Platelet Reactivity in Stent Thrombosis Patients (MAPCAT)

• The magnitude of platelet reactivity as measured with several commercial available platelet function tests before and 6 hours after the ingestion of the loading dose. [ Time Frame: platelet reactivity measured at baseline and 6 hours after a 600 mg clopidogrel loading dose. ] [ Designated as safety issue: No ]
• Exploratory Endpoint: prevalence of various genetic polymorphisms that might influence the pharmacokinetics of clopidogrel [ Time Frame: blood obtained for genetic sampeling at timepoint of first study blood collection ] [ Designated as safety issue: No ]

• The magnitude of platelet reactivity as measured with several commercial available platelet function tests before and 6 hours after the ingestion of the loading dose. [ Time Frame: baseline platelet reactivity and 6 hours after a 600 mg clopidogrel loading dose ] [ Designated as safety issue: No ]
• Exploratory Endpoint: prevalence of various genetic polymorphisms that might influence the pharmacokinetics of clopidogrel [ Time Frame: at study entry ] [ Designated as safety issue: No ]

Recent studies have demonstrated a marked interindividual variability of clopidogrel's capacity to inhibit platelet aggregation with a substantial proportion (11-34%) of the patients considered non-responders to clopidogrel treatment. Variable intestinal absorption is suggested to contribute to the inconsistencies in response to clopidogrel. However, little is known about intestinal absorption in subjects who had suffered from a stent thrombosis. The MAPCAT-study has been designed to investigate whether plasma pharmacokinetics (represented by Cmax, Tmax and the AUC) after a 600 mg loading dose are significantly different between subjects who have suffered a stent thrombosis and subjects who have not suffered a stent thrombosis.

Objectives:

The first objective of the MAPCAT-study is to investigate whether plasma pharmacokinetics (Cmax, Tmax and AUC) of an additional 600 mg loading dose are impaired in patients with a history of stent thrombosis.

The second objective of the MAPCAT study is to investigate whether genetic polymorphisms in receptors, enzymes and ligands involved in the process of thrombosis and haemostasis as well in the conversion-process of clopidogrel into its metabolites do have influence on both the absolute magnitude of platelet inhibition and Cmax, Tmax and AUC.

• Active Comparator: stent thrombosis patients
  Patients with a history of a stent thrombosis
  Intervention: Drug: Clopidogrel
• Active Comparator: Patients without a history of a stent thrombosis
  Patients without a history of stent thrombosis
  Intervention: Drug: Clopidogrel

• Elsenberg EH, van Werkum JW, van de Wal RM, Zomer AC, Bouman HJ, Verheugt FW, Berg JM, Hackeng CM. The influence of clinical characteristics, laboratory and inflammatory markers on 'high on-treatment platelet reactivity' as measured with different platelet function tests. Thromb Haemost. 2009 Oct;102(4):719-27.
• Taubert D, Bouman HJ, van Werkum JW. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 May 21;360(21):2249-50; author reply 2251. No abstract available.
• van Werkum JW, Heestermans AA, Zomer AC, Kelder JC, Suttorp MJ, Rensing BJ, Koolen JJ, Brueren BR, Dambrink JH, Hautvast RW, Verheugt FW, ten Berg JM. Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry. J Am Coll Cardiol. 2009 Apr 21;53(16):1399-409.
• Heestermans AA, van Werkum JW, Schömig E, ten Berg JM, Taubert D. Clopidogrel resistance caused by a failure to metabolize clopidogrel into its metabolites. J Thromb Haemost. 2006 May;4(5):1143-5. No abstract available.
• Taubert D, von Beckerath N, Grimberg G, Lazar A, Jung N, Goeser T, Kastrati A, Schömig A, Schömig E. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 2006 Nov;80(5):486-501.
• Bouman HJ, van Werkum JW, Breet NJ, ten Cate H, Hackeng CM, ten Berg JM. A case-control study on platelet reactivity in patients with coronary stent thrombosis. J Thromb Haemost. 2011 May;9(5):909-16.

Inclusion Criteria:

• Patients with a history of a stent thrombosis in the period 2004-2008.

Exclusion Criteria:

• Persistent acute ST-segment elevation
• Successful revascularization during the qualifying hospitalization, prior to study entry
• Acute pulmonary edema, hypotension, or evidence of cardiogenic shock
• Clinically significant liver disease
• End stage kidney disease requiring dialysis
• Use at study entry of drugs that are strong inhibitors of cytochrome P450 3A4 and CYP3A5 (i.e. clarithromycin, erythromycin, itraconazole, ketoconazole)
• Contraindications to antithrombotic/antiplatelet therapy
• Failed coronary intervention in the previous 2 weeks
• Malignancies
• Increased risk of bleeding (previous stroke in the past months, active bleeding or bleeding diathesis, recent trauma or major surgery in the last month, suspected aortic dissection, oral anticoagulation therapy with coumarin derivate within 7 days, recent use of GPIIb/IIIa inhibitors within 14 days, severe uncontrolled hypertension >180 mmHg unresponsive to therapy)
• Relevant hematologic deviations (haemoglobin <100g/L (6,2 mmol/L) or hematocrit <34%, platelet count <100 x 109 /L or platelet count > 600 x 109/L)
• Known allergy to clopidogrel
• Pregnancy (present or suspected)
• uncontrolled hypertension at time of randomization