Cardiovasc Drugs Ther DOI 10.1007/s10557-014-6528-7
ORIGINAL ARTICLE
Biodegradable Polymer Drug-Eluting Stents Versus Second-Generation Drug-Eluting Stents for Patients With Coronary Artery Disease: An Update Meta-Analysis Yanyu Wang & Pingshuan Dong & Ling Li & Xiaoling Li & Hongyun Wang & Xuming Yang & Shaoxin Wang & Zhuanzhen Li & Xiyan Shang
# Springer Science+Business Media New York 2014
Abstract Objective Permanent polymer drug-eluting stents (DES) are associated with a higher risk of late and very late stent thrombosis (ST); biodegradable polymer drug-eluting stents (BPDES) were designed to reduce these risks. However, their benefits are not completely clear. Method We undertook a meta-analysis of randomized studies identified in systematic searches of MEDLINE, EMBASE, and the Cochrane Database. Eligible studies were those that compared BP-DES with second-generation permanent polymer DES in patients undergoing percutaneous coronary intervention. Results Five studies (8,740 patients) with a mean follow-up of 19.2 months were included. Overall, BP-DES were associated with a broadly equivalent risk of definite and probable ST (odds ratio [OR], 1.07; 95 % confidence interval [CI], 0.67 to 1.71; P=0.76; I2 =5.0 %), target vessel revascularization (OR, 1.04; 95 % CI, 0.87 to 1.24; P=0.68; I2 =38.0 %), all-cause mortality (OR, 1.10; 95 % CI, 0.87 to 1.41; P=0.42; I2 = 0.0 %), and major adverse cardiac events (OR, 1.03; 95 % CI, 0.88 to 1.20; P=0.74; I2 =0.0 %) when compared with second-generation DES. However, BP-DES significantly decreased in-stent late luminal loss (standard mean difference [SMD], −0.01; 95 % CI, −0.12 to 0.11; P=0.93; I2 =0.0 %) Y. Wang : L. Li (*) Department of Cardiology, First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, Henan 0086-470052, China e-mail: [email protected] Y. Wang First Affiliated Hospital of Henan University of Science and Technology, Henan, China P. Dong : X. Li : H. Wang : X. Yang : S. Wang : Z. Li : X. Shang Department of Cardiology, First Affiliated Hospital of Henan University of Science and Technology, Henan, China
and in-segment late luminal loss (SMD, −0.06; 95 % CI, −0.17 to 0.05; P=0.27; I2 =0.0 %) compared with secondgeneration DES. Conclusions Compared with second-generation permanent polymer DES, biodegradable stents appear to have equivalent short- to medium-term clinical benefits, and it remains unclear whether they reduce the incidence of very late ST. Keywords Biodegradable polymer . Everolimus-eluting stent . Zotarolimus-eluting stent . Stent thrombosis . Target vessel revascularization
Introduction Drug-eluting stents (DES) decrease the risk of stent restenosis and ischemia-driven target vessel revascularization compared with bare-metal stents in a broad range of patients and coronary lesions [1]. Second-generation DES, such as everolimus(EES) and zotarolimus- eluting stents (ZES), have been reported to markedly decrease the risk of early stent thrombosis and repeat revascularization compared with first-generation drug-eluting and bare metal stents [2]. Nevertheless these new stents still have limitations, not least the requirement for prolonged dual-antiplatelet therapy (DAPT) and an apparent increase in the incidence of Academic Research Consortium (ARC) definite early and late stent thrombosis (ST) [3], which are likely caused by delayed vessel healing, impaired endothelialization, allergy, inflammation, and the presence of durable polymers [4]. The new generation of DES made from polymers that biodegrade when drug elution is complete may reduce the risk of in-stent restenosis and ST [5]. Furthermore, biodegradable polymer drug-eluting stents (BP-DES) are reported, on the basis of angiography data, to be non-inferior to EES with
Cardiovasc Drugs Ther
regard to in-segment late loss (0.03±0.39 versus 0.06±0.45, P=0.52) 9 months after deployment [6]. As the evidence base has recently expanded [7, 8], we undertook a meta-analysis to evaluate the risk of ST, target vessel revascularization (TVR), mortality, and major adverse cardiac events (MACE) for patients with coronary artery disease implanted with BPDES or second-generation DES during percutaneous coronary intervention (PCI).
Methods Data Sources and Search Strategies We searched MEDLINE (source, PubMed from 2005 to December 2013), EMBASE (2005 to December 2013), the Cochrane Controlled Clinical Trials Register Database (to December 2013), and the ClinicalTrials.gov website (to December 2013) using the terms “biodegradable polymer”, “drug-eluting stent”, “everolimus-eluting stent”, “zotarolimus-eluting stent”, “coronary artery disease”, “stent thrombosis”, “target vessel revascularization”, and “percutaneous coronary intervention”. Manual reference checking of the bibliographies of all relevant articles was performed. No restrictions were applied.
