Abstract
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.
Methods
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.
Results
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).
Conclusions
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.
Similar content being viewed by others
References
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: 71–86
Patrono Coller, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 2001; 119: 39–63
Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345: 1809–17
Helgason CM, Bolin KM, Hoff JA, et al. Development of aspirin resistance in persons with previous ischaemic stroke. Stroke 1994; 25: 2331–6
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: 230–5
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: 397–403
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: 1003–7
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: 1650–5
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: 961–5
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: 1122–6
Born GVR, Cross M. The aggregation of blood platelets. J Physiol 1963; 168: 178–95
Papp E, Havasi V, Bene J, et al. Glycoprotein IIIA gene (PIA) polymorphism and aspirin resistance: is there any correlation? Ann Pharmacother 2005; 39: 1013–8
Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237–46
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: 867–75
Klose HJ, Volger E, Brechtelsbauer H, et al. Microrheology and light transmission of blood. Pflugers Arch 1972; 333: 126–39
Toth K, Wenby RB, Meiselman HJ. Inhibition of polymer-induced red blood cell aggregation by poloxamer 188. Biorheology 2000; 37: 301–12
Patrono C. Aspirin resistance: definition, mechanisms and clinical read-outs. J Thromb Haemost 2003; 8: 1710–3
Eikelboom JW, Hankey GJ. Aspirin resistance: a new independent predictor of vascular events? J Am Coll Cardiol 2003; 41: 966–8
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: 130
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: 20–5
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: 115–9
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: 371–7
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: 1746–51
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: 1306–7
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: 1440–5
Puccetti L, Pasqui AL, Auteri A, et al. Mechanisms for antiplatelet action of statins. Curr Drug Targets Cardiovasc Haematol Disord 2005; 5: 121–6
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: 32–7
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: 1744–9
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: 921–4
Muller I, Besta F, Schulz C, et al. Effects of statins on platelet inhibition by a high loading dose of clopidogrel. Circulation 2003; 108: 2195–7
Baskurt OK, Levi R, Caglayan S, et al. The role of hemorheologic factors in the coronary circulation. Clin Hemorheol 1991; 11: 121–7
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: 674–9
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: 1006–10
Kesmarky G, Toth K, Habon L, et al. Hemorheological parameters in coronary artery disease. Clin Hemorheol Microcirc 1998; 18: 245–51
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: 1347–52
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: 1814–20
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: 836–44
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: 1934–40
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): 63–6
Sztriha LK, Sas K, Vecsei L. Aspirin resistance in stroke: 2004. J Neurol Sci 2005; 229–230: 163–9
Hankey GJ, Eikelboom JW. Aspirin resistance. BMJ 2004; 328: 477–9
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Feher, G., Koltai, K., Papp, E. et al. Aspirin Resistance. Drugs Aging 23, 559–567 (2006). https://doi.org/10.2165/00002512-200623070-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002512-200623070-00002