Safety and efficacy of degradable vs. permanent polymer drug-eluting stents: A meta-analysis of 18,395 patients from randomized trials

International Journal of Cardiology 173 (2014) 100–109

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Safety and efficacy of degradable vs. permanent polymer drug-eluting stents: A meta-analysis of 18,395 patients from randomized trials Yuqing Wang a,1, Shijian Liu b,1, Yuanlin Luo a, Fangjuan Wang a, Huanyun Liu a, Lufeng Li a, Xiaohui Zhao a,⁎, Lan Huang a a b

Cardiovascular Disease Research Center, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China

a r t i c l e

i n f o

Article history: Received 18 November 2013 Received in revised form 7 January 2014 Accepted 13 February 2014 Available online 22 February 2014 Keywords: Drug-eluting stents (DES) Biodegradable polymer Outcomes Percutaneous coronary intervention (PCI)

a b s t r a c t Background: Degradable polymer drug-eluting stents (DP-DES) represent a promising strategy to improve the delayed healing and hypersensitive reaction in the vessel. However, the efficacy and safety of DP-DES vs. permanent polymer drug-eluting stents (PP-DES) are less well defined. The aim of this meta-analysis was to compare the total, short (b 30 days), mid (30 days–1 year) and long (N 1 year) term outcomes of DP-DES vs. PP-DES. Methods: PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials to compare any of approved DP- and PP-DES. Efficacy endpoints were target-lesion revascularization (TLR) and in-stent late loss (ISLL). Safety endpoints were death, myocardial infarction (MI), and composite of definite and probable stent thrombosis (ST). Results: The meta-analysis included 19 RCTs (n = 18,395) with interesting results. As compared with DES, there was a significantly reduced very late ST (OR [95% CI] = 0.42 [0.24–0.77], p = 0.852) and ISLL (OR [95% CI] = − 0.07 [− 0.12–0.02], p = 0.000) in DP-DES patients. However, there were no differences between DP-DES and PP-DES for other safety and efficiency outcomes, except that the stratified analysis showed a significant decreased TLR with DP-DES as compared to paclitaxel-eluting stent (OR [95% CI] = 0.41 [0.20–0.81], p = 0.457). Conclusions: DP-DES are more effective in reducing very late ST and ISLL, as well as comparable to PP-DES with regard to death, TLR and MI. Further large RCTs with long-term follow-up are warranted to better define the relative merits of DP-DES. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Permanent polymer drug-eluting stents (PP-DES) are currently widely used to reduce restenosis and the need for repeat revascularization, representing a major advance for percutaneous coronary intervention [1]. However, the presence of a polymer is a potential cause of stent thrombosis (ST) and a late catch-up phenomenon, as a consequence of delayed healing and hypersensitive reaction [2,3]. Therefore, great efforts have been prompted to develop alternative stents with degradable polymers (DP) for drug delivery, which degrade over time, and therefore may eliminate the problems of polymer-induced late phases of inflammation.

⁎ Corresponding authors at: 183# Xinqiao Street, Shapingba District, Chongqing 400037, China. Tel.: +86 23 68774569; fax: +86 23 68755601. E-mail addresses: [email protected], [email protected] (X. Zhao). 1 Yuqing Wang and Shijian Liu contribute equally to this work.

http://dx.doi.org/10.1016/j.ijcard.2014.02.023 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

However, uncertainty exists regarding the relative performance of DP- versus PP-DES in percutaneous coronary intervention (PCI). The aim of this meta-analysis is to compare total-, short-, mid- and long term safety and efficacy of DP- vs. PP-DES. 2. Methods Established methods [4] were used in compliance with the PRISMA statement for reporting systematic reviews and meta-analyses in health care interventions [5]. 2.1. Search strategy We searched Embase, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) for studies on DP-DES until November 2013. The search strategy was formulated as the AND-combination of terms 1) polymer 2) stent in randomized controlled trials. There was no language restriction for the search. References of meta-analyses, review articles, and original studies identified by the electronic searches were manually checked for additional trials. For studies that did not report outcomes of interest, efforts to contact authors were performed to obtain further details. Internet-based sources of information on the results of clinical trials in cardiology (www.theheart.org, www.cardiosource.com/clinicaltrials, www.clinicaltrialresults.com, and www.tctmd.com) were also searched. In addition, we searched conference abstracts

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of the following societies: American College of Cardiology, Transcatheter Cardiovascular Therapeutics, American Heart Association, European Society of Cardiology, Society of Cardiovascular Angiography and Intervention and Euro-PCR.

