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Comparison of the safety between first- and second-generation drug eluting stents
International Journal of Cardiology 160 (2012) 181–186
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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Comparison of the safety between first- and second-generation drug eluting stents Meta-analysis from 19 randomized trials and 16,924 patients Roberto Martín-Reyes a,⁎, Raul Moreno b, Angel Sánchez-Recalde b, Felipe Navarro a, Juan Franco a, Antonio Piñero a, José Luis López Sendón b a b
Fundación Jiménez Díaz University Hospital,Madrid, Spain La Paz University Hospital,Madrid, Spain
a r t i c l e
i n f o
Article history: Received 7 December 2010 Received in revised form 21 March 2011 Accepted 14 April 2011 Available online 4 May 2011 Keywords: Meta-analysis Randomized controlled trials Stent thrombosis First generation drug eluting stent Second generation drug eluting stent Percutaneous coronary intervention
a b s t r a c t Background/Objective: Despite the effectiveness of first generation drug eluting stent, DES-1 (Taxus and Cypher) in avoiding restenosis and the need for new revascularizations, a slightly increase in stent thrombosis, ST have been published. Second generation drug eluting stent, DES-2 has been developed to optimize the results of percutaneous coronary intervention in terms of efficacy and safety, for avoiding early and late ST. Our objective was to compare the risk of ST between DES-1 and DES-2. Methods: We performed a meta-analysis of 19 randomized trials. Overall 16,924 patients; 7294 were allocated to DES-1 and 9630 were allocated to DES-2. The primary endpoint was to compare the risk of overall ST during the first year. Other clinical outcomes of interest were to compare the incidence of early (b 1 month) and late ST (N 1 month–b 1 year). Results: The incidence of overall ST was not increased in patients receiving DES-1 (1.13% DES-1 vs 0.75% DES2, OR 0.79, 95% CI:0.45–1.40, p 0.43). There were no significant differences in the incidence of; early ST (0.85% DES-1 vs 0.53% DES-2, OR 0.68, 95% CI:0.31–1.51, p 0.35) and late ST (0.40% DES-1 vs 0.25% DES-2, OR 0.69, 95% CI:0.39–1.24, p 0.22). Conclusions: During the first year after stent implantation, we didn't found differences in ST between DES-1 and DES-2. Most of ST was produced under appropriate anti-platelet therapy so it is possible that many other factors such as; clopidogrel resistance, procedural complications or stent malapposition were implicated. Safety after longer follow-up (N 1 year) remains unclear. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction First generation drug eluting stents (DES-1) have become the cornerstone of percutaneous coronary interventions (PCI) in the last 5 years, because these devices have demonstrated to dramatically reduce both angiographic restenosis and the need for new revascularizations in comparison with bare-metal stents in randomized trials [1–8]. This benefit is explained by inhibiting fibromuscular hyperplasia through targeted delivery of cytostatic drugs, such as sirolimus or paclitaxel, from surface coatings using durable polymers. Along with the increasing number of patients receiving DES and the availability of long-term follow-up data, concern has arisen regarding the safety of these devices. Some studies [9–14] have showed that DES1 (Cypher and Taxus), might present a slightly higher incidence of early and late stent thrombosis (ST) compared with bare metal stents. It was hypothesized that incomplete neointimal healing could preclude stent ST and thus a very low in-stent late loss (ISLL) could ⁎ Corresponding author at: Fundación Jiménez Díaz University Hospital, Avda Reyes Católicos 2, ZP: 28040, Spain. Tel.: + 34 607425611; fax: + 34 915497033. E-mail address: [email protected] (R. Martín-Reyes). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.04.004
increase the risk of ST, but recent data [15] has demonstrated that the risk of ST after DES implantation is not related to ISLL values. When compared Cypher and Taxus (DES-1), previous published metaanalysis [16] did not show statistical significant differences between both stents in terms of ST. Despite the effectiveness of DES-1, second-generation DES (DES-2) have been developed to optimize the results of PCI not only at short term (improved stent platforms) but also at long-term, by theoretically reducing the risk of stent thrombosis. Long term safety has been mainly associated with delayed vessel healing and hypersensitivity on polymer carriers. New DES presented biocompatible polymers and drugs specifically developed for local application for avoiding stent thrombosis. DES-2 include DES with new drugs (everolimus, zotarolimus, biolimus, dual DES), new stent platforms (cobalt chromium, lower strut thickness) and different polymers (absence of polymer, biodegradable polymer) (Table 1). DES-2 presented lower strut and polymer, thickness compared with DES-1. The objective of this study was to compare the risk of stent thrombosis between DES-1, and DES-2. For this purpose, a metaanalysis from 19 randomized trials comparing both types of DES was performed.
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Table 1 DES 1 and DES 2 generation features. DES
Manufacturer
Stent platform
Strut thickness (μm)
Polymer
Type of polymer
Polymer thickness (μm)
Drug (dose)
Cypher Taxus express Taxus liberte Dual-DES
Cordis Corporation Boston Scientific Boston Scientific N/A
Stainless Stainless Stainless Stainless
140 132 97 87
PEVAPMBA Translute Translute No polymer
Durable Durable Durable No polymer
13.7 17.8 17.8 None
Endeavor Xcience V Costar Nobori Yukon Biomatrix Zomaxx
Medtronic Inc Abbot Vascular Cordis Corporation Terumo Translumina GmbH Biosensors International, Ltd. Abbott Vascular
Cobalt chromium Cobalt chromium Cobalt chromium Cobalt chromium Stainless steel Stainless steel Cobalt chromium
91 81 89 120–149 87 112 81
Phosphorylcholine Fluoropolymer PLGA PLA No polymer PLA Phosphorylcholine
Durable Durable Bioabsorbable Bioabsorbable No polymer Bioabsorbable Durable
4.8 7.8 N/A N/A None N/A 5.0
Sirolimus (1.4 μg/mm2 Paclitaxel (1 μg/mm2) Paclitaxel (1 μg/mm2) Sirolimus (120 μg/cm2) + Probucol (100 μg/mm2) Zotarolimus (10 μg/mm) Everolimus (1 μg/mm2) Paclitaxel (N/A) Biolimus A9 Sirolimus Biolimus A9 (15.6 μg/mm) Zotarolimus (10 μg/mm)
steel steel steel steel
PLA, polylactic acid; PLGA, poly (lactide-co-glycolide); PEVA, polyethylene-co-vinyl acetate; PBMA, poly-n-butyl methacrylate.