Quality Assessment Two reviewers (Y.W. and L.L.) assessed the quality of the selected studies. Components used for quality assessment were means of generation of random sequence, allocation concealment, blinding of outcome assessment, and selective outcome reporting. The Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement [10] was followed. Data Synthesis and Analysis Results were analyzed quantitatively with Review Manager 5.1 using the DerSimonian and Laird random-effects model [11]. We calculated the pooled odds ratio (OR) for dichotomous outcomes and the standard mean difference (SMD) for continuous data with 95 % confidence intervals (CI). Heterogeneity was examined by the I2 statistic and the chisquared test. A value of I2 >50 % was considered as a substantial level of heterogeneity [12]. For outcomes with significant heterogeneity (I2 >50 %), the random-effects model is reported in the text and figures; for all others, the fixed-effects models are reported. All analyses were performed according to the intention-to-treat principle. Sensitivity analyses were conducted to determine the influence of individual trials on
Study Selection We first conducted an initial screening of titles and abstracts; the second evaluation was based on full-text review. Trials were considered eligible if they met these criteria: 1) the study was a prospective randomized controlled trial (RCT) conducted in patients undergoing PCI; 2) intervention consisted of the deployment of a BP-DES or second-generation DES such as the Endeavor® or Resolute® ZESs, or the Xience V® or PROMUS Element® EES [9]; 3) the outcomes of interest were ST, mortality, myocardial infarction (MI), TVR, or angiographic data. Data Extraction Two reviewers (Y.W. and L.L.) extracted data concerning patient characteristics, the biodegradable polymer used in stent manufacture, study quality, and clinical outcomes using a standard data-collection form. Disagreements were resolved by discussion. Primary outcomes were definite and probable ST according to the ARC definition (early, ≤1 month; late, >1 month to ≤1 year; or very late, >1 year) [3]. Secondary outcomes were MACE (i.e., cardiac death, MI, TVR) and angiographic follow-up data.
Fig. 1 Flow chart showing the study selection process
192 197 3,235 2,707 458
2013 24 2013 24
2013 12 2013 12 2013 12
Male, %
Hypertension, %
69.1/69.3 77.0/77.0 81.0/82.0 63.0/62.7 74.4/74.3 54.8/56.3 58.7/59.6 69.2/68.4 57.7/59.7
64.9/62.1 69.9/79.6 61.3/69.4 62.9/62.1 69.7/79.6 71.7/69.4
66.7/66.7 75.3/77.8 69.1/67.8
Age, yrs
46.0/46.0 21.8/21.6 13.7/16.9
17.2/22.4 18.2/22.4
29.0/28.2
Diabetes, %
17.1/15.5 PLA 57.9/57.8 PLA 71.4/71.9 PLA
22.6/21.1 PLGA 30.6/21.1 PLGA 6–9 6–9 6
4 4
1–2
Polymer Degradation rate, M
41.7/41.3 PLA
ACS, %
99.4/99.5 94.1/97.9 98.2/99.1
98.9/100 98.0/100
NR
Stent used,%
9–12 NR 9
6 6
6–8
Angiographic follow-up, M
3 12 12
6 6
6
DAPT, M
Year Biodegradable polymer DES
PLA (20 um) 45 (30) PLA
biolimus Sirolimus (3 um/mm)
58.7/59.6
PLA (20 um) 45 (30)
50 % (60)
PLGA
69.2/68.4
6–9
6–9
3
3
50 % (60)
PLGA
69.2/68.4
SS
SS
PtCr
PtCr
SS
Duration of Metal biodegradation (months)
50 % (9–11) 7
Release kinetics (days)
PLA
Polymer
Sirolimus (125 ug/19 mm) Everolimus (56 ug/20 mm) Everolimus (113 ug/20 mm) biolimus
Drug (concentration)
86
120
120
71
71
87
Xience V® EES
Xience V® EES PROMUS® EES.
Xience V® EES PROMUS® EES.
PROMUS Element® EES.
PROMUS Element® EES.
