mmm BRIEF Incidence, Predictors, and Outcome of Thrombosis After Successful Implantation of Drug-Eluting Stents Toannis lakovou, MD Thomas Schmidt, MD aio Bon aD TeiGe, MD Giuseppe M. Sangiorgi, MD Gor cone, MD. Flavio Airoldi, MD Nlaide Chietfo, MD Matteo Montorfa Mauro Carlino, MD. Michev, MD MD ins N ola Corvaja, MD. ‘alo Bri Ulrich Gercken ESPITE MAJOR IMPROVE- ments in antiplatelet therapy, thrombotic events remain the primary cause of death after percutaneous coronary in- lerventions.'2Sirolimus-eluting stents and polymer-based paclitaxel-cluting stents have been shown to reduce neo- intimal hyperplasia and risk of reste- nosis without increasing the risk of stent Uhrombosis."” Operators are now us- ing drug-eluting stents for a wide va Hiety of clinical and anatomic situa- tions, many of which have not been evaluated in randomized studies." We analyzed the incidence, predictors, and For editorial comment see p 2154, Context Traditionally, stent thrombosis has been regarded as a complication of per- Ggtaneous coronary interventions during the fst 30 posprocedural dys. However, delayed endathelaization associated with the implantation of drug-eluting stents may extend the risk of thrombosis beyond 30 days. Data are limited regarding the risks and the impact of this phenomenon outside clinical trials. Objective To evaluate the incidence, predictors and clinical outcome of stent throm- bosisafterimplantation of solimus-eluting and pacitaxe-eluting stents in routine cli cal practice Design, Setting, and Patients. Prospective observational cohort study conducted at 1 academic hospital and 2 community hospitals in Germany and Italy. A total of 2229 consecutive patients underwent successful implantation of srolimus-eluting (1062, Patients, 1996 lesions, 2272 stents) or pacitaxeleluting (1167 patients, 1801 lesions, 2223 stents) stents between April 2002 and January 2004. Interventions Implantation of a drug-eluting stent (sirolimus or paclitaxel) ll pa tients were pretreated with ticlopidine or clopidogrel and aspirin. Aspirin was contin- ued indefinitely and clopidogrel or ticlapidine for at least 3 months after sirolimus- eluting and for atleast 6 months after pacltaxel-eluting stent implantation. ‘Main Outcome Measures Subacute thrombosis (rom procedure end through 30, days), late thrombosis (>30 days), and cumulative stent thrombosis. Results At 9-month follow-up, 29 patients (1.3%) had stent thrombosis (9 [0.8%] with sirolimus and 20 [1.7%] with pacitaxe; P=.09). Fourteen patients had subacute thrombosis (0.6%) and 15 patients had late thrombosis (0.7%). Among these 29 pa- tients, 13 died (case fatality rate, 45%). Independent predictors of stent thrombosis, were premature antiplatelet therapy discontinuation (hazard ratio [HR], 89.78; 95% Cl, 29.90-269.60; P-<.001), renal failure (HR, 6.49; 95% Cl, 2.60-16.15, P= 001), bifurcation lesions (HR, 6.42; 95% Cl, 2.93-14.07; P-.001), diabetes (HR, 3.71; 95% Cl, 1.74-7.89; P=.001), and alower ejection fraction (HR, 1.09; 95% Cl, 1.05-1.36; P<.001 for each 10% decrease). Conclusions The cumulative incidence of stent thrombosis 9 months after success- ful drug-eluting stent implantation in consecutive “real-world” patients was substan- tially higher than the rate reported in clinical trials. Premature antiplatelet therapy dis- continuation, renal fllue, bifurcation lesions, diabetes, and low ejection fraction were Identified as predictors of thrombotic events JAMA, 20052932126-2130 ww jamacom Author Afflation: Centro Cuore Columbus and Gr Segburg. Germany rsh Gercens and San Rafael Hosptial lan fly (Deakovou, Ce, Grube and inet of Mad Sisties snd Bom Sangor, Sarsove, Ae, Cho, Montara. Car” ey, Urey of Milan, lan tay (Or Bonzzen, froriictes, con, iguor anaColmbe Meso- Conesponding Author: Antonia Clem, MD, EMO lapum CroResearh Min ty (OrSangorg)De- Centro Cure Columbus, 48 Via Muonaret, 20185, ptmentorCardalog) KinaunSeburgRhen Seg Mua, fly (nfodemocaumbs 22426 JAMA stay 42005 Vol 293, No. 17 Reprinted) (©2005 American Medical Association. AU rights reserved Downloaded From: by a Newcastle University User on 06/02/2018clinical outcome of stent thrombosis at 9-month follow-up in an observa- tional cohort study. METHODS: We identified 2229 consecutive pa- lients who underwent successful im- plantation with sirolimus-cluting stents (2062 patients, 1996 lesions, 2272 stents) or paclitaxel-cluting stents (1167 patients, 1801 lesions, 