Kontrolle der Thrombozytenaggregationshemmung unter Therapie mit Azetylsalizylsäure und/oder Clopidogrel mit einem modifizierten Thrombozytenaggregationstest

Zusammenfassung

Patienten mit Atherothrombose erhalten prophylaktisch ASS und/oder Clopidogrel zur Hemmung der Plättchenaggregation. Es wurde untersucht, ob ein aggregometrisches Verfahren den Effekt aggregationshemmender Substanzen (ASS 30, 50, 100, 300 mg/d, Clopidogrel 75 mg/d oder ASS 100 + Clopidogrel 75 mg/d) abbilden kann. Ein modifizierter Plättchenaggregationstest diente der Bestimmung der maximalen Aggregation nach Induktion mit ADP, Kollagen, Adrenalin und Arachidonsäure. Aus Werten eines gesunden Kollektivs wurden Referenzwerte abgeleitet und ein einfaches System zur Detektion inadäquater Plättchenhemmung entwickelt. Im Vergleich zur Kontrollgruppe zeigte sich eine signifikante Hemmung der maximalen Aggregation mit allen Induktoren bei Patienten unter ASS und der Kombination ASS + Clopidogrel. Bei Patienten unter Clopidogrel fand sich eine Hemmung der Aggregation nach Induktion mit ADP, Kollagen und Arachidonsäure. Unter 100 mg ASS/d trat eine ungenügende Hemmung bei 27%, unter 75 mg Clopidogrel/d bei 26% und unter der Kombinationstherapie bei 7% der Patienten auf. Die Ergebnisse zeigen, dass bei vielen Patienten mit arteriellen Thrombosen eine inadäquate Plättchenhemmung vorliegt.

Summary

Therapy with acetylsalicylic acid (ASA) and/or clopidogrel is used to achieve prophylactic inhibition of platelet aggregation in patients with arterial thrombosis. We examined if aggregometry can be used to see the effect of antiplatelet drugs (ASA 30, 50, 100, 300 mg/d, clopidogrel 75mg/d or ASA 100 + clopidogrel 75 mg/d). A modified platelet aggregation test was used to investigate maximum aggregation in response to ADP, collagen, adrenalin and arachidonic acid. Reference values were established based on healthy individuals. We devised a simple scoring system for detection of inadequate platelet inhibition. Compared with the control group, we detected a significant delay of maximum aggregation in response to all agonists in patients on ASA and combination therapy ASA + clopidogrel. Patients on clopidogrel alone were found to have prolonged aggregation when induced with ADP, collagen and arachidonic acid. The failure rate to achieve adequate platelet inhibition on 100 mg/d ASA, 75 mg/d clopidogrel or combination therapy was 27%, 26% and 7%, respectively. Our results demonstrate that platelet inhibition in aggregometry is inadequate in many patients with arterial thrombosis.

Schlüsselwörter

Thrombozytenaggregationstest - Aggregationshemmung - ASS - Clopidogrel

Keywords

Platelet aggregation test - platelet inhibition - ASA - clopidogrel

• Literatur

• 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. Br Med J 2002; 324: 71-86.
• 2 Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962; 194: 927-929.
• 3 Born GV, Dearnley R, Foulks JG. et al. Quantification of the morphological reactions of platelets to aggregating agents and of its reversal by aggregation inhibitors. J Physiol 1978; 280: 193-212.
• 4 Breddin K, Ziemen M, Bauer O. et al. Time and temperature dependent changes of ADP-and collagen- induced and ‘spontaneous’ aggregation. Thromb Res 1980; 19: 621-638.
• 5 Brunner-La-Rocca HP, Kaiser C, Pfisterer M. Targeted stent use in clinical practice based on evidence from the Basel Stent Cost Effectiveness Trial (BASKET). Eu Heart J. published online on February 13, 2007.
• 6 Buchanan MR, Brister SJ. Individual variation in the effects of ASA on platelet function: implications for the use of ASA clinically. Canadian Journal of Cardiology 1995; 11: 221-227.
• 7 CAPRIE Steering Committee.. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-1339.
• 8 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: 1122-1126.
• 9 Clopidogrel and Metoprolol in Myocardial Infarction Trial. COMMIT/CCS-2. American College of Cardiology 54th Annual Scientific Session in Orlando, Fla. March 9, 2005.
• 10 Diener H, Bogousslavsky J, Brass L. et al. on behalf of the MATCH investigators. Acetylsalicylic acid on a background of clopidogrel in high-risk patients randomised after recent ischaemic stroke or transient ischaemic attack: the MATCH trial results. Lancet 2004; 364: 331-334.
• 11 Eikelboom JW, Hirsh J, Weitz JI. et al. Aspirinresistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105: 1650-1655.
• 12 Gawaz M. Das Blutplättchen: Physiologie, Pathophysiologie, Membranrezeptoren, antithrombozytäre Wirkstoffe und antithrombozytäre Therapie bei koronarer Herzerkrankung. Stuttgart: Thieme; 1999
• 13 Grotemeyer KH, Scharafinski HW, Husstedt IW. Two-year follow-up of aspirin responder and aspirin non responder. A pilot-study including 180 poststroke patients. Thromb Res 1993; 71: 397-403.
• 14 Gum PA, Kottke-Marchant K, Poggio ED. et al. Profile and prevalence of aspirin resistance in patient with cardiovascular disease. The American J Cardiol 2001; 88: 230-235.
• 15 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: 961-965.
• 16 Gurbel PA, Bliden KP, Hiatt BL. et al. Response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908.
• 17 Haubelt H, Simon M, Anders C. et al. Plättchenfunktionstests zum Monitoring der Azetylsalizylsäuretherapie. Hämostaseologie 2004; 24: 196-202.
• 18 Helgason CM, Tortorice KL, Winkler SR. et al. Aspirin response and failure in cerebral infarction. Stroke 1993; 24: 345-350.
• 19 Lau WC, Gurbel PA, Watkins PB. et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004; 109: 166-171.
• 20 Mason PJ, Freedman JE, Jacobs AJ. Aspirin resistance: Current concepts. Rev Cardiovasc Med 2004; 5: 156-163.
• 21 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
• 22 Müller I, Besta F, Schulz C. et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89: 783-787.
• 23 Patrono C, Bachmann F, Baigent C. et al. Expert consensus document on the use of antiplatelet agents – the task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European Society of Cardiology. Eu Heart J 2004; 25: 166-181.
• 24 Pfisterer M, Brunner-la Rocca HP, Buser PT. et al. BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006; 48: 2584-2591.
• 25 Pulcinelli FM, Pignatelli P, Celestini A. et al. Inhibition of platelet aggregation by aspirin progressively decreases in long-term treated patients. J Am Coll Cardiol 2004; 43: 979-984.
• 26 Ridker PM, Cook NR, Lee IM. et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352: 1293-1304.
• 27 Sabatine MS, Cannon CP, Gibson CM. et al. CLARITY- TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
• 28 Schrör K. Antithrombotische Pharmaka. Frechen: Dr. Schrör Verlag; 2002
• 29 Steinhubl SR, Berger PB, Mann JT. et al. CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288: 2411-2420.
• 30 Weber AA, Zimmermann KC, Meyer-Kirchrath J. et al. Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet 1999; 353: 900-1001.
• 31 Yusuf S, Zhao F, Metha SR. et al. for the Clopidogrel in Unstable Angina to prevent Recurrent Events trial (CURE) Investigators. Effects of Clopidogrel in addition to Aspirin in patients with acute coronary syndromes without ST-Segment elevation. N Engl J Med 2001; 345: 494-502.