a b s t r a c t

Stent thrombosis is a morbid complication after percutaneous coronary intervention. Dual Antiplatelet therapy significantly reduces stent thrombosis risk and forms currently the basis in acute ST elevation myocardial infarction pharmacologic treatment. The introduction of clopidogrel has made a major advance in the acute coronary syndrome treatment. However, there is growing evidence about failure in antiplatelet response after clopidogrel, which may lead to subsequent risk of future thrombotic events. The antiplatelet inhibitory effect of clopidogrel varies widely among individuals. High on-treatment platelet reactivity has been repeatedly associated with a hazard for cardiovascular events, including stent thrombosis. Laboratory monitoring of antiplatelet therapy efficacy may help identify patients with insufficient antiplatelet response. Prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance. We report a case of diabetic patient in whom myocardial reinfarction due to stent thrombosis developed. Clopidogrel resistance was detected in this patient using light transmission aggregometry and vasodilator- stimulated phosphoprotein phosphorylation assessment. After prasugrel administration, no other ischemic event occurred, and patient was released to outpatient care in good general condition.

(C) 2014

Introduction

Dual antiplatelet therapy containing aspirin and P2Y₁₂ adenosine diphosphate (ADP) receptor antagonist forms currently the basis in acute ST-elevation myocardial infarction pharmacologic treatment. The introduction of P2Y₁₂ ADP receptor antagonists has made a major advance in the acute coronary syndrome (ACS) treatment [1]. Stent thrombosis is a morbid complication after percutaneous coronary intervention (PCI). It is more frequently encountered in acute coronary syndrome patients and in patients with diabetes mellitus , bifurcation stents, or in those who discontinue prematurely dual antiplatelet therapy [2-4].

? This study was supported by project APVV (Slovak research and development Agency) 0222-11, by project CEPV II [IT Monitoring System for Structural funds and Cohesion Fund (ITMS) 26220120036], which is cofinanced from European Commission (EC) sources and by research project of Slovak Society of Cardiology 2012-2015 and by Young Heart Science organization.

?? Conflict of interest: The authors have no conflict of interest to declare.

* Corresponding author. Department of Internal Medicine I Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Kollarova 2, 036 59 Martin, Slovak Republic. Tel.: +421 907 612 943, +421 43 4203 820.

E-mail address: [email protected] (M. Samos).

Dual antiplatelet therapy significantly reduces stent thrombosis risk. Nevertheless, there is a wide variability in pharmacodynamic response to clopidogrel administration, which is linked to several factors, including genotype polymorphisms [5]. Nowadays, there is growing amount of data about failure in antiplatelet response after clopidogrel administration, which is specifically associated with insulin resistance and DM [6,7]. This incomplete antiplatelet response may contribute to a worse prognosis of acute myocardial infarction in patients with DM. High platelet reactivity after clopidogrel adminis- tration is associated with increased risk of stent thrombosis and other Ischemic events [8,9]. High variability in antiplatelet response to clopidogrel administration points to the suitability of laboratory monitoring of antiplatelet therapy efficacy in patients with ACS. Laboratory monitoring of antiplatelet therapy by ex vivo Platelet function tests may help identify individuals with poor antiplatelet response [10]. High platelet reactivity after clopidogrel administration represents also major reason for introduction of new P2Y₁₂ ADP receptor antagonists with more favorable pharmacodynamic profile to clinical practice [11]. Prasugrel, a new P2Y₁₂ ADP receptor antagonist, provides more consistent inhibition of P2Y₁₂ ADP receptor and has lower intraindividual variability in efficacy compared with clopidogrel. Benefit of prasugrel therapy seems to be the highest in

0735-6757/$ – see front matter (C) 2014 http://dx.doi.org/10.1016/j.ajem.2014.01.006

patients with DM [12]. Prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance [13,14].

We report a case of diabetic patient admitted for acute anterior STEMI, in whom myocardial reinfarction due to stent thrombosis occurred. Clopidogrel resistance using light transmission aggregome- try (LTA) with specific inducer (10 umol/L ADP) and vasodilator- stimulated phosphoprotein (VASP) phosphorylation assessment was consequently identified in this patient. After prasugrel administration, no other ischemic event occurred, and patient was in a good general condition released to outpatient care.

Case report

Eighty-two-year-old patient with Arterial hypertension, type 2 DM in stage of organ complications (diabetic macroangiopathy), treated by oral antidiabetic agents, was admitted to internal department with a diagnosis of acute anterior STEMI to realize urgent coronary angiography. In the prehospital phase, the patient was treated with loading dose of aspirin 400 mg and clopidogrel 600 mg along with 5000 IU of unfractionated heparin intravenously. Urgent coronary angiography revealed acute subocclusion of left anterior descending coronary artery , which was subsequently treated with Primary percutaneous coronary intervention with bare metal stent (BMS) implantation with good angiographic effect (Fig. 1).