2. Methods 2.1. Criteria for study selection To be selected for this meta-analysis, studies had to include patients with symptoms or objective signs of myocardial ischemia due to coronary artery disease (CAD) who were randomly allocated to receive DES-1 or DES-2. All studies had to report the outcomes of interest during a follow-up period of at least 9 months after the index procedure. DES-1 included Cypher and Taxus (Express and Liberte) stents. DES-2 included: Endeavor, Nobori, Xcience V, Yukon, Costar, Biomatrix, Dual DES and Zomaxx stents. Data sources: We searched PubMed and the Cochrane Central Register of Controlled Trials for randomized trials comparing DES-1 with DES-2 in patients with coronary artery disease. In addition, we searched conference proceedings from the American College of Cardiology, American Heart Association, and European Society of Cardiology, Transcatheter Cardiovascular Therapeutics and Paris Coronary Revascularization. Searches were restricted to the period from 2006 to May 2010. Relevant reviews and editorials from major medical journals published within the last year were identified and assessed for possible information on trials of interest. Internet based sources of information on the results of clinical trials in cardiology (http://www. theheart.org and http://www.tctmd.com) were also searched. The search was performed using the following limits: English language, randomized controlled trials, comparative studies and human trials. The keywords were: “everolimus eluting stent”, “zotarolimus eluting stent”, “biolimus eluting stent”, “rapamycin eluting stent” and “costar eluting stent”. From this sample, only19 were studies that compared ST between DES-1 and DES-2. Another trials were evaluated but were not finally included;
X-SEARCH (Xience V Stent Evaluated at Rotterdam Cardiac Hospital) registry study with only 6-month clinical follow up, DIVERGE study in bifurcations lesions, CIBELES study that include total chronic occlusion. We included 19 randomized trials; eleven trials comparing Taxus with DES-2 stents and eight trials comparing Cypher with DES-2 stents. Among all the trials [17–26], Taxus was compared with six different types of DES-2, in eleven trials including 12,319 patients; Costar II trial (1675 patients) comparing with Costar stent, Endeavor IV trial (1490 patients) and Zest AMI trial (218 patients) comparing with Endeavor stent, ISAR Test trial (450 patients) comparing with Yukon stent, Nobori I trial (360 patients) comparing with Nobori stent, Spirit II (296 patients), Spirit III (971 patients), Spirit IV (3611 patients) and Compare trial (1800 patients) comparing with Xcience V and Zomaxx I (396 patients) and II (1052 patients) comparing with Zomaxx stent. Cypher was compared in eight trials [26–31] including 4605 patients, with five different types of DES-2; the Endeavor III trial (429 patients), ISAR Test 2 (Endeavor) trial (674 patients) and Zest AMI trial (218 patients) comparing with Endeavor stent, ISAR Test 2 (Dual) (668 patients) comparing with dual DES stent (probucol and sirolimus), ISAR Test 3 (BP = Biodegradable-polymer, 404 patients) and ISAR Test 3 (PF = Polymer-free, 403 patients) comparing with Rapamycin stent, Leaders trial (1707 patients) comparing with Biomatrix stent and Nobori Core trial (102 patients) comparing with Nobori stent (Table 2). 2.2. Endpoints and outcomes The primary endpoint was to compare the difference in ST within the first year after stent implantation between DES-1 and DES-2. Other clinical outcomes of interest were to compare the incidence of early and late ST, between both types of DES.
Table 2 Baseline features and procedural outcomes among 19 trials. Trials
N = 16,908
Type of DES
Primary end point
Mean age
FU
ACS
DM
Mean LVEF
MVD
MSL (mm)
MLL (mm)
COMPARE1 COSTAR II2 ENDEAVOR III1 ENDEAVOR IV1 ISAR-TEST2 ISAR-TEST 2 (DUAL)2 ISAR-TEST 2 (ENDEA)2 ISAR-TEST 3 (BP)1 ISAR-TEST 3 (PF)1 LEADERS1 NOBORI CORE2 NOBORI I1 SPIRIT II1 SPIRIT III1 SPIRIT IV1 ZEST-AMI CYPHER1 ZEST-AMI TAXUS1 ZOMAXX1 ZOMAXX II1
1800 1675 429 1490 450 668 674 404 403 1707 102 360 296 971 3611 218 218 396 1052
Tax Liberte vs Xcience V Tax vs Costar Cyp vs Endeavor Tax vs Endeavor Tax vs Yukon Cyp vs Dual DES Cyp vs Endeavor Cyp vs Rapamycin Cyp vs Rapamycin Cyp vs Biomatrix Cyp vs Nobori Tax vs Nobori Tax vs Xcience V Tax Express vs Xcience V Tax Express vs Xcience V Cyp vs Endeavor Tax vs Endeavor Tax Express vs Zomaxx Tax Express vs Zomaxx
Mace 12 MO Mace 8 MO In segment-LLL 8 MO TVF 9 MO In stent-LLL 8MO In segment reestenosis 8MO In segment reestenosis 8M0 In stent-LLL 8MO In stent-LLL 8MO Mace 9 MO In stent-LLL 9 MO In stent-LLL 9 MO In stent-LLL 6 MO In segment-LLL 8 MO TLF 12 MO Mace 12 MO Mace 12 MO In segment-LLL 9 MO TVR 9 MO
63.2 63.6 61.4 63.5 66.7 67.0 67.0 65.7 65.9 64.5 57.1 64.3 62.0 63.0 63.3 59.8 58.5 63.0 63.0
12 MO 12 MO 12 MO 12 MO 9 MO 12 MO 12 MO 12 MO 12 MO 12 MO 12 MO 9 MO 12 MO 12 MO 12 MO 12 MO 12 MO 9 MO 9 MO
59.5%* 30.5% 52.2% 53.2% 43.0% 40.5% 41.5% 30.4% 30.5% 55.2%* 37.3% 31 .3% 28.2% 20.8% 28.1% 55.5%* 55.0%* 25.0% 33.5%
18% 28.0% 29.3% 30.8% 29% 28% 26.5% 27.5% 26.8% 24.2% 23.4% 20.6% 23.2% 29.0% 32.1% 29.0% 29.0% 24.0% 27.0%
N/A 58.2% 55.7% 57.4% 54.6% 52.5% 53.5% 54.3% 54.2% 55.6% N/A N/A N/A N/A N/A 61% 61% 65% 62%
26.5% 20.6% 38.8% 43.9% N/A 83.5% 84.5% 84.6% 82.6% 22.5% N/A 35.6% N/A N/A N/A 48.0% 46.5% 49.0% 45.0%
28.0 20.5 22.5 N/A 22.3 N/A N/A N/A N/A 24.6 24.2 18.5 N/A 22.4 21.9 28.4 28.4 21.05 20.95
16.4 15.2 14.97 13.6 12.75 14.4 14.7 14.2 14.4 14.8 14.26 11.24 13.1 14.7 14.7 N/A N/A 14.75 14.55
Abbreviations and Acronyms: Tax: Taxus, Cyp: Cypher, FU ACS: Acute coronary syndrome, LVEF: Left ventricular ejection fraction, MACE: Major cardiac adverse events, LLL: Late lumen loss, TVF: Target vessel failure, TLF: Target lesion failure, TVR: Target vessel revascularization, MO: Month, FU: Follow up, DM: Diabetes mellitus, MVD: Multivessel disease, MSL: Mean stented lesion, MLL: Mean lesion length. Stent thrombosis criteria: 1 ARC Definition, 2 Protocol definition, *Studies including STEMI.