Xience V® EES
Strut thickness (um) Permanent polymer DES In control group
M month; N number; yrs year; BP biodegradable polymer; ACS acute coronary syndrome; PLA polylactic acid; PLGA polylactic-co-glycolic acid; DAPT dual-antiplatelet therapy; NR not reported; HD half dose of everolimus; ISAR-TEST-4 intracoronary stenting and angiographic results: test efficacy of 3 limus-eluting stents; NEXT the NOBORI™ biolimus-eluting versus XIENCE™/PROMUS™ everolimus-eluting stent trial; COMPARE comparison of the everolimus-eluting XIENCE-V stent with the paxlitaxel-eluting TAXUS LIBERTE stent in all comers
ISAR-TEST-4 [14] 2011 Supralimus™ (Sahajanand Medical Technologies Ltd) EVOLVE [15] 2013 SYNERGY (Boston Scientific Corp., Natick, Massachusetts) EVOLVE HD [15] 2013 SYNERGY (Boston Scientific Corp., Natick, Massachusetts) NEXT [6] 2013 Nobori (Terumo Corporation, Tokyo, Japan) COMPARE II [7] 2013 Nobori (Terumo Corporation, Tokyo, Japan) TARGET 1 [8] 2013 FIREHAWK (MicroPort Medical, Shanghai, China)
RCTs [Ref. #]
Table 2 Characteristics of biodegradable polymer and permanent polymer drug-eluting stents used in our study
M month; N number; yrs year; BP biodegradable polymer; ACS acute coronary syndrome; PLA polylactic acid; PLGA polylactic-co-glycolic acid; DAPT dual-antiplatelet therapy; NR not reported; HD half dose of everolimus; ISAR-TEST-4 Intracoronary stenting and angiographic results: test efficacy of 3 limus-eluting stents; NEXT the NOBORI™ biolimus-eluting versus XIENCE™/PROMUS™ everolimus-eluting stent trial; COMPARE comparison of the everolimus-eluting XIENCE-V stent with the paxlitaxel-eluting TAXUS LIBERTE stent in all comers
1,951
2011 36
ISAR-TEST-4 [14] EVOLVE [15] EVOLVE HD [15] NEXT [6] COMPARE II [7] TARGET 1 [8]
Patients, N.
Year Follow., M.
RCTs [Ref. #]
Table 1 Characteristics of patients from BP-DES and second-generation DES groups
Cardiovasc Drugs Ther
Cardiovasc Drugs Ther Fig. 2 Methodological assessment based on the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement
the overall pooled results [13]. Statistical significance was set at 0.05 for the I2 test for heterogeneity and the Z-test for relative risk (RR).
Results Search Results We initially identified 254 potentially relevant articles. Thirtyone were considered to be of interest and were retrieved for full-text review. Twenty-six articles were excluded owing to duplication or incorrect comparisons. Ultimately, five studies were included in the analysis. Figure 1 is a flow chart showing the process of study selection. Study Characteristics The five published RCTs [6–8, 14, 15] that included a total of 8,740 patients represented six treatment comparisons in our meta-analysis. One study [15] was a three-arm comparison of a BP-DES with two dose formulations of SYNERGY with a control group; both were included as treatment groups in the meta-analysis. The total number of patients in each study was in the range of 192–3,235, and the mean duration of follow-up was 19.2 months. The participants’ ages were in the range of 18– 85 years (mean age, 64.2 years). Most (mean, 65.9 %) patients Fig. 3 Incidence of definite and probable stent thrombosis identified in the meta-analysis of six trials. Fixed-effect model (I2 = 0.0 %; P=0.69). Abbreviations: OR odds ratio; CI confidence interval; ST stent thrombosis
had hypertension, 25.9 % had diabetes mellitus, and 40.2 % were diagnosed with acute coronary syndrome (ACS). The biodegradable polymer in one study was poly(lactic-coglycolic acid) (PLGA), the remaining four studies used poly(lactic acid) (PLA); all were designed to have degraded completely within 9 months. The control groups were implanted with EES in five studies, and ZES in one. More than 6 months of post-procedural DAPT was recommended for all trials except one [6] (Tables 1 and 2). Methodological Quality Assessment Five trials [6–8, 14, 15] randomized the participants, and four studies [6, 7, 14, 15] used satisfactory methods of concealed treatment allocation. Blinding of participants and personnel was reported in three studies [6, 7, 14], and blinding of outcome assessment was undertaken in two [8, 15]. There was no risk of attrition bias and reporting bias in any of the studies (Fig. 2). ARC Definite and Probable ST Five trials [6–8, 14, 15] provided data about ARC definite and probable ST. There were 5,131 patients in the BP-DES group, and ST occurred in 47 patients (0.9 %). There were 3,609 patients in the second-generation DES group, and ST occurred in 29 (0.8 %). There was no difference in the risk of definite and probable ST (OR, 1.07; 95 % CI, 0.67 to 1.71; P=0.76; I2 =5.0 %) between the two groups (Fig. 3). Sensitivity
Cardiovasc Drugs Ther Fig. 4 All-cause mortality identified in the meta-analysis of six trials. Fixed-effect model (I2 =5.0 %; P=0.35). Abbreviations: OR odds ratio; CI confidence interval
analyses showed that the results would not have been influenced by the exclusion of any study. Notably, only two studies [6, 7] reported the incidence of early and late ST: BP-DES was associated with comparable rate of early ST (OR, 1.90; 95 % CI, 0.61 to 5.87; P=0.27; I2 = 0.0 %) and late ST (OR, 3.60; 95 % CI, 0.42 to 30.79; P=0.24; I2 =0.0 %) compared with controls. No study reported the risk of very late ST.
