A case of resistance to clopidogrel and prasugrel after percutaneous coronary angioplasty

Abstract

Dual antiplatelet therapy (aspirin and clopidogrel) is the standard therapy to prevent stent thrombosis after percutaneous coronary angioplasty. Clopidogrel is a prodrug which requires two-step activation through oxidative metabolism, involving various cytochrome P-450 (CYP) enzymes [1]. Carriers of defective alleles for CYP2C19 (*2) and CYP2C9 (*2, *3) have a reduced antiplatelet effect in response to clopidogrel [2, 3]. In addition, CYP3A4 in vivo activity measured by the erythromycin breath test is significantly correlated with the ability of clopidogrel to inhibit platelet aggregation [4]. Lastly, it has been reported that omeprazole and atorvastatin—which are inhibitors of CYP2C19 and CYP3A4, respectively—can reduce the effect of clopidogrel in man [5, 6]. Thus, there is clinical evidence that the activity of at least three cytochromes determines the effectiveness of clopidogrel in vivo. We report a case of early stent thrombosis associated with clopidogrel resistance in a 60-year-old male patient with effort angina (weight: 87 kg; height: 175 cm). The patient was successfully treated with balloon angioplasty followed by implant of two docetaxel eluting stents. An excellent angiographic result was obtained at the end of the procedure and there were no complications. The patient was then treated with clopidogrel (75 mg q.d.) and aspirin (100 mg q.d.). Three days later he developed chest pain, with ST elevation in all precordial leads and cardiac enzyme elevation (troponin-I: 343,8 ng/ml). Transthoracic echography demonstrated an LVEF of 46% with apical and anteroseptal akinesia, and an ECG showed signs of anterior necrosis. Since the patient was provisionally considered resistant to antiplatelet therapy, the dose of clopidogrel was increased to 75 mg b.i.d. To confirm the clinical suspicion of resistance, we tested residual platelet reactivity by light transmittance aggregometry induced by 1 mM arachidonic acid, and 10 lM ADP to measure the effects of aspirin and clopidogrel, respectively. Aggregation by arachidonic acid was completely blocked, indicating a full response to aspirin; the plasma concentration of salicylic acid measured 3 h after aspirin administration was 0.69 mcg/ml. Conversely, ADP induced residual aggregation of 53% (normal responsivity B30%; resistance: C70%) [7]. To examine the causes of the partial response to clopidogrel, we phenotyped the activities of CYP2C19 and CYP3A4, using omeprazole as probe drug [8, 9]. Three hours after a 20-mg oral dose, the metabolic (MR) ratio log[omeprazole/5OH-omeprazole]— a marker of CYP2C19 activity—was 1.06 (range: -1.25 to 1.75) and the MR log[omeprazole/omeprazole sulphone]— a marker of CYP3A4 activity—was 0.83 (range: -0.47 to 0.95). These results indicate the very low functional activity of two cytochromes involved in clopidogrel activation. To complete screening for thrombosis risk factors, we also genotyped CYP2C19 and CYP2C9, measured the levels of antithrombin III, protein C, protein S, homocysteine and antiphosopholipid antibodies, and checked for the presence of prothrombin G20210A variant and Factor V Leiden mutation. Matching the results of the omeprazole test, the patient was homozygous for slow activity variant M. Silvano V. Pengo M. Napodano Department of Cardiothoracic and Vascular Sciences, University of Padova, Padova, Italy