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European Heart Journal Advance Access originally published online on November 29, 2006
European Heart Journal 2007 28(1):26-32; doi:10.1093/eurheartj/ehl412
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

The long-term value of sirolimus- and paclitaxel-eluting stents over bare metal stents in patients with diabetes mellitus

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; online publish-ahead-of-print 29 November 2006.

* Corresponding author. Tel: +31 10 4635260; fax: +31 10 4369154. E-mail address: p.w.j.c.serruys{at}erasmusmc.nl


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
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 mechanisms of action of both drugs it is currently unknown which device is the best option to treat these high-risk patients.

Methods and results The study compares the 2-year clinical outcome of 708 consecutive diabetic patients (25% insulin treated) treated with either a BMS (n = 252), a SES (n = 206), or a PES (n = 250), as part of the RESEARCH and T-SEARCH registries. Target vessel revascularization was 19.5% in the BMS group, vs. 15.3% in the SES group and 9.7% in the PES group. PES (21.2%), but not SES (28.9%), were superior to BMS (29.7%) in reducing major adverse cardiac events. After propensity analyses, none of the differences remained significant. The incidence of stent thrombosis (ST) was high in both DES groups.

Conclusion There was a trend towards a more favourable outcome associated with the use of PES over BMS. There was no significant difference between SES and PES in each of the clinical endpoints, and neither in the NIDDM patients, which are hypothesized to be better-off with PES.

Key Words: Diabetes • Sirolimus-eluting stent • Paclitaxel-eluting stent • Restenosis


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 
Patients with diabetes mellitus (DM) are known to have a higher incidence of mortality and cardiovascular disease compared with non-diabetic patients.1 Major reasons are the more diffuse and accelerated form of atherosclerosis, accompanied by longer lesion lengths, smaller vessel size, and greater plaque burden.2–5 Insulin-requiring diabetics are, especially, more susceptible to adverse cardiac events.6

Several trials that pre-date the drug-eluting stent (DES) era showed that the event-free survival was significantly higher in patients treated with coronary artery bypass surgery over percutaneous coronary intervention (PCI) with balloon angioplasty or bare metal stents (BMS), mainly due to the high restenosis rates, inability to fully revascularize multiple ischaemic areas, and the rapid progression of atherosclerosis.7–11 To date, both sirolimus- and paclitaxel-eluting stents (SES and PES) proved to be more effective in reducing restenosis and target vessel revascularization (TVR) in diabetic patients when compared with BMS up until 1 year of follow-up in several retrospective subset analysis of randomized controlled trials and small single-centre experiences.12–16 Whether besides these benefits, the long-term hard clinical endpoints as mortality and myocardial infarction (MI) remain comparable between both groups remains questionable.17,18.

Of interest is that patients with type II diabetes exhibit a breakdown in the PI3-kinase insulin signal transduction pathway, the pathway in which mammalian target of rapamycin (mTOR) is involved.19 It can be hypothesized that in this situation, inhibiting protein synthesis by blocking mTOR with rapamycin may be less effective. Paclitaxel conversely, inhibits signalling downstream, independent of insulin resistance. Whether this hypothesis can be translated into clinical practice remains puzzling and is currently illustrated by various studies focusing on differences between SES and PES in selected patients up to 1 year of follow-up.20–22 Our goal is to present the 2-year clinical outcome of 708 consecutive diabetic patients treated with a BMS, SES, or a PES.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
Study design and patient population
In April 2002, our institution began to use SES (Cypher®; Cordis Corporation, Warren, NJ, USA) as a default strategy for all patients undergoing PCI. In February 2003, the PES (Taxus, Boston Scientific Corp., Natick, MA, USA) replaced the SES as the default treatment. From April 2002 to February 2003, 206 consecutive patients were treated exclusively with SES. From February 2003 to April 2004, 250 consecutive DM patients received a PES. A group of 252 consecutive diabetic patients treated with BMS immediately before April 2002 were retrospectively selected as a control group. The present diabetic population (n = 708) comprises 20% of the patients treated within the framework of the consecutive and similarly designed RESEARCH and T-SEARCH registries, which are described elsewhere.23,24 Patients were eligible for inclusion if they were undergoing pharmacological treatment with either insulin or hypoglycaemic agents at the time of the index procedure and patients with transient hyperglycaemia were not included in the present analysis.