Angiographic Data Angiographic follow-up at 9 months was reported in three trials [6, 8, 15]. There were 619 patients in the BP-DES group and 628 patients in the control group. There was no significant difference in the angiographic data of in-segment late luminal loss (SMD, −0.06; 95 % CI, −0.17 to 0.05; P=0.27; I2 =0.0 %) and in-stent late luminal loss (SMD, −0.01; 95 % CI, −0.12 to 0.11; P=0.93; I2 =0.0 %) between the groups.
All-Cause Mortality, MI, and TVR Five trials [6–8, 14, 15] provided data about all-cause mortality. There were 5,131 patients in the BP-DES group, of whom 193 died (3.7 %). There were 3,609 patients in the DES group, of whom 110 died (3.0 %). There was no difference in the risk of all-cause mortality (OR, 1.10; 95 % CI, 0.87 to 1.41; P= 0.42; I2 =0.0 %) between the groups (Fig. 4), nor was there a significant difference in the risk of cardiac death between the groups (OR, 1.10; 95 % CI, 0.79 to 1.52; P=0.58; I2 =0.0 %). The incidence of MI was reported in all studies [6–8, 14, 15]: MI was diagnosed in 172 patients in the BP-DES group (3.3 %), and 104 in the controls (2.9 %). This difference was not statistically significant (OR, 1.14; 95 % CI, 0.88 to 1.46; P=0.32; I2 =0.0 %). The rate of TVR was reported in five trials [6–8, 14, 15]. There were 5,131 patients in the BP-DES group, of whom 348 were diagnosed with TVR (6.7 %). There were 3,609 patients in the DES group, of whom 227 had TVR (6.2 %). The incidences of TVR and MACE were broadly comparable in the BP-DES group and second-generation DES controls (for TVR: OR, 1.04; 95 % CI, 0.87 to 1.24; P=0.68; I2 =38.0 %; for MACE: OR, 1.03; 95 % CI, 0.88 to 1.20; P=0.74; I2 = 0.0 %) (Figs. 5 and 6, respectively). Fig. 5 Incidence of target vessel revascularization identified in the meta-analysis of five trials. Fixed-effect model (I2 =38.0 %; P=0.15). Abbreviations: OR odds ratio; CI confidence interval; TVR target vessel revascularization
Discussion Our meta-analysis shows that BP-DES has an equivalent clinical benefit to EES and ZES treatment with regard to ST, TVR, and MI. Meanwhile, angiographic data showed that instent and in-segment late luminal loss was significantly less common in the BP-DES group. Given the clinical benefit, BPDES appears to be a safe and effective alternative DES for patients undergoing PCI. Biodegradable polymers, as opposed to durable polymers, can be completely metabolized, potentially reducing the risk of late complications such as stent uncovering, malapposition, and endothelial dysfunction [16]. The LEADERS study [17] showed that biodegradable polymer biolimuseluting stents were associated with a non-significant trend of lower definite stent thrombosis (2.6 % versus 4.2 %, P= 0.057) compared with sirolimus-eluting stents (SES). These results were confirmed by a patient-level meta-analysis of three randomized trials (LEADERS, ISART-TEST-3, and ISAR-TEST-4) of biodegradable polymer stents versus SES (hazard ratio [HR], 0.22, 95 % CI 0.08 to 0.61, P=0.004) [18].