2.2. Selection criteria Inclusion criteria were: 1. human studies, 2. randomized controlled studies (RCTs), 3. enrollment of at least 100 patients, 4. PP-DES as control, and 5. ability to report the outcomes of interest. Exclusion criteria were: 1. non-RCTs, 2. sub-study of the RCTs, and 3. studies dedicated to specific lesion subsets including bifurcation lesions, left main, chronic total occlusions, long lesions and venous grafts. Two authors (Yuqing Wang and Yuanlin Luo) independently assessed trial bias risk and extracted data.

2.3. Data extraction and synthesis Based on the time point of eluting drug release, short (b30 days), mid (30 days– 1 year) and long-term (N1 year) efficacy and safety outcomes were evaluated. For midterm outcomes, the outcomes closest to 1 year were abstracted. For total outcomes, the longest reported follow-up events, including short and mid-term outcomes, were abstracted. Fig. 1. Flow diagram of the review process. 2.4. Definitions Efficacy outcomes were target-lesion revascularization (TLR) and in-stent late loss (ISLL). Safety outcomes were death, myocardial infarction (MI) and stent thrombosis (ST). Stent thrombosis was defined by the Academic Research Consortium (ARC) as “definite” or “probable” stent thrombosis [6]. TLR was defined as any revascularization procedure involving the target lesion owing to luminal re-narrowing in the presence of symptoms or objective signs of ischemia.

2.5. Statistical analyses The chi-square test was used to examine differences in categorical variables, such as the frequencies. A p value less than .05 was considered statistically significant. Summary estimate includes odds ratio (OR), relative risk (RR), and weighted mean difference (WMD) and its 95% confidence intervals (CI) were used as summary statistics in forest plot. Heterogeneity was assessed by Cochran's Q test, with a 2-tailed p ≥ 0.1. The statistical inconsistency test (I2) {[(Q − df) / Q] × 100%, where Q is the chi-squared statistic and df is degrees of freedom} was also employed to overcome the low statistical power of Cochran's Q test. Pooled ORs were calculated using a fixed effect model with the Mantel–Haenszel method. The DerSimonian and Laird random effects model was used in case of significant heterogeneity and/or moderate or significant inconsistency (p b 0.1 or I2 N 50%) across studies. Potential publication bias was examined by Egger's test, in which p b 0.05 indicated that there was significant publication bias. We conducted a sensitivity analysis in which one study was removed and the rest were analyzed to evaluate whether the results were affected statistically significantly. Review Manager (RevMan) 5.2.6 (The Nordic Cochrane Center, Copenhagen, Denmark) and Stata 12.0 (College Station, Texas, USA) were used for statistical analysis.

3.2. Baseline characteristics The baseline characteristics and quality analysis are described in Table 1. Mean lesion length was 15.2 mm in the DP-DES group as compared to 14.6 mm in the PP-DES group. Mean vessel size was 2.85 mm in DP-DES and 2.86 mm in PP-DES. Mean age was similar in the two groups (63.5 vs. 62.9). Men represented 73.3% of the DP-DES and 74.3% of the PP-DES population. There were 25.1% patients with diabetes in the DP-DES group and 24.7% in the PP-DES group. Protocols of dual antiplatelet therapy (DAPT) in our meta-analysis are summarized in Table 2. Mean dual anti-platelet duration was 8 months.

3.3. Safety endpoints 3.3.1. Death There was no significant difference in the rate of death with DP-DES as compared with PP-DES: 2.78% (274/9849) in the DP-DES group and 3.14% (269 of 8546) in the PP-DES group (OR [95% CI] = 0.96 [0.81– 1.14], p = 0.891) (Fig. 2). Subgroup analysis of short-, mid- and long term of death between DP-DES and PP-DES didn't show any difference (Supplement 1).

