Case Report

Very Late Drug-Eluting Stent Thrombosis and Cardiogenic Shock: 1,249 Days after Implantation

Jack P. Chen, MD From Saint Joseph’s Hospital, Atlanta, Georgia. The author has no conflicts to declare, and no grants were received for the preparation of this manuscript. Manuscript submitted May 29, 2007, provisional acceptance given July 19, 2007, manuscript accepted August 24, 2007. Address for correspondence: Jack P. Chen, MD, FACC, FSCAI, FCCP, 5670 Peachtree, Dunwoody Road, #880, Atlanta, GA 30342. E-mail: chenjackapollo@yahoo.com
Jack P. Chen, MD From Saint Joseph’s Hospital, Atlanta, Georgia. The author has no conflicts to declare, and no grants were received for the preparation of this manuscript. Manuscript submitted May 29, 2007, provisional acceptance given July 19, 2007, manuscript accepted August 24, 2007. Address for correspondence: Jack P. Chen, MD, FACC, FSCAI, FCCP, 5670 Peachtree, Dunwoody Road, #880, Atlanta, GA 30342. E-mail: chenjackapollo@yahoo.com

ABSTRACT: The marked reduction of in-stent restenosis of drug-eluting stents (DES) has dramatically affected modern interventional therapy for coronary artery disease. The promises of this potential panacea, however, have been recently attenuated by the specter of late stent thrombosis. Stent thrombosis and in-stent restenosis reduction represent the double-edged sword of neointimal inhibition. J INVASIVE CARDIOL 2007;19:E381–E384
We present a patient who suffered acute myocardial infarction and cardiogenic shock 1,249 days post drug-eluting stent (DES) implantation 2 years after clopidogrel therapy cessation. In our review of OVID-Medline, we believe this to be the most delayed case of DES late stent thrombosis (LST) reported. The Food and Drug Administration has concluded that although there is a slight increase in DES LST as compared to bare-metal stents (BMS), there are no overall differences in infarction or mortality rates. Additionally, dual antiplatelet therapy for a minimum of 1 year is strongly recommended. We review the pathophysiology of stent thrombosis, as well as case reports of DES LST. This case serves as a sobering reminder of the rare but ongoing, risk of LST. Case Report. A 50-year-old male, status post implantation of 2 sirolimus-eluting stents (SES) (Cypher™, Cordis Corp., Miami Lakes, Florida) in his right coronary artery (RCA) 3 years ago, presented with cardiac arrest and an acute inferior ST-segment elevation myocardial infarction (STEMI). 1,249 days prior, the patient was admitted for a non-STEMI and underwent cardiac catheterization. A previous ostial left anterior descending (LAD) stent was totally occluded, with excellent collateralization by the RCA. The dominant RCA contained a 90% proximal and an 85% mid stenosis. The left ventricular ejection fraction was 50%, with evidence of anterolateral and apical akinesis. When presented with the therapeutic options, the patient promptly elected for right coronary percutaneous intervention over bypass surgery. He thus underwent direct stenting with nonoverlapping 3.5 x 13 mm and 3.0 x 18 mm SES in the proximal and mid RCA, respectively. After discharge, he continued on lovastatin, atenolol and dual antiplatelet therapy (DAT) with aspirin and clopidogrel for 14 months. Thereafter, he self-terminated clopidogrel and continued aspirin monotherapy. During the ensuing 2 years, the patient failed to return for follow-up evaluation. Two months prior to admission, he began experiencing exertional angina but did not return for cardiac evaluation. On the day of admission, after 3 hours of severe intermittent substernal pressure, he finally presented to the emergency room in cardiac arrest. After full resuscitative efforts and intubation with mechanical ventilation, a borderline blood pressure of 81/52 mmHg was maintained on high-dose dopamine infusion. On electrocardiography, prominent ST-elevations were seen in the inferior leads (Figure 1). Intravenous heparin, eptifibatide and amiodarone infusions were initiated. Emergent cardiac catheterization revealed in-stent occlusion in the distal segment of the mid RCA drug-eluting stent (DES) (Figure 2). The patient’s left ventricular ejection fraction was markedly reduced at 25%, with inferior, in addition to the previous anterolateral and apical, akinesis. Left ventricular end-diastolic pressure was 44 mmHg. Emergent intervention was performed using a 6 Fr Judkins right-4 guide catheter. The occlusion was easily crossed with a 0.014 inch Choice PT wire (Boston Scientific Corp., Natick, Massachusetts). Aspiration with an Export catheter (Medtronic Inc., Minneapolis, Minnesota) yielded moderate thrombus volume and Thrombolysis in Myocardial Infarction (TIMI) grade 3 coronary flow. The lesion was subsequently predilated with a 3.0 x 15 mm Maverick balloon (Boston Scientific), with a 40% residual stenosis. Given the in-stent location of this stenosis and