Incidence, Predictors and Outcome of Drug-Eluting Stent Thrombosis in Real-World Practice

ABSTRACT: Background. Traditionally, stent thrombosis (STH) has been regarded as a complication of percutaneous coronary interventions during the first 30 post-procedural days. However, delayed endothelialization associated with the implantation of drug-eluting stents (DES) may extend the risk of thrombosis beyond 30 days. Data are limited regarding the risks and the impact of this phenomenon outside clinical trials. Objectives. To evaluate the incidence, predictors and clinical outcomes of STH and premature discontinuation of thienopyridines after implantation of DES in real-world practice. Methods. We prospectively collected data from consecutive unselected patients who underwent at least 1 DES implantation at our center from February 2006 until January 2007. The patients were followed by a phone interview or by collecting data from admission files over the course of 2 years after the implantation. Confirmed and suspected STH was defined as accepted in the medical literature. Results. Three hundred fourteen patients were successfully treated with DES (436 lesions). At 20 ± 6.7 months’ follow up (median 22 months), 14 patients (4.4%) had STH (incidence density 2.7 cases/100 patients-years). Five patients had early thrombosis (0–30 days), 5 patients had late STH (31–360 days from the procedure) and 4 patients had very late STH (> 360 days). Five of the 14 patients with STH died (case fatality rate, 36%). In multivariant logistic regression analysis, history of a non-cardiac thrombotic event was a risk factor for STH (p = 0.006, odds ratio [OR] 7.7, confidence interval [CI] 1.8–32.9). Clopidogrel therapy lasting less than 3 months was an independent predictor of late and very late STH (p = 0.001, OR 10.8, CI 2.7–42.9). Independent predictors of early discontinuation of thienopyridines (less than or equal to 3 months) were Arab ethnic origin (p = 0.005, OR 19.2, CI 2.4-142), absence of cardiology follow up (p = 0.05, OR 4.7, CI 1–23.1) and absence of explanation about the clopidogrel importance at the time of hospital discharge (p = 0.001, OR 10.8, CI 2.7–42.9). Conclusions. The incidence of STH at 22-month follow up in real-world patients was substantially higher than the rate reported in previous clinical trials. Subsidizing the cost of thienopyridines, providing a clear explanation to the patient and encouraging cardiology follow up may prevent premature discontinuation of thienopyridines after implantation of DES and reduce the incidence of STH after DES implantation. J INVASIVE CARDIOL 2010;22:461–464 ———————————————————————————————————— In recent years, the introduction of drug-eluting stents (DES) during percutaneous coronary intervention (PCI) has been one of the major breakthroughs in interventional procedures. Several observational and randomized studies have shown a significantly lower restenosis rate and a reduction in the need for repeat revascularization with DES compared with bare-metal stents (BMS).^1–4 Despite theoretical concerns that DES could be associated with higher rates of stent thrombosis (STH) due to delayed endothelialization, the randomized studies and registries confirmed the efficacy and safety of DES were not powered to detect any increase in STH.^1–8 Subsequent studies suggested that the use of DES might be associated with an increase in the rate of STH when compared with BMS.^9–14 These cases have raised concerns that the STH rate may be higher in the population treated outside of controlled clinical trials. Four studies have assessed the incidence of early and late STH during prospective follow up of DES implantations performed outside of controlled clinical trials. In three studies the incidence of STH was 1%,¹⁵ 1.3%¹⁶ and 1.35%,¹⁷ respectively, during 6–18 months of follow up. This rate was nearly similar to historical reports with BMS (0.5–1.9%).¹⁸ In the ERACI 3 study, over 36 months of follow up, the rate of STH in DES was 3.1%.¹⁹ In a large two-institutional cohort study, definite STH occurred with an incidence of 1/100 patient-years and a cumulative incidence of 2.9% at 3 years and 3.3% at 4 years.^20,21 STH with DES is unexpected and can occur either early after hospital discharge or very late in the follow-up phase when many patients have discontinued antiplatelet therapy.^9–17,19 The risk of STH after DES implantation is related to acute coronary syndrome (ACS), younger age, paclitaxel-eluting stent use,^20,21 stent length,^6,8 premature antiplatelet therapy discontinuation, renal failure and lower ejection fraction.¹⁶ It still remains uncertain whether DES alter the risk of STH. Therefore, we sought to prospectively investigate the incidence of STH in a non-selected DES population in a “real-word” practice and to find clinical and angiographic risk factors for STH.