Cardiovasc Drugs Ther Fig. 6 Incidence of major adverse cardiac events identified in the meta-analysis of five trials. Fixed-effect model (I2 =0.0 %; P=0.96). Abbreviations: OR odds ratio; CI confidence interval; MACE major adverse cardiac events
Compared with first-generation DES, the second-generation stents such as EES and ZES were reported to significantly reduce the risk of repeat revascularization, ST and MI [19]. The NEXT [6] and COMPARE II [7] studies reported similar rates of ST after deployment of BP-DES and EES (RR, 1.65; 95 % CI, 0.54 to 5.05; P=0.38). However, owing to the limited number of patients enrolled, the two studies were conducted as non-inferiority trials. Combining the results of five studies involving 8,740 patients, we further confirmed that biodegradable polymer stents were associated with an equivalent risk of ST compared with second-generation DES. Furthermore, we found that there was no significant difference in early or late ST between BP-DES and secondgeneration stents. Although the incidences of early and late ST were comparable between the groups, BP-DES may reduce the incidence of very late ST owing to better stent endothelialization [20]. Intravascular coherence tomography showed that use of a biodegradable polymer SES substantially decreased the risk of uncovered struts (6.8 % versus 17.5 %) compared with EES [21]. The NEXT trial [6] reported that deployment of BP-DES significantly lowered the in-segment late loss (0.03±0.39 mm versus 0.06±0.45 mm, P for non-inferiority
ORIGINAL ARTICLE
Biodegradable Polymer Drug-Eluting Stents Versus Second-Generation Drug-Eluting Stents for Patients With Coronary Artery Disease: An Update Meta-Analysis Yanyu Wang & Pingshuan Dong & Ling Li & Xiaoling Li & Hongyun Wang & Xuming Yang & Shaoxin Wang & Zhuanzhen Li & Xiyan Shang
# Springer Science+Business Media New York 2014
Abstract Objective Permanent polymer drug-eluting stents (DES) are associated with a higher risk of late and very late stent thrombosis (ST); biodegradable polymer drug-eluting stents (BPDES) were designed to reduce these risks. However, their benefits are not completely clear. Method We undertook a meta-analysis of randomized studies identified in systematic searches of MEDLINE, EMBASE, and the Cochrane Database. Eligible studies were those that compared BP-DES with second-generation permanent polymer DES in patients undergoing percutaneous coronary intervention. Results Five studies (8,740 patients) with a mean follow-up of 19.2 months were included. Overall, BP-DES were associated with a broadly equivalent risk of definite and probable ST (odds ratio [OR], 1.07; 95 % confidence interval [CI], 0.67 to 1.71; P=0.76; I2 =5.0 %), target vessel revascularization (OR, 1.04; 95 % CI, 0.87 to 1.24; P=0.68; I2 =38.0 %), all-cause mortality (OR, 1.10; 95 % CI, 0.87 to 1.41; P=0.42; I2 = 0.0 %), and major adverse cardiac events (OR, 1.03; 95 % CI, 0.88 to 1.20; P=0.74; I2 =0.0 %) when compared with second-generation DES. However, BP-DES significantly decreased in-stent late luminal loss (standard mean difference [SMD], −0.01; 95 % CI, −0.12 to 0.11; P=0.93; I2 =0.0 %) Y. Wang : L. Li (*) Department of Cardiology, First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, Henan 0086-470052, China e-mail: [email protected] Y. Wang First Affiliated Hospital of Henan University of Science and Technology, Henan, China P. Dong : X. Li : H. Wang : X. Yang : S. Wang : Z. Li : X. Shang Department of Cardiology, First Affiliated Hospital of Henan University of Science and Technology, Henan, China
and in-segment late luminal loss (SMD, −0.06; 95 % CI, −0.17 to 0.05; P=0.27; I2 =0.0 %) compared with secondgeneration DES. Conclusions Compared with second-generation permanent polymer DES, biodegradable stents appear to have equivalent short- to medium-term clinical benefits, and it remains unclear whether they reduce the incidence of very late ST. Keywords Biodegradable polymer . Everolimus-eluting stent . Zotarolimus-eluting stent . Stent thrombosis . Target vessel revascularization
Introduction Drug-eluting stents (DES) decrease the risk of stent restenosis and ischemia-driven target vessel revascularization compared with bare-metal stents in a broad range of patients and coronary lesions [1]. Second-generation DES, such as everolimus(EES) and zotarolimus- eluting stents (ZES), have been reported to markedly decrease the risk of early stent thrombosis and repeat revascularization compared with first-generation drug-eluting and bare metal stents [2]. Nevertheless these new stents still have limitations, not least the requirement for prolonged dual-antiplatelet therapy (DAPT) and an apparent increase in the incidence of Academic Research Consortium (ARC) definite early and late stent thrombosis (ST) [3], which are likely caused by delayed vessel healing, impaired endothelialization, allergy, inflammation, and the presence of durable polymers [4]. The new generation of DES made from polymers that biodegrade when drug elution is complete may reduce the risk of in-stent restenosis and ST [5]. Furthermore, biodegradable polymer drug-eluting stents (BP-DES) are reported, on the basis of angiography data, to be non-inferior to EES with
Cardiovasc Drugs Ther
regard to in-segment late loss (0.03±0.39 versus 0.06±0.45, P=0.52) 9 months after deployment [6]. As the evidence base has recently expanded [7, 8], we undertook a meta-analysis to evaluate the risk of ST, target vessel revascularization (TVR), mortality, and major adverse cardiac events (MACE) for patients with coronary artery disease implanted with BPDES or second-generation DES during percutaneous coronary intervention (PCI).
Methods Data Sources and Search Strategies We searched MEDLINE (source, PubMed from 2005 to December 2013), EMBASE (2005 to December 2013), the Cochrane Controlled Clinical Trials Register Database (to December 2013), and the ClinicalTrials.gov website (to December 2013) using the terms “biodegradable polymer”, “drug-eluting stent”, “everolimus-eluting stent”, “zotarolimus-eluting stent”, “coronary artery disease”, “stent thrombosis”, “target vessel revascularization”, and “percutaneous coronary intervention”. Manual reference checking of the bibliographies of all relevant articles was performed. No restrictions were applied.
