ABSTRACT: This work describes the longest reported interval between drug-eluting stent (DES) placement and very late stent thrombosis (VLST). A 69-year-old male presented with substernal chest pain associated with ST-segment myocardial infarction (STEMI) after having a DES deployed 6.9 years (2506 days) prior. The patient’s medical history revealed several risk factors for VLST. The patient suspended clopidogrel therapy in preparation for elective cystoscopy approximately 10 days before presenting.
J INVASIVE CARDIOL 2011;23(12):E273-E276
Early, late, and very late stent thrombosis (VLST) have been recognized complications of DES implantation for several years.1,2 However, the beneficial effect of DES compared to bare-metal stents (BMS) in significantly reducing the incidence of restenosis continues to warrant their popular usage in percutaneous intervention (PCI).3,4 The implementation of dual antiplatelet therapy has been shown to significantly mitigate the risk of late stent thrombosis and VLST in the general population.5 It is well-established, however, that the complexities of this management arise in situations when bleeding is a significant risk,6 or when dual antiplatelet therapy must be temporarily suppressed for elective procedures.7 Several studies showed that the risk of VLST persists for 4 years post procedure.8 This correlates with the majority of reported VLST cases, where thrombosis occurred less than 4 years after PCI. To our knowledge, the longest reported time intervals of VLST in DES are around 4.5 years,9,10 unlike BMS, where thrombosis has occurred as long as 13 years after deployment.11
This report describes a case of a definite VLST (as defined by the Academic Research Consortium) occurring 6.9 years after DES deployment, which is approximately 1.5 times longer than previously reported cases of VLST. A possible contributing factor, although unsubstantiated in the literature, includes the abrupt cessation of clopidogrel usage approximately 10 days before the presenting event.
A 69-year-old male presented with anterior wall ST-elevation myocardial infarction (STEMI) due to in-stent thrombosis of a DES placed 2506 days previously. The patient discontinued clopidogrel as part of long-term dual antiplatelet therapy 10 days prior for an elective cystoscopy.
The patient had a history of hypertension and hyperlipidemia, but was not diabetic. He was mildly obese and was a heavy smoker from the age of 20 until the age of 45. He had established coronary artery disease (CAD) that led to a total of 2 DES placements in June 2003 and March 2006. Thrombosis of the 2003 stent led to the STEMI presentation in April 2010. Other comorbidities at presentation included gout and osteoarthritis.
The patient’s first PCI was in April 2003, which was an elective procedure indicated by stable angina and a positive stress test. Angiography revealed a thrombotic lesion occluding 90-95% of the mid-left anterior descending (LAD) artery, which was treated with a 3 x 23 mm Cypher DES (Cordis Corporation) deployed using a pressure of 20 atm for 10 seconds 2 times. A 3.5 mm Powersail balloon catheter (Abbott Vascular) was then used at a pressure of 18 atm for 10 seconds 3 times. Angiography also showed mild diffuse disease in the first diagonal of the LAD and circumflex arteries, which was not treated at that time. The procedure was uneventful and good stent apposition was achieved leading to total reperfusion (TIMI flow grade 3). The patient reported that his anginal symptoms resolved following the intervention.
A second 3.5 x 13 mm Cypher DES was placed electively in March 2006 when the patient experienced new-onset stable angina, which was evidenced by a positive stress test. The causal thrombotic lesion was proximal to the 2003 DES, producing 60-70% ostial stenosis. A single DES was deployed using a pressure of 16 atm for 10 seconds followed by post-dilatation with a 4 mm Powersail balloon catheter at 10 atm for 15 seconds (TIMI flow grade 3).
Prior to the 2006 intervention, the patient’s regular medication regime included aspirin, atenolol, amlodipine, celecoxib, losartan, and hydrochlorothiazide. He did not recall the dosage and length of time for which he was taking celecoxib between the 2003 and 2006 procedures, but was advised to discontinue it at the time of the 2006 intervention.
Following the 2006 intervention, the patient was prescribed dual antiplatelet therapy (81 mg aspirin daily and 75 mg clopidogrel bisulfate daily) for the following year. He reported being very compliant and continued taking it from March 2006 until 10 days before the April 2010 STEMI presentation. At that point, the patient discontinued clopidogrel and continued only aspirin in preparation for a planned cystoscopy. The purpose of this procedure was to explore episodes of prostate-related dysuria without evidence of hematuria.