3. Results 3.1. Study selection We identified 19 randomized clinical trials (28 published studies) that satisfied our inclusion criteria (Fig. 1) [7–34]. Additional followup data on safety and efficacy were available for ISAR-TEST-3, ISAR TEST-4, NEVO RES-I and LEADERS [12,27,28,31]. Altogether, 19 trials (n = 18,395) with results of interest were finally analyzed to compare the clinical outcomes with 9849 and 8546 allocated to the DP- and PP-DES, respectively. Eleven trials (n = 5828) were used for angiography evaluation with 2977 and 2851 allocated to the DP- and PP-DES as well. There are four 3-arm trials. For ISAR TEST-4, data was abstracted to compare DP- to PP-DES (sirolimus + everolimus) [28,29]. We included the standard everolimus DP-DES as opposed to the half-dose everolimus DP-DES arm of the EVOLVE trial because standard everolimus DP-DES are the currently used stent type [15]. For GENESIS trial, we included the pimecrolimus DES as opposed to the paclitaxel/pimecrolimus DES arm as the control group [11]. The ISAR TEST-3 trial data included were the DP-DES and PP-DES arms only, with the polymer free arm of the trial excluded [16,27].

3.3.2. Myocardial infarction There was no significant difference in the rate of MI with DP-DES as compared with PP-DES: 3.51% (346/9849) in the DP-DES group and 3.35% (286/8546) in the PP-DES group (OR [95% CI] = 1.08 [0.92–1.27], p = 0.932) (Fig. 3). Subgroup analysis of short-, mid- and long term of MI between DP-DES and PP-DES didn't show any difference (Supplement 2).

3.3.3. Stent thrombosis There was no significant difference in the rate of total ST with DP-DES as compared with PP-DES: 0.92% (91/9849) in the DP-DES group and 1.21% (103/8546) in the PP-DES group (OR [95% CI] = 0.82 [0.61–1.09], p = 0.308) (Supplement 3). Subgroup analysis of early and late (30 days–1 year) ST between DP-DES and PP-DES didn't show any difference (Fig. 4A and B). Seven studies (6206 patients) with a mean follow-up of 30 months were included to compare the outcome of very late ST between DP- and PP-DES. The meta-analysis showed a significant decreased very late ST in patients treated with DP-DES (0.45%,14/3107) as compared to patients receiving PP-DES (1.12%, 35/3099) (OR [95% CI] = 0.42 [0.24–0.77], p = 0.852) (Fig. 4C).

Table 1

Baseline patient characteristics. Published

Trial

FUa months

Byrne et al. [27,29] Meredith et al. [15]

ISAR-TEST-4 EVOLVE

12 6

3 4 5

Serruys et al. [34] Christiansen et al. [24] Verheye et al. [11]

6 7 8 9 10 11 12 13 14 15 16 17 18 19

Ormiston et al. [14] Krucoff et al. [19] Kadota et al. [21] Chevalier et al. [25] Chevalier et al. [26] Mehilli et al. [16] Li et al. [17] Smits et al. [13] Xu et al. [8] Gao et al. [13] Zhang et al. [7] Ahmad et al. [30] Maamoun [33] Natsuaki et al. [32]

LEADERS SORT OUT V GENESIS GENESIS NEVO RES-I COSTAR II NOBORI-JAPAN NOBORI 1-phase 2 NOBORI 1-phase 1 ISAR-TEST-3

48 12 6 6 6 8 9 9 9 12 12 12 24 12 24 12 24 12

No.

Published

COMPARE II NOYA I TARGET I

NEXT Diabetes %

Sample

Male (%)

Age (year + SD)

PP

DP

PP

DP

PP

DP

1299 94 99 857 1229 49 49 198 989 190 153 85 202 115 1795 148 227 341 100 62 1617

1304 98 98 850 1239 97 100 189 686 128 90 35 202 113 912 150 231 321 100 83 1618

Sirolimus Everolimus Evero-half Biolimus Biolimus Paclitaxel Paclitaxel Sirolimus Paclitaxel Biolimus Biolimus Biolimus Sirolimus Sirolimus Biolimus Sirolimus Sirolimus Sirolimus Biolimus Biolimus Biolimus

Sirolimus (Cypherb)/Everolimus (Xience Vc) Promus Elementc

75 69.9 69.7 75 74.6 71.4 71.4 78 73.1 71.6 74.5 69 78.2 77.2 74.4 66.7 69.2 69.2 66 87.1 77

77 79.6 79.6 74.6 75.1 78.4 80 74 71.1 72 68.9 66 81.7 73.5 74.3 72 68.4 68.5 64 85.5 77

