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Comparison of drug-eluting balloon versus drug-eluting stent in patients with in-stent restenosis: Insight from randomized controlled trials
International Journal of Cardiology 179 (2015) 424–429
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Comparison of drug-eluting balloon versus drug-eluting stent in patients with in-stent restenosis: Insight from randomized controlled trials Wahafu Mamuti a, Alimjan Ablimit a, Wumaierjiang Kelimu a, Fang Rao a, Abulimiti Jiamali a, Wei Zhang a, Xiaoli