On the second day of hospitalization, a strong rest chest pain appeared in patient. Twelve lead electrocardiogram (ECG) previewed ST-segment elevation suggestive of acute re-STEMI of anterior wall (Fig. 2). The patient had been consequently treated with antagonists of glycoprotein IIb/IIIa receptor, and immediately, another urgent coronary angiography was performed. Second coronary angiography found the acute closure of LAD as a result of acute stent thrombosis. Acute closure was being subsequently treated with catheter throm- bextraction and with implantation of 2 BMS. (Fig. 3). Because of suspected clopidogrel resistance, antiplatelet treatment with prasu- grel was initiated/loading dose of 60 mg followed by a 10 mg/daily maintenance dose.

Examination of the antiplatelet therapy efficacy using LTA with specific inducer and measurement of VASP protein phosphorylation in a blood sample taken before the first coronary angiography (1.5 hours after clopidogrel loading dose administration) revealed the patient’s insufficient antiplatelet response to clopidogrel-platelet aggregation after the induction with 10 umol/L ADP 84% (reference value b 50%), the phosphorylation of VASP protein 81% (reference value b 50%). Similarly, second examination of antiplatelet therapy efficacy, from the sample taken 1 hour after administration of first clopidogrel maintenance dose (20.3 hours after clopidogrel loading dose admin-

istration) and approximately 1 hour before acute re-STEMI develop- ment, measured using VASP phosphorylation assessment confirmed patient’s insufficient antiplatelet response to clopidogrel-VASP phos- phorylation rate 57% (reference value b 50%).

After initiation of prasugrel antiplatelet therapy, no further ischemic events during the course of hospitalization developed, and patient was finally hemodynamically stable and in a good overall condition released to outpatient care. Laboratory examination showed good antiplatelet response on prasugrel-VASP phosphoryla- tion rate 26%, LTA after the induction with 10 umol/L ADP 22% (reference value b 50%). Echocardiography revealed a reduced left ventricular systolic function, with an akinesia of anterior and lateral wall, left ventricular ejection fraction was approximately 30%. Despite the patient’s high age (which is a relative contraindication for prasugrel treatment), prasugrel therapy was well tolerated, and no bleeding was seen during hospitalization and next 6-month of follow-up.

Discussion

Stent thrombosis is a morbid complication after PCI. It is more frequently encountered in patients with ACS and DM, bifurcation stents, or in those who discontinue prematurely dual antiplatelet therapy [2-4]. Dual antiplatelet therapy significantly reduces stent thrombosis risk and forms currently the basis in acute STEMI pharmacologic treatment. The intervention of several complementary ways of platelet activation and aggregation is necessary to ensure effective treatment and prevention of Coronary thrombosis. The introduction of P2Y₁₂ ADP receptor antagonists has made a major advance in the ACS treatment. Thienopyridine clopidogrel given in the Clopidogrel in Unstable Angina to Prevent Recurrent Events study in patients with ACS significantly reduced the incidence of cardiac death and nonfatal myocardial infarction or stroke compared with patients treated with aspirin alone [1]. A 600 mg clopidogrel loading dose leads to a faster onset of action and has a greater platelet inhibitory effect than a loading dose of 300 mg [15,16]. Although several large clinical trials have demonstrated the efficacy of clopidogrel in the treatment of ACS, there is growing amount of data about failure in antiplatelet response after clopidogrel administration [6,7]. Variability of anti- platelet response (antiplatelet therapy resistance) may lead to antiplatelet therapy insufficient efficacy and subsequent Risk of thrombotic events. The antiplatelet inhibitory effect of the thienopyr- idine clopidogrel varies widely among individuals. This wide variabil- ity in pharmacodynamic response to clopidogrel administration is linked to several factors, including genotype polymorphisms [5]. High on-treatment platelet reactivity has been associated with a substantial

Fig. 1. Urgent coronary angiography in patient with acute STEMI showing an acute subocclusion of LAD and angiography after pPCI on LAD with implantation of BMS.

Fig. 2. Twelve lead ECG record with ST-segment elevation suggestive of acute re-STEMI of anterior wall.

hazard for post-PCI cardiovascular events, including stent thrombosis [8,9,17]. Laboratory monitoring of antiplatelet therapy efficacy using ex vivo platelet function tests may help identify patients with insufficient antiplatelet response. High platelet reactivity after clopidogrel administration represents also major reason for introduc- tion of new P2Y₁₂ ADP receptor antagonists with more favorable pharmacodynamic profile to clinical practice [11].

