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European Heart Journal Advance Access published November 29, 2006
The long-term value of sirolimus- and paclitaxel-elutingstents over bare metal stents in patients with diabetesmellitus Joost Daemen, Hector M. Garcia-Garcia, Neville Kukreja, Farshad Imani, Peter P.T. de Jaegere,Georgios Sianos, Ron T. van Domburg, and Patrick W. Serruys* Thoraxcenter, Erasmus Medical Center, Ba-583 Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands Received 23 August 2006; revised 8 October 2006; accepted 9 November 2006 Aims To investigate the outcome of a real world diabetic patient cohort treated with bare metal stents (BMS), sirolimus-, or paclitaxel-eluting stents (SES and PES, respectively). Due to the different mechan- isms of action of both drugs it is currently unknown which device is the best option to treat these high- Methods and results The study compares the 2-year clinical outcome of 708 consecutive diabeticpatients (25% insulin treated) treated with either a BMS (n ¼ 252), a SES (n ¼ 206), or a PES(n ¼ 250), as part of the RESEARCH and T-SEARCH registries. Target vessel revascularization was19.5% in the BMS group, vs. 15.3% in the SES group and 9.7% in the PES group. PES (21.2%), but notSES (28.9%), were superior to BMS (29.7%) in reducing major adverse cardiac events. After propensityanalyses, none of the differences remained significant. The incidence of stent thrombosis (ST) washigh in both DES groups.
Conclusion There was a trend towards a more favourable outcome associated with the use of PES overBMS. There was no significant difference between SES and PES in each of the clinical endpoints, andneither in the NIDDM patients, which are hypothesized to be better-off with PES.
the long-term hard clinical endpoints as mortality andmyocardial infarction (MI) remain comparable between Patients with diabetes mellitus (DM) are known to have a both groups remains questionable.17,18.
higher incidence of mortality and cardiovascular disease Of interest is that patients with type II diabetes exhibit a compared with non-diabetic patients.1 Major reasons are breakdown in the PI3-kinase insulin signal transduction the more diffuse and accelerated form of atherosclerosis, pathway, the pathway in which mammalian target of rapa- accompanied by longer lesion lengths, smaller vessel size, mycin (mTOR) is involved.19 It can be hypothesized that in and greater plaque burden.2–5 Insulin-requiring diabetics this situation, inhibiting protein synthesis by blocking are, especially, more susceptible to adverse cardiac events.6 mTOR with rapamycin may be less effective. Paclitaxel con- Several trials that pre-date the drug-eluting stent (DES) versely, inhibits signalling downstream, independent of era showed that the event-free survival was significantly insulin resistance. Whether this hypothesis can be translated higher in patients treated with coronary artery bypass into clinical practice remains puzzling and is currently surgery over percutaneous coronary intervention (PCI) with illustrated by various studies focusing on differences balloon angioplasty or bare metal stents (BMS), mainly due between SES and PES in selected patients up to 1 year of to the high restenosis rates, inability to fully revascularize follow-up.20–22 Our goal is to present the 2-year clinical multiple ischaemic areas, and the rapid progression of outcome of 708 consecutive diabetic patients treated with atherosclerosis.7–11 To date, both sirolimus- and paclitaxel- eluting stents (SES and PES) proved to be more effective inreducing restenosis and target vessel revascularization(TVR) in diabetic patients when compared with BMS up until 1 year of follow-up in several retrospective subsetanalysis of randomized controlled trials and small single- centre experiences.12–16 Whether besides these benefits, In April 2002, our institution began to use SES (Cypherw; CordisCorporation, Warren, NJ, USA) as a default strategy for all patientsundergoing PCI. In February 2003, the PES (Taxus, Boston Scientific * Corresponding author. Tel: þ 31 10 4635260; fax: þ 31 10 4369154.
E-mail address: [email protected] Corp., Natick, MA, USA) replaced the SES as the default treatment.
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected] From April 2002 to February 2003, 206 consecutive patients were were contacted for additional information. Finally, follow-up was treated exclusively with SES. From February 2003 to April 2004, 250 available for 98% of the patients in both DES groups and for 97% in consecutive DM patients received a PES. A group of 252 consecutive diabetic patients treated with BMS immediately before April 2002were retrospectively selected as a control group. The present diabeticpopulation (n ¼ 708) comprises 20% of the patients treated within the framework of the consecutive and similarly designed RESEARCH andT-SEARCH registries, which are described elsewhere.23,24 Patients Continuous variables are presented as mean + SD. Categorical vari- were eligible for inclusion if they were undergoing pharmacological ables are expressed as counts and percentages. Comparisons among treatment with either insulin or hypoglycaemic agents at the time the three groups were performed by the F-test from an analysis of of the index procedure and patients with transient hyperglycaemia variance for continues variables and Pearson’s x2 test for categori- were not included in the present analysis.