despite the thrombotic nature, the decision was made to implant a DES. A 3.0 x 8 mm Taxus® paclitaxel-eluting stent (PES) (Boston Scientific) was successfully deployed inside the previous mid RCA stent (Figure 3) with an excellent final angiographic result (Figure 4). Intra-aortic balloon counterpulsation was initiated and immediate aspirin 325 mg and clopidogrel 600 mg were administered via a nasogastric tube. Creatine kinase and troponin I levels peaked at 3,864 IU/L and 432 ng/mL, respectively. The hospitalization was complicated by pneumonia, emergent cholecystectomy, septic shock and renal failure requiring dialysis. On day 13, cardiac arrest recurred and the patient was unable to be revived. Discussion. Although DES represent a potential milestone in the battle against restenosis, recent enthusiasm has been tempered by the threat of a potential increase in LST. Albeit rare, LST usually occurs with devastating and potentially lethal myocardial injury, as illustrated in our patient. There is convincing pathological evidence for incomplete or absent neointimal healing, as well as hypersensitivity reactions. This finding underscores the importance of sustained dual antiplatelet therapy beyond the initial manufacturers’ recommendations. Nonetheless, these potential hazards are offset against the more common, but not necessarily benign, risks of BMS restenosis.1 The Academic Research Consortium has classified stent thromboses according to the relative certainty of the diagnosis. Definite thrombosis includes angiographic confirmation of total occlusion of the target vessel (as occurred in our patient) or intrastent thrombus. Probable thrombosis is defined as acute MI in the target vessel territory, while possible thrombosis is any unexplained death in a patient with a history of previous DES implantation.2 Based upon our Medline-OVID literature search using keywords “stent”, “late thrombosis” and “myocardial infarction”, we believe our patient to represent the most delayed presentation of definite stent thrombosis, as defined above. Pathophysiology. LST and prevention of in-stent restenosis represent two sides of the double-edged sword of DES neointimal inhibition. While insufficient endothelialization predisposes a patient to thrombosis, excessive neointima results in scarring or in-stent restenosis. Platelet adhesion to foreign surfaces such as stent struts results from binding of von Willebrand’s factor, glycoproteins-Ib and Ia/IIa, as well as collagen. Subsequently, activated platelets are linked into an aggregate meshwork by glycoprotein IIb/IIIa, serotonin and fibrinogen, resulting in thrombosis.3 Endothelial proliferation is triggered by loss of contact inhibition from adjacent cells. At 6 months, pathological specimens demonstrate neointimal surface areas of 30 mm2 and 10­–15 mm2 for BMS and DES, respectively.4 In one series, angioscopic evaluation at 6 months demonstrated complete endothelialization in 100% of BMS, but only a striking 13.3% of DES.5 Guagliumi and coinvestigators found that at 16 months, DES exhibit only 80% endothelial coverage, with significant platelet and fibrin deposition. Conversely, BMS were 90% endothelialized, with virtually no platelet or visible fibrin.6 Hypersensitivity may be an underrecognized component of stent thrombosis, especially LST. Allergic reactions can occur with both the anti-inflammatory agent sirolimus, as well the antineoplastic compound paclitaxel. Virmani and colleagues previously reported autopsy findings of a 58-year-old male from the E-SIRIUS (European-SIRIUS) trial who suffered fatal LST 18 months post-SES placement. Aneurysmal dilatation and local hypersensitivity reaction were evident in the stented segment. The polymer matrix was thus postulated to be the culprit compound, as sirolimus is non-detectable beyond 60 days. This unintended positive remodeling thus created a thrombogenic gap between the stent struts and vascular wall.7 Subsequently, other isolated reports of aneurysm-associated DES LST have surfaced.8,9 Reports of LST. The presentation of stent thrombosis is frequently catastrophic. In their large series, Kuchulakanti and colleagues found 38 cases of DES thrombosis in 2,974 patients (1.27%). Stent thrombosis conferred a mortality rate of 31% versus 3% for the comparator nonthrombosis group.10 In the e-Cypher (electronic-Cypher) registry, clinical predictors of stent thrombosis were identified as acute coronary syndrome, advanced age, reduced TIMI flow grade, multicoronary intervention, chronic total occlusions, calcified lesions and insulin-dependent diabetes mellitus.11 Unfortunately, there is significant overlap with risk factors for BMS restenosis, further complicating appropriate patient selection. Those individuals most likely to benefit from DES are also at higher risk for LST. Baim presented data pooled from randomized trials involving 3,445 PES patients, demonstrating