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Fig. 1. Odds Ratio of stent thrombosis during the first year associated with DES 1 and DES 2 generation.
2.3. Definitions Most of the studies used the academic research consortium (ARC) definitions of ST. Only three of the trials used protocol criteria for ST definition because their entire protocol was completed before the later publication of the consensus Academic Research Consortium definition in 2007 [32]. We included patients with definitive and probable ST according to definitions of the ARC. Definitive ST was defined as an acute coronary syndrome with angiographic documentation of either vessel occlusion or thrombus within or adjacent to a previously successfully stented vessel. Probable ST was diagnosed in the absence of angiographic confirmation, either acute myocardial infarction in the distribution of the treated vessel or death from cardiac causes within 30 days. The trials that used protocol criteria included patients with an acute coronary syndrome and angiographic documentation of ST. The ST was classified as early and late (within or after more than 1 month after stenting procedure). 2.4. Statistical methods The review was conducted according to the Quality of reports of Meta-Analyses of Randomized clinical trials (QUOROM) recommendations [33]. The reviewer manager 5.0 (Cochrane Collaboration) and the SPSS 15.0 (Chicago, Illinois) statistical packages were used. Baseline characteristics of study patients were summarized in terms of frequencies and percentages for categorical variables and by means with standard deviations (SD) for continuous variables. The Odds Ratio (OR) for ST and their 95% confidence intervals (CI) were calculated comparing DES-1 and DES-2 rates using raw data for each study and for the pooled population (intention-to-treat basis). The pooled OR was computed with the Mantel-Haenszel method. To assess heterogeneity across trials, we used the Cochran Q test based on the pooled OR by Mantel-Haenszel. Heterogeneity was also assessed by means of an I2 statistic as proposed by Higgins et al. [34]. If no heterogeneity was presented fixed-effect model was used. If heterogeneity was presented Der Simonian and Laird random-effect model was used. A funnel plot as well as the adjusted rank correlation test, according to the method of Begg and Mazumdar, was used to assess publication bias with respect to the primary outcome of interest, stent thrombosis. Results were considered statistically significant at p b 0.05.
revascularization was a secondary end point in most of the trials. The diagnosis of stent thrombosis was based on the ARC definition in fourteen trials, whereas only five studies used protocol criteria for ST that was defined in all cases as acute coronary syndrome with angiographic documentation of stent thrombosis. Baseline characteristics and procedural outcomes are shown in Table 2. A loading dose of 300 to 600 mg of clopidogrel was administered to all patients either before or at the end of the procedure in all trials. Maintenance therapy with clopidogrel consisted of a daily dose of 75 mg. The recommended duration of clopidogrel therapy was N6 months in most trials, whereas 1 trial recommended ≥3 months and 5 studies ≥ 12 months. In all studies, patients received aspirin indefinitely. The use of IIb–IIIa glycoprotein inhibitors was left to the discretion of the physician. Overall clinical follow-up rate was 99%. Clinical follow up length was 12 months in 15 trials and 9 months in the remaining 4 studies. Routine follow-up angiography was part of the study protocol in all studies. Angiography follow up was performed in 79% of the patients. Twelve month routine follow-up angiography was performed in two trials, nine month angiography was performed in eight trials, eight month angiography was performed in eight trials and six month angiographic follow up was performed in one trial. Intravascular ultrasound (IVUS) was performed in some patients in eight trials. IVUS
3. Results 3.1. Characteristics of the patients included in the trials Our search identified 19 randomized trials, which compared DES-1 and DES-2 in 16,924 patients. Out of these patients, 7294 were allocated to DES-1 and 9630 to DES-2. The features of DES-1 and DES2 patients are shown in Table 1. Binary angiographic restenosis was the primary end point in three trials, late lumen loss at follow was the primary endpoint in eight trials and the combined incidence of death, MI, target lesion failure in one trial and target lesion revascularization was the primary endpoint in the remaining five studies. Target lesion
Fig. 2. Funnel plot and rank correlation test associated with DES 1 and DES 2 generation.
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Fig. 3. Odds Ratio of early stent thrombosis associated with DES 1 and DES 2 generation.
baseline was performed in 29% of the patients and IVUS at the follow up was performed in 19.81% of the overall patients. There were no significant differences between patients treated with the DES-1 and DES-2 regarding main entry clinical characteristics. The main inclusion criteria for percutaneous coronary intervention was stable angina in 61%, whereas 27% of the patients presented acute coronary syndrome, although only 4 trials (Compare, Leadres, Zest AMI Taxus and Zest AMI Cypher) included patients with ST segment elevation acute myocardial infarction. The mean age of the patients included was 63 years. The prevalence of diabetes mellitus was 27%, and the mean left ventricular ejection function was 57%. 3.2. Comparison between DES-1 and DES-2 in the rate of stent thrombosis The primary endpoint (ST) occurred in 83 of 7294 DES-1 patients (1.13%) and in 73 of 9630 DES-2 patients (0.75%) (OR 0.79, 95% CI:0.45– 1.40, p = 0.43) (Figs. 1 and 5). No evidence of publication bias with respect to ST was found using the Begg funnel plot and rank correlation test (Fig. 2). The rate of early and late stent thrombosis was provided in 14 trials. Early ST was presented in 52 (0.85%) of 6107 patients in DES-1 patients in comparison with 44 (0.53%) of 8240 in DES-2 patients (OR 0.68, 95% CI:0.31–1.51; p 0.35) (Figs. 3 and 5). No evidence of
publication bias with respect to ST was found using the Begg funnel plot and rank correlation test. Late ST occurred in 23 (0.40%) of 5713 patients in DES-1 in comparison with 20 (0.25%) of 7735 DES-2 patients (OR 0.69; 95% CI: 0.39–1.24; p 0.22) (Figs. 4 and 5). There was no significant heterogeneity among trials (p 0.64). No evidence of publication bias with respect to ST was found using the Begg funnel plot and rank correlation test. 3.3. Sub-analysis comparing Taxus and Xcience V When we analyzed the studies that compared the rate of ST between Taxus and Xcience V stents (Fig. 6), we found that ST was presented in 40 (1.60%) of 2493 patients in Taxus group and in 20 (0.47%) of 4185 patients in Xcience V group (OR 0.31; 95% CI: 0.18– 0.54; p b 0.0001). 4. Discussion Despite the clearly demonstrated clinical benefits of DES over BMS (mainly reduction in the need for new revascularization procedures due to a significant reduction of restenosis), the possibility of an increased risk of stent thrombosis has been always an important concern when using these devices. During the first year after stent implantation, randomized trials did not showed an increased risk of
Fig. 4. Odds Ratio of late stent thrombosis associated with DES 1 and DES 2 generation.
