Very Late Thrombosis of Drug-Eluting Stents: A Brief Literature Review and Case Example

ABSTRACT: Thrombosis late after implantation is an infrequent but increasingly recognized complication following revascularization with drug-eluting stents (DES). The window of vulnerability for this complication with DES remains undefined. Intermediate-term follow up from pivotal trials and registries suggests continuous separation of event curves out to at least 3 years. We briefly review the evolving body of literature on DES thrombosis and report a case of very late thrombosis 53 months after implantation of a sirolimus-eluting stent. The event occurred despite chronic aspirin monotherapy and represents the longest latency from implantation to thrombosis described in the literature for a DES. J INVASIVE CARDIOL 2008;20:655–658 Drug-eluting stents (DES) were approved for clinical use on the basis of a marked reduction in angiographic and clinical restenosis along with an acceptable short-term safety profile.1,2 Interventional cardiologists rapidly adopted both the sirolimus-eluting stent (SES) and subsequent paclitaxel-eluting stent (PES) platforms, with their estimated use in more than 80% of percutaneous coronary interventions (PCI).3 Since then, cases of late (> 30 days post implantation) and very late (> 12 months post implantation) stent thrombosis (ST) have appeared with increasing frequency. The case presented here highlights very late DES thrombosis, followed by a brief literature review follows on the evolution of this important issue. Case Presentation A 46-year-old Indian male with hypertension, dyslipidemia and a family history of coronary artery disease sustained an anterior ST-elevation myocardial infarction (MI) in September 2002, which was treated with thrombolytics at an outside institution. Routine coronary angiography in January 2003 revealed significant disease of the proximal left anterior descending artery (LAD) and the right coronary artery (RCA), both amenable to percutaneous treatment. The LAD lesion was predilated with a 2.5 mm balloon and treated with a 2.75 x 23 mm Cypher™ sirolimus-eluting stent (Cordis Corp., Miami Lakes, Florida). The RCA lesion was also predilated and treated with a Cypher stent (2.75 x 23 mm). The final angiographic result was excellent. Following an uncomplicated course, the patient was discharged on aspirin (150 mg/day) indefinitely, clopidogrel (75 mg/day) for 3 months, ramipril and simvastatin. In September 2003, follow-up angiography was performed elsewhere despite the patient’s asymptomatic status. By report, there was no evidence of restenosis, thrombosis or target vessel failure. Exercise treadmill testing was performed annually and, as recently as October 2006, the patient showed good functional status without evidence of inducible ischemia. The patient remained well on aspirin, ramipril and simvastatin. During the last week of April 2007, the patient presented with sudden-onset retrosternal chest pain, presyncope and diaphoresis. The electrocardiogram showed precordial ST-segment elevation, consistent with anterior MI, and his cardiac enzymes were elevated. He received loading doses of aspirin (300 mg) and clopidogrel (300 mg) in addition to a tirofiban bolus and infusion. Emergent angiography showed patency of the RCA stent, but complete occlusion of the proximal LAD by a large thrombus within the stent (Figure 1). A coronary guidewire was passed easily to the distal vessel. Suction thrombectomy was performed using an Export™ catheter (Medtronic Inc., Minneapolis, Minnesota), and two linear pieces of thrombus were retrieved, (Figure 2). Balloon inflation within the stent restored thrombolysis in myocardial infarction (TIMI) 3 antegrade flow and eliminated visible thrombus, obviating the need for additional stent placement (Figures 3A and B). There was no apparent evidence of stent fracture or late-acquired malapposition. The patient had an uneventful recovery and was discharged on an indefinite course of aspirin (300 mg/day) and clopidogrel (75 mg/day). Platelet functional assays were not available to assess for evidence of aspirin and/or clopidogrel resistance. Hypercoagulability evaluation for abnormalities in antithrombin III, Factor V Leiden, protein C and APC resistance, protein S, and thrombin mutation was unrevealing. The patient was doing well at 8-month follow up. Bare-Metal Stent Thrombosis Thrombosis post implantation has been a concern since early clinical investigation of intracoronary stents two decades ago. High initial rates of acute and subacute thrombosis of bare-metal stents (BMS) were markedly reduced with improvements in technique, high-pressure postdilatation4 and adjunct pharmacologic treatment, namely aspirin and thienopyridine dual antiplatelet therapy.5 Most events occurred within 30 days of the procedure and often were associated with an interruption in antiplatelet therapy.6 Outside of vein graft intervention and brachytherapy with additional stent placement, BMS thrombosis beyond 1 year has rarely been reported. Drug-Eluting Stent Thrombosis Early reports. DES were enthusiastically received in 2002 by interventional cardiologists worldwide. By 