Quality Assessment Two reviewers (Y.W. and L.L.) assessed the quality of the selected studies. Components used for quality assessment were means of generation of random sequence, allocation concealment, blinding of outcome assessment, and selective outcome reporting. The Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement [10] was followed. Data Synthesis and Analysis Results were analyzed quantitatively with Review Manager 5.1 using the DerSimonian and Laird random-effects model [11]. We calculated the pooled odds ratio (OR) for dichotomous outcomes and the standard mean difference (SMD) for continuous data with 95 % confidence intervals (CI). Heterogeneity was examined by the I2 statistic and the chisquared test. A value of I2 >50 % was considered as a substantial level of heterogeneity [12]. For outcomes with significant heterogeneity (I2 >50 %), the random-effects model is reported in the text and figures; for all others, the fixed-effects models are reported. All analyses were performed according to the intention-to-treat principle. Sensitivity analyses were conducted to determine the influence of individual trials on
Study Selection We first conducted an initial screening of titles and abstracts; the second evaluation was based on full-text review. Trials were considered eligible if they met these criteria: 1) the study was a prospective randomized controlled trial (RCT) conducted in patients undergoing PCI; 2) intervention consisted of the deployment of a BP-DES or second-generation DES such as the Endeavor® or Resolute® ZESs, or the Xience V® or PROMUS Element® EES [9]; 3) the outcomes of interest were ST, mortality, myocardial infarction (MI), TVR, or angiographic data. Data Extraction Two reviewers (Y.W. and L.L.) extracted data concerning patient characteristics, the biodegradable polymer used in stent manufacture, study quality, and clinical outcomes using a standard data-collection form. Disagreements were resolved by discussion. Primary outcomes were definite and probable ST according to the ARC definition (early, ≤1 month; late, >1 month to ≤1 year; or very late, >1 year) [3]. Secondary outcomes were MACE (i.e., cardiac death, MI, TVR) and angiographic follow-up data.
Fig. 1 Flow chart showing the study selection process
192 197 3,235 2,707 458
2013 24 2013 24
2013 12 2013 12 2013 12
Male, %
Hypertension, %
69.1/69.3 77.0/77.0 81.0/82.0 63.0/62.7 74.4/74.3 54.8/56.3 58.7/59.6 69.2/68.4 57.7/59.7
64.9/62.1 69.9/79.6 61.3/69.4 62.9/62.1 69.7/79.6 71.7/69.4
66.7/66.7 75.3/77.8 69.1/67.8
Age, yrs
46.0/46.0 21.8/21.6 13.7/16.9
17.2/22.4 18.2/22.4
29.0/28.2
Diabetes, %
17.1/15.5 PLA 57.9/57.8 PLA 71.4/71.9 PLA
22.6/21.1 PLGA 30.6/21.1 PLGA 6–9 6–9 6
4 4
1–2
Polymer Degradation rate, M
41.7/41.3 PLA
ACS, %
99.4/99.5 94.1/97.9 98.2/99.1
98.9/100 98.0/100
NR
Stent used,%
9–12 NR 9
6 6
6–8
Angiographic follow-up, M
3 12 12
6 6
6
DAPT, M
Year Biodegradable polymer DES
PLA (20 um) 45 (30) PLA
biolimus Sirolimus (3 um/mm)
58.7/59.6
PLA (20 um) 45 (30)
50 % (60)
PLGA
69.2/68.4
6–9
6–9
3
3
50 % (60)
PLGA
69.2/68.4
SS
SS
PtCr
PtCr
SS
Duration of Metal biodegradation (months)
50 % (9–11) 7
Release kinetics (days)
PLA
Polymer
Sirolimus (125 ug/19 mm) Everolimus (56 ug/20 mm) Everolimus (113 ug/20 mm) biolimus
Drug (concentration)
86
120
120
71
71
87
Xience V® EES
Xience V® EES PROMUS® EES.
Xience V® EES PROMUS® EES.
PROMUS Element® EES.
PROMUS Element® EES.