a 0.5% increase of LST over BMS patients (p = 0.02). However, there were no cumulative increases in MI or deaths (cardiac or noncardiac); he thus theorized that this small excess in thrombotic risk was offset by the 10% absolute reduction in reintervention.12 Chen described a patient who experienced acute MI from DES LST 14 months post implantation. DAT was withheld for upcoming colonoscopy; unfortunately, the patient suffered from the coronary event prior to the procedure.13 Another interesting report outlined 2 cases of DES LST at 11 and 12 months post implantation, after antiplatelet therapy cessation. Ironically, in both patients, preexisting BMS in other vessels were widely patent.14 The French literature reported 1 case of LST 27 months post implantation immediately after inguinal herniorrhaphy. Preoperatively, DAT had been replaced by the nonsteroidal anti-inflammatory agent flurbiprofen, as recommended by their scientific societies.15 Other cases of LST have occurred from 1 year,16 17 months17 and 2 years18 after the intervention, almost always associated with recent discontinuation of either clopidogrel or DAT. A recent Japanese series of 725 SES cases found 4 cases of LST at 60, 180, 215 and 508 days. Three patients died, and all but 1 were in the setting of DAT interruption.19 Moreover, in a literature search by Artang and coworkers, they analyzed 845 cases of LST and found the median deployment-to-LST duration to be 242 days (range from 39 to 927 days). Additionally, if DAT or clopidogrel alone were discontinued, the median time from therapy interruption to LST were 7 and 30 days, respectively.20 Henderson and Gunalingam further presented a patient with LST 41 months after SES implantation. The patient had continued dual antiplatelet therapy for 6 months post procedure, with aspirin monotherapy thereafter. Reintervention with a PES was successful and followed by indefinite combined aspirin/clopidogrel therapy.21 To our knowledge, this case represented the most delayed instance of LST aside from our patient. While some may debate the similar decision to redeploy another DES in our patient, we felt there may have been a restenotic component. While the available data strongly suggest an increased risk of DES LST after termination of antiplatelet therapy, LST occurred almost 2 years after clopidogrel cessation in our patient. Albeit rare, LST has also been demonstrated in non-DES patients. Manjappa and colleagues described 1 case of BMS LST at day 717.22 Another report delineated a young patient who underwent balloon angioplasty for BMS LST at 1 year after 1 month of ticlopidine and aspirin therapy. She resumed DAT for 9 months thereafter and suffered yet another LST 2 months later. Subsequent hematologic workup revealed no prothrombotic disorders.23 In addition, covered stent thrombosis has likewise been reported 52 days post implantation.24 Conclusion. The specter of DES LST has clearly had an impact on clinical decision making for the interventional cardiologist. The counterbalancing 10–15% absolute reduction in target lesion revascularization as well as the resultant lower periprocedural MI rate have conferred neutral major adverse cardiac event (MACE) rates for DES in most trials and series. The estimated excess risk of DES LST beyond the first year appears to be 0.2–0.6% per year.25 Clearly, patients with a higher likelihood of antiplatelet medication discontinuation due to upcoming surgery or other compliance issues should be considered for BMS implantation. Moreover, clopidogrel, even in its generic form, may be cost-prohibitive for financially-challenged patients. Accordingly, in their series, Spertus and coauthors found predictors of early DAT discontinuation to include lack of high school graduation, preexisting coronary history, advanced age, single marital status, lack of cardiac rehabilitation referral and lack of discharge instructions. These patients had a 10-fold mortality increase in the initial 12 months.26 On December 7th and 8th, 2006, the Food and Drug Administration’s Circulatory System Devices Panel issued guidelines regarding DES safety and efficacy. First, DES use is associated with a real, albeit rare, increased incidence of LST, which not infrequently results in potentially fatal MI. Additionally, prolonged and uninterrupted dual antiplatelet therapy with clopidogrel and aspirin for at least 1 year is strongly recommended in patients without an excessive bleeding risk. However, when these devices are used for “on-label” indications, they dramatically reduce in-stent restenosis without evidence of excesses in cumulative DES-related MI or mortality rates. By strict criteria, “on-label” uses include treatment of symptomatic patients with native coronary stenoses of 27 Finally, our patient’s DES LST presentation was somewhat atypical. Although he was only on aspirin monotherapy at the time, he had discontinued clopidogrel almost 2 years prior. It is only speculative whether continued dual antiplatelet therapy would have prevented this event. Unfortunately, indefinite continuation of such treatment in all DES patients would be infeasible. In addition, the time interval from DES implantation to thrombosis was longer than previously reported. This case serves as a sobering reminder of the rare, but potentially continuous, devastating threat of DES LST. References 1. Stone GW, Ellis SG, Colombo A, et al. Offsetting impact of thrombosis and restenosis on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare metal stent implantation. Circulation 2007;115:2842–2847. 