66.7 64.9 62.9 64.6 65 64.4 64.4 63 63.5 67.1 62.7 65 66.5 60.1 63 56.6 58.7 67.5 60.6 56.7 69.1

Sirolimus (Cypherb) Sirolimus (Cypherb) Pimecrolimus d Paclitaxel + pimecrolimusd Paclitaxel (Liberteb) Paclitaxel (TAXUSb) Sirolimus (Cypherb) Paclitaxel (Liberteb) Paclitaxel (TAXUSb) Sirolimus (Cypherb) Sirolimus (Cypherb) Everolimus (Xience V/Promusc) Sirolimus (Firbird2 c) Everolimus (Xience Vc) Sirolimus (Partnerb) Everolimus (Xience Vc) Paclitaxel/Sirolimuse Everolimus (Xience V/Promusc)

PP 10.7 11 10.2 10.8 10.6 9.6 9.6 10 10.8 10.3 NAe 11 11.6 11.9 11.1 10.2 9.4 9.79 9.1 11 9.8

29 22.4 22.4 22.5 15.3 17.5 32 20

2.79 NA NA 2.6 3.2 2.81 2.81 2.64

0.47 NA NA 0.61 NA 0.47 0.47 0.41

2.8 NA NA 2.6 3.3 2.87 2.79 2.68

0.52 NA NA 0.57 NA 0.5 0.45 0.43

14.8 13.4 13.6 12.7 18 14.4 14.4 13.8

8.6 6.3 5.8 8.1 NA 6 6 6.6

15 14.62 14.62 12.4 18 13.8 14.9 13.7

8.8 5.81 5.81 8.5 NA 5.4 5.5 6.1

De novo, native De novo, native 28 mm, 2.25 to 3.5 mm All comer 2.25–3.5 mm All comer De novo, 25 mm, 2.5–3.5 mm De novo, native, 2.5–3.5 mm De novo,native, 30 mm, 2.5–3.5 mm De novo, 30 mm, 2.5–3.5 mm De novo, native, 5–25 mm, 2.5–3.5 mm De novo, native, 5–25 mm, 2.5–3.5 mm De novo, native STEMIg, 2.5–3.5 mm All comer, 2.0–4.0 mm De novo, native, 30 mm, 2.25–4.0 mm De novo, native, 24 mm, 2.5–4.0 mm Coronary artery disease All comer, 2.5–3.5 mm Coronary artery disease All comer

PP

Serruys et al. [34] Christiansen et al. [24] Verheye et al. [11]

6

Ormiston et al. [14]

7

Krucoff et al. [19]

27.4

28.9

NA

NA

NA

NA

15.4

6.5

15.1

6.5

8 9

Kadota et al. [21] Chevalier et al. [25]

38.7 16.3

39.4 27.8

2.68 2.72

0.57 NA

2.68 2.73

0.54 NA

12.6 10.6

5.5 NA

12.82 10.84

6.81 NA

10

Chevalier et al. [26]

18

26

2.7

0.44

2.71

0.52

11.4

4.5

11.03

4.75

11 12 13 14

Mehilli et al. [16] Li et al. [17] Smits et al. [13] Xu bo et al. [8]

28.7 32.5 21.8 22

26.4 19.5 21.6 20

13.9 3.05 2.9 NA

7.2 0.45 0.5 NA

14.6 3.03 2.9 NA

7 0.44 0.5 NA

2.74 NA 16.8 17.7

0.5 NA 9.8 9.3

2.75 NA 17.7 18.72

0.51 NA 10.6 9.98

15

Gao et al. [13]

13.7

16.9

2.87

0.47

2.9

0.5

15.7

7.1

15.7

6.7

16 17 18 19

Zhang et al. [7] Ahmad et al. [30] Maamoun [33] Natsuaki et al. [32]

32.2 28 35.5 46

27.7 32 NA 46

3.26 2.97 NA 2.6

2.4 0.22 NA 0.6

3.13 2.96 NA 2.6

0.45 0.29 NA 0.5

29.2 NA NA 19.2

17 NA NA 12

24. 7 NA NA 19.3

14.47 NA NA 13.1

e

f g

LMf LM; bifurcation; occlusion

DP

PP

3 4 5

d

Exclusion of lesion subsets

Lesion length (mm + SD)