2003, the mood was tempered following initial reports of thrombosis. McFadden et al sounded a cautionary note with the description of 4 patients, more than 300 days after device implantation, who suffered ST within 2 weeks of stopping dual antiplatelet therapy for invasive or operative procedures.7 Virmani and colleagues raised mechanistic possibilities with a case report of fatal SES thrombosis 18 months post implantation.8 Histopathology showed evidence of hypersensitivity involving eosinophils, lymphocytes and giant cells. With the known elution kinetics of sirolimus from this platform, they posited a proinflammatory effect of the nonerodible polymer reservoir. Real-world experience. Ensuing real-world reports provided conflicting data on the short- and intermediate-term safety of DES. From a prospective cohort, Iakovou et al analyzed 9-month outcomes in 2229 patients without ST-elevation MI who were revascularized using DES.9 They determined a 1.3% rate of definite and probable ST, higher than that reported from pivotal trials. Ong and colleagues from Rotterdam presented a sequential cohort of 2512 patients treated with BMS or DES.10 Thirty-day rates of stent thrombosis were very similar (BMS 1.4%, SES 1.5%, PES 1.6%). In 2006, Pfisterer reported more worrisome results from the BASKET-LATE study.11 He and colleagues followed 746 patients randomized to DES or BMS in the BASKET study who remained event-free at 6 months, when thienopyridine therapy was discontinued. Between 6 and 18 months, they observed higher rates of death or MI in the DES group (4.9% vs. 1.3%). Angiographic late ST was more frequent in the DES group (2.6% vs. 1.3%). With the caveat of limited study size, these investigators raised the possibility that clinicians were trading a reduction in restenosis for higher rates of thrombosis and, possibly, mortality. Meta-analyses of published SES and PES trials presented at the 2006 European Society of Cardiology and Transcatheter Cardiovascular Therapeutics meetings showed low but continuous rates of late thrombosis (0.2–0.6%/year) out to at least 3–4 years. Results from the Swedish SCAAR registry, presented at the 2006 American Heart Association (AHA) meeting, included 6033 DES and 13,738 BMS patients with 3-year follow up.12 No difference was noted in the composite endpoint, but investigators found a higher mortality rate in the DES group at the study’s end (relative risk [RR] 18%) and between 6 months and 3 years (RR 32%). In March 2007, the New England Journal of Medicine published 5 original papers on the subject of DES thrombosis and safety with overlap of the trials included in the different studies. Groups led by Mauri,13 Spaulding14 and Stone15 found little difference in overall thrombosis rates between stent types, but did identify thrombosis in DES more frequently than in BMS after 1 year. These analyses were received with guarded optimism and appeared to corroborate the relative safety of DES for on-label uses. Off-label use. With most DES usage, by some estimates, in off-label indications, questions remained about thrombosis risks in the setting of acute coronary syndromes, ostial and left main lesions, bifurcation lesions and in-stent restenosis. The large Western Denmark registry included patients receiving DES (n = 3548) or BMS (n = 8847) with 15-month follow up.16 There was no difference in mortality or in Academic Research Consortium (ARC)-defined ST, but thrombosis beyond 1 year was more frequent in the DES group. Beohar et al analyzed a prospective, multicenter registry to categorize DES use in 5541 patients as on-label, off-label or untested.17 There was no difference in the composite endpoint of death, MI or ST at 1 year. They did note higher target lesion revascularization and overall event rates for off-label and untested compared to on-label uses (7.6%, 6.7% and 4.4%, respectively). Marroquin and colleagues more recently described a similar analysis of 6551 patients from the NHLBI Dynamic Registry.18 Off-label use in the DES and BMS waves were similar at 49% and 55%, respectively. More long and Type C lesions were treated in the DES group. One-year death and composite events were no different. Risk factors. The risk for stent thrombosis is likely multi-factorial and influenced by clinical, anatomic and procedural characteristics. Early analyses by Iakovou9 and Kuchulakanti19 identified predictors including premature discontinuation of antiplatelet therapy, renal failure and treatment of bifurcation lesions. Park et al reported a consecutive series of 1545 SES and 366 PES patients with a 0.8% ST rate at a median follow up of 19 months.20 Identified predictors included premature cessation of antiplatelet therapy, treatment for acute MI and stent length. From the e-Cypher registry of 15,157 patients, Urban and colleagues determined that age, diabetes, acute coronary syndrome, treatment of chronic total occlusion and multivessel PCI were predictors for ST.21 Fujii et al used intravascular ultrasound (IVUS) to study patients with ST and those with patent DES.22 IVUS predictors included a small stent cross-sectional area, stent underexpansion and significant residual disease in