The protocol was approved by the hospital Ethics Committee and is in accordance with the Declaration of Helsinki. Written informed consent was obtained from every patient.

Procedures and post-intervention medications
All procedures were performed according to standard clinical guidelines.24 Angiographic success was defined as a residual stenosis ≤ 30% by visual analysis in the presence of Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow. All patients were pretreated with 300 mg of clopidogrel. At least 1-month of clopidogrel treatment (75 mg/day) was recommended for patients treated in the BMS phase. Patients who received a PES were prescribed ≥ 6 months of clopidogrel (75 mg/day), and those who received an SES were prescribed clopidogrel for ≥ 3 or 6 months depending on the complexity of the procedure.25 All patients were advised to maintain aspirin (≥80 mg/day) lifelong.

Endpoint definitions and clinical follow-up
DM was defined by the presence of therapy: patients taking solely oral medication were classified as non-insulin dependent diabetes mellitus (NIDDM) and those on insulin therapy as insulin-dependent diabetes mellitus (IDDM).

The primary endpoint was the occurrence of major cardiac events, defined as a hierarchical composite of all-cause death, non-fatal MI, or TVR. MI was diagnosed by an increase in creatine kinase-MB fraction of greater than three times the normal upper limit.26 Target lesion revascularization (TLR) was defined as a repeat intervention (surgical or percutaneous) to control a luminal stenosis within the stent or in the 5-mm proximal or distal segments adjacent to the stent. TVR was defined as a re-intervention of a lesion in the same epicardial vessel. Subacute angiographic stent thrombosis was defined as an angiographically documented complete occlusion (TIMI grade 0 or 1 flow) or a flow-limiting thrombus (TIMI grade 1 or 2 flow) in the first 30 days after a successful procedure. Late-stent thrombosis was defined as angiographically defined thrombosis (TIMI grade 0 or 1 flow or the presence of a flow-limiting thrombus) occurring at least 1 month after DES implantation accompanied by acute symptoms.27 Creatinine clearance was used as the measure of renal function with the baseline creatinine clearance calculated from most recent preprocedural creatinine value according to the formula proposed by Cockcroft and Gault.28 Hypercholesterolaemia was defined as a fasting serum cholesterol level > 5.5 mmol/L or use of lipid-lowering therapy at the time of the procedure.29

Two-year follow-up data
Survival data for all patients were obtained from municipal civil registries. A health questionnaire was subsequently sent to all living patients with specific questions on re-hospitalization and major adverse cardiac events. Patients treated with BMS or SES were contacted at 6 months, 1 year, and 2 years post-procedure, whereas patients treated with PES were contacted at 1 and 2 year(s) post-procedure. All repeat interventions and re-hospitalizations were prospectively collected during follow-up and entered into a dedicated database. When needed, referring physicians and institutions were contacted for additional information. Finally, follow-up was available for 98% of the patients in both DES groups and for 97% in the BMS group.

