Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is necessary to reduce the risk of adverse cardiovascular events, such as stent thrombosis, after percutaneous coronary intervention (PCI). Nevertheless, stent thrombosis occurs in up to 3.1% of patients who undergo drug-eluting stent (DES) implantation, and this is partly related to their poor response to clopidogrel.¹

Prasugrel is a 3rd-generation thienopyridine that might overcome the limitations of clopidogrel, such as slow onset of action and wide variability of response among patients. We report the case of a woman with a laboratory-documented poor response to clopidogrel, who sequentially sustained very late and subacute stent thrombosis; and we discuss the outcome of her subsequent prasugrel therapy.

Case Report

In June 2011, a 64-year-old woman was admitted to the emergency department with ongoing chest pain. An electrocardiogram showed anterior-wall ST-segment elevation. The patient had a history of hypertension and of stable angina, diagnosed 51 months previously. At that time, she had undergone the implantation of 2 Taxus^® Liberté^® paclitaxel-eluting stents (Boston Scientific Corporation; Natick, Mass)—3 × 20 mm and 2.75 × 24 mm—in the proximal-to-mid left anterior descending coronary artery (LAD). She was currently taking 100 mg/d of aspirin after the termination of 24 months of DAPT (100 mg/d of aspirin and 75 mg/d of clopidogrel). The presumptive diagnosis was ST-elevation myocardial infarction (STEMI). Emergency coronary angiograms showed occlusion of the proximal-to-mid LAD with in-stent thrombosis, and thrombi at the orifice of the left circumflex coronary artery (LCx) (Fig. 1A). This was classified as definite stent thrombosis in accordance with Academic Research Consortium criteria, and as very late stent thrombosis.²

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We performed balloon angioplasty with the administration of the glycoprotein IIb/IIIa inhibitor abciximab (a 0.25-mg/kg bolus followed by a continuous infusion of 0.125 μg/kg/min for 12 hr). Numerous treatments—involving a 600-mg loading dose of clopidogrel, anticoagulation with use of unfractionated heparin, the intracoronary administration of adenosine and nicorandil, repetitive thrombus aspiration with use of a 6F Thrombuster II^® Thrombus Aspiration Catheter (Kaneka Medix Corporation; Osaka, Japan), and balloon dilation—achieved suboptimal reperfusion of Thrombolysis In Myocardial Infarction (TIMI) flow grade 1. No-reflow and cardiogenic shock developed. We deployed a 3 × 38-mm Resolute Integrity^® zotarolimus-eluting stent (Medtronic Inc.; Minneapolis, Minn) in the left main coronary artery (LMCA) to the proximal LAD. The result was TIMI-3 flow (Fig. 1B). Platelet function studies of blood samples, with use of a VerifyNow^® rapid platelet-function analyzer (Accriva Diagnostics; San Diego, Calif), revealed an elevated level of 310 P2Y₁₂ resistance units (PRU) (target range for sufficient platelet inhibition, <240 PRU), indicating a poor response to clopidogrel. The aspirin resistance unit value of 408 was within the range for sufficient platelet inhibition (<550). We placed the patient on triple antiplatelet therapy (TAPT) to compensate for her poor response to clopidogrel: aspirin (100 mg/d), clopidogrel (75 mg/d), and cilostazol (200 mg/d).

After a 7-day hospitalization, the patient was discharged without sequelae. Thirteen days after the index PCI, she was readmitted with acute pyelonephritis and was treated with intravenous 3rd-generation cephalosporin. On the 26th day after PCI, she reported acute chest pain, and an electrocardiogram showed ST-segment elevation in leads V₁ through V₄. Coronary angiograms showed stent occlusion from the LMCA to the LAD and LCx ostium (Fig. 2A). Cardiogenic shock (blood pressure, 70/40 mmHg) developed, and an intra-aortic balloon pump was placed. After several attempts at balloon dilation, including use of the kissing-balloon technique at the LMCA, LAD, and LCx (Fig. 2B), we were able to restore TIMI-3 flow. The results of postprocedural intravascular ultrasonography (IVUS) confirmed that no mechanical factors, such as stent underexpansion or dissections, underlay the subacute stent thrombosis. To prevent recurrences, we changed the antiplatelet agent to prasugrel, gave the patient a 60-mg loading dose, and placed her on DAPT of aspirin (100 mg/d) and prasugrel (10 mg/d). She improved well and was discharged from the hospital, without sequelae, on the 14th day after the subacute stent thrombosis. Coronary angiograms showed stent patency. As of December 2014, no sequelae had been detected during outpatient monitoring.