DP

29 17.2 18.2 26 15.1 36.7 36.7 18

c

Inclusion

Vessel size (mm + SD) PP

Byrne et al. [27,29] Meredith et al. [15]

b

11.1 10 10 10.7 10.3 10.1 10 9.9 10.6 9.3 NA 11 10.7 10.8 11 9.2 9.4 11.1 10.2 10.2 9.8

DP 1 2

a

66.8 62.1 62.1 64.5 65.2 59.9 64.1 64.4 63.7 67.7 63.2 63 65 59.7 62.7 56.7 59.6 65.8 62.3 54.3 69.3

FU: follow-up. 1st generation stent. 2nd generation stent. Not available for sale. NA: not available. LM: left main. STEMI: ST segment elevation myocardial infarction.

None None LM, bifurcation, severe calcification LM, bifurcation, occlusion; severe calcification LM, bifurcation, occlusion; ostium LM LM, bifurcation, occlusion; severe calcification; ostium LM, occlusion; severe calcification; LM LM None LM, bifurcation, occlusion LM, bifurcation, occlusion LM None LM None

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1 2

Drugs

DP

102

No.

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Table 2 Protocols of dual anti-platelet therapy (DAPT). No.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 a b c d e f

Published

Byrne et al. [27,29] Meredith et al. [15] Serruys et al. [34] Christiansen et al. [24] Verheye et al. [11] Ormiston et al. [14] Krucoff et al. [19] Kadota et al. [21] Chevalier et al. [25] Chevalier et al. [26] Mehilli et al. [16] Li et al. [17] Smits et al. [13] Xu bo et al. [8] Gao et al. [13] Zhang Y et al. [7] Ahmad et al. [30] Maamoun [33] Natsuaki et al. [32]

Trial

Regimes DP/PP

ISAR-TEST-4 EVOLVE LEADERS SORT OUT V GENESIS NEVO RES-I COSTAR II NOBORI-JAPAN NOBORI 1-phase 2 NOBORI 1-phase 1 ISAR-TEST-3 COMPARED II NOYA I TARGET I

NEXT

b

A A A A A A A A A A A A A A A A A A A

c

+C +C +C +C +C +C +C + C or Td +C +C +C +C + C or Pe +C +C +C +C +C + C or T

Prior intervention DP/PP

600 mg C 300 mg C NA 75 mg A + 600 mg C 100–300 mg A + 300 mg C 300 mg A or C NA NA 100 mg A + 300–600 mg C 100 mg A + 300–600 mg C 600 mg C 300 mg A + 600 mg C 300 mg A + 300–600 mg C 300 mg A + 300 mg C 300 mg A + 75–300 mg C 300 mg A + 300–600 mg C 100 mg A + 300 mg C 300 mg A + 300–600 mg C NAf

After intervention DP/PP

200 mg/day A + 75 mg/day C N75 mg/day A + 75 mg/day C N75 mg/day A + 75 mg/day C 75 mg/day A + 75 mg/day C 100–300 mg/day A; 75 mg/day C 100–300 mg/day A + 75 mg/day C 325 mg/day A + 75 mg/day C ≥81 mg/day A + 75 mg/day C or 200 mg/day T 100 mg/day A + 75 mg/day C 100 mg/day A + 75 mg/day C 200 mg/day A + 75 mg/day C 100 mg/day A + 75 mg/day C 100 mg/day A + 75 mg/day C or 10 mg/day P 100 mg/day A + 75 mg/day C 100 mg/day A + 75 mg/day C 100 mg/day A + 75 mg/day C 100 mg/day A + 75 mg/day C 100 mg/day A + 75 mg/day C ≥81 mg/day A + 75 mg/day C or 200 mg/day T

DAPT: dual anti-platelet therapy. A: aspirin. C: clopidogrel. T: ticlopidine. P: prasugrel. NA: not available.

Fig. 2. Individual and summary odds ratios for total death in patients treated with DP- vs. PP-DES.

DAPTa months DP

PP

6 6 12 12 6 6 6 3 6 6 6 12 12 12 12 12 12 6 3

6 6 12 12 6 6 6 3 6 6 6 12 12 12 12 12 12 12 3

104

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Fig. 3. Individual and summary odds ratios for total myocardial infarction in patients treated with DP- vs. PP-DES.