cal variables. The cumulative incidence of adverse events was esti- The protocol was approved by the hospital Ethics Committee and mated according to the Kaplan–Meier method and the log-rank test is in accordance with the Declaration of Helsinki. Written informed was used to evaluate differences between groups. Cox proportional consent was obtained from every patient.
hazards regression analysis was performed to correct for indepen-dent predictors of adverse events. Independent predictors, using Procedures and post-intervention medications all the baseline and procedural characteristics listed in Tables 1and 2, were determined for each of the endpoints in the three com- All procedures were performed according to standard clinical guide- pared groups (SES vs. BMS; SES vs. PES; PES vs. BMS). Independent lines.24 Angiographic success was defined as a residual stenosis 30% predictors of outcome (P , 0.1), were forced into the model, by visual analysis in the presence of Thrombolysis In Myocardial together with the stent-type (¼crude hazard ratios) and the Infarction (TIMI) grade 3 flow. All patients were pretreated with assumptions of the proportional hazards model were tested using 300 mg of clopidogrel. At least 1-month of clopidogrel treatment Omnibus tests of model coefficients. In order to avoid chance pre- (75 mg/day) was recommended for patients treated in the BMS dictors, all predictors were carefully evaluated and none of them phase. Patients who received a PES were prescribed 6 months of was in contrast to previously known risk factors. Control of potential clopidogrel (75 mg/day), and those who received an SES were pre- confounders was attempted by constructing a propensity score using scribed clopidogrel for 3 or 6 months depending on the complexity logistic regression.30 The propensity score was the probability that a of the procedure.25 All patients were advised to maintain aspirin patient would receive either a BMS, an SES, or a PES, and was com- puted using an extensive, non-parsimonious, logistic regressionmodel including the following variables: age, gender, clinical pres- Endpoint definitions and clinical follow-up entation, previous PCI, previous MI, previous coronary arterybypass surgery, multivessel disease, hypertension, dyslipidaemia, DM was defined by the presence of therapy: patients taking solely family history of coronary artery disease, smoking, diabetes, creati- oral medication were classified as non-insulin dependent diabetes nine clearance, body mass index (BMI), glycoprotein IIb/IIIa inhibitor mellitus (NIDDM) and those on insulin therapy as insulin-dependent use, bifurcation treatment, vessel treated (RCA, LAD, LCX, LM, bypass graft), lesion type, chronic total occlusion, average stent The primary endpoint was the occurrence of major cardiac diameter, number of stents, and total stented length. The selection events, defined as a hierarchical composite of all-cause death, non- of the variables was made so as to get the best discriminating model fatal MI, or TVR. MI was diagnosed by an increase in creatine as assessed by the C-statistics. Covariate interactions and higher- kinase-MB fraction of greater than three times the normal upper order terms for the continuous variables proved unnecessary for limit.26 Target lesion revascularization (TLR) was defined as a the balance of baseline characteristics across quintiles. In the PES repeat intervention (surgical or percutaneous) to control a luminal vs. BMS comparison, the propensity score became significant in stenosis within the stent or in the 5-mm proximal or distal segments the model for which we deleted the first quintile. In the PES vs.
adjacent to the stent. TVR was defined as a re-intervention of a SES comparison, we deleted the fifth quintile. The resulting propen- lesion in the same epicardial vessel. Subacute angiographic stent sity score was then included in the Cox proportional hazards model thrombosis was defined as an angiographically documented com- as a continuous variable. The final results are presented as adjusted plete occlusion (TIMI grade 0 or 1 flow) or a flow-limiting thrombus HRs. Patients lost to follow-up were considered at risk until the date (TIMI grade 1 or 2 flow) in the first 30 days after a successful pro- of last contact, at which point they were censored. In all cases, cedure. Late-stent thrombosis was defined as angiographically P , 0.05 was considered significant. Statistical analysis were per- defined thrombosis (TIMI grade 0 or 1 flow or the presence of a flow- formed with SPSS 12.0.2 for Windows (SPSS Inc., Chicago IL, USA).