At the time of the STEMI presentation in April 2010, angiography revealed complete occlusion of the mid-LAD artery with in-stent thrombosis of the DES (placed 2506 days before) (Figure 2A). The patient’s creatinine was 1.5 mg/dL, blood pressure was 176/101 mm Hg, and heart rate was 75 bpm. During PCI, the guidewire easily passed through the lesion, indicating that it was thrombotic. An Angiojet thrombectomy system (Medrad, Inc.) was used to clear the clot and restore blood flow (Figure 2B). Subsequently, a Vision 3.5 x 18 mm BMS (Abbott) was deployed and blood flow was restored. The DES placed in 2006 was found patent.
Heparin, morphine sulfate, abciximab, and nitroglycerin were given during the procedure. The patient was discharged on once daily 325 mg aspirin, 0.4 mg tamsulosin hydrochloride, 20 mg atorvastatin calcium, 5 mg lisinopril, 500 mg niacin, 75 mg clopidogrel bisulfate, and twice daily 25 mg metoprolol.
At 3-month follow-up exam, clopidogrel response and aspirin sensitivity were measured for the first time. This procedure revealed 44% platelet inhibition and aspirin sensitivity. It was recommended that the patient continue dual antiplatelet therapy indefinitely. Between the time of follow-up and the presentation of the MI, the patient was diagnosed with benign prostatic hyperplasia.
This case shows that the risk of VLST may persist well beyond previously reported time intervals. Cessation of dual antiplatelet therapy may remain a predictive factor of ST for an unknown amount of time after deployment.
VLST (>1 year) is a well-known complication of DES usage. However, the time interval following PCI during which the patient is at substantial risk is not well-established. Past studies that have addressed this issue were limited by follow-up time.12 The longest follow-up period to our knowledge was 7 years,13 which seemed sufficient in the past given that the longest time interval between PCI and VLST presentation was reported to be approximately 4.5 years (1659 days).9 Beyond these follow-up times, significant data have not been obtained because VLST is rare and FDA approval for DES only occurred in 2003.14
This case illustrates the occurrence of VLST well beyond the longest time interval previously reported. Patients at high risk for VLST may need continuous lifelong dual antiplatelet therapy despite current guidelines. Temporary cessation of dual antiplatelet therapy for elective procedures may put these patients at risk many years after stent placement.
Several studies have established predictive factors for VLST in DES recipients. Risk factors relevant to this patient’s medical and PCI history include renal insufficiency, possible malignancy, and coronary artery disease proximal to the target lesion.15 A recent study showed the cut-off length to be 31.5 mm, above which there is significant risk.16 Given that the DES in this case was 23-mm long, stent length was not considered to be a risk factor.
Renal insufficiency is an independent risk factor for ST. Studies such as Rift showed that there is an increased thrombosis rate in patients with moderate or severe renal impairment.17 The patient’s creatinine level at the time of the STEMI was 1.5 mg/dL. While acceptable for a patient with a past history of nephrectomy, this corresponds to stage 3 chronic kidney disease and thus implies a moderate degree of insufficiency. The treatment of patients with moderate to severe renal insufficiency has been controversial in that some say they should be treated with BMS as opposed to DES due to an associated increased risk of VLST.18 A recent meta-analysis, however, has shown better outcomes with the use of DES, but with the large array of other associated risk factors, stent type must be considered on an individual basis.19
The possibility of malignancy15 as a risk factor was raised in light of the patient’s dysuria, which prompted him to pursue elective cystoscopy and temporarily cease his clopidogrel treatment. However, 3-month follow-up after the STEMI revealed no evidence of cancer.
A further predictive factor is that he had arterial disease proximal to the stent thrombosis,15 as reported at the time of 2003 PCI, which became symptomatic and later required intervention with placement of the 2006 stent.