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Fig. 5. Rates of overall stent thrombosis, early and late stent thrombosis.
thrombosis after DES vs BMS. A slight increase (0.1–0.2% per year) in the risk of late stent thrombosis beyond 1 year after implantation has been shown in some meta-analysis [16,35,36]. Second generation DES have been developed partly to obtain improved stent platforms that could facilitate the procedure, but the possibility of a decrease in the risk of late stent thrombosis in comparison with first-generation DES has been also an important rationale for developing new stents with different drugs and/or modified kinetic release. The main finding of our study is that, at least during the first year after stent implantation, DES-2 is not associated with lower risk of stent thrombosis in comparison with DES-1. Most of the ST both with DES-1, and DES-2 occurred within the first month (early ST), when the patients were still on dual antiplatelet therapy (DAPT) so it is possible that many other factors like initial resistance to clopidogrel, procedural complications or stent malapposition could play a role in these outcomes. And this was the case with both generation DESs tested. The late ST also resulted in the same rate of ST with both generation stents probably due to longer (N6 months) duration of DAPT recommendation in most of the trials. In this meta-analysis from 19 randomized trials including more than 16,000 patients, we did not found any significant differences in the rate of stent thrombosis between DES-1 and DES-2 during the first year after stent implantation including early and late ST. However when Taxus and Xcience V stents were compared we found significant differences in terms of ST within the first year between both stent. We believe that the noted difference in ST rates relates to the differences between the two devices such as; changes in platform device (opencell, thin-strut stent frame mounted on a semicompliant balloon might result in better apposition), differences in polymer (thinner layer of polymer on the everolimus-eluting stent might also play a part) and differences in the type of drug (preclinical data have shown that the everolimus eluting stent has more rapid and more extensive endothelialisation than paclitaxel eluting stent). It may be that the potential benefit of DES-2 in safety of coronary stenting is only evident after longer follow-up periods (more than 1 year). There are currently three studies following up to 2 years that showed controversial results: Spirit III, Nobori I and Endeavor IV.
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Spirit III, Endeavor IV and Nobori I trials showed a slightly increase in the rate of very late ST in the DES-1 group that did not reach significance difference. In Spirit III trial [33] very late ST (N1 year) rate was 0.3% in Xcience group and 1% in Taxus group (p 0.34). In Nobori I trial there was no significance difference between 1st and 2nd generation DES, Nobori group presented 0% of very late ST and in the Taxus group presented a rate of very late ST of 0.8% that did not reach statistical significance difference. In Endeavor IV trial, Taxus group presented a very late ST rate (0.8%) higher than Endeavor group (0.1%) that did not reach statistical significance difference (p 0.069). In spite of longer follow up (up to 2 years) the benefits are not clear in terms of safety, between 2nd generation DESs over 1st generation DESs. Although it did not reach a statistical significant difference there seemed to be a tendency toward a high rate of very late ST in the 1st generation DES group probably due to several factors like; changes in polymer: (bioabsorbable polymer, lower permanent thickness), lower strut thickness and new drugs that could avoid incomplete neointimal healing. 4.1. Study limitations This study has some limitations. First, as with other meta-analyses, inclusion criteria may be different among all trials as we have analyzed six types of 2nd generation DESs. Second, clinical follow up was limited to 12 months in most trials, so the possibility of very late stent thrombosis necessitates a more extended follow up. However six trials have extended the follow up more than 1 year (Endeavor IV, Spirit II, Spirit III, Spirit IV, Nobori I and ISAR test 3 trial) with low risk of additional ST. Third, intravascular ultrasound was not performed in cases suffering ST, therefore the underlying mechanism of ST was not well determined. Fourth, overall ST could be underestimated due to exclusion criteria (left main, bifurcations, recent myocardial infarction, chronic total occlusions) in most of the trials. This latter could lead to a lack of power in our study. Acknowledgments We are indebted to the principal investigators of all the trials included in this meta-analysis for their contribution to publishing these trials and, in some cases for providing us some unpublished data from suffering stent thrombosis in these studies. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [37]. References [1] Morice MC, Serruys PW, Sousa JE, et al. Randomized study with the sirolimuscoated Bx velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions. A randomized comparison of a sirolimuseluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–80. [2] Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: 1315–23.
Fig. 6. Odds Ratio of stent thrombosis associated with Taxus and Xcience V stents.
