Thromb Haemost 2012; 107(01): 69-79
DOI: 10.1160/TH11-06-0436
Platelets and Blood Cells
Schattauer GmbH

Dose-dependent effect of early antiplatelet therapy in acute ischaemic stroke

Saskia H. Meves
1   Department of Neurology, St. Josef – Hospital, Ruhr University Bochum, Bochum, Germany
,
Ursula Overbeck
1   Department of Neurology, St. Josef – Hospital, Ruhr University Bochum, Bochum, Germany
,
Heinz G. Endres
2   Department of Medical Informatics, Biometry and Epidemiology, Ruhr University Bochum, Bochum, Germany
,
Christos Krogias
1   Department of Neurology, St. Josef – Hospital, Ruhr University Bochum, Bochum, Germany
,
Horst Neubauer
3   Cardiovascular Center, St. Josef – Hospital, Ruhr University Bochum, Bochum, Germany
› Author Affiliations
Financial support: This study was supported by a grant of the FoRUM program of the Ruhr-University Bochum, Germany (FoRUM, F654R-09).
Further Information

Publication History

Received: 26 June 2011

Accepted after major revision: 14 October 2011

Publication Date:
29 November 2017 (online)

Summary

Antiplatelet agents are essential in treating patients with acute ischaemic stroke (AIS) to prevent recurrent ischaemic events. The aim of this study was to evaluate the effectiveness of early antiplatelet therapy with different aspirin (ASA) dosages in patients with AIS. This observational study included 454 patients with AIS in whom antiplatelet treatment was initiated. The antiplatelet effect was determined by whole blood aggregometry within 48 hours after antplatelet therapy was initiated. An impedance change exceeding 0 Ω after stimulation with arachidonic acid was defined as ASA low response (ALR) and ≥5 Ω in ADP-stimulated specimen as clopidogrel LR. Of the study group 53.5% patients were treated with 200 mg ASA orally, 27.5% with 500 mg ASA intravenously, 8.6% with 100 mg ASA orally, and 7.7% with 75 mg clopidogrel. A dose-dependent antiplatelet effect of ASA treatment was found: 18.4% of patients with 500 mg ASA intravenously were ALR, in contrast to 32.5% on 200 mg and 35.9% on 100 mg ASA orally. Clopidogrel treatment without a loading dose resulted in a high proportion of LR (45.7%). Using the propensity score method revealed a three times higher risk for ALR for patients treated with ASA 200 mg [odds ratio 2.99 (1.55–5.79)] compared to treatment with ASA 500 mg. In conclusion, initiating antiplatelet therapy in patients with AIS resulted in a dose-dependent insufficient platelet inhibitory effect. Our findings suggest using a loading dose of 500 mg ASA intravenously as this seems to be favourable when a sufficient early platelet inhibitory effect is wanted.