Xience V® EES
Strut thickness (um) Permanent polymer DES In control group
M month; N number; yrs year; BP biodegradable polymer; ACS acute coronary syndrome; PLA polylactic acid; PLGA polylactic-co-glycolic acid; DAPT dual-antiplatelet therapy; NR not reported; HD half dose of everolimus; ISAR-TEST-4 intracoronary stenting and angiographic results: test efficacy of 3 limus-eluting stents; NEXT the NOBORI™ biolimus-eluting versus XIENCE™/PROMUS™ everolimus-eluting stent trial; COMPARE comparison of the everolimus-eluting XIENCE-V stent with the paxlitaxel-eluting TAXUS LIBERTE stent in all comers
ISAR-TEST-4 [14] 2011 Supralimus™ (Sahajanand Medical Technologies Ltd) EVOLVE [15] 2013 SYNERGY (Boston Scientific Corp., Natick, Massachusetts) EVOLVE HD [15] 2013 SYNERGY (Boston Scientific Corp., Natick, Massachusetts) NEXT [6] 2013 Nobori (Terumo Corporation, Tokyo, Japan) COMPARE II [7] 2013 Nobori (Terumo Corporation, Tokyo, Japan) TARGET 1 [8] 2013 FIREHAWK (MicroPort Medical, Shanghai, China)
RCTs [Ref. #]
Table 2 Characteristics of biodegradable polymer and permanent polymer drug-eluting stents used in our study
M month; N number; yrs year; BP biodegradable polymer; ACS acute coronary syndrome; PLA polylactic acid; PLGA polylactic-co-glycolic acid; DAPT dual-antiplatelet therapy; NR not reported; HD half dose of everolimus; ISAR-TEST-4 Intracoronary stenting and angiographic results: test efficacy of 3 limus-eluting stents; NEXT the NOBORI™ biolimus-eluting versus XIENCE™/PROMUS™ everolimus-eluting stent trial; COMPARE comparison of the everolimus-eluting XIENCE-V stent with the paxlitaxel-eluting TAXUS LIBERTE stent in all comers
1,951
2011 36
ISAR-TEST-4 [14] EVOLVE [15] EVOLVE HD [15] NEXT [6] COMPARE II [7] TARGET 1 [8]
Patients, N.
Year Follow., M.
RCTs [Ref. #]
Table 1 Characteristics of patients from BP-DES and second-generation DES groups
Cardiovasc Drugs Ther
Cardiovasc Drugs Ther Fig. 2 Methodological assessment based on the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement
the overall pooled results [13]. Statistical significance was set at 0.05 for the I2 test for heterogeneity and the Z-test for relative risk (RR).
Results Search Results We initially identified 254 potentially relevant articles. Thirtyone were considered to be of interest and were retrieved for full-text review. Twenty-six articles were excluded owing to duplication or incorrect comparisons. Ultimately, five studies were included in the analysis. Figure 1 is a flow chart showing the process of study selection. Study Characteristics The five published RCTs [6–8, 14, 15] that included a total of 8,740 patients represented six treatment comparisons in our meta-analysis. One study [15] was a three-arm comparison of a BP-DES with two dose formulations of SYNERGY with a control group; both were included as treatment groups in the meta-analysis. The total number of patients in each study was in the range of 192–3,235, and the mean duration of follow-up was 19.2 months. The participants’ ages were in the range of 18– 85 years (mean age, 64.2 years). Most (mean, 65.9 %) patients Fig. 3 Incidence of definite and probable stent thrombosis identified in the meta-analysis of six trials. Fixed-effect model (I2 = 0.0 %; P=0.69). Abbreviations: OR odds ratio; CI confidence interval; ST stent thrombosis
had hypertension, 25.9 % had diabetes mellitus, and 40.2 % were diagnosed with acute coronary syndrome (ACS). The biodegradable polymer in one study was poly(lactic-coglycolic acid) (PLGA), the remaining four studies used poly(lactic acid) (PLA); all were designed to have degraded completely within 9 months. The control groups were implanted with EES in five studies, and ZES in one. More than 6 months of post-procedural DAPT was recommended for all trials except one [6] (Tables 1 and 2). Methodological Quality Assessment Five trials [6–8, 14, 15] randomized the participants, and four studies [6, 7, 14, 15] used satisfactory methods of concealed treatment allocation. Blinding of participants and personnel was reported in three studies [6, 7, 14], and blinding of outcome assessment was undertaken in two [8, 15]. There was no risk of attrition bias and reporting bias in any of the studies (Fig. 2). ARC Definite and Probable ST Five trials [6–8, 14, 15] provided data about ARC definite and probable ST. There were 5,131 patients in the BP-DES group, and ST occurred in 47 patients (0.9 %). There were 3,609 patients in the second-generation DES group, and ST occurred in 29 (0.8 %). There was no difference in the risk of definite and probable ST (OR, 1.07; 95 % CI, 0.67 to 1.71; P=0.76; I2 =5.0 %) between the two groups (Fig. 3). Sensitivity
Cardiovasc Drugs Ther Fig. 4 All-cause mortality identified in the meta-analysis of six trials. Fixed-effect model (I2 =5.0 %; P=0.35). Abbreviations: OR odds ratio; CI confidence interval
analyses showed that the results would not have been influenced by the exclusion of any study. Notably, only two studies [6, 7] reported the incidence of early and late ST: BP-DES was associated with comparable rate of early ST (OR, 1.90; 95 % CI, 0.61 to 5.87; P=0.27; I2 = 0.0 %) and late ST (OR, 3.60; 95 % CI, 0.42 to 30.79; P=0.24; I2 =0.0 %) compared with controls. No study reported the risk of very late ST.
