Subacute Stent Thrombosis Owing to Complete Clopidogrel Resistance Successfully Managed with Prasugrel


Michael P. Flaherty, MD, PhD, Peter V. Johnston, MD*, Jeffrey J. Rade, MD*

ABSTRACT: This report describes a case of an acute anterior myocardial infarction secondary to subacute stent thrombosis of a drug-eluting stent within the proximal segment of the left anterior descending artery (LAD) 5 days after percutaneous transluminal coronary angioplasty and stenting (PCI). The patient was initially managed with conventional dual-antiplatelet therapy (aspirin and clopidogrel) and was subsequently found to have complete absence of adenosine diphosphate (ADP) receptor P2Y12 receptor inhibition. Following additional PCI of the LAD and substitution of clopidogrel for the thienopyridine prasugrel, therapeutic platelet inhibition was achieved without recurrence of stent thrombosis.

J INVASIVE CARDIOL 2011;23:300–304


The act of performing high-pressure balloon inflations and the advent of peri-procedural dual-antiplatelet therapy [aspirin plus a member of the thienopyridine class of adenosine diphosphate (ADP) receptor P2Y12 inhibitors (ticlopidine, clopidogrel)] has significantly reduced the risk of developing an acute myocardial infarction (MI) due to early or late thrombotic occlusion of a stented coronary artery segment (stent thrombosis; ST). Nevertheless, ST still occurs in 0.6–1.3% of elective cases and in up to 6% of patients with acute coronary syndromes, and thus remains the primary cause of death after percutaneous coronary interventions (PCI) despite the judicious use of antiplatelet therapy.1,2 Although ST can occur acutely in the catheterization lab, most instances of ST are seen in the early (subacute phase occurring from procedure end through 30-day follow-up; 0.6%) and late days following PCI (occurring greater than 30 days; 0.06–0.5%).3,4 Mechanistically, acute and subacute ST are most attributable to lesion-specific and procedural issues, such as residual dissection, stent malapposition/underexpansion, impaired vessel in/out-flow, the use of long stents and stenting of small vessels (< 3.0 mm). In the absence of these features, the primary factor contributing to subacute coronary atherothrombotic events is premature cessation of dual-antiplatelet therapy, namely clopidogrel and/or aspirin,1,4 or more rarely, an intrinsic relative “resistance” to one or both of these agents.5 Although there is no current consensus as to what percentage of patients undergoing PCI inadequately responds to aspirin or clopidogrel (so-called poor- or non-responders), the literature is replete with reports detailing a significantly heightened risk for subacute ST in these patients — presumably a consequence of high residual platelet reactivity.5 Recently, prasugrel, a third-generation thienopyridine, has become available and has shown superior efficacy when compared to clopidogrel, owing to a more rapid onset and greater inhibition of P2Y12 receptor-mediated platelet aggregation.6 Here, we present an unusual case of subacute ST 5 days after coronary artery stenting with laboratory confirmation of complete resistance to clopidogrel therapy. 

Case Report

A 45-year-old South Asian male presented initially with unstable angina and underwent PCI of his proximal left anterior descending artery (LAD) (Figure 1A). Briefly, a 0.014˝ Asahi Prowater guidewire (Abbott Vascular, Abbott Park, Illinois) was placed across the LAD lesion into the distal LAD. Using a 20 MHz Eagle Eye Gold intravascular ultrasound (IVUS) imaging system (Volcano Corporation, San Diego, California), the reference vessel diameter was estimated at approximately 3.8 mm proximally and 4.3 mm distally; a notable post-stenotic dilatation can be seen within the diseased segment (Figure 1A). Angioplasty was then performed with a 3.5 mm x 15 mm Voyager balloon (Abbott Vascular) inflated to 15 atm, followed by deployment of a 3.5 mm x 23 mm Xience drug-eluting stent (Abbott Vascular). Finally, the stent was post-dilated with 4.0 and 4.5 mm Quantum Maverick balloons (Boston Scientific, Natick, Massachusetts) proximally and distally, respectively, at high pressures. Figure 1B demonstrates a good angiographic result. Notably, there was no residual dissection visualized angiographically or by IVUS, and both stent apposition and expansion were optimal. The patient had been loaded 3 hours prior to the procedure with 600 mg of clopidogrel and 325 mg of aspirin. Following the procedure, the patient was continued on both clopidogrel (75 mg) and aspirin (325 mg) daily. He was discharged home the following day.