Statistical analysis
Continuous variables are presented as mean ± SD. Categorical variables are expressed as counts and percentages. Comparisons among the three groups were performed by the F-test from an analysis of variance for continues variables and Pearson's {chi}2 test for categorical variables. The cumulative incidence of adverse events was estimated according to the Kaplan–Meier method and the log-rank test was used to evaluate differences between groups. Cox proportional hazards regression analysis was performed to correct for independent predictors of adverse events. Independent predictors, using all the baseline and procedural characteristics listed in Tables 1 and 2, were determined for each of the endpoints in the three compared groups (SES vs. BMS; SES vs. PES; PES vs. BMS). Independent predictors of outcome (P < 0.1), were forced into the model, together with the stent-type (= crude hazard ratios) and the assumptions of the proportional hazards model were tested using Omnibus tests of model coefficients. In order to avoid chance predictors, all predictors were carefully evaluated and none of them was in contrast to previously known risk factors. Control of potential confounders was attempted by constructing a propensity score using logistic regression.30 The propensity score was the probability that a patient would receive either a BMS, an SES, or a PES, and was computed using an extensive, non-parsimonious, logistic regression model including the following variables: age, gender, clinical presentation, previous PCI, previous MI, previous coronary artery bypass surgery, multivessel disease, hypertension, dyslipidaemia, family history of coronary artery disease, smoking, diabetes, creatinine clearance, body mass index (BMI), glycoprotein IIb/IIIa inhibitor use, bifurcation treatment, vessel treated (RCA, LAD, LCX, LM, bypass graft), lesion type, chronic total occlusion, average stent diameter, number of stents, and total stented length. The selection of the variables was made so as to get the best discriminating model as assessed by the C-statistics. Covariate interactions and higher-order terms for the continuous variables proved unnecessary for the balance of baseline characteristics across quintiles. In the PES vs. BMS comparison, the propensity score became significant in the model for which we deleted the first quintile. In the PES vs. SES comparison, we deleted the fifth quintile. The resulting propensity score was then included in the Cox proportional hazards model as a continuous variable. The final results are presented as adjusted HRs. Patients lost to follow-up were considered at risk until the date of last contact, at which point they were censored. In all cases, P < 0.05 was considered significant. Statistical analysis were performed with SPSS 12.0.2 for Windows (SPSS Inc., Chicago IL, USA).


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  		Table 1 Baseline clinical characteristics

 

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  		Table 2 Angiographic and procedural characteristics

 

   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
Baseline and procedural characteristics
Baseline, angiographic, and procedural characteristics are included in Tables 1 and 2. There were more patients requiring insulin treatment in both DES groups: 31% (SES), 28% (PES), than in the BMS group (18%), P < 0.002. Both hypertension and hypercholesterolaemia increased over time and so was the presence of multivessel disease and the duration of clopidogrel prescription. The complexity of the procedures also increased over time, reflected by the treatment of type C lesions, incidence of multivessel treatment, number of stented vessels, number of implanted stents, total stented length, average stent diameter, and treatment of chronic total occlusions.

Two-year follow-up
Two-year cumulative incidence of mortality was comparable among the three groups: 9.8% in the BMS group vs. 13.3% and 11.5% in the SES and PES groups, respectively (Figure 1A). However, a significantly higher number of patients in the SES group died in the second year: 12 (5.8%) when compared with only three (1.2%) in the PES group (P = 0.007). Eight patients (3,2%) died in the second year in the BMS group. MI was more frequent in the BMS (7.7%) and SES (5.1%) groups when compared with the PES group (3.4%) (P = 0.048 PES vs. BMS). The cumulative incidence of the combined endpoint of death and MI occurred in 15.4% of the BMS patients, vs. 18.2% and 14.7% of the SES and PES patients, respectively (P = 0.33 SES vs. PES). TLR was performed in a remarkably low percentage of PES patients (5.3%) when compared with the BMS (15.6%) and SES (13.2%) patients (P = 0.0037 SES vs. PES; P = 0.0004 PES vs. BMS). Also, TVR was significantly lower in the PES group (9.7%) when compared with the BMS group (19.5%) (P = 0.0034). The cumulative incidence of TVR in the SES group was 15.3% and was neither inferior to PES (P = 0.06) nor superior to BMS (P = 0.97) (Figure 1B). The composite endpoint of MACE was found in 29.7% of the BMS patients, almost comparable with the SES group, in which a 28.9% incidence of MACE was found. MACE rates in the PES group (21.2%) were significantly lower when compared with the BMS group (29.7%), P = 0.04 (Figure 1C). Of interest was the high incidence of ST, which occurred in 4.4% of the SES patients (3.4% early ST) compared with 2.4% in the PES group (2.0% early ST) and only 0.8% in the BMS group (0.8% early ST) (P-values: SES vs. BMS, 0.015; PES vs. BMS, 0.18; SES vs. PES, 0.29). Of the total 17 patients with ST, two died, seven presented with an MI, and 12 patients were still on dual-antiplatelet therapy at the time of the event.