Methods

Patients. This prospective study included all unselected patients who underwent implantation of at least 1 DES at the Rambam Health Care Campus from February 2006 until January 2007. There were no exclusion criteria. Follow-up. Patients were followed by telephone contact. When patients could not be contacted, major efforts were made to contact family members and the treating physician. Medical records regarding hospitalization in our hospital or any other hospital in Israel were reviewed. Survival data were obtained from the national mortality register. All patients or their families were contacted at least 12 months following implantation. Stent thrombosis. Stent thrombosis (STH) was defined following the recommendation of the Academic Research Consortium ARC.²² Definite STH required the presence of an ACS with angiographic or autopsy evidence of coronary thrombus or occlusion. Probable STH included patients who experienced unexpected cardiac sudden death or had an ST-segment elevation myocardial infarction (STEMI) involving the target-vessel territory. For the purpose of this study, total STH was defined as the total of definite and probable STH. STH was then classified as early (0–30 days after stent implantation), late (31–360 days) and very late (> 360 days). Percutaneous coronary intervention. PCI was performed according to standard techniques. Glycoprotein IIb/IIIa platelet inhibitors were given according to physician preference. The decision to implant a DES as opposed to a BMS was made according to the instruction of the Israeli Ministry of Health and the recommendation of the Israeli Society of Interventional Cardiology at the time. In general, DES as opposed to BMS were implanted for the following indications: 1) lesion at high clinical risk (such as a left main lesion); 2) patients at relatively high risk for restenosis (such as patients with diabetes mellitus). The decision to use a specific DES was made according to operator preference or availability. Antiplatelet prescription. Patients not receiving antiplatelet treatment prior to DES implantation were given aspirin >/= 100 mg prior to the procedure and clopidogrel >/= 300 mg prior to or immediately after the procedure. All patients were advised to maintain daily aspirin 100 mg lifelong and to take clopidogrel 75 mg daily for 1 year. Statistical analysis. Quantitative variables are presented as mean ± standard deviation. We calculated the risk of STH as the number of thrombotic events that occurred during the clinical follow up divided by the number of individuals at risk. Two group comparisons were performed using Fisher’s exact test or Pearson’s chi-square test for categorical variables and the Mann-Whitney U-test for quantitative variables. All p-values were two-tailed with statistical significance set at 0.05. Predictors with a p-value less than or equal to 0.1 were entered in a multivariate logistic regression analysis to test the independence of these predictors. Analysis was performed using SPSS software version 15.0 (SPSS, Inc., Chicago, Illinois).