the reference segment. Chen described a patient on aspirin therapy who suffered thrombosis 42 months after SES implantation.23 In-stent restenosis was considered a predisposing factor, and the lesion was treated with a Taxus PES. Feres and colleagues shared a case of SES thrombosis at 40 months post implantation.24 With the benefit of serial IVUS, these investigators demonstrated dynamic and marked acquired incomplete stent apposition as a potential mechanism for ST. Although controversial, the concept of resistance or impaired response to antiplatelets has also been offered as a possible risk factor for DES thrombosis. Buonamici and colleagues reported a prospective cohort of patients receiving either SES or PES.25 Patients were classified by response to clopidogrel according to light transmittance aggregometry. While the overall 6-month incidence of definite or probable ST was 3.1%, nonresponsiveness to clopidogrel conferred a 3-fold increase in risk. Delayed endothelialization. A prolonged window of vulnerability to thrombosis with DES has been a concern with pre-clinical studies demonstrating delayed healing and endothelialization.26 Both sirolimus and paclitaxel effectively suppress endothelial cell proliferation in vitro.27,28 Both compounds may also exert a local thrombogenic effect via upregulation of monocyte and endothelial cell tissue factor expression. Using neointimal formation as a surrogate for endothelialization, Awata et al performed serial angioscopy up to 22 months after implantation of SES (n = 17) or BMS (n = 11).29 They found neointimal coverage of stent struts complete in the BMS group by 3–6 months. In the DES group, there was evidence of slow and ongoing neointimal formation even at 2 years. Joner and colleagues described an autopsy registry of 23 DES (implanted > 30 days) and 25 BMS.30 Fourteen of the 23 DES had evidence of late thrombosis. Overall, DES had more fibrin and less endothelialization compared to BMS. Prevention and considerations. Patients with the greatest expectation for benefit from DES due to clinical (i.e., diabetes, renal failure) and anatomic (i.e., long lesion, small vessel) characteristics might, in fact, be at highest risk for ST. A careful and explicit assessment of risk and benefit is imperative. Anticipated invasive or operative procedures may warrant deferral of PCI or use of BMS if the probability of restenosis is not high. Attention to technique with optimal lesion preparation and device deployment may also reduce the risk of ST. The appropriate course of dual antiplatelet therapy remains unknown, although the ACC/AHA/SCAI PCI guidelines recommend at least 12 months of clopidogrel for DES patients in the absence of significant bleeding risk. Airoldi et al reported on 3021 consecutive patients treated with DES.31 The ST rate was 1.9% at 18 months. During the first 6 months, discontinuation of thienopyridine therapy was a strong predictor of ST. After 6 months, however, it was no longer an independent risk predictor. In a 24-month observational study of BMS (n = 3165) and DES (n = 1501) patients, investigators at Duke performed 6- and 12-month landmark analyses categorizing patients by stent type and clopidogrel use.32 They found lower event rates in DES patients with continued clopidogrel use at both time points. No difference was observed in the BMS group. A provocative finding is that DES patients continuing on clopidogrel had the lowest rate of death or MI at 24 months. The optimal duration of antiplatelet therapy awaits study in larger randomized trials. Conclusion As follow up after DES implantation lengthens, cases similar to ours may become more frequent. Our patient did not have clear clinical, anatomic or procedural characteristics associated with increased risk for ST. He remained stable on aspirin monotherapy for 53 months following a standard 3-month course of clopidogrel. Although multivessel PCI with DES was performed during the index procedure, only the LAD stent manifested thrombotic occlusion with wide angiographic patency of the RCA stent. Without IVUS or other adjunct imaging information, we can only speculate about the predisposing factors such as incomplete stent apposition, underexpansion or significant residual reference-segment disease. While efforts continue to better understand and prevent this feared complication, clinicians are left with limited information upon which to base clinical decisions. Managing the risk of ST will continue to be a multi-step process: careful assessment of thrombosis, restenosis and bleeding risks; meticulous attention to procedural technique, including use of high-pressure post dilatation and, if appropriate, complementary imaging modalities such as IVUS; and, perhaps, prolonged administration of dual antiplatelet therapy. Iterative device development focusing on drug pharmacodynamics and pharmacokinetics, polymer biocompatibility and stent platform may eventually mitigate the risks of ST. While available safety data for the next-generation DES appears promising, guarded optimism is warranted while larger patient numbers and longer follow-up periods accrue.

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