Figure 4121
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  		Figure 1 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 PES, respectively.

 
When patients were classified with respect to the use of insulin, the cumulative incidence of mortality was significantly higher in IDDM patients (16.7%) compared with the NIDDM patients (9.6%); (P = 0.013). TVR was performed in a comparable number of IDDM patients (17.1%) as in NIDDM patients (14.1%); (P = 0.36). Comparing TVR rates in the NIDDM patients (Figure 1D), the outcomes remained comparable to those of the overall population, showing no significant superiority of PES to SES.

Cox multivariable regression models were used to correct for differences and independent predictors of adverse events between each pair of groups (SES vs. BMS; PES vs. BMS; and PES vs. SES) (Table 3). After correcting for independent predictors of adverse events, the use of PES remained significantly superior to BMS in terms of TVR at both 1 (HR 0.66; 95% CI 0.49–0.89) and 2 years (HR 0.69; 95% CI 0.53–0.89), and MACE at 2 years (HR 0.75; 95% CI 0.60–0.94). The use of SES was neither significantly superior to BMS nor significantly inferior to PES. Of interest was that when the propensity score was added to the models, none of the comparisons remained significant although a trend remained towards a better outcome with PES when compared with both BMS and SES.


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  		Table 3 Multivariable predictors of major adverse cardiac events at 2 years (Cox proportional hazards model)

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
The present study, comprising a series of 708 consecutive diabetic patients, showed that in contrast to the SES-treated patients, the crude relative risk for both TVR and MACE was significantly lower in the PES group over the BMS group, at 2 years of clinical follow-up. However, after propensity analyses, these differences did not remain significant. Although hypothesized, PES was not superior to SES in the NIDDM subset in reducing TVR or MACE. When compared with IDDM, NIDDM was associated with a better long-term survival.

The 2-year event-free survival rate in this diabetic subset was 24.8%, irrespective of the stent type used, and was substantially lower than reported in DES trials including a general population.31–33 This latter confirms again the detrimental effect of DM on the prognosis following PCI, despite the use of DES in the majority of our patients.34

Both SES and PES have been shown to be superior to BMS in patients with DM up until 1 year of follow-up.15,16 In a randomized trial by Dibra et al., there was no significant difference between both devices in any of the clinical endpoints at 9 months of follow-up, despite the superiority of SES in reducing late lumen loss and binary restenosis.20 A meta-analyses of randomized trials comparing either SES or PES to BMS showed that when the diabetic subsets were pooled, the use of SES was associated with a 65% reduction in in-stent restenosis compared with PES, albeit there was again no significant difference between both SES and PES in reducing TVR and MACE.35 Because of its clinical approach, the present report is not completely comparable to these previous studies with angiographic primary endpoints, which show that inconsistencies between clinical and angiographic endpoints are far from being resolved. Nevertheless, our results are in line with other registries. The STENT registry, including 1680 diabetic patients, confirmed the comparable results achieved with both devices at 9 months of follow-up and the SOLACI registry showed even lower TVR rates in diabetics treated with PES, compared to those treated with SES.21,36