ClinicalTrials.gov Identifier: NCT01273935

 
  • References

  • 1 Adams Jr HP, del Zoppo G, Alberts MJ. et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007; 38: 1655-1711.
  • 2 European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee. Guidelines for Management of Ischaemic Stroke and Transient Ischaemic Attack. Cerebrovasc Dis 2008; 25: 457-507.
  • 3 Antithrombotic Trialists' Collaboration. 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.
  • 4 Kuliczkowski W, Witkowski A, Polonski L. et al. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2009; 30: 426-435.
  • 5 Weber AA, Adamzik M, Bachmann HS. et al. Methods to evaluate the pharmacology of oral antiplatelet drugs. Herz 2008; 33: 287-296.
  • 6 Zimmermann N, Hohlfeld T. Clinical implications of aspirin resistance. Thromb Haemost 2008; 100: 379-390.
  • 7 Alberts MJ. Platelet Function Testing for Aspirin Resistance Is Reasonable to Do. Yes! Stroke 2010; 41: 2400-2401.
  • 8 Bath PM. Antiplatelet activity should be measured routinely: no. Stroke 2009; 40: 2273-2274.
  • 9 Krasopoulos G, Brister SJ, Beattie WS. et al. Aspirin „resistance“ and risk of cardiovascular morbidity: systematic review and meta-analysis. Br Med J 2008; 336: 195-198.
  • 10 Alberts MJ, Bergman DL, Molner E. et al. Antiplatelet effect of aspirin in patients with cerebrovascular disease. Stroke 2004; 35: 175-178.
  • 11 Gengo FM, Rainka M, Robson M. et al. Prevalence of platelet nonresponsiveness to aspirin in patients treated for secondary stroke prophylaxis and in patients with recurrent ischemic events. J Clin Pharmacol 2008; 48: 335-343.
  • 12 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.
  • 13 Schwammenthal Y, Tsabari R, Shenkman B. et al. Aspirin responsiveness in acute brain ischaemia: association with stroke severity and clinical outcome. Cerebrovasc Dis 2008; 25: 355-361.
  • 14 Zytkiewicz M, Gielwanowska L, Wojtasinska E. et al. Resistance to acetylsalicylic acid in patients after ischemic stroke. Pol Arch Med Wewn 2008; 118: 727-733.
  • 15 Adams HP, Bendixen BH, Kappelle LJ. et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment Stroke 1993; 24: 35-41.
  • 16 Neubauer H, Lask S, Engelhardt A. et al. How to optimise clopidogrel therapy? Reducing the low-response incidence by aggregometry-guided therapy modification. Thromb Haemost 2008; 99: 357-362.
  • 17 Ivandic BT, Schlick P, Staritz P. et al. Determination of clopidogrel resistance by whole blood platelet aggregometry and inhibitors of the P2Y12 receptor. Clin Chem 2006; 52: 383-388.
  • 18 Ivandic BT, Giannitsis E, Schlick P. et al. Determination of aspirin responsiveness by use of whole blood platelet aggregometry. Clin Chem 2007; 53: 614-619.
  • 19 Lordkipanidzé M, Pharand C, Schampaert E. et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007; 28: 1702-1708.
  • 20 Joffe MM, Rosenbaum PR. Invited commentary: propensity scores. Am J Epidemiol 1999; 150: 327-333.
  • 21 Rubin DB, Thomas N. Matching using estimated propensity scores: relating theory to practice. Biometrics 1996; 52: 249-264.
  • 22 Berger C, Fiorelli M, Steiner T. et al. Hemorrhagic transformation of ischemic brain tissue: asymptomatic or symptomatic?. Stroke 2001; 32: 1330-1335.
  • 23 Stoll G, Kleinschnitz C, Nieswandt B. Combating innate inflammation: a new paradigm for acute treatment of stroke?. Ann NY Acad Sci 2010; 1207: 149-154.
  • 24 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.
  • 25 Elwood PC, Beswick AD, Sharp DS. et al. Whole blood impedance platelet aggregometry and ischemic heart disease. The Caerphilly Collaborative Heart Disease Study. Arteriosclerosis 1990; 10: 1032-1036.
  • 26 Blais N, Pharand C, Lordkipanidzé M. et al. Response to aspirin in healthy individuals. Cross-comparison of light transmission aggregometry, VerifyNow system, platelet count drop, thromboelastography (TEG) and urinary 11-dehydro-thromboxane B(2). Thromb Haemost 2009; 102: 404-411.
  • 27 Talelli P, Greenwood RJ. Recurrent stroke: where do we stand with the secondary prevention of noncardioembolic ischaemic strokes?. Ther Adv Cardiovasc Dis 2008; 02: 387-405.
  • 28 Fong J, Cheng-Ching E, Hussain MS. et al. Predictors of Biochemical Aspirin and Clopidogrel Resistance in Patients With Ischemic Stroke. J Stroke Cerebrovasc Dis 2011; 20: 227-230.
  • 29 McCabe DJ, Harrison P, Mackie IJ. et al. Assessment of the antiplatelet effects of low to medium dose aspirin in the early and late phases after ischaemic stroke and TIA. Platelets 2005; 16: 269-280.