limiting thrombus) occurring at least 1 month after DES implan-tation accompanied by acute symptoms.27 Creatinine clearancewas used as the measure of renal function with the baseline creati-nine clearance calculated from most recent preprocedural creati- nine value according to the formula proposed by Cockcroft andGault.28 Hypercholesterolaemia was defined as a fasting serum cholesterol level .5.5 mmol/L or use of lipid-lowering therapy atthe time of the procedure.29 Baseline, angiographic, and procedural characteristics areincluded in Tables 1 and 2. There were more patients requir- ing insulin treatment in both DES groups: 31% (SES), 28%(PES), than in the BMS group (18%), P , 0.002. Both hyper- Survival data for all patients were obtained from municipal civil regis- tension and hypercholesterolaemia increased over time tries. A health questionnaire was subsequently sent to all living and so was the presence of multivessel disease and the patients with specific questions on re-hospitalization and major duration of clopidogrel prescription. The complexity of the adverse cardiac events. Patients treated with BMS or SES were con- procedures also increased over time, reflected by the treat- tacted at 6 months, 1 year, and 2 years post-procedure, whereaspatients treated with PES were contacted at 1 and 2 year(s) post- ment of type C lesions, incidence of multivessel treatment, procedure. All repeat interventions and re-hospitalizations were number of stented vessels, number of implanted stents, prospectively collected during follow-up and entered into a dedi- total stented length, average stent diameter, and treatment cated database. When needed, referring physicians and institutions Long-term outcome of SES and PES in diabetics Clinical presentationStable angina, n (%) Angiographic and procedural characteristics Total stented length per patient (mm + SD) Chronic total occlusion (.3 months), n (%) Angiographic success of all lesions, n (%) Values are means + SD or percentages.
aExpressed as percentage of patients with vessel type treated. Total exceeds 100%.
bExpressed as percentage of patients with lesion type. Total exceeds 100%.
with only three (1.2%) in the PES group (P ¼ 0.007). Eight Two-year cumulative incidence of mortality was comparable patients (3,2%) died in the second year in the BMS group.
among the three groups: 9.8% in the BMS group vs. 13.3% and MI was more frequent in the BMS (7.7%) and SES (5.1%) 11.5% in the SES and PES groups, respectively (Figure 1A).
However, a significantly higher number of patients in the (P ¼ 0.048 PES vs. BMS). The cumulative incidence of the SES group died in the second year: 12 (5.8%) when compared combined endpoint of death and MI occurred in 15.4% of Two-year cumulative incidence of mortality (A), TVR (B), major adverse cardiac events (C), and TVR in NIDDM (D), in patients treated with BMS, SES, or the BMS patients, vs. 18.2% and 14.7% of the SES and PES died, seven presented with an MI, and 12 patients were patients, respectively (P ¼ 0.33 SES vs. PES). TLR was per- still on dual-antiplatelet therapy at the time of the event.
formed in a remarkably low percentage of PES patients When patients were classified with respect to the use of (5.3%) when compared with the BMS (15.6%) and SES insulin, the cumulative incidence of mortality was signifi- (13.2%) patients (P ¼ 0.0037 SES vs. PES; P ¼ 0.0004 PES cantly higher in IDDM patients (16.7%) compared with the vs. BMS). Also, TVR was significantly lower in the PES NIDDM patients (9.6%); (P ¼ 0.013). TVR was performed in group (9.7%) when compared with the BMS group (19.5%) a comparable number of IDDM patients (17.1%) as in NIDDM (P ¼ 0.0034). The cumulative incidence of TVR in the SES patients (14.1%); (P ¼ 0.36). Comparing TVR rates in the group was 15.3% and was neither inferior to PES (P ¼ 0.06) NIDDM patients (Figure 1D), the outcomes remained com- nor superior to BMS (P ¼ 0.97) (Figure 1B). The composite parable to those of the overall population, showing no sig- endpoint of MACE was found in 29.7% of the BMS patients, almost comparable with the SES group, in which a 28.9% Cox multivariable regression models were used to correct incidence of MACE was found. MACE rates in the PES group for differences and independent predictors of adverse (21.2%) were significantly lower when compared with the events between each pair of groups (SES vs. BMS; PES vs.