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[21] Stone GW, Midei M, Newman W, et al. Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial. JAMA 2008 Apr 23;299(16):1903–13. [22] Kedhi E, Joesoef KS, McFadden E, et al. Secondgeneration everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial. Lancet Jan 16 2010;375(9710):201–9. [23] Nikolsky E, Lansky AJ, Sudhir K, et al. SPIRIT IV trial design: a large-scale randomized comparison of everolimus-eluting stents and paclitaxel-eluting stents in patients with coronary artery disease. Am Heart J Oct 2009;158(4):520–526.e2. [24] Leon MB, Mauri L, Popma JJ, et al. A randomized comparison of the ENDEAVOR zotarolimus-eluting stent versus the TAXUS paclitaxel-eluting stent in de novo native coronary lesions 12-month outcomes from the ENDEAVOR IV trial. J Am Coll Cardiol Feb 9 2010;55(6):543–54. [25] Chevalier B, Di Mario C, Neumann FJ, et al. A randomized, controlled, multicenter trial to evaluate the safety and efficacy of zotarolimus- versus paclitaxel-eluting stents in de novo occlusive lesions in coronary arteries. The ZoMaxx I trial. JACC Cardiovasc Interv Oct 2008;1(5):524–32. [26] Lee CW, Park DW, Lee SH, et al. Comparison of the efficacy and safety of zotarolimus-, sirolimus-, and paclitaxel-eluting stents in patients with STelevation myocardial infarction. Am J Cardiol Nov 15 2009;104(10):1370–6. [27] Kandzari DE, Leon MB, Popma JJ, et al. Comparison of zotarolimus-eluting and sirolimus-eluting stents in patients with native coronary artery disease a randomized controlled trial. J Am Coll Cardiol Dec 19 2006;48(12):2440–7. [28] Mehilli J, Byrne RA, Wieczorek A, et al. Intracoronary stenting and angiographic restenosis investigators-test efficacy of rapamycin-eluting stents with different polymer coating strategies (ISAR-TEST-3). Randomized trial of three rapamycineluting stents with different coating strategies for the reduction of coronary restenosis. Test efficacy of rapamycin-eluting stents with different polymer coating strategies (ISAR-TEST-3). Eur Heart J 2008;29:1975–82. [29] Windecker S, Serruys PW, Wandel S, et al. Biolimus-eluting stent with biodegradable polymer versus sirolimuseluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised noninferiority trial. Lancet 2008;372:1163–73. [30] Ostojic M, Sagic D, Beleslin B, et al. First clinical comparison of Nobori-Biolimus A9 eluting stents with Cypher-Sirolimus stents: NOBORI CORE nine months angiographic and one year clinical outcomes. EuroIntervention 2008;3:574–9. [31] Byrne RA, Kastrati A, Tiroch K, et al. 2-year clinical and angiographic outcomes from a randomized trial of polymer-free dual drug-eluting stents versus polymerbased Cypher and Endeavor [corrected] drug-eluting stents. J Am Coll Cardiol Jun 8 2010;55(23):2536–43. [32] Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344–51. [33] Moher D, Cook DJ, Eastwood S, Olkin I, Rennie S, Stroup DF. Improving the quality of reports of meta-analysis of randomised controlled trials: the QUOROM statement. Lancet 1999;354:1896–900. [34] Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002 Jun 15;21(11):1539–58. [35] Roukoz H, Bavry AA, Sarkees ML, et al. Comprehensive meta-analysis on drugeluting stents versus bare-metal stents during extended follow up. Am J Med 2009 Jun;122(6):581.e1–581.e10. [36] Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drugeluting stents: a meta-analysis of randomized clinical trials. Am J Med 2006 Dec;119(12):1056–61. [37] Shewan LG, Coats AJ. Ethics in the authorship and publishing of scientific articles. Int J Cardiol 2010;144:1–2.
Contents lists available at ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Comparison of the safety between first- and second-generation drug eluting stents Meta-analysis from 19 randomized trials and 16,924 patients Roberto Martín-Reyes a,⁎, Raul Moreno b, Angel Sánchez-Recalde b, Felipe Navarro a, Juan Franco a, Antonio Piñero a, José Luis López Sendón b a b
Fundación Jiménez Díaz University Hospital,Madrid, Spain La Paz University Hospital,Madrid, Spain
a r t i c l e
i n f o
Article history: Received 7 December 2010 Received in revised form 21 March 2011 Accepted 14 April 2011 Available online 4 May 2011 Keywords: Meta-analysis Randomized controlled trials Stent thrombosis First generation drug eluting stent Second generation drug eluting stent Percutaneous coronary intervention
a b s t r a c t Background/Objective: Despite the effectiveness of first generation drug eluting stent, DES-1 (Taxus and Cypher) in avoiding restenosis and the need for new revascularizations, a slightly increase in stent thrombosis, ST have been published. Second generation drug eluting stent, DES-2 has been developed to optimize the results of percutaneous coronary intervention in terms of efficacy and safety, for avoiding early and late ST. Our objective was to compare the risk of ST between DES-1 and DES-2. Methods: We performed a meta-analysis of 19 randomized trials. Overall 16,924 patients; 7294 were allocated to DES-1 and 9630 were allocated to DES-2. The primary endpoint was to compare the risk of overall ST during the first year. Other clinical outcomes of interest were to compare the incidence of early (b 1 month) and late ST (N 1 month–b 1 year). Results: The incidence of overall ST was not increased in patients receiving DES-1 (1.13% DES-1 vs 0.75% DES2, OR 0.79, 95% CI:0.45–1.40, p 0.43). There were no significant differences in the incidence of; early ST (0.85% DES-1 vs 0.53% DES-2, OR 0.68, 95% CI:0.31–1.51, p 0.35) and late ST (0.40% DES-1 vs 0.25% DES-2, OR 0.69, 95% CI:0.39–1.24, p 0.22). Conclusions: During the first year after stent implantation, we didn't found differences in ST between DES-1 and DES-2. Most of ST was produced under appropriate anti-platelet therapy so it is possible that many other factors such as; clopidogrel resistance, procedural complications or stent malapposition were implicated. Safety after longer follow-up (N 1 year) remains unclear. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction First generation drug eluting stents (DES-1) have become the cornerstone of percutaneous coronary interventions (PCI) in the last 5 years, because these devices have demonstrated to dramatically reduce both angiographic restenosis and the need for new revascularizations in comparison with bare-metal stents in randomized trials [1–8]. This benefit is explained by inhibiting fibromuscular hyperplasia through targeted delivery of cytostatic drugs, such as sirolimus or paclitaxel, from surface coatings using durable polymers. Along with the increasing number of patients receiving DES and the availability of long-term follow-up data, concern has arisen regarding the safety of these devices. Some studies [9–14] have showed that DES1 (Cypher and Taxus), might present a slightly higher incidence of early and late stent thrombosis (ST) compared with bare metal stents. It was hypothesized that incomplete neointimal healing could preclude stent ST and thus a very low in-stent late loss (ISLL) could ⁎ Corresponding author at: Fundación Jiménez Díaz University Hospital, Avda Reyes Católicos 2, ZP: 28040, Spain. Tel.: + 34 607425611; fax: + 34 915497033. E-mail address: [email protected] (R. Martín-Reyes). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.04.004
increase the risk of ST, but recent data [15] has demonstrated that the risk of ST after DES implantation is not related to ISLL values. When compared Cypher and Taxus (DES-1), previous published metaanalysis [16] did not show statistical significant differences between both stents in terms of ST. Despite the effectiveness of DES-1, second-generation DES (DES-2) have been developed to optimize the results of PCI not only at short term (improved stent platforms) but also at long-term, by theoretically reducing the risk of stent thrombosis. Long term safety has been mainly associated with delayed vessel healing and hypersensitivity on polymer carriers. New DES presented biocompatible polymers and drugs specifically developed for local application for avoiding stent thrombosis. DES-2 include DES with new drugs (everolimus, zotarolimus, biolimus, dual DES), new stent platforms (cobalt chromium, lower strut thickness) and different polymers (absence of polymer, biodegradable polymer) (Table 1). DES-2 presented lower strut and polymer, thickness compared with DES-1. The objective of this study was to compare the risk of stent thrombosis between DES-1, and DES-2. For this purpose, a metaanalysis from 19 randomized trials comparing both types of DES was performed.