Stent thrombosis in both DES arms was high (SES: 4.4%, PES: 2.4%) when compared with the BMS patients (0.8%). Studies focusing on the incidence of ST following treatment with DES in a general population, reported ST rates of 1.0–1.6% and depicted diabetes as an independent predictor of ST.27,37 The present report emphasizes the need for longer-term follow-up and confirms that ST, mainly in the DES-treated patients, continues to occur after 6–12 months of follow-up.38 As 78% of the patients with ST were still on dual-antiplatelet therapy, lifelong prescription of clopidogrel, additionally associated with higher bleeding risks, higher costs, and a potential of clopidogrel resistance, does not seem warranted.39–41 Nevertheless, we feel that these numbers should encourage researchers to continue to follow their patients and not to stop their follow-up when the initial (≤1 year) results look promising.

Of interest are the mechanisms of action of both drugs. Sirolimus is a natural macrocyclic lactone that is capable of inhibiting the mTOR and blocking the cell-cycle during the transition from G1 to S phase.42 mTOR is dependent of the PI3-kinase pathway, which is hypothesized to be degraded in insulin-resistant diabetics.19 This latter suggests SES to be less effective in diabetic patients (comprising ~70% NIDDM). Paclitaxel on the other hand stabilizes microtubules, which are known to be responsible for cell division, and acts completely independent of the PI3-kinase pathway. This hypothesis is partly supported by the results of the present study. We observed an almost identical occurrence of MACE in the SES and BMS groups, providing some evidence for the non-superiority of SES in diabetics. Although many would refer to previously published studies, which did 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 coronary syndrome, chronic total occlusions, and (un)protected left main (LM) stenosis, but also the typical diabetics with diffuse disease in multiple vessels, requiring extensive revascularization were often excluded.12,14,15 In this study, these high-risk patients comprised ~60% of the present population. Although we were not able to show a superiority of PES over SES, there were two interesting findings. First, MACE rates were significantly higher in the SES group when compared with the PES group at 1 year (propensity analysis), which is in agreement with NIDDM arm, the large-scale STENT registry.43 Secondly, there was a significantly higher mortality rate during the second year in the SES group. Although this difference could be due to ST, focusing on the combined endpoint of death and MI revealed comparable rates in all three groups, especially when correcting for independent predictors. Moreover, it has to be commented that the overall mortality rate (11.4%) in the present population was higher than reported in previous trials and is most likely related to the high complexity of the present population. Excluding patients presenting with multivessel disease, LM lesions and presentation with acute myocardial infarction resulted in a 2-year mortality rate of only 7.6%.

The present study suffers from the inherent limitations of a non-randomized trial. The compared groups were not completely identical, which was mainly due to the relatively large inclusion period in which the complexity of the procedures increased. In order to partly compensate for the differences in baseline characteristics, with an increasing risk over time, we performed a multivariable analysis and a propensity analysis. Thereby, the TLR rate might be less accurate in predicting clinical restenosis compared with a non-diabetic population, since diabetic patients are known to have a significantly greater incidence of silent ischaemia than non-diabetics and the lack of an angiographic follow-up.44 Finally, ST related only to angiographically document ST, using a definition consistent with previous reports on ST either after DES or BMS implantation. This latter may have led to an underestimation of the actual incidence of ST, particularly, in patients suffering from sudden cardiac death or silent stent occlusion.

Nevertheless, this report focuses on the 2-year ‘clinical’ outcome of the unrestricted use of BMS, SES, and PES in diabetic patients in a ‘real world’ setting and demonstrates the importance of longer-term follow-up. More larger scale and randomized trials are needed to elucidate the best treatment for patients with DM and the possible superiority of one DES compared to another, also taking into account the long-term adverse events like ST.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
Although there was a trend towards lower MACE rates in the PES group at 2 years of clinical follow-up, the superiority of both SES and PES over BMS in diabetic patients remains questionable. There was no significant difference between SES and PES in the NIDDM patients, who are hypothesized to be better-off with PES, and ST was more frequent in both DES groups.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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