3.4. Efficacy endpoints 3.4.1. Target lesion revascularization The meta-analysis didn't show a significant decreased TLR in patients treated with DP-DES (4.36%, 386/8860) as compared to patients receiving PP-DES (5.59%, 439/7860) (OR [95% CI] = 0.86 [0.75–1.00], p = 0.068) (Fig. 5). Subgroup analysis of short-, mid- and long term of TLR between DP-DES and PP-DES didn't show any difference (Supplement 4). 3.4.2. In-stent late loss Eleven studies (5828 patients) were included with a mean follow-up of 7 months. ISLL significantly decreased in DP-DES group (0.19 mm) compared to PP-DES group (0.28 mm) (SMD [95% CI] = − 0.07 [−0.12; −0.02], p = 0.000) (Fig. 6). 3.4.3. Sensitivity and stratified analyses Sensitivity analysis was performed by removing each of the studies one at a time, which did not detect any influence of any single study on the overall results. Stratified analysis for the specific type of DES (paclitaxel, biolimus or sirolimus) didn't show any difference between DP-DES and PP-DES in regard to MI, death, ST and TLR(Supplements 9–86) except that a significant decreased TLR with DP-DES (2.98%, 13/436) was detected as compared to patients receiving paclitaxel-DES (7.0%, 22/314) (OR [95% CI] = 0.41 [0.20– 0.81], p = 0.457) (Fig. 7). With regard to ISLL, the overall results in favor of DP-DES were confirmed when analyzed separately for the specific DES type used: 1. sirolimus as control group: VMD (95% CI) = − 0.07 (− 0.14, 0.00), p = 0.000 (sirolimus); 2. sirolimus as therapy group: VMD

(95% CI) = − 0.03 (− 0.06, 0.00), p = 0.852; 3. biolimus as therapy group: VMD (95% CI) = − 0.05 (− 0.13,0.03), p = 0.005; 4. sirolimus as both therapy and control group: VMD (95% CI) = − 0.03 (− 0.07; 0.01), p = 0.557 (Supplements 5–8). 4. Discussion This meta-analysis of 18,395 patients first compared short-, mid-, long term outcomes between DP- and PP-DES. The main finding is that patients allocated to DP-DES showed significantly less very late ST and ISLL, with comparable MI, death, TLR, early-, late- and total ST to those treated with PP-DES. Drug-eluting stents (DES) reduce restenosis by inhibiting fibromuscular hyperplasia through local release of anti-restenosis drugs, from surface coatings using permanent polymer [35,36]. However, durable polymer residue in the coronary milieu may induce inflammatory changes at the vessel-wall and then contributes to late thrombotic stent as well as neointimal overgrowth [2,3]. Degradable-polymer DES has been developed by providing similar controlled drug release with subsequent degradation of the polymer in 3–9 months and, therefore, appears to be a promising solution to overcome this problem [7–31]. However, most published studies reported non-inferior or comparable safety and efficiency between DP- and PP-DES, indicating a great challenge to detect the difference in relatively rarely occurring clinical events such as ST and MI, without aggregate long-term data from large-scale studies. A meta-analysis with 8 RCTs (n = 7481) showed that DP-DES are at least as safe as standard PP-DES with regard to survival and MI and more effective in reducing late definite/probable/possible ST, as well as a six-month ISLL [37]. In 2012, a pooled analysis of individual patient data from the ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials

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Fig. 4. Individual and summary odds ratios for stent thrombosis in patients treated with DP- vs. PP-DES. A. early ST, B. late ST and C. very late ST.

(4062 patients, 4 years) showed that the risk of TLR was significantly lower with DP-DES vs. PP-DES, as well as definite stent thrombosis which was thought to be primarily driven by a significant risk reduction in terms of very late definite stent thrombosis [38]. However, in another meta-analysis comprising 7 randomized trials comparing DP-DES (3778 patients) and PP-DES (3291 patients), the risks of TLR and definite ST at 1-year were not significantly different [39]. They thought that possible

inflammatory reactions induced biodegradable polymers may be a reason [40]. The findings of the current study are novel and important for at least 4 reasons. First, our meta-analysis tends to be statistically more powerful than the previous ones, with a total of 18,395 enrolled patients. We didn't show a significant difference in death (from 2.78% to 3.15%) and MI (from 3.51% to 3.35%) for DP-DES, as compared to PP-DES. It is our

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Fig. 5. Individual and summary odds ratios for total TLR in patients treated with DP- vs. PP-DES.