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Table 1 DES 1 and DES 2 generation features. DES
Manufacturer
Stent platform
Strut thickness (μm)
Polymer
Type of polymer
Polymer thickness (μm)
Drug (dose)
Cypher Taxus express Taxus liberte Dual-DES
Cordis Corporation Boston Scientific Boston Scientific N/A
Stainless Stainless Stainless Stainless
140 132 97 87
PEVAPMBA Translute Translute No polymer
Durable Durable Durable No polymer
13.7 17.8 17.8 None
Endeavor Xcience V Costar Nobori Yukon Biomatrix Zomaxx
Medtronic Inc Abbot Vascular Cordis Corporation Terumo Translumina GmbH Biosensors International, Ltd. Abbott Vascular
Cobalt chromium Cobalt chromium Cobalt chromium Cobalt chromium Stainless steel Stainless steel Cobalt chromium
91 81 89 120–149 87 112 81
Phosphorylcholine Fluoropolymer PLGA PLA No polymer PLA Phosphorylcholine
Durable Durable Bioabsorbable Bioabsorbable No polymer Bioabsorbable Durable
4.8 7.8 N/A N/A None N/A 5.0
Sirolimus (1.4 μg/mm2 Paclitaxel (1 μg/mm2) Paclitaxel (1 μg/mm2) Sirolimus (120 μg/cm2) + Probucol (100 μg/mm2) Zotarolimus (10 μg/mm) Everolimus (1 μg/mm2) Paclitaxel (N/A) Biolimus A9 Sirolimus Biolimus A9 (15.6 μg/mm) Zotarolimus (10 μg/mm)
steel steel steel steel
PLA, polylactic acid; PLGA, poly (lactide-co-glycolide); PEVA, polyethylene-co-vinyl acetate; PBMA, poly-n-butyl methacrylate.
2. Methods 2.1. Criteria for study selection To be selected for this meta-analysis, studies had to include patients with symptoms or objective signs of myocardial ischemia due to coronary artery disease (CAD) who were randomly allocated to receive DES-1 or DES-2. All studies had to report the outcomes of interest during a follow-up period of at least 9 months after the index procedure. DES-1 included Cypher and Taxus (Express and Liberte) stents. DES-2 included: Endeavor, Nobori, Xcience V, Yukon, Costar, Biomatrix, Dual DES and Zomaxx stents. Data sources: We searched PubMed and the Cochrane Central Register of Controlled Trials for randomized trials comparing DES-1 with DES-2 in patients with coronary artery disease. In addition, we searched conference proceedings from the American College of Cardiology, American Heart Association, and European Society of Cardiology, Transcatheter Cardiovascular Therapeutics and Paris Coronary Revascularization. Searches were restricted to the period from 2006 to May 2010. Relevant reviews and editorials from major medical journals published within the last year were identified and assessed for possible information on trials of interest. Internet based sources of information on the results of clinical trials in cardiology (http://www. theheart.org and http://www.tctmd.com) were also searched. The search was performed using the following limits: English language, randomized controlled trials, comparative studies and human trials. The keywords were: “everolimus eluting stent”, “zotarolimus eluting stent”, “biolimus eluting stent”, “rapamycin eluting stent” and “costar eluting stent”. From this sample, only19 were studies that compared ST between DES-1 and DES-2. Another trials were evaluated but were not finally included;
X-SEARCH (Xience V Stent Evaluated at Rotterdam Cardiac Hospital) registry study with only 6-month clinical follow up, DIVERGE study in bifurcations lesions, CIBELES study that include total chronic occlusion. We included 19 randomized trials; eleven trials comparing Taxus with DES-2 stents and eight trials comparing Cypher with DES-2 stents. Among all the trials [17–26], Taxus was compared with six different types of DES-2, in eleven trials including 12,319 patients; Costar II trial (1675 patients) comparing with Costar stent, Endeavor IV trial (1490 patients) and Zest AMI trial (218 patients) comparing with Endeavor stent, ISAR Test trial (450 patients) comparing with Yukon stent, Nobori I trial (360 patients) comparing with Nobori stent, Spirit II (296 patients), Spirit III (971 patients), Spirit IV (3611 patients) and Compare trial (1800 patients) comparing with Xcience V and Zomaxx I (396 patients) and II (1052 patients) comparing with Zomaxx stent. Cypher was compared in eight trials [26–31] including 4605 patients, with five different types of DES-2; the Endeavor III trial (429 patients), ISAR Test 2 (Endeavor) trial (674 patients) and Zest AMI trial (218 patients) comparing with Endeavor stent, ISAR Test 2 (Dual) (668 patients) comparing with dual DES stent (probucol and sirolimus), ISAR Test 3 (BP = Biodegradable-polymer, 404 patients) and ISAR Test 3 (PF = Polymer-free, 403 patients) comparing with Rapamycin stent, Leaders trial (1707 patients) comparing with Biomatrix stent and Nobori Core trial (102 patients) comparing with Nobori stent (Table 2). 2.2. Endpoints and outcomes The primary endpoint was to compare the difference in ST within the first year after stent implantation between DES-1 and DES-2. Other clinical outcomes of interest were to compare the incidence of early and late ST, between both types of DES.
