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Drug-Specific Thienopyridine Resistance in Patient with Recurrent Coronary Stent Thrombosis
From the Department for Cardiovascular Diseases, Zagreb University Hospital Centre, Zagreb, Croatia. The authors report no conflicts of interest regarding the content herein. Manuscript submitted January 5, 2009, provisional acceptance given May 19, 2009, final version accepted May 28, 2009. Address for correspondence: Daniel Lovric, MD, Department for Cardiovascular Diseases, Zagreb University Hospital Centre, Kispaticeva 12, Zagreb; 10000, Croatia. E-mail: daniel.lovric@mac.com
_______________________________________________ ABSTRACT: A 56-year-old male was admitted for elective percutaneous coronary intervention. Four days later he developed subacute stent thrombosis in the proximal stent in his right coronary artery. Using the Multiplate® ASPI and ADP test, we detected combined aspirin and clopidogrel resistance. The doses of aspirin and clopidogrel were increased to 300 mg and 150 mg, respectively. This resulted with optimization of aspirin response, but clopidogrel resistance was dose-independent. Three days later, the patient developed a new episode of ST-elevation myocardial infarction due to recurrent subacute thrombosis in the proximal stent. Consequently, clopidogrel was switched to ticlopidine 250 mg twice daily with resultant optimal platelet inhibition in the ADP test and the patient became clinically stable. This case indicates the clinical benefit from routine assessment of platelet responsiveness to antiaggregation therapy in patients with stent thrombosis. Also, clopidogrel resistance is drug-specific and not necessarily a class-effect phenomenon. By modifying drugs’ doses, type of thienopyridine, or both, we can optimize antiplatelet therapy and the clinical course. Key words: Platelet function, acute MI, anticoagulation, stenting, complications
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J INVASIVE CARDIOL 2009;21:e157–e160 Stents serve as a mechanical support for dilated lesions, thus reducing the incidence of restenosis.1 However, a stent’s structure and local endothelial damage that results from its deployment are associated with thrombosis. The combination of aspirin and thienopyridine in the periprocedural period and in the months following stent implantation has strikingly reduced the risk of stent thrombosis. Because of its faster onset of action and improved safety profile, clopidogrel (second generation of thienopyridine) has replaced ticlopidine. Acute and subacute stent thrombosis are defined as angiographically confirmed in-stent thrombosis occurring within 24 hours or up to 30 days, respectively, following percutaneous coronary intervention (PCI). Subacute stent thrombosis (SAT) occurs in ~1% of patients with coronary bare-metal stents,2 with a 20–25% mortality rate.3 Thrombotic risk depends on multiple factors such as the structure of stent (material and strut thickness), complexity of lesion (small vessels and long lesions), procedural complication (hypoexpansion and residual dissection), as well as the thrombogeneity of blood (resistance to antiplatelet drugs, acute coronary syndromes, diabetes mellitus).4–8 Poor response to antiplatelet drugs has been proven to represent a high risk of SAT.7,9 Resistance to clopidogrel was reported to be drug-specific and not a class-associated characteristic, and switching to ticlopidine can be helpful in achieveing adequate platelet inhibition in the majority of patients.10 Case Presentation. A 56 year-old male with a history of anterior infarction and formation of ventricular aneurysm presented to our center with symptoms of Canadian Cardiovascular Society (CCS) Class IV angina pectoris. Coronary angiography revealed a chronic total occlusion of the proximal left anterior descending artery (LAD) and significant stenoses of the mid-right coronary artery (RCA) and its posterolateral branch (PLB) (Figure 1). He was taking 100 mg aspirin and 75 mg clopidogrel once daily. After direct stenting of the PLB stenosis, a small dissection at the proximal end of the stent appeared and we decided to cover it with another stent. However, the patient suddenly went into cardiopulmonary arrest. The control angiogram showed acute thrombosis of the PLB (Figure 2). An intracoronary bolus of eptifibatide was administered and we began cardiopulmonary resuscitation (CPR) including implantation of a temporary pacemaker and intra-aortic balloon pump counterpulsation. After successful CPR we proceeded with PCI on the PLB and mid-RCA with a final optimal result (Figure 3). Intravenous (IV) infusion of eptifibatide was continued throughout the next 24 hours. The patient was mobilized on the fourth day after PCI. However, he suddenly developed severe chest pain that was accompanied by ST-elevation in the electrocardiogram’s inferior leads and cardiogenic shock. Coronary angiography showed