The recommended duration of dual antiplatelet usage following DES placement has been a controversial issue for several years,20 leading to ongoing changes in the American College of Cardiology guidelines. The guidelines suggest that dual antiplatelet therapy should be continued for at least 1 year after DES implantation if there is no significant bleeding risk.21 Several reputable studies have found no statistical benefit in continuing clopidogrel further,22 despite the fact that clopidogrel cessation is the most significant risk factor for stent thrombosis when stopped before 30 days.23
Interestingly, this patient was taking aspirin alone for the immediate years following placement of the first DES in 2003 and only started dual antiplatelet therapy after the placement of the second DES in 2006. Clopidogrel responsiveness and aspirin sensitivity demonstrated that this patient was receptive to this treatment. Therefore, the occurrence of in-stent thrombosis may have been caused by a rebound effect after the well-established clopidogrel therapy was suddenly stopped. However, a recent double-blind randomized trial revealed no statistical evidence for the existence of clopidogrel rebound effect.24
In this case, in-stent thrombosis may have been caused by a combination of clopidogrel cessation and deployment parameters of the stent placement itself, which may have led to acquired stent malapposition (ASM). Deployment parameters, such as undersizing of the stent or mismatch between the stent diameter and target vessel wall diameter, have been shown to increase the likelihood of in-stent thrombosis.25 Cook et al found incomplete stent apposition in 77% of patients presenting with DES thrombosis compared to matched controls,26 which suggests a significant prevalence despite suitable apposition as determined by the interventionalist. The fact that only 1 of 2 identical DES thrombosed supports the likelihood that its occurrence is related to operational parameters. Moreover, a recent intravascular ultrasound study of 4 patients with ASM27 (from a study of 6) revealed that 3 of those patients had discontinued clopidogrel within a month of presentation. ASM might explain the long time delay in presentation. Furthermore, clopidogrel protection may have been revealed when the drug was stopped. Unfortunately, neither intravascular ultrasound nor optical coherence tomography were performed in this case so the presence of malapposition is unknown.
The use of celecoxib was also considered in the explanation as to why only the first of the 2 DES thrombosed. The COREA-TAXUS trial showed that celecoxib reduced the incidence of restenosis in DES at 6 months by inhibiting target vessel revascularization.28 While advantageous for restenosis prevention, incomplete endothelialization of the 2003 DES may have resulted from the use of celecoxib by similar antiproliferative mechanisms. Incomplete endothelialization has been shown to be a central mechanism behind VLST in DES.29 Given that celecoxib was taken for several months after deployment of the first DES but before implantation of the second DES, it is possible that a complete neointimal layer never had the opportunity to be established. Introduction of a second DES in close proximity to the first may have further exposed the original DES to high antiproliferative drug dosing. Significant recall bias makes it difficult to determine whether or not the timing in this case supports this theory.
Another controversial issue regarding the use of celecoxib in patients at risk of cardiovascular events is that the drug itself may be prothrombotic. This may occur through its inhibition of prostacyclin, which balances thromboxane A2 to maintain a euthrombotic state.30 However, it is unlikely that this effect could have been relevant because the celecoxib was stopped several years before the thrombotic event.
A small but significant risk of ST associated with first-generation DES has been clearly established. Hope now resides in the development of second-generation everolimus-eluting stents that will alleviate such complications. Early studies have shown that there is a significant reduction in the incidence of stent thrombosis and myocardial infarction in non-diabetic patients within the first year after deployment.31 Performance at very late stages is yet to be determined.
The incidence of VLST is a rare complication of DES usage, making the establishment of significant risk factors difficult. This work illustrates the important point that thrombosis following DES placement may occur at post-PCI time intervals much greater than previously thought. Lifetime dual antiplatelet therapy without interruption may be indicated in certain patients with established risk factors for VLST. The mechanism that prompted stent thrombosis at such a late stage and its relationship to clopidogrel cessation and celecoxib usage is unclear.
- Pfisterer M, Brunner-LaRocca HP, Buser PT, et al; for the BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting stents versus bare-metal stents. J Am Coll Cardiol. 2006;48(12):2584-2591.
- Mauri L, Hsieh WH, Massaro JM, Ho KK, D'Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356(10):1020-1029.
- Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346(23):1773-1780.
- Stone GW, Ellis SG, Cox DA, et al; for the TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004;350(3):221-231.
- Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297(2):159-168.
- Bhatt DL, Fox KA, Hacke W, et al; for the CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706-1717.
- Rossini R, Musumeci G, Lettieri C, et al. Long-term bleeding in patients on prolonged dual oral antiplatelet therapy after DES implantation: prevalence, predictors, and prognostic implications. J Am Coll Cardiol. 2010;55(10):A198.E1865.
- Wenaweser P, Daemen J, Zwahlen M, et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-institutional cohort study. J Am Coll Cardiol. 2008;52(14):1134-1140.
- Al-Dehneh A, Virk H, Alkhouri Y, Hamdan A, Bikkina M. Drug-eluting stent thrombosis 1659 days after stent deployment: case report and literature review. Texas Heart Inst J. 2010;37(3):343-346.
- Agarwal SK, Shawl F, Raman VK, Binbrek AS. Very late thrombosis of drug-eluting stents: a brief literature review and case example. J Invasive Cardiol. 2008;20(12):655-658.