Table 2 Baseline features and procedural outcomes among 19 trials. Trials
N = 16,908
Type of DES
Primary end point
Mean age
FU
ACS
DM
Mean LVEF
MVD
MSL (mm)
MLL (mm)
COMPARE1 COSTAR II2 ENDEAVOR III1 ENDEAVOR IV1 ISAR-TEST2 ISAR-TEST 2 (DUAL)2 ISAR-TEST 2 (ENDEA)2 ISAR-TEST 3 (BP)1 ISAR-TEST 3 (PF)1 LEADERS1 NOBORI CORE2 NOBORI I1 SPIRIT II1 SPIRIT III1 SPIRIT IV1 ZEST-AMI CYPHER1 ZEST-AMI TAXUS1 ZOMAXX1 ZOMAXX II1
1800 1675 429 1490 450 668 674 404 403 1707 102 360 296 971 3611 218 218 396 1052
Tax Liberte vs Xcience V Tax vs Costar Cyp vs Endeavor Tax vs Endeavor Tax vs Yukon Cyp vs Dual DES Cyp vs Endeavor Cyp vs Rapamycin Cyp vs Rapamycin Cyp vs Biomatrix Cyp vs Nobori Tax vs Nobori Tax vs Xcience V Tax Express vs Xcience V Tax Express vs Xcience V Cyp vs Endeavor Tax vs Endeavor Tax Express vs Zomaxx Tax Express vs Zomaxx
Mace 12 MO Mace 8 MO In segment-LLL 8 MO TVF 9 MO In stent-LLL 8MO In segment reestenosis 8MO In segment reestenosis 8M0 In stent-LLL 8MO In stent-LLL 8MO Mace 9 MO In stent-LLL 9 MO In stent-LLL 9 MO In stent-LLL 6 MO In segment-LLL 8 MO TLF 12 MO Mace 12 MO Mace 12 MO In segment-LLL 9 MO TVR 9 MO
63.2 63.6 61.4 63.5 66.7 67.0 67.0 65.7 65.9 64.5 57.1 64.3 62.0 63.0 63.3 59.8 58.5 63.0 63.0
12 MO 12 MO 12 MO 12 MO 9 MO 12 MO 12 MO 12 MO 12 MO 12 MO 12 MO 9 MO 12 MO 12 MO 12 MO 12 MO 12 MO 9 MO 9 MO
59.5%* 30.5% 52.2% 53.2% 43.0% 40.5% 41.5% 30.4% 30.5% 55.2%* 37.3% 31 .3% 28.2% 20.8% 28.1% 55.5%* 55.0%* 25.0% 33.5%
18% 28.0% 29.3% 30.8% 29% 28% 26.5% 27.5% 26.8% 24.2% 23.4% 20.6% 23.2% 29.0% 32.1% 29.0% 29.0% 24.0% 27.0%
N/A 58.2% 55.7% 57.4% 54.6% 52.5% 53.5% 54.3% 54.2% 55.6% N/A N/A N/A N/A N/A 61% 61% 65% 62%
26.5% 20.6% 38.8% 43.9% N/A 83.5% 84.5% 84.6% 82.6% 22.5% N/A 35.6% N/A N/A N/A 48.0% 46.5% 49.0% 45.0%
28.0 20.5 22.5 N/A 22.3 N/A N/A N/A N/A 24.6 24.2 18.5 N/A 22.4 21.9 28.4 28.4 21.05 20.95
16.4 15.2 14.97 13.6 12.75 14.4 14.7 14.2 14.4 14.8 14.26 11.24 13.1 14.7 14.7 N/A N/A 14.75 14.55
Abbreviations and Acronyms: Tax: Taxus, Cyp: Cypher, FU ACS: Acute coronary syndrome, LVEF: Left ventricular ejection fraction, MACE: Major cardiac adverse events, LLL: Late lumen loss, TVF: Target vessel failure, TLF: Target lesion failure, TVR: Target vessel revascularization, MO: Month, FU: Follow up, DM: Diabetes mellitus, MVD: Multivessel disease, MSL: Mean stented lesion, MLL: Mean lesion length. Stent thrombosis criteria: 1 ARC Definition, 2 Protocol definition, *Studies including STEMI.
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Fig. 1. Odds Ratio of stent thrombosis during the first year associated with DES 1 and DES 2 generation.
2.3. Definitions Most of the studies used the academic research consortium (ARC) definitions of ST. Only three of the trials used protocol criteria for ST definition because their entire protocol was completed before the later publication of the consensus Academic Research Consortium definition in 2007 [32]. We included patients with definitive and probable ST according to definitions of the ARC. Definitive ST was defined as an acute coronary syndrome with angiographic documentation of either vessel occlusion or thrombus within or adjacent to a previously successfully stented vessel. Probable ST was diagnosed in the absence of angiographic confirmation, either acute myocardial infarction in the distribution of the treated vessel or death from cardiac causes within 30 days. The trials that used protocol criteria included patients with an acute coronary syndrome and angiographic documentation of ST. The ST was classified as early and late (within or after more than 1 month after stenting procedure). 2.4. Statistical methods The review was conducted according to the Quality of reports of Meta-Analyses of Randomized clinical trials (QUOROM) recommendations [33]. The reviewer manager 5.0 (Cochrane Collaboration) and the SPSS 15.0 (Chicago, Illinois) statistical packages were used. Baseline characteristics of study patients were summarized in terms of frequencies and percentages for categorical variables and by means with standard deviations (SD) for continuous variables. The Odds Ratio (OR) for ST and their 95% confidence intervals (CI) were calculated comparing DES-1 and DES-2 rates using raw data for each study and for the pooled population (intention-to-treat basis). The pooled OR was computed with the Mantel-Haenszel method. To assess heterogeneity across trials, we used the Cochran Q test based on the pooled OR by Mantel-Haenszel. Heterogeneity was also assessed by means of an I2 statistic as proposed by Higgins et al. [34]. If no heterogeneity was presented fixed-effect model was used. If heterogeneity was presented Der Simonian and Laird random-effect model was used. A funnel plot as well as the adjusted rank correlation test, according to the method of Begg and Mazumdar, was used to assess publication bias with respect to the primary outcome of interest, stent thrombosis. Results were considered statistically significant at p b 0.05.
revascularization was a secondary end point in most of the trials. The diagnosis of stent thrombosis was based on the ARC definition in fourteen trials, whereas only five studies used protocol criteria for ST that was defined in all cases as acute coronary syndrome with angiographic documentation of stent thrombosis. Baseline characteristics and procedural outcomes are shown in Table 2. A loading dose of 300 to 600 mg of clopidogrel was administered to all patients either before or at the end of the procedure in all trials. Maintenance therapy with clopidogrel consisted of a daily dose of 75 mg. The recommended duration of clopidogrel therapy was N6 months in most trials, whereas 1 trial recommended ≥3 months and 5 studies ≥ 12 months. In all studies, patients received aspirin indefinitely. The use of IIb–IIIa glycoprotein inhibitors was left to the discretion of the physician. Overall clinical follow-up rate was 99%. Clinical follow up length was 12 months in 15 trials and 9 months in the remaining 4 studies. Routine follow-up angiography was part of the study protocol in all studies. Angiography follow up was performed in 79% of the patients. Twelve month routine follow-up angiography was performed in two trials, nine month angiography was performed in eight trials, eight month angiography was performed in eight trials and six month angiographic follow up was performed in one trial. Intravascular ultrasound (IVUS) was performed in some patients in eight trials. IVUS
3. Results 3.1. Characteristics of the patients included in the trials Our search identified 19 randomized trials, which compared DES-1 and DES-2 in 16,924 patients. Out of these patients, 7294 were allocated to DES-1 and 9630 to DES-2. The features of DES-1 and DES2 patients are shown in Table 1. Binary angiographic restenosis was the primary end point in three trials, late lumen loss at follow was the primary endpoint in eight trials and the combined incidence of death, MI, target lesion failure in one trial and target lesion revascularization was the primary endpoint in the remaining five studies. Target lesion
Fig. 2. Funnel plot and rank correlation test associated with DES 1 and DES 2 generation.