  • 30 Garlichs CD, Kozina S, Fateh-Moghadam S. et al. Upregulation of CD40-CD40 ligand (CD154) in patients with acute cerebral ischemia. Stroke 2003; 34: 1412-1418.
  • 31 Htun P, Fateh-Moghadam S, Tomandl B. et al. Course of platelet activation and platelet-leukocyte interaction in cerebrovascular ischemia. Stroke 2006; 37: 2283-2287.
  • 32 Lukasik M, Rozalski M, Luzak B. et al. Platelet activation and reactivity in the convalescent phase of ischaemic stroke. Thromb Haemost 2010; 103: 644-650.
  • 33 Marquardt L, Ruf A, Mansmann U. et al. Course of platelet activation markers after ischemic stroke. Stroke 2002; 33: 2570-2574.
  • 34 Fateh-Moghadam S, Htun P, Tomandl B. et al. Hyperresponsiveness of platelets in ischemic stroke. Thromb Haemost 2007; 97: 974-978.
  • 35 McCabe DJ, Harrison P, Sidhu PS. et al. Circulating reticulated platelets in the early and late phases after ischaemic stroke and transient ischaemic attack. Br J Haematol 2004; 126: 861-869.
  • 36 Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet 2006; 367: 606-617.
  • 37 Wallén NH, Held C, Rehnqvist N. et al. Effects of mental and physical stress on platelet function in patients with stable angina pectoris and healthy controls. Eur Heart J 1997; 18: 807-815.
  • 38 Hohlfeld T, Weber AA, Junghans U. et al. Variable platelet response to aspirin in patients with ischemic stroke. Cerebrovasc Dis 2007; 24: 43-50.
  • 39 Chen ZM, Sandercock P, Pan HC. et al. Indications for early aspirin use in acute ischemic stroke: A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000; 31: 1240-1249.
  • 40 Rothwell PM, Giles MF, Chandratheva A. et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison. Lancet 2007; 370: 1432-1442.
  • 41 Hovens MM, Snoep JD, Eikenboom JC. et al. Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review. Am Heart J 2007; 153: 175-181.
  • 42 Perneby C, Wallén NH, Rooney C. et al. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost 2006; 95: 652-658.
  • 43 Aarons L, Hopkins K, Rowland M. et al. Route of administration and sex differences in the pharmacokinetics of aspirin, administered as its lysine salt. Pharm Res 1989; 06: 660-666.
  • 44 Meves SH, Neubauer H, Overbeck U. et al. Is there an ideal way to initiate antiplatelet therapy with aspirin? A crossover study on healthy volunteers evaluating different dosing schemes with whole blood aggregometry. BMC Res Notes 2011; 04: 106.
  • 45 Bach J, Kammerer I, Isgro F. et al. The impact of intravenous aspirin administration on platelet aspirin resistance after on-pump coronary artery bypass surgery. Platelets 2009; 20: 150-157.
  • 46 Fuchs I, Spiel AO, Frossard M. et al. Platelet hyperfunction is decreased by additional aspirin loading in patients presenting with myocardial infarction on daily aspirin therapy. Crit Care Med 2010; 38: 1423-1429.
  • 47 Amann R, Peskar BA. Anti-inflammatory effects of aspirin and sodium salicylate. Eur J Pharmacol 2002; 447: 1-9.
  • 48 Zheng Z, Schwab S, Grau A. et al. Neuroprotection by early and delayed treatment of acute stroke with high dose aspirin. Brain Res 2007; 1186: 275-280.
  • 49 England TJ, Bath PM, Sare GM. et al. Asymptomatic hemorrhagic transformation of infarction and its relationship with functional outcome and stroke subtype: assessment from the Tinzaparin in Acute Ischaemic Stroke Trial. Stroke 2010; 41: 2834-2839.
  • 50 Büttner T, Hellwig K, Müller T. et al. Intravenously administered acetylsalicylic acid in combination with low-dose heparin in acute ischemic stroke: a safety analysis. Clin Neuropharmacol 1998; 21: 48-51.
  • 51 MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 2003; 361: 573-574.
  • 52 Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited. Lancet 2009; 373: 155-166.
  • 53 Bates ER, Lau WC, Bleske BE. Loading, pretreatment, and interindividual variability issues with clopidogrel dosing. Circulation 2005; 111: 2557-2559.
  • 54 Meyer DM, Albright KC, Allison TA. et al. LOAD: a pilot study of the safety of loading of aspirin and clopidogrel in acute ischemic stroke and transient ischemic attack. J Stroke Cerebrovasc Dis 2008; 17: 26-29.
  • 55 Kennedy J, Hill MD, Ryckborst KJ. et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol 2007; 06: 961-969.
  • 56 Lordkipanidzé M.. Why an aspirin a day no longer keeps the doctor away …. Thromb Haemost 2011; 105: 209-210.