2. Faxon DP. Debate: Should drug-eluting stent use be curtailed in the milieu of mounting safety concerns? Transcatheter Cardiovascular Therapeutics Annual Meeting 2006. Washington, D.C. 3. Boden WE. Understanding systemic atherothrombosis: pathophysiology and epidemiology of risk in Long-term Antiplatelet Therapy: Patient Selection, Therapeutic Choices. (monogram) 2006. Academy of Healthcare, Inc. 4. Hong MK, Mintz GS, Lee CW, et al. Asian Paclitaxel-Eluting Stent Clinical Trial Investigators. Paclitaxel coating reduces in-stent intimal hyperplasia in human coronary arteries: A serial volumetric intravascular ultrasound analysis from the Asian Paclitaxel-Eluting Stent Clinical Trial (ASPECT). Circulation 2003;107:517–520. 5. Kotani J-I, Awata M, Nanto S, et al. Incomplete neointimal coverage of sirolimus-eluting stents: Angioscopic findings. J Am Coll Cardiol 2006;47:2108–2111. 6. Guagliumi G, Farb A, Musumeci G, et al. Images in cardiovascular medicine. Sirolimus-eluting stent implanted in human coronary artery for 16 months: Pathological findings. Circulation 2003;107:1340–1341. 7. Virmani R, Guagliumi G, Farb, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: Should we be cautious? Circulation 2004;109:701–705. 8. Aziz S, Morris JL, Perry RA. Late stent thrombosis associated with coronary aneurysm formation after sirolimus-eluting stent implantation. J Invasive Cardiol 2007;19:E96–E98. 9. Nilsen DW, Melberg T, Larsen AI. Late complications following the deployment of drug eluting stents. Int J Cardiol 2006;109:398–401. 10. Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006;113:108–1113. 11. Urban P, Gershlick AH, Guagliumi G, et al. Safety of coronary sirolimus-eluting stents in daily clinical practice: One-year follow-up of the e-Cypher registry. Circulation 2006;113:1434–1441. 12. Baim DS. Update-DES stent thrombosis and long-term safety profile. (Monogram) 2006. 13. Chen JP. Late Angiographic Stent Thrombosis (LAST): The cloud behind the drug-eluting stent silver lining? J Invasive Cardiol 2007;19:395–400. 14. Stabile E, Cheneau E, Kinnaird T, et al. Late thrombosis in Cypher stents after the discontinuation of antiplatelet therapy. Cardiovasc Rad Med 2004;5:173–176. 15. Digne F, Gerardin B, Pilliere R, et al. Very late intrastent thrombosis—At 27 months! Archives des Maladies du Coeur et des Vaisseaux 2007;100:217–220. 16. Chrissoheris MP, Mruthyunjayanna V, Donohue TJ. Late thrombosis of drug-eluting stents after discontinuation of clopidogrel: Report of two cases and review of the literature. Connecticut Medicine 2006;70:485–490. 17. Karvouni E, Korovesis S, Katritsis DG. Very late thrombosis after implantation of sirolimus eluting stent. Heart 2005;91:e45–e47. 18. Kruth P, Heer T, Senges J. Acute myocardial infarction after discontinuing aspirin two years after implantation of a drug-eluting stent. Deutsche Medizinische Wochenschrift 2007;132:201–204. 19. Takahashi S, Kaneda H, Tanaka S. Late angiographic stent thrombosis after sirolimus-eluting stent implantation. Circulation 2007;71:226–228. 20. Artang R, Dieter RS. Analysis of 36 reported cases of late thrombosis in drug-eluting stents placed in coronary arteries. Am J Cardiol 2007;99:1039–1043. 21. Henderson D, Gunalingam B. Very late stent thrombosis of a sirolimus-eluting stent. Catheter Cardiovasc Interv 2006;68:406–408. 22. Manjappa N, Agarwal A, Cavusoglu E, et al. Very late bare-metal stent thrombosis. A case report and review of the literature. J Invasive Cardiol 2006;18:E203–E206. 23. Kitazume R, Yasuga Y, Hayasi N, et al. Young woman with repeated late stent thrombosis: A case report. J Cardiol 2005;45:19–26. 24. Kwok OH, Ng W, Chow WH. Late stent thrombosis after successful rescue of a major coronary artery rupture with polytetrafluoroethylene-covered stent. J Invasive Cardiol 2001;13:391–394. 25. Wijns W. Analysis of DES safety concerns. Transcatheter Cardiovascular Therapeutics Annual Meeting 2006. Washington, D.C. 26. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: Results from the PREMIER registry. Circulation 2006;113:2803–2809. 27. U.S. Food and Drug Administration CDRH. Update to FDA Statement on Coronary Drug-Eluting Stents. http://www.fda.gov/cdrh/news/010407.html. 2007.