Fig. 6. Individual and summary odds ratios for ISLL in patients treated with DP- vs. PP-DES.

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Fig. 7. Individual and summary odds ratios for ISLL in patients treated with DP- vs. paclitaxel-eluting stents.

opinion that even an analysis with that amount of patients was unable to detect a significant advantage may be interpreted as a truly limited difference between DP-DES and PP-DES. Second, our study is the first meta-analysis of RCTs to address the comparison of short-, mid- and long term outcomes between DP- and PP-DES, which provides more detailed information regarding profiles of DP-DES safety and efficiency. However, these results need to be confirmed by further investigation, especially in the consideration that not all the data are available in landmark analysis. Third, we for the first time reported a significant reduction of DP-DES in very late (30 months) definite/probable ST, as was recommended by the ARC for best characterizing this aspect of DES safety [6]. This finding is supported by the results of previous metaanalysis regarding reduced very late definite ST and late any ST [34,35]. It is our opinion that similar findings with different ST classification used to compare the true rates of late ST across different trials further clarified the safety profile of DP-DES, as compared to PP-DES. This difference was not detected in the included individual trials which may indicate a lack of statistical power with a single study. Fourth, our results indicated an improved anti-restenotic efficacy of DP-DES vs. PP-DES with lower ISLL in 7 months. However, we didn't show a significant reduction of total TLR (OR [95% CI] = 0.86 [0.75– 1.00], p = 0.068) and long term TLR (OR [95% CI] = 0.86 [0.65–1.12], p = 0.355). These results are not consistent with the previous pooled analysis, which reported a significant lower TLR among patients treated with DP-DES vs. PP-DES (HR = 0.82, [95% CI] = 0.68–0.98, p = 0.029). In our opinion, these differences can be explained with the following reasons: 1. we used odds ratio (OR) not hazard ratio (HR) to compare the outcomes of DP- vs. PP-DES. 2. Although the result is contradicted, only little difference exists between those data 95% CI (0.75–1.00) vs. 95% CI (0.68–0.98). 3. They used sirolimus-DES as a control group. However, in our trial, sirolimus-, everolimus- and paclitaxel-DES are all included in the control group. Furthermore, the stratified analysis showed a significant decreased TLR (2.98% vs. 7.0%) with DP-DES as compared to paclitaxel-eluting stent (OR [95% CI] = 0.41 [0.20–0.81], p = 0.457). These results should be interpreted carefully and further large RCTs with long-term follow-up are warranted to better define the relative merits of DP-DES.

First generation DES have required extension of dual anti-platelet therapy from 1 month up to 12 months and beyond due to delayed endothelialization. At present, DAPT with aspirin (75–100 mg/day) and a P2Y12 inhibitor (e.g., clopidogrel 75 mg/day) is the current standard of care for all patients receiving DES [41,42], which reduces the risk of stent thrombosis but is also associated with increased risk of bleeding. However, availability of DP-DES has shown far earlier endothelialization (28 days) and therefore indicated the feasibility of considerable earlier DAPT discontinuation [43]. Previous trials found that patients treated with a DP-DES had similar rates of repeat revascularization and ST compared with their PP-DES counterparts, despite stopping DAPT sooner [33,44,45]. It was confirmed by our meta-analysis, which showed reduced ISLL and very late ST of DP-DES vs. PP-DES, with a shorter DAPT duration (8 months). In NOBORI-JAPAN and NEXT trials, patients receiving DP-DES showed a low rate of revascularization and ST, with a further reduction of DAPT duration (3 months) [21,32]. However, large RCTs designed to clarify the criteria of DP-DES safely allowing early DAPT withdrawal are still needed. Most of the included studies excluded patients with left main, bifurcation, chronic total occlusion, long lesion and severe calcification. Thus, data that confirm the improvements of DP-DES on different lesion subsets are scarce. Up to now, only few subgroup analysis of LEADERS trial showed that biolimus-eluting stent with a biodegradable polymer leads to superior efficacy in bifurcation lesions [46], decreased cardiac mortality in patients with high SYNTAX score [47] and similar major adverse cardiac events (MACE) in long lesions [48], as compared with sirolimus-eluting stent. The findings of a reduced very late ST and as well as ISLL with DP-DES as compared to PP-DES in our meta-analysis are clinically significant and support the assumption that biodegradation of the polymer will improve arterial healing and translates into reduced risk of very late ST and improved antirestenotic efficacy. 4.1. Limitations The limitations of the study are as follows: 1. The limitations of the meta-analytical approach are well known and documented [49]. 2. We didn't have data for all trials at each time period; therefore, this limited comparison of rates across time within a specific end point. 3. Little

