routine antiplatelet medication and the efficacy of long-term aspirin and thienopyridine therapies [abstract]. 12th World Congress on Heart Disease; 2005 Jul 16–19; Vancouver. J Heart Dis 2005; 4: 130Google Scholar
  20. 20.
    Pertikova M, Jancinova V, Nosal R, et al. Carvedilol: a beta-blocker with considerable antiaggregatory effect on human blood platelets. Bratisl Lek Listy 2005; 106: 20–5Google Scholar
  21. 21.
    Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). Am J Cardiol 1997; 79: 115–9PubMedCrossRefGoogle Scholar
  22. 22.
    Peterson JG, Topol EJ, Sapp SK, et al. Evaluation of the effects of aspirin combined with angiotensin-converting enzyme inhibitors in patients with coronary artery disease. Am J Med 2000; 109: 371–7PubMedCrossRefGoogle Scholar
  23. 23.
    Gibbs CR, Blann AD, Watson RD, et al. Abnormalities of hemorheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm: effects of angiotensin-converting enzyme inhibitor and beta-blocker therapy. Circulation 2001; 103: 1746–51PubMedCrossRefGoogle Scholar
  24. 24.
    Laufs U, Wassmann S, Hilgers S, et al. Rapid effects on vascular function after initiation and withdrawal of atorvastatin in healthy, normocholesterolemic men. Am J Cardiol 2001; 88: 1306–7PubMedCrossRefGoogle Scholar
  25. 25.
    West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOP). Circulation 1998; 97: 1440–5CrossRefGoogle Scholar
  26. 26.
    Puccetti L, Pasqui AL, Auteri A, et al. Mechanisms for antiplatelet action of statins. Curr Drug Targets Cardiovasc Haematol Disord 2005; 5: 121–6PubMedCrossRefGoogle Scholar
  27. 27.
    Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation a new drug-drug interaction. Circulation 2003; 107: 32–7PubMedCrossRefGoogle Scholar
  28. 28.
    Neubauer H, Gunesdogan B, Hanefeld C, et al. Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function: a flow cytometry study. Eur Heart J 2003; 24: 1744–9PubMedCrossRefGoogle Scholar
  29. 29.
    Saw J, Steinhubl SR, Berger PB, et al. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation 2003; 108: 921–4PubMedCrossRefGoogle Scholar
  30. 30.
    Muller I, Besta F, Schulz C, et al. Effects of statins on platelet inhibition by a high loading dose of clopidogrel. Circulation 2003; 108: 2195–7PubMedCrossRefGoogle Scholar
  31. 31.
    Baskurt OK, Levi R, Caglayan S, et al. The role of hemorheologic factors in the coronary circulation. Clin Hemorheol 1991; 11: 121–7Google Scholar
  32. 32.
    Carter C, McGee D, Reed D, et al. Hematocrit and the risk of coronary heart disease: The Honolulu Heart Program. Am Heart J 1983; 105: 674–9PubMedCrossRefGoogle Scholar
  33. 33.
    Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: Insights from the Framingham Study. Am Heart J 1987; 113: 1006–10PubMedCrossRefGoogle Scholar
  34. 34.
    Kesmarky G, Toth K, Habon L, et al. Hemorheological parameters in coronary artery disease. Clin Hemorheol Microcirc 1998; 18: 245–51PubMedGoogle Scholar
  35. 35.
    Ma J, Hennekens CH, Ridker PM, et al. A prospective study of fibrinogen and risk of myocardial infarction in the Physicians’ Health Study. J Am Coll Cardiol 1999; 33: 1347–52PubMedCrossRefGoogle Scholar
  36. 36.
    Sweetnam PM, Thomas HF, Yarnell JWG, et al. Fibrinogen, viscosity and the 10-year incidence of ischemic heart disease: the Caerphilly and Speedwell studies. Eur Heart J 1996; 17: 1814–20PubMedCrossRefGoogle Scholar
  37. 37.
    Yarnell JW, Baker IA, Sweetnam PM, et al. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemie heart disease: the Caerphilly and Speedwell collaborative heart disease studies. Circulation 1991; 83: 836–44PubMedCrossRefGoogle Scholar
  38. 38.
    Woodward M, Lowe GD, Francis LM, CADET Study Investigators, et al. A randomized comparison of the effects of aspirin and clopidogrel on thrombotic risk factors and C-reactive protein following myocardial infarction: the CADET trial. J Thromb Haemost 2004; 2: 1934–40PubMedCrossRefGoogle Scholar
  39. 39.
    Grundmann K, Jaschonek K, Kleine B, et al. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol 2003 Jan; 250(1): 63–6PubMedCrossRefGoogle Scholar
  40. 40.
    Sztriha LK, Sas K, Vecsei L. Aspirin resistance in stroke: 2004. J Neurol Sci 2005; 229–230: 163–9PubMedCrossRefGoogle Scholar
  41. 41.
    Hankey GJ, Eikelboom JW. Aspirin resistance. BMJ 2004; 328: 477–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Gergely Feher
    • 1
  • Katalin Koltai
    • 1
  • Elod Papp
    • 1
  • Balint Alkonyi
    • 1
  • Alexander Solyom
    • 1
  • Peter Kenyeres
    • 1
  • Gabor Kesmarky
    • 1
  • Laszlo Czopf
    • 1
  • Kaiman Toth
    • 1
  1. 1.First Department of Medicine, Medical SchoolUniversity of PecsPecsHungary

Personalised recommendations