High on-treatment platelet reactivity after clopidogrel is also responsible for stent thrombosis in presented case with high probability. Our patient showed insufficient antiplatelet response after clopidogrel loading dose (600 mg) administration as well as when platelet reactivity after the administration of maintenance dose was measured. Intravascular ultrasound (IVUS) examination was not performed to exclude stent malposition in our case. In case of using

IVUS during second urgent coronary angiography in patient with acute STEMI, the “needle-to-balloon” time would be extended. Examining physician therefore decided not to perform IVUS exami- nation in second coronary angiography to reduce the duration of therapeutic procedure. Although IVUS was not performed, good angiographic effect seen after first stent implantation (see Fig. 1) makes stent malposition in this patient improbable. No thrombotic events occurred in our patient on prasugrel therapy, and patient might be released in good overall condition to outpatient care. This fact also supports the failure in antiplatelet response on clopidogrel as a factor leading to stent thrombosis.

The mechanism of clopidogrel resistance in our patient remains unclear. A short time interval from drug administration until blood sample examination is not probable, clopidogrel antiplatelet

Fig. 3. Urgent coronary angiography in patient with acute re-STEMI of anterior wall showing an acute stent thrombosis of LAD and angiography after repeated pPCI on LAD with catheter thromboextraction and implantation of 2 BMS.

response was not sufficient even in sample taken next day after clopidogrel loading dose administration. Variability in Cytochrome P450 2C9 and 3A4 activity may also affect the rapidity of thienopyridine antagonist antiplatelet activity onset [18,19]; how- ever, pharmacokinetic interactions at this level are not probable in our patient. Simultaneous treatment with strong inducers or strong inhibitors of cytochrome P450 enzyme complex was not adminis- trated in this patient. Cytochrome P 450 polymorphisms testing were not performed in our patient because of technical matter, and therefore the impact of low-inherited activity of CYP P450 on insufficient antiplatelet response cannot be completely excluded. Abnormal metabolism of antiplatelet drugs due to genetically reduced activity of CYP P 450 2C19 and 3A4 complex was previously verified in a rare case of resistance to both clopidogrel and prasugrel in patient with acute STEMI due to stent thrombosis [20]. Recently, there is also growing number of data reporting a failure in antiplatelet response after clopidogrel administration, which is specifically associated with insulin resistance and DM [6,7]. Several recently published studies showed worse clinical outcome and an increased incidence of stent thrombosis in patients with DM [2,21,22]. diabetic patients treated with clopidogrel have signifi- cantly higher platelet aggregation after ADP stimulation compared with nondiabetic subjects, and significantly higher number of nonresponders to clopidogrel administration can be also seen in the group of diabetic patients [22]. Patients with DM have lower clinical effect from clopidogrel treatment, which was being consistently referred in results of several published randomized trials with clopidogrel [1,23,24]. The mechanism of clopidogrel resistance in patients with DM remains unexplained. Erlinge et al

[7] showed a significantly higher incidence of insufficient antiplate-

let response in group of diabetic patients treated with clopidogrel. It is interesting that, in this trial, platelets of diabetic patients with inadequate antiplatelet response after clopidogrel administration responded well to ex vivo administration of clopidogrel active metabolite. This finding indicates a low level of resistance on P2Y₁₂ ADP platelet receptor and supports potential interaction between DM and pharmacokinetic processes of clopidogrel metabolism. Our case of stent thrombosis developed in patient with long-term duration of type 2 DM with organ complications. The interac- tion of DM and stress hyperglycemia with pharmacokinetic processes of clopidogrel metabolism in our patient can not be completely excluded as well, and DM may present a potential risk factor for stent thrombosis due to insufficient antiplatelet response after clopidogrel.

Prasugrel, a new, potent, irreversible tienopyridine P2Y₁₂ ADP receptor antagonist, provides faster and more consistent inhibition of platelet function compared with clopidogrel [12]. Although several cases pointing on insufficient antiplatelet response after prasugrel had been previously reported [20,25], prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance [13,14]. In our patient, prasugrel treatment achieved good antiplatelet response (measured by VASP phosphor- ylation assessment and LTA), and no ischemic events developed on prasugrel therapy. According to our case, it looks that prasugrel treatment may be safe also in borderline patients (low-weight or high-age patients) when appropriate clinical supervision is assigned. Despite the patient’s high age (which is a relative contraindication for prasugrel treatment), prasugrel therapy was well tolerated, and no Bleeding complications were seen during hospitalization and also during the next 6-month of follow-up.

Conclusion

Presented patient case shows that stent thrombosis due to clopidogrel resistance may represent an important problem in clinical

practice. Laboratory monitoring of antiplatelet therapy can help identify patients with insufficient antiplatelet response. Routine laboratory monitoring of antiplatelet treatment in selected patients (eg, patients with acute STEMI) therefore deserves consideration. Patients with insufficient response after clopidogrel may benefit from new P2Y₁₂ ADP receptor antagonists treatment. Our case suggests that prasugrel therapy may be safe also in borderline and DM patients, if appropriate clinical supervision is assigned.

Acknowledgments

We thank Mrs E. Venenyova, MSc, RN and Mrs B. Tvarozna, RN for blood samples taking and Mrs M. Mandova for VASP phosphory- lation assessment.

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