Angiographic Data Angiographic follow-up at 9 months was reported in three trials [6, 8, 15]. There were 619 patients in the BP-DES group and 628 patients in the control group. There was no significant difference in the angiographic data of in-segment late luminal loss (SMD, −0.06; 95 % CI, −0.17 to 0.05; P=0.27; I2 =0.0 %) and in-stent late luminal loss (SMD, −0.01; 95 % CI, −0.12 to 0.11; P=0.93; I2 =0.0 %) between the groups.
All-Cause Mortality, MI, and TVR Five trials [6–8, 14, 15] provided data about all-cause mortality. There were 5,131 patients in the BP-DES group, of whom 193 died (3.7 %). There were 3,609 patients in the DES group, of whom 110 died (3.0 %). There was no difference in the risk of all-cause mortality (OR, 1.10; 95 % CI, 0.87 to 1.41; P= 0.42; I2 =0.0 %) between the groups (Fig. 4), nor was there a significant difference in the risk of cardiac death between the groups (OR, 1.10; 95 % CI, 0.79 to 1.52; P=0.58; I2 =0.0 %). The incidence of MI was reported in all studies [6–8, 14, 15]: MI was diagnosed in 172 patients in the BP-DES group (3.3 %), and 104 in the controls (2.9 %). This difference was not statistically significant (OR, 1.14; 95 % CI, 0.88 to 1.46; P=0.32; I2 =0.0 %). The rate of TVR was reported in five trials [6–8, 14, 15]. There were 5,131 patients in the BP-DES group, of whom 348 were diagnosed with TVR (6.7 %). There were 3,609 patients in the DES group, of whom 227 had TVR (6.2 %). The incidences of TVR and MACE were broadly comparable in the BP-DES group and second-generation DES controls (for TVR: OR, 1.04; 95 % CI, 0.87 to 1.24; P=0.68; I2 =38.0 %; for MACE: OR, 1.03; 95 % CI, 0.88 to 1.20; P=0.74; I2 = 0.0 %) (Figs. 5 and 6, respectively). Fig. 5 Incidence of target vessel revascularization identified in the meta-analysis of five trials. Fixed-effect model (I2 =38.0 %; P=0.15). Abbreviations: OR odds ratio; CI confidence interval; TVR target vessel revascularization
Discussion Our meta-analysis shows that BP-DES has an equivalent clinical benefit to EES and ZES treatment with regard to ST, TVR, and MI. Meanwhile, angiographic data showed that instent and in-segment late luminal loss was significantly less common in the BP-DES group. Given the clinical benefit, BPDES appears to be a safe and effective alternative DES for patients undergoing PCI. Biodegradable polymers, as opposed to durable polymers, can be completely metabolized, potentially reducing the risk of late complications such as stent uncovering, malapposition, and endothelial dysfunction [16]. The LEADERS study [17] showed that biodegradable polymer biolimuseluting stents were associated with a non-significant trend of lower definite stent thrombosis (2.6 % versus 4.2 %, P= 0.057) compared with sirolimus-eluting stents (SES). These results were confirmed by a patient-level meta-analysis of three randomized trials (LEADERS, ISART-TEST-3, and ISAR-TEST-4) of biodegradable polymer stents versus SES (hazard ratio [HR], 0.22, 95 % CI 0.08 to 0.61, P=0.004) [18].
Cardiovasc Drugs Ther Fig. 6 Incidence of major adverse cardiac events identified in the meta-analysis of five trials. Fixed-effect model (I2 =0.0 %; P=0.96). Abbreviations: OR odds ratio; CI confidence interval; MACE major adverse cardiac events
Compared with first-generation DES, the second-generation stents such as EES and ZES were reported to significantly reduce the risk of repeat revascularization, ST and MI [19]. The NEXT [6] and COMPARE II [7] studies reported similar rates of ST after deployment of BP-DES and EES (RR, 1.65; 95 % CI, 0.54 to 5.05; P=0.38). However, owing to the limited number of patients enrolled, the two studies were conducted as non-inferiority trials. Combining the results of five studies involving 8,740 patients, we further confirmed that biodegradable polymer stents were associated with an equivalent risk of ST compared with second-generation DES. Furthermore, we found that there was no significant difference in early or late ST between BP-DES and secondgeneration stents. Although the incidences of early and late ST were comparable between the groups, BP-DES may reduce the incidence of very late ST owing to better stent endothelialization [20]. Intravascular coherence tomography showed that use of a biodegradable polymer SES substantially decreased the risk of uncovered struts (6.8 % versus 17.5 %) compared with EES [21]. The NEXT trial [6] reported that deployment of BP-DES significantly lowered the in-segment late loss (0.03±0.39 mm versus 0.06±0.45 mm, P for non-inferiority