- Sarkees ML, Bavry AA, Galla JM, Bhatt DL. Bare-metal stent thrombosis 13 years after implantation. Cardiovasc Revasc Med. 2009;10(1):58-59.
- Vaknin-Assa H, Assali A, Lev EI, Ukabi S, Tamir B, Kornowski R. Failure of drug-eluting stents presented as definite stent thrombosis. Cath Cardiovasc Interv. 2010;76(1):93-97.
- Costa RA, Sousa A, Moreira A, et al. Incidence and predictors of stent thrombosis up to 7 years follow-up following drug-eluting stent implantation in unselected patients with complex coronary lesions treated in the real-world clinical practice — a sub analysis from the drug-eluting stent in the real world desire registry. J Am Coll Cardiol. 2010;55(10):A191.E1790.
- Serruys PW, Kutryk MJ, Ong AT. Coronary-artery stents. N Engl J Med. 2006;354(5):483-495.
- Van Werkum JW, Heestermans AA, Zomer AC, et al. Predictors of coronary stent thrombosis: the Dutch stent thrombosis registry. J Am Coll Cardiol. 2009;53(16):1399-1409.
- Suh J, Park DW, Lee JY, et al. The relationship and threshold of stent length with regard to risk of stent thrombosis after drug-eluting stent implantation. JACC Cardiovasc Interv. 2010;3(4):383-389.
- Zhu ZB, Zhang RY, Zhang Q, et al. Moderate-severe renal insufficiency is a risk factor for sirolimus-eluting stent thrombosis: the RIFT study. Cardiology. 2009;112(3):191-199.
- Rosenblum MA, Robbins MJ, Farkouh ME, Winston JA, Kim MC. Diminished benefits of drug-eluting stents versus bare-metal stents in patients with severe renal insufficiency. Nephron Clin Pract. 2009;113(3):1660-2110.
- El-Menyar AA, Al Suwaidi J, Holmes DR Jr. Use of drug-eluting stents in patients with coronary artery disease and renal insufficiency. Mayo Clin Proc. 2010;85(2):165-171.
- Roy P, Bonello L, Torguson R, et al. Temporal relation between clopidogrel cessation and stent thrombosis after drug-eluting stent implantation. Am J Cardiol. 2009;103(6):801-805.
- King SB 3rd, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2008;51(2):172-209.
- Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med. 2010;362(15):1374-1382.
- Rossini R, Lettieri C, Zoccai GB, et al. Early and late discontinuation of oral antiplatelet therapy after DES implantation: prevalence, predictors, and long-term prognosis. J Am Coll Cardiol. 2010;55(10):A208.E1960.
- Sibbing D, Stegherr J, Braun S, et al. A double-blind, randomized study on prevention and existence of a rebound phenomenon of platelets after cessation of clopidogrel treatment. J Am Coll Cardiol. 2010;55(6):558-565.
- De Benedetti E, Urban P. Coronary stenting: why size matters. Heart. 2007;93(12):1500-1501.
- Cook S, Wenaweser P, Togni M, et al. Incomplete stent apposition and very late stent thrombosis after drug-eluting stent implantation. Circulation. 2007;115(18):2416-2434.
- Kimura M, Ebisawa S, Tanaka N, et al. Differences in coronary intravascular ultrasound findings in early, late, and very late stent thrombosis after sirolimus-eluting stent implantation. J Am Coll Cardiol. 2010;55(10):A191.E1788.
- Koo BK, Kim YS, Park KW, et al. Effect of celecoxib on restenosis after coronary angioplasty with a Taxus stent (COREA-TAXUS trial): an open-label randomized control study. Lancet. 2007;370(9587):567-574.
- Jiménez-Valero S, Moreno R, Sánchez-Racalde A. Very late drug-eluting stent thrombosis related to incomplete stent enothelialization: in vivo demonstration by optical coherence tomography. J Invasive Cardiol. 2009;21(9):488-490.
- Caughey GE, Cleland LG, Penglis PS, Gamble JR, James MJ. Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2. J Immunol. 2001;167(5):2831-2838.
- Stone GW, Rizvi A, Newman W, et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med. 2010;362(18):1663-1674.
From the 1University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital and 2Mount Sinai Medical Center, Coronary Care Unit.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted February 28, 2011, provisional acceptance given March 21, 2011, final version accepted June 3, 2011.
Address for correspondence: Jennifer E. Taylor-Sutton, PhD, 55 North Water Street, Norwalk, CT 06854. Email: email@example.com