BMS group (29.7%), P ¼ 0.04 (Figure 1C). Of interest was BMS; and PES vs. SES) (Table 3). After correcting for inde- the high incidence of ST, which occurred in 4.4% of the SES pendent predictors of adverse events, the use of PES patients (3.4% early ST) compared with 2.4% in the PES remained significantly superior to BMS in terms of TVR at group (2.0% early ST) and only 0.8% in the BMS group (0.8% both 1 (HR 0.66; 95% CI 0.49–0.89) and 2 years (HR 0.69; early ST) (P-values: SES vs. BMS, 0.015; PES vs. BMS, 0.18; 95% CI 0.53–0.89), and MACE at 2 years (HR 0.75; 95% CI SES vs. PES, 0.29). Of the total 17 patients with ST, two 0.60–0.94). The use of SES was neither significantly superior Long-term outcome of SES and PES in diabetics Multivariable predictors of major adverse cardiac events at 2 years (Cox proportional hazards model) MACE (Death, MI, and TVR) at 2 years (%)a aCrude HRs without propensity scores.
to BMS nor significantly inferior to PES. Of interest was that and angiographic endpoints are far from being resolved.
when the propensity score was added to the models, none of Nevertheless, our results are in line with other registries.
the comparisons remained significant although a trend The STENT registry, including 1680 diabetic patients, con- remained towards a better outcome with PES when com- firmed the comparable results achieved with both devices at 9 months of follow-up and the SOLACI registry showedeven lower TVR rates in diabetics treated with PES, com- Stent thrombosis in both DES arms was high (SES: 4.4%, The present study, comprising a series of 708 consecutive PES: 2.4%) when compared with the BMS patients (0.8%).
diabetic patients, showed that in contrast to the SES- Studies focusing on the incidence of ST following treatment treated patients, the crude relative risk for both TVR and with DES in a general population, reported ST rates of MACE was significantly lower in the PES group over the 1.0–1.6% and depicted diabetes as an independent predictor BMS group, at 2 years of clinical follow-up. However, after of ST.27,37 The present report emphasizes the need for propensity analyses, these differences did not remain signifi- longer-term follow-up and confirms that ST, mainly in the cant. Although hypothesized, PES was not superior to SES in DES-treated patients, continues to occur after 6–12 the NIDDM subset in reducing TVR or MACE. When compared months of follow-up.38 As 78% of the patients with ST were with IDDM, NIDDM was associated with a better long-term still on dual-antiplatelet therapy, lifelong prescription of clopidogrel, additionally associated with higher bleeding The 2-year event-free survival rate in this diabetic subset risks, higher costs, and a potential of clopidogrel resistance, was 24.8%, irrespective of the stent type used, and was sub- does not seem warranted.39–41 Nevertheless, we feel that stantially lower than reported in DES trials including a these numbers should encourage researchers to continue general population.31–33 This latter confirms again the detri- to follow their patients and not to stop their follow-up mental effect of DM on the prognosis following PCI, despite when the initial (1 year) results look promising.
the use of DES in the majority of our patients.34 Of interest are the mechanisms of action of both drugs.
Both SES and PES have been shown to be superior to BMS in Sirolimus is a natural macrocyclic lactone that is capable patients with DM up until 1 year of follow-up.15,16 In a ran- of inhibiting the mTOR and blocking the cell-cycle during domized trial by Dibra et al., there was no significant differ- the transition from G1 to S phase.42 mTOR is dependent of ence between both devices in any of the clinical endpoints the PI3-kinase pathway, which is hypothesized to be at 9 months of follow-up, despite the superiority of SES in degraded in insulin-resistant diabetics.19 This latter suggests reducing late lumen loss and binary restenosis.20 A SES to be less effective in diabetic patients (comprising meta-analyses of randomized trials comparing either SES 70% NIDDM). Paclitaxel on the other hand stabilizes micro- or PES to BMS showed that when the diabetic subsets were tubules, which are known to be responsible for cell division, pooled, the use of SES was associated with a 65% reduction and acts completely independent of the PI3-kinase pathway.
in in-stent restenosis compared with PES, albeit there was This hypothesis is partly supported by the results of the again no significant difference between both SES and PES present study. We observed an almost identical occurrence in reducing TVR and MACE.35 Because of its clinical of MACE in the SES and BMS groups, providing some evidence approach, the present report is not completely comparable for the non-superiority of SES in diabetics. Although many to these previous studies with angiographic primary end- would refer to previously published studies, which did points, which show that inconsistencies between clinical prove this superiority, one has to realize that these studies included only highly selected patients not reflecting daily clinical practice. Not only patients presenting with acute cor-onary syndrome, chronic total occlusions, and (un)protected 1. Grundy SM, D’Agostino Sr RB, Mosca L, Burke GL, Wilson PW, Rader DJ, Cleeman JI, Roccella EJ, Cutler JA, Friedman LM. Cardiovascular risk left main (LM) stenosis, but also the typical diabetics with assessment based on US cohort studies: findings from a National Heart, diffuse disease in multiple vessels, requiring extensive revas- Lung, and Blood Institute Workshop. Circulation 2001;104:491–496.
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Conflict of interest: none declared.
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Source: http://www.bostonscientific.com.br/news/European_Heart_Journal.pdf