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Discussion

Despite the proven efficacy of DAPT consisting of aspirin and clopidogrel, life-threatening cardiovascular events such as stent thrombosis can occur after PCI. Variable clopidogrel resistance is regarded as a major factor: 20% to 40% of patients who are given clopidogrel are classified as nonresponsive, poorly responsive, or resistant to clopidogrel because of low inhibition of platelet aggregation or activation.^3,4 It has been shown that reduced responsiveness to clopidogrel therapy is a powerful independent predictor of stent thrombosis.^5,6 Although some study results have indicated that TAPT (including cilostazol) is superior to DAPT in terms of greater reduction of platelet reactivity,⁷ TAPT has not yielded a better clinical prognosis than conventional DAPT.^8,9

Prasugrel, a 3rd-generation oral thienopyridine, manifests more rapid and potent platelet inhibition than does clopidogrel, as well as less response variability. In comparison with clopidogrel, the antiplatelet effects of prasugrel have significantly reduced the incidence of ischemic events, particularly myocardial infarction and stent thrombosis in patients with acute coronary syndrome.¹⁰ In the triton-timi 38 trial, prasugrel was more beneficial than clopidogrel in PCI patients who had STEMI, diabetes mellitus, and stent thrombosis.¹¹

Our report is of a rare case with recurrence of very late and subacute stent thrombosis in the same target vessel despite concomitant standard DAPT and TAPT. Many factors might contribute to the occurrence of stent thrombosis. Early thrombosis (within 30 d) is mainly due to mechanical issues, whereas late thrombosis, particularly in the DES era, is associated with incomplete re-endothelialization, late stent malapposition or fracture, and de novo plaque rupture. The definitive treatment of very late stent thrombosis is still under debate. Although most thrombotic stent occlusions can be managed by means of balloon angioplasty alone (perhaps aided by thrombus aspiration), additional stenting is frequently performed in real practice.^12,13 In our patient, the implantation of a new DES was necessary to manage her intractable no-reflow and cardiogenic shock, even after balloon angioplasty and thrombus aspiration during the first episode of very late stent thrombosis. The additional DES implantation might have contributed to the subsequent episode of subacute stent thrombosis. Because of risks such as high thrombotic burden and cardiogenic shock, we did not perform IVUS to exclude mechanical causes of stent thrombosis during the first thrombotic episode. However, IVUS after the 2nd episode revealed no obvious mechanical factors.

Although we newly implanted another type of DES at the prior paclitaxel-eluting stent site, DES type might not play a substantial role in stent thrombosis. Investigators who conducted an observational comparison of sirolimus-, paclitaxel-, and zotarolimus-eluting stents found no differences in the rate of occurrence of stent thrombosis according to the type of DES.¹⁴ Other authors have postulated that inflammatory reactions caused by recent acute infection might trigger coronary stent thrombosis by means of coronary endothelial dysfunction.¹⁵ In this context, our patient's acute urinary tract infection might have promoted the subacute stent thrombosis.

Our patient's case suggests that conventional TAPT might not be enough to overcome clopidogrel resistance in every patient, especially those who respond poorly to clopidogrel. Although the optimal management of clopidogrel resistance is unresolved, our use of DAPT (aspirin and prasugrel) was particularly beneficial in this patient who had poor platelet response to clopidogrel. Prospective studies are needed to clarify the potential role of prasugrel in patients who do not respond well to clopidogrel.