SAT in the proximal stent of the RCA (Figure 4). After recanalization of the artery with implantation of 2 additional stents, the patient recovered (Figure 5). Again, the patient received continuous IV infusion of eptifibatide over the next 24 hours. Additionally, we performed a platelet aggregation study using the Multiplate® ASPI test (Dynabyte GmbH, Munich Germany) for evaluation of aspirin response and the ADP test for evaluation of clopidogrel response. The Multiplate whole blood impedance platelet aggregometry is a fast, standardized method that is comparable to the classic “gold standard”, i.e., light transmission aggregometry (LTA), as well as PFA-100® (Siemens).11–13 Sibbing et al showed a significant correlation for ADP-induced platelet aggregation when using the classic LTA or the Multiplate ADP test in 149 patients who received a single 600 mg dose of clopidogrel.12 LTA and Multiplate ASPI and ADP tests also exhibited similar accuracy in detecting aspirin and clopidogrel effects.13 There was significant dual antithrombotic hyporesponsiveness (ASPI-test = 82.5 U; cut-off value for hyporesponsiveness in our population is 31 U; ADP test = 87.4 U; cut-off value for our population is 77 U). We increased daily doses of aspirin and clopidogrel to 300 mg and 150 mg, respectively. While the aspirin response optimized (ASPI test = 24.1 U), the response to clopidogrel was still unfavorable (ADP test = 78.9 U). Three days later the patient developed another reinfarction accompanied by cardiogenic shock. Recurrent SAT in the proximal stent was evident (Figure 6), and we again successfully recanalized the artery (Figure 7). We decided to switch from clopidogrel to ticlopidine (250 mg twice daily), which resulted in optimal platelet inhibition according to the ADP test (49.4 U). During the rest of his stay the patient remained clinically stable, with no further adverse coronary events. Discussion. The combination of aspirin and thienopyridine in the periprocedural period has markedly reduced the risk of stent thrombosis. Because of its faster onset of action and improved safety profile, clopidogrel (second generation of thienopyridine) has replaced ticlopidine. SAT occurs in ~1% of patients after stent implantation, often with catastrophic clinical consequences.2 The incidence of resistance to aspirin and/or clopidogrel is observed more frequently than SAT.14 Nevertheless, poor response to antiplatelet drugs represents a risk factor for adverse coronary events, including SAT.7,9 The resistance to clopidogrel is generally drug-specific and not a class-associated characteristic, and switching to ticlopidine can lead to adequate ADP-mediated platelet inhibition in the majority of patients.10 There is no clear explanation for this observation, but we believe it may be related to complex thienopyridines’ metabolism. Both ticlopidine and clopidogrel are activated in vivo through complex system of cytochrome P450 (CYP)-mediated oxidation. These prodrugs have a different affinity to certain CYP isoforms, a fact that can result in unequal production of the active substance and in varying antiplatelet efficacy, depending on the individual CYP’s metabolism.15 It is optimal to exclude possible mechanical causes of stent thrombosis. In our case IVUS was not performed because the system was unfortunately not functioning at the time. However, the focus of this article was not the general problem of stent thrombosis, but how to deal with the issue of suboptimal antiaggregation in this setting. Because of the catastrophic nature of stent thrombosis, our opinion is that the assessment of platelet inhibition in this circumstance is advisable and that patients can benefit from subsequent alteration of the standard antiplatelet approach. In our patient it is notable that the recurrence of stent thrombosis did not stop until platelet inhibition was optimized by modifying the patient’s antiaggregation treatment. Bedside methods like the Multiplate system can provide such information within minutes. In patients with suboptimal platelet inhibition, potentially reversible causes such as noncompliance with daily therapy or drug interactions (NSAIDs like ibuprofen and naproxen with aspirin, or CYP3A4-metabolized statins or proton-pump inhibitors with clopidogrel) should be eliminated. Secondly, dosing of aspirin and/or clopidogrel should be increased (aspirin to 300 mg once daily and clopidogrel 75 mg twice daily). However, if clopidogrel hyporesponsiveness is dose-independent, as in our case, an alternative thienopyridine, i.e., ticlopidine should be used (250 mg twice daily). If this fails, the addition of warfarin should be considered. Prasugrel, a third-generation thienopyridine, with a stronger antiplatelet response and less interindividual variability compared to standard doses of clopidogrel, will soon become a superior alternative to clopidogrel.16
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