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Fig. 3. Odds Ratio of early stent thrombosis associated with DES 1 and DES 2 generation.
baseline was performed in 29% of the patients and IVUS at the follow up was performed in 19.81% of the overall patients. There were no significant differences between patients treated with the DES-1 and DES-2 regarding main entry clinical characteristics. The main inclusion criteria for percutaneous coronary intervention was stable angina in 61%, whereas 27% of the patients presented acute coronary syndrome, although only 4 trials (Compare, Leadres, Zest AMI Taxus and Zest AMI Cypher) included patients with ST segment elevation acute myocardial infarction. The mean age of the patients included was 63 years. The prevalence of diabetes mellitus was 27%, and the mean left ventricular ejection function was 57%. 3.2. Comparison between DES-1 and DES-2 in the rate of stent thrombosis The primary endpoint (ST) occurred in 83 of 7294 DES-1 patients (1.13%) and in 73 of 9630 DES-2 patients (0.75%) (OR 0.79, 95% CI:0.45– 1.40, p = 0.43) (Figs. 1 and 5). No evidence of publication bias with respect to ST was found using the Begg funnel plot and rank correlation test (Fig. 2). The rate of early and late stent thrombosis was provided in 14 trials. Early ST was presented in 52 (0.85%) of 6107 patients in DES-1 patients in comparison with 44 (0.53%) of 8240 in DES-2 patients (OR 0.68, 95% CI:0.31–1.51; p 0.35) (Figs. 3 and 5). No evidence of
publication bias with respect to ST was found using the Begg funnel plot and rank correlation test. Late ST occurred in 23 (0.40%) of 5713 patients in DES-1 in comparison with 20 (0.25%) of 7735 DES-2 patients (OR 0.69; 95% CI: 0.39–1.24; p 0.22) (Figs. 4 and 5). There was no significant heterogeneity among trials (p 0.64). No evidence of publication bias with respect to ST was found using the Begg funnel plot and rank correlation test. 3.3. Sub-analysis comparing Taxus and Xcience V When we analyzed the studies that compared the rate of ST between Taxus and Xcience V stents (Fig. 6), we found that ST was presented in 40 (1.60%) of 2493 patients in Taxus group and in 20 (0.47%) of 4185 patients in Xcience V group (OR 0.31; 95% CI: 0.18– 0.54; p b 0.0001). 4. Discussion Despite the clearly demonstrated clinical benefits of DES over BMS (mainly reduction in the need for new revascularization procedures due to a significant reduction of restenosis), the possibility of an increased risk of stent thrombosis has been always an important concern when using these devices. During the first year after stent implantation, randomized trials did not showed an increased risk of
Fig. 4. Odds Ratio of late stent thrombosis associated with DES 1 and DES 2 generation.
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Fig. 5. Rates of overall stent thrombosis, early and late stent thrombosis.
thrombosis after DES vs BMS. A slight increase (0.1–0.2% per year) in the risk of late stent thrombosis beyond 1 year after implantation has been shown in some meta-analysis [16,35,36]. Second generation DES have been developed partly to obtain improved stent platforms that could facilitate the procedure, but the possibility of a decrease in the risk of late stent thrombosis in comparison with first-generation DES has been also an important rationale for developing new stents with different drugs and/or modified kinetic release. The main finding of our study is that, at least during the first year after stent implantation, DES-2 is not associated with lower risk of stent thrombosis in comparison with DES-1. Most of the ST both with DES-1, and DES-2 occurred within the first month (early ST), when the patients were still on dual antiplatelet therapy (DAPT) so it is possible that many other factors like initial resistance to clopidogrel, procedural complications or stent malapposition could play a role in these outcomes. And this was the case with both generation DESs tested. The late ST also resulted in the same rate of ST with both generation stents probably due to longer (N6 months) duration of DAPT recommendation in most of the trials. In this meta-analysis from 19 randomized trials including more than 16,000 patients, we did not found any significant differences in the rate of stent thrombosis between DES-1 and DES-2 during the first year after stent implantation including early and late ST. However when Taxus and Xcience V stents were compared we found significant differences in terms of ST within the first year between both stent. We believe that the noted difference in ST rates relates to the differences between the two devices such as; changes in platform device (opencell, thin-strut stent frame mounted on a semicompliant balloon might result in better apposition), differences in polymer (thinner layer of polymer on the everolimus-eluting stent might also play a part) and differences in the type of drug (preclinical data have shown that the everolimus eluting stent has more rapid and more extensive endothelialisation than paclitaxel eluting stent). It may be that the potential benefit of DES-2 in safety of coronary stenting is only evident after longer follow-up periods (more than 1 year). There are currently three studies following up to 2 years that showed controversial results: Spirit III, Nobori I and Endeavor IV.
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Spirit III, Endeavor IV and Nobori I trials showed a slightly increase in the rate of very late ST in the DES-1 group that did not reach significance difference. In Spirit III trial [33] very late ST (N1 year) rate was 0.3% in Xcience group and 1% in Taxus group (p 0.34). In Nobori I trial there was no significance difference between 1st and 2nd generation DES, Nobori group presented 0% of very late ST and in the Taxus group presented a rate of very late ST of 0.8% that did not reach statistical significance difference. In Endeavor IV trial, Taxus group presented a very late ST rate (0.8%) higher than Endeavor group (0.1%) that did not reach statistical significance difference (p 0.069). In spite of longer follow up (up to 2 years) the benefits are not clear in terms of safety, between 2nd generation DESs over 1st generation DESs. Although it did not reach a statistical significant difference there seemed to be a tendency toward a high rate of very late ST in the 1st generation DES group probably due to several factors like; changes in polymer: (bioabsorbable polymer, lower permanent thickness), lower strut thickness and new drugs that could avoid incomplete neointimal healing. 4.1. Study limitations This study has some limitations. First, as with other meta-analyses, inclusion criteria may be different among all trials as we have analyzed six types of 2nd generation DESs. Second, clinical follow up was limited to 12 months in most trials, so the possibility of very late stent thrombosis necessitates a more extended follow up. However six trials have extended the follow up more than 1 year (Endeavor IV, Spirit II, Spirit III, Spirit IV, Nobori I and ISAR test 3 trial) with low risk of additional ST. Third, intravascular ultrasound was not performed in cases suffering ST, therefore the underlying mechanism of ST was not well determined. Fourth, overall ST could be underestimated due to exclusion criteria (left main, bifurcations, recent myocardial infarction, chronic total occlusions) in most of the trials. This latter could lead to a lack of power in our study. Acknowledgments We are indebted to the principal investigators of all the trials included in this meta-analysis for their contribution to publishing these trials and, in some cases for providing us some unpublished data from suffering stent thrombosis in these studies. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [37]. References [1] Morice MC, Serruys PW, Sousa JE, et al. Randomized study with the sirolimuscoated Bx velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions. A randomized comparison of a sirolimuseluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–80. [2] Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: 1315–23.
Fig. 6. Odds Ratio of stent thrombosis associated with Taxus and Xcience V stents.
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