Results

Baseline characteristics and in-hospital outcomes. The study population included 314 consecutive patients receiving 436 DES. Clinical characteristics are listed in Table 1. Sirolimus-eluting stents (SES) were implanted in 194 lesions in 149 patients. Paclitaxel-eluting stents (PES) were implanted in 181 lesions in 133 patients, and zotarolimus-eluting stents (ZES) were implanted in 61 lesions in 50 patients. All stents were deployed successfully. There were no significant differences between the stent groups regarding procedural complications and in-hospital outcomes. Twenty-seven patients (8.5%) received 1 or more BMS in addition to the DES. Characteristics of the index procedures are listed in Table 2. During hospitalization, 3 patients (1%) developed a new STEMI and another 5 patients (1.6%) were diagnosed as having a N-STEMI. All 3 STEMIs were due to early STH of a DES and were treated immediately by PCI with no deaths. There was 1 in-hospital death, which was not caused by STH. At discharge, all patients were treated with clopidogrel and 97.5% were on dual antiplatelet therapy. Follow up. No patient was lost to follow up. Mean follow up was 20 ± 6.7 months (median 22 months, maximal 32 months). Fourteen patients developed STH during follow up (cumulative incidence 4.4%, incidence density 2.7 cases/100 patients-years). Ten patients (3.1%) died during follow up. Death was related to STH in 5 patients (50%). One patient died after coronary artery bypass graft and 4 patients died from non-cardiac causes. The incidence of N-STEMI during the follow up was 9.8%, and the clinical restenosis rate was 4.1%, 12 ± 6 months after DES implantation. Timing and clinical outcome of stent thrombosis. Five patients had early STH, 5 had late and 4 had very late STH. Early STH occurred at 1, 2, 3, 5 and 10 days after implantation. Late or very late STH occurred after a median period of 9 months (range 1.5–29 months). Five cases of STH (35.7%) presented as sudden death and 9 cases (64.3%) as STEMI. Angiographic documentation of coronary artery thrombosis was available in 8 of the 14 patients with STH. Among the 14 cases of STH, 9 occurred while on dual antiplatelet therapy (5 cases were early, 3 cases were late and 1 was very late STH), and 5 while on single antiplatelet therapy. Among the 208 patients (66.2%) who discontinued clopidogrel at some point during follow up, five patients developed STH. Mean time from discontinuing clopidogrel therapy to STH was 8.1 ± 9.3 months (median 6 months, range 1–24 months). Predictors of stent thrombosis. In multivariate logistic regression analysis, a past history of non cardiac thrombotic event prior to stent implantation was an independent predictor of total STH (p = 0.006, OR 7.7, CI 1.8–32.9). Clopidogrel therapy Antiplatelet therapy during the follow up. Twenty-eight patients (10.4%) discontinued clopidogrel therapy within 3 months of stent implantation. By multivariable logistic regression, discontinuing clopidogrel therapy within 3 months was related to non Jewish status (OR 19.2, CI 2.4–142, p = 0.005.), lack of follow up by a cardiologist (OR 4.7, CI 1–23.1, p = 0.05), and lack of proper explanation about the importance of taking clopidogrel by the medical staff at the time of discharge from the hospital (OR 10.8, CI 2.7–42.9, p = 0.001). By 12 months, 173 patients (64.3%) had discontinued clopidogrel therapy. Bleeding and non-cardiac invasive procedures. Sixty-two patients (19.7%) on dual antiplatelet therapy experienced bleeding events. Eighty-five percent of those events were minor. Seven patients (2.2%) were hospitalized due to bleeding and 6 patients (1.9%) required blood transfusions. Five patients (1.6%) stopped clopidogrel therapy due to bleeding. Twenty-six patients (8.3%) underwent a non-cardiac invasive procedure during the follow-up period. Twelve of the 26 patients (46%) stopped clopidogrel therapy before the procedure. No STH was related to that temporary discontinuation. One of the 14 patients who did not stop clopidogrel before endoscopic colon polypectomy was admitted with acute rectal bleeding and required blood transfusions.