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information was available from the various RCTs on the specific lesion subsets that warrant further investigations. 4. Inclusion criteria were not equivalent across the included trials, however, reflects the broadly inclusive nature of the included patient population. 5. The majority of patients in the control group received first generation DES [2,7,14,16,19,21,24–26,29,34], for example sirolimus, which is not a current practice anyway. Therefore, large RCTs with long-term follow-up regarding the relative performance of DP-DES versus current popular PP-DES (e.g. 2nd generation DES) are desirable. 5. Conclusions DP-DES are more effective in reducing very late ST and ISLL, as well as comparable with standard DES in regard to death, TLR and MI. Further large RCTs with long-term follow-up are warranted to better define the relative merits of DP-DES. Funding sources This study was supported by grants from the National Natural Science Foundation of China (81070168 and 81370213) and Third Military Medical University (2010XLC28). References [1] Bangalore S, Kumar S, Fusaro M, et al. Short- and long-term outcomes with drugeluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117,762 patient-years of follow-up from randomized trials. Circulation 2012;125(23): 2873–91. [2] Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation 2004;109(6):701–5. [3] Finn AV, Kolodgie FD, Harnek J, et al. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 2005;112(2):270–8. [4] The Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions. Available at www.cochrane.org/resources/handbook/. [updated February 2010]. [5] Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009;6(7):e1000100. [6] Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115(17):2344–51. [7] Zhang Y, Shen J, Li Z, et al. Two-year clinical outcomes of different drug-eluting stents with different polymer coating strategies in coronary artery heart disease: a multi-centre, randomised, controlled clinical trial. Int J Cardiol 2013;168(3): 2646–52. [8] Xu B, Dou K, Yang Y, et al. Nine-month angiographic and 2-year clinical follow-up of the NOYA biodegradable polymer sirolimus-eluting stent in the treatment of patients with de novo native coronary artery lesions: the NOYA I trial. EuroIntervention 2012;8(7):796–802. [9] Wykrzykowska J, Serruys P, Buszman P, et al. The three year follow-up of the randomised “all-comers” trial of a biodegradable polymer biolimus-eluting stent versus permanent polymer sirolimus-eluting stent (LEADERS). EuroIntervention 2011;7(7):789–95. [10] Windecker S, Serruys PW, Wandel S, et al. Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial. Lancet 2008;372(9644): 1163–73. [11] Verheye S, Agostoni P, Dawkins KD, et al. The GENESIS (randomized, multicenter study of the pimecrolimus-eluting and pimecrolimus/paclitaxel-eluting coronary stent system in patients with de novo lesions of the native coronary arteries) trial. JACC Cardiovasc Interv 2009;2(3):205–14. [12] Stefanini GG, Kalesan B, Serruys PW, et al. Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial. Lancet 2011;378(9807):1940–8. [13] Smits PC, Hofma S, Togni M, et al. Abluminal biodegradable polymer biolimuseluting stent versus durable polymer everolimus-eluting stent (COMPARE II): a randomised, controlled, non-inferiority trial. Lancet 2013;381(9867):651–60. [14] Ormiston JA, Abizaid A, Spertus J, et al. Six-month results of the NEVO res-elution I (NEVO RES-I) trial: a randomized, multicenter comparison of the NEVO sirolimuseluting coronary stent with the TAXUS Liberte paclitaxel-eluting stent in de novo native coronary artery lesions. Circ Cardiovasc Interv 2010;3(6):556–64. [15] Meredith IT, Verheye S, Dubois CL, et al. Primary endpoint results of the EVOLVE trial: a randomized evaluation of a novel bioabsorbable polymer-coated, everolimuseluting coronary stent. J Am Coll Cardiol 2012;59(15):1362–70.

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