Five days later, the patient developed acute-onset substernal chest pain associated with hypotension and ST-segment elevations in leads V1–V4. Coronary angiography demonstrated complete in-stent thrombotic occlusion of the proximal LAD (Figure 2A). Following intra-aortic balloon pump placement, he underwent emergent aspiration thrombectomy with an Export XT catheter (Medtronic, Minneapolis, Minnesota), followed by balloon angioplasty (3.0 mm Voyager balloon) with partial restoration of TIMI-3 flow (Figure 2B). Further thrombus debulking was achieved with rheolytic therapy following temporary pacemaker placement (AngioJet-Ultra thrombectomy catheter; Medrad, Minneapolis, Minnesota) (Figures 2C–2D). Copious amounts of intracoronary nicardipine and adenosine were given to treat any distal embolization. Further IVUS evaluation revealed an adherent filling defect in the distal stent identified as thrombus (Figure 2D). Therefore, re-stenting was performed in an overlapping fashion across the distal edge of the stent using a 4.0 mm x 12 mm Xience stent deployed at nominal pressure and post-dilated with 4.5 mm and 5.0 mm x 15 mm Quantum Maverick balloons proximally and distally, respectively, with a very good angiographic result (Figure 3) confirmed once again with IVUS.

Post-procedural clopidogrel was continued at 75 mg twice daily. Of note, he received no therapies with known thienopyridine drug-drug interactions, namely, proton-pump inhibitors.7,8 Given the patient’s unique and dangerous presentation, unfractionated heparin was continued and platelet function studies were initiated using the Accumetrics VerifyNow P2Y12® rapid analyzer platelet function assay (Accumetrics, Inc., San Diego, California) in search of suspected drug resistance to clopidogrel.

Accumetrics VerifyNow® Platelet Function Testing

Our patient was maintained on clopidogrel (600 mg bolus prior to catheterization and 75 mg once daily, every day thereafter) from the index procedure 5 days prior to his acute presentation and for the next 7 days following his second PCI (where another 600 mg bolus was given, followed by 75 mg twice daily, every day thereafter) in addition to adjunctive intravenous unfractionated heparin and aspirin 325 mg every day. To prevent interference with our platelet function testing, whole blood samples for all laboratory studies including platelet reactivity testing were obtained 7 days following cessation of the glycoprotein IIb/IIIa inhibitor eptifibatide used during his acute presentation and PCI (ST). The inhibitory effect of clopidogrel in our patient was measured using the VerifyNow P2Y12 rapid analyzer, according to the manufacturer’s test protocol, which has been described in detail by others.9 Briefly, the VerifyNow system is a cartridge-based rapid platelet-function assay designed to directly measure the effects of thienopyridines on the P2Y12 platelet receptor. The VerifyNow instrument measures platelet-induced aggregation as an increase in light transmittance and uses a proprietary algorithm to report values in P2Y12 reaction units (PRU). A higher PRU reflects less platelet inhibition or greater ADP-mediated platelet reactivity (high on-treatment reactivity) and a low PRU reflects greater platelet inhibition or less ADP-mediated platelet reactivity (low on-treatment reactivity). The VerifyNow test was then repeated on day 8 (the following day) for confirmation. On day 8, clopidogrel and unfractionated heparin were stopped following administration of a 60 mg loading dose of prasugrel. One hour after prasugrel loading, its platelet inhibitory effect was measured using the VerifyNow P2Y12 rapid analyzer.

Pharmacologic platelet inhibition in response to thienopyridine treatment is depicted in Table 1. After a total of 12 days of clopidogrel treatment, including 1,200 mg in loading doses and twice-daily dosing after his acute presentation, our patient demonstrated 0% platelet inhibition with the same (yet, numerically higher) relative PRUs in the test result as in the baseline values. Conversely, within 1 hour of prasugrel loading, our patient demonstrated 76% platelet inhibition and an 80% reduction in PRUs. Moreover, as depicted in Table 2, no obvious underlying acquired or genetic thrombophilias appear to be contributing to the development of stent thrombosis in our patient. He remained on prasugrel for the following 4–6 months without incident. These results indicate complete resistance to the antiplatelet effect of clopidogrel, an effect that was rescued with prasugrel treatment in our patient. Optimal diagnostic cut-off measures used here are congruent with previous reports utilizing the VerifyNow system.7,10


Indeed, the most potent predictor of drug-eluting ST (in the absence of procedural failure) is early discontinuation of antiplatelet therapy.1,2 However, even in the most compliant patients, ST still occurs as a result of high residual platelet reactivity owing, ostensibly, to variability in degrees of platelet responsiveness to thienopyridine inhibition.8 Accordingly, trials looking both retrospectively and prospectively at the effects of platelet reactivity following PCI have demonstrated strong correlations between a poor response to the antiplatelet effects of thienopyridines (referred to as high ‘on-treatment’ platelet reactivity) and drug-eluting ST, thus confirming that platelet reactivity is a powerful predictor of adverse clinical outcomes following PCI.11,12 Here, we highlight the deleterious effects of complete platelet unresponsiveness to clopidogrel in our patient who underwent an event-free index PCI with IVUS confirmation of procedural success.

Michael Harrissays: November 10.2011 at 06:31 am

Was the patient Genotyped to determine if he was a Homozygote or Poor Metabolizer?

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