Discussion

In a cohort of consecutive patients undergoing DES implantation, we noted a cumulative STH incidence of 4.4% for a median follow up of 22 months. The incidence density of STH was 2.7 cases/100 patients-years. Half of all deaths recorded during follow up in our group were due to STH, emphasizing the importance of this complication and of its prevention. Ten patients had STH within 1 year of implantation (3.2%), and 4 patients had very late STH (later than 1 year following implantation). These rates are substantially higher than those reported in major clinical trials with DES. For example, Moreno et al. reported DES rates in ten randomized studies comparing DES versus BMS. Rates of STH in DES patients varied between 0–2% with a mean of 0.58% for a follow up of 6–12 months.⁶ Van Werkum et al. and Spaulding reported STH rates of 2% and 3.6% for a mean follow up of 30.9 months and 1,440 days, respectively.^9,23 Planer et al. evaluated the long-term (3.4 years) outcomes of 488 patients receiving SES in 8 Israeli centers. Using the broad definition of the Academic Research Consortium of STH,²² they noted 19 cases (4%) of definite or probable sirolimus-eluting STH, an incidence density of 0.9 cases/100 patients-years.²⁴ The relatively high rate of STH in our study may be related to the 100% follow up rate, the relatively long follow up period, the lack of participation in randomized studies and the insistence on identifying all the cases, including sudden cardiac deaths outside the hospital, that could have gone undetected. Our population included a high percentage of patients at higher risk for developing STH: 44% were diabetics, 60% had an ACS and 13% had a STEMI. Though we could not correlate these factors with an increased rate of STH in our study, the reason is probably related to the small size of our patient population. Other authors using larger populations have indicated that diabetes and ACS are among many factors associated with a higher risk of STH.^9,21 With the widespread availability of DES, the scope of PCI has been expanded to more complex lesions and patients. Another possible reason for the high rate of STH noted in our study may be related to the variable definition used in different studies. Some reports included only patients with evidence of definite STH. We included patients with definite and probable STH. Including patients with probable STH might have led to an overestimation of the true rate of STH. On the other hand, cases of STH that were presented as N-STEMI or that were clinically silent remained undetected. Thus, we believe that our observed rate of STH is probably close to the true prevalence of STH in our population. Stent implantation was performed according to accepted standards at that time. We do not believe that the high rate of STH in our study is related to inappropriate stent implantation technique. Early cessation of clopidogrel may have been a factor in causing STH in some patients.^25,26 Our study confirms this and emphasizes the need for a detailed explanation by the physician discharging the patient following DES implantation. Our study also shows the importance of follow up by a dedicated physician/cardiologist who is well aware of the importance of continuing clopidogrel for at least 1 year after DES implantation. As reported by others, we noted that STH of DES may occur in patients receiving appropriate therapy.^9,21,24 STH occurring under dual antiplatelet therapy may be related to aspirin and/or clopidogrel resistance²⁷ and may be prevented by increasing the dose of clopidogrel or by the use of other antiplatelet aggregation agents such as prasugrel.²⁸ In other patients, STH might be related to hypersensitivity to stent components and might be prevented by new developments in stent technology.²⁸ STH might also be related to local anatomic factors and be basically unavoidable, if not unpredictable, on an individual basis.²⁶ We noted that a past history of a non-cardiac thrombotic event was a predictor of STH. The literature contains few reports of thrombotic complications such as hyperhomocysteinemia, protein C and S deficiencies, factor 5 leiden and primary antiphospholipid syndrome determining stent thrombosis.^29–31 This may be related to a personal genetic or environmental tendency to a hypercoagulable state and may raise the role of activation of intrinsic or extrinsic coagulation in this process. Such patients are not common but should be identified by a careful history prior to the cardiac procedure. Dual antiplatelet therapy increases the rate of bleeding. The incidence of minor and major bleeding was 19.7% and 2.2%, respectively. Minor bleeding most often involved the skin. Patients with major bleeding were hospitalized and 85% received transfusions. All bleeding events were treated successfully. Eight percent of patients underwent invasive procedures during follow up. The risk of STH should be weighed against the risk for bleeding. Although there are cases of STH after temporary discontinuation of clopidogrel before invasive procedures, in our study, 46.2% of the patients stopped clopidogrel therapy before the procedure and there were no STH. One patient who did not stop clopidogrel therapy experienced rectal bleeding after an endoscopic polypectomy. Subsequent randomized trials will be critically important.

Conclusions

STH was detected in 4.4% of a consecutive real-word, high-risk patients receiving a DES during a median follow up period of 22 months. We should be cautious about implanting DES in patients with a history of a non-cardiac thrombotic event. Better patient selection and meticulous attention to dual antiplatelet use during the first year after implantation might reduce this serious and often lethal complication of DES implantation.

References

1. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of sirolimus-eluting stent with a standard stent of coronary revascularization. N Engl J Med 2002;346:1773–1780. 2. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents vs. standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323. 3. Stone G, Ellis S, Cox D, Hermiller J, et al. A polymer based paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350: 221–231. 4. Colombo A, Drzewiecki J, Banning A, et al. Randomized study to assess the effectiveness of slow and moderate release polymer based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003;108:788–794. 5. Bavry AA, Kumbhani DJ, Helton TJ, Bhatt DL. What is the risk of stent thrombosis associated with the use of paclitaxel eluting stent for percutaneous coronary intervention? A meta-analysis. J Am Coll Cardiol 2005;45:941–946. 6. Moreno R, Fernandez C, Hernandez R, et al. Drug-eluting stent thrombosis: Results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol 2005;45:954–959. 7. Indolfi C, Pavia M, Angelillo IF. Drug-eluting stents versus bare-metal stents in percutaneous coronary interventions. Am J Cardiol 2005;95:1146–1152. 8. Pandhi P, Shafiq N, Malhotra S. Drug-eluting stents do not increase the risk of stent thrombosis, but longer stents may be associated with greater incidence of thrombosis. Evid Based Cardiovasc Med 2005;9:184–186. 9. Van Werkum JW, Heestermans AA, Zomer AC, et al. Predictors of coronary stent thrombosis. The Dutch stent thrombosis registry. J Am Coll Cardiol 2009;53:1399–1409. 10. Listro F, Colombo A. Late acute thrombosis after paclitaxel-eluting stent implantation. Heart 2001;86:262–264. 11. Win HK, Caldera AE, Maresh K, et al. Clinical outcomes and stent thrombosis following off label use of drug-eluting stent. JAMA 2007;2001–2009. 12. McFadden EP, Stabile E, Regar E, et al Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364:1519–1521. 13. Waters RE, Kandzari DE, Phillips HR, et al. Late thrombosis following treatment of in stent restenosis with drug eluting stents after discontinuation of antiplatelet therapy. Catheter Cardiovasc Interv 2005;65:520–524. 14. Stabile E, Cheneau E, Kinnaird T, et al. Late thrombosis in cipher stents after the discontinuation of antiplatelet therapy. Cardiovasc Radiat Med 2004;5:173–176. 15. Jeremias A, Sylvia B, Bridges J, et al. Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation 2004;109:1930–1932. 16. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence predictors and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126–2130. 17. Ong AT, McFadden EP, Regar E, et al. Late angiographic stent thrombosis (LAST) events with drug eluting stents. J Am Coll Cardiol 2005;45:2088–2092. 18. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: A pooled analysis of multicenter coronary stent clinical trials. Circulation 2002; 106:1949–1956. 19. Rodriguez AE, Mieres J, Fernandez Pereira C, et al. Coronary stent thrombosis in the current drug eluting stent era: Insights from ERACI 3 trial. J Am Coll Cardiol 2006;47:205–207. 20. Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: Data from a large two institutional cohort study. Lancet 2007;369: 667–678. 21. Wenaweser P, Daemen J, Zwahlen M, et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. J Am Coll Cardiol 2008;52:1134–1140. 22. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356:1020–1029. 23. Spaulding C, Daemen J, Boersma E, et al. A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007;356:989–997. 24. Planer D, Beyar R, Almagor Y, et al. Long term outcome and predictors of clinical events after insertion of sirolimus-eluting stent in one or more native coronary arteries (from the Israeli arm of the e- Cypher registry). Am J Cardiol 2008;101:953–959. 25. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007;297:159–168. 26. Chhatriwalla AK, Bhatt DL. Should dual antiplatelet therapy after drug-eluting stent be continued for more than 1 year? Dual antiplatelet therapy after drug-eluting stent should be continued for more than 1 year and preferably indefinitely. Circ Cardiovasc Intervent 2008;1:217–225. 27. Patti G, Nusca A, Mangiacapra F, et al. Point of care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDAPRO study. J Am Coll Cardiol 2008;52:1128-1133. 28. Virmani R, Farb A, Guagliumi G, Kolodgie FD. Drug-eluting stents: Caution and concerns for long term outcome. Coron Artery Dis 2004;15:313–318. 29. Olivier AC, Hollman JL. Late in stent thrombosis in a patient with systemic lupus erythematosus and hyperhomocysteinemia while on clopidogrel and aspirin. J Invasive Cardiol 2006;18:E185–E187. 30. Acar G, Dogan A, Altinbas A, Turker Y. Recurrent acute stent thrombosis associated with protein C and S deficiencies. Int J Cardiovasc Imaging 2006;22:333–337. 31. Santos JL, Cruz I, Herrero FM, et al. Recurrent coronary thrombosis, gactor 5 leiden, primary antiphospholipid syndrome and HIV. Rev Esp Cardiol 2004;57:997–999.

———————————————————————————————————— From the Department of Cardiology, Rambam Health Care Campus and the Technion Medical School, Haifa, Israel. The authors report no conflicts of interest related to the content herein. Manuscript submitted May 21, 2010, provisional acceptance given June 23, 2010, final version accepted July 13, 2010. Address for correspondence: Miry Blich, MD, Rambam Health Care Campus, Department of Cardiology, Haalia, Haifa, 91096 Israel. E-mail: m_blich@rambam.health.gov.il