2223 stents) be- tween April 2002 and january 2004. Pa- Lents were treated at 2community hos- pitals or 1 academichospital in Germany. and Italy. Patients with ST-elevation acute myocardial infarction (MI) less than 48 hoursbefore the procedure, with intraprocedural stent thrombosis those treated with both types of stents ‘were excluded. All patients were pre- treated with ticlopidine or clopidogrel and aspirin; a loading dose of 300 mg ‘of clopidogrel was given to patients not previously taking the agent. Aspirin was continued indefinitely and clopidogrel (oF ticlopidine for at least 3 months al- ler sirolimus-cluting stent implanta- tion and for at least 6 months alter pa cltaxel-eluting stent implantation, Stent implantation methods have been de- thed previously." Glycoprotein IIb/ La inhibitors were administered atthe physician's diseretion, Standard quali- lative and quantitative analysesand def- nitions were used for the angiographic analysis." Al patients signed an informed con- sent document and local institutional review boards approved the study as, planned. Clinical Definitions and Follow-up Stent thrombosis was determined asthe occurrence of any of the following events: angiographic documentation of partial or total stent occlusion detected. ‘within 30 days of the procedure (an acute clinical ischemic event in addi- lion toangiographic documentation had. to be present when the event occurred. alter 30 days), or sudden cardiac death ‘or postprocedural MI alter successful stent implantation not clearly autribut- able to another coronary lesion. Stent thrombosis cases were categorized ac- (©2005 American Medical Assoc 1, All rights reserved. "THROMBOSIS AFTER DRUG-ELUTING STENT IMPLANTATION cording to the timing of aceurrence into subacute (from procedure end through 30 days) and late (>30 days), Major adverse cardiac events were defined as death (all-cause), Q-wave ML target lesion revascularization, and tar- get vessel revascularization, Statistical Analysis Differences in proportions were tested with the x? or Fisher exact test. SAS ver- sion 8.2 (SAS Institute Inc, Cary, NC) was used for data analysis, ‘A otal sample of 2300 observations was computed to achieve 80% power ata 2-sided 05 significance level to de- tect a hazard ratio (HR) equal to or greater than 3.0 with a Cox regression of the log HR on a binary risk factor with a 25% or greater prevalence. The sample size was adjusted for an anti pated event rate of 1.5% Relationships of event incidence to covariates were investigated with wnt variate Cox regression models, The pro- portional hazard assumption was checked forall sereened covariates and no relevant violations were found. The predictive robustness of univariate find ings was subsequently tested by means of bootstrap subset selection method in which multivariable Cox regres- sion analysis using a stepwise elimina don process was repeated for each of 1000 bootstrap samples.” The rela- Live frequency of selection of “impor tant” variables was used as a criterion {or inclusion of predictors in the final multivariable model, Variables were re- tained if the selection frequency of the bootstrap samples was at least 50% oF Af they were clinically relevant. Be- cause of the small absolute number of events, we performed an internal va dation process to test model adequacy and quantify “overfitting The proportion of total variability was estimated by means ofthe Nagelkerke In- dex (pseudo R), which was calculated when the models were fitted to 1000 bootstrap replications (training sample) and o the original data (test sample). The Nagelkerke Index oblained from each bootstrap sample was then subtracted from the initial index value ofthe origi- nal population. The average of the dil. ferences was considered as a measure of ‘optimism in the model fit, where opti- mism is the proportion of variability ascribed to overfitting. Finally, a cor- rected index was calculated by subtract- ing the average of the optimism esti- mates from the original Nagelkerke Index. The estimates of slope shrink age, which were used to identify over- parameterized models, were obtained for the multivariable models using the same bootstrapping validation process. Thus ‘we were reassured that, although based con few events, overfitting did not sub- stantially bias out final model. RESULTS Baseline Characteristics and In-Hospital Outcomes Baseline, angiographic, and procedural characteristics are shown in Taste 1, All stents were deployed successfully. There were no significant differences be- tween the 2stent groups regarding pro- ccedural complications and in-hospital outcome. The rates for Q-waveand non Q-wave Ml were 0.3% and 99%, respee- tively. There were + in-hospital deaths, ‘of which 2 were determined to be caused by stent thrombosis. Incidence, Timing, Presentation, and Clinical Outcome of Stent Thrombosis AL9-month follow-up (available in all patients), 29 patients (1.3%) had stent thrombosis (9 [0.8%] in the sirolimus ‘group and 20 [1.7%] in the paclitaxel ‘group; P=.00). Fourteen patients had subacute thrombosis (0.6%), 4 in the sirolimus group and 10 in the pacli- taxel group (0.496 vs 0.8%; P=.19) and 15 patients had late thrombosis (0.7%), 5 in the sirolimus group and 10 in the paclitaxel group (0.5% vs 0.8%; P= 30) A total of 71% (10/14) of the sub- acute eases occurred within 1 week of the procedure (median, #days) and 53% (8/15) of the late thrombosis cases oc- curred within 3 months of the proc dure (median, 57 days). Seven cases (24%) presented as death, 20 (69%) as, nonfatal MI, and 2 (7%) as unstable angina (Reprinted) JAMA, May 4, 2005 Vol 293, No. 17 2437‘THROMBOSIS AFTER DRUG-ELUTING STENT IMPLANTATION At follow-up the case-fatality rate— including death at presentation—was 45% (13/29). Angiographic documen- 12 Table 1. Bessine Chncal- Angiographic, and Procedural haracienroer Accorang to Stent Type ‘Sirolimus Eluing Pacitaxor ating “Sent Stent lation of thrombosis was availabl (= 1002) of the 22 patients (55%) with stent 38 2} thrombosis (including both patients Bio) that presented with unstable angina) ‘Gincal characteris, No" vse! sc sgectnn N O 2a1 26) that did not present with death. In- hospital data were available forall pa ae a Lients who presented with acute ML and Hipererein Tey had no angiographic evidence of stent Fjperchoastariaa 720 (8) thrombosts Giaret oking ara i} ALO-month follow-up, target lesion, Frevous myocardal neon 7086 46) Si revascularization was performed in 141 Pea presaro THEA) ay patients (6.3%) (58 [5.5%] in the siro- —m — aT limus group vs 83 [7.196] in the pacli- — = = taxel group; P=.13). Major adverse car- dine events occurred in 242 patients Feral ane BEES) ‘ (aitverieuar qin Faction, =e Cho.) (109 [20.3] a the Hiroe went rus group vs 133 [11.4%] in the pa Teabtesl clitaxel group; P=42) Leaner descending ary 436 at) Sahenoca ven graft Tia Predictors of Stent Thrombosis eal gat 2.08) The incidence of stent thrombosis ac- ‘ions, 7996 cording to selected patient character- ascn charactrtos No istics and the univariate predictors of ‘Ostalecaton 318 (10) ‘cumulative sent thrombosis ate shown Biren 265 3) in TAnL2. Five of 17 patients with pre- al 7586 (79) matureantiplatelet therapy discontini- Taian Zra ta) ation had stent thrombosis; in 1 of them irsentrestenoae EE caly clopidogrel was discontinued. In- Prorbrecrtnarapy 75109 dependent predictors of subacute, late, and cumulative stent thrombosis are shown in TARLe 3. The key predictors ‘of stent thrombosis were premature an- tiplatelet therapy discontinuation, 208,042 3081051) nal failure, bifurcation lesions, diabe- TOES) 75a Bete (3A 7 Fracasiral characteratee, mean SD ‘imam baloon camer. mm ‘aamumbatoon lao, im ‘Sant ngih par oso, 5 tes, and low ejection fraction. For subacute thrombosis, stent length was aN. also a predictor: for each ‘Tyeoproten samt, No) 06 2) crease in length, there was 1.03 times Frocedral compteatons, No.5 sreater risk of thrombosis. iim tow 502 200.) Fert 30 Soa «COMMENT Crantiaie coomayangegamy. Ne a7 1998 Teor In a large cohort of consecutive pa- Prartansnton, cases a liens undergoing drug-eluting stent m- (lees wi besa 260071) Lantation, we noted #9-month cum. nero art ree ie) GRSOZ— auive stent thrombosis incidence of Samelesenoss, Sere) stg) 75} 1394, substantially higher than rates re- _beson/ength,mm F812 (1149) AS58119) 141011012) ported in major clinical trials (0.4% at Foster, maa srertena S eos 2005) _27eq0q 1 Year for srolimus and 0.0% at 9 —— — os ot months for paclitaxel)."® With wide- eee ea spread availability of drug-eluting Shea teres ceaha epoca mason sents the scope of percutaneous coro- a a nary intervention has been expanded 2428 JAMA stay 42005 Vol 299, No. 17 Reprinted) (©2005 American Medical Association. All rights reserved. Downloaded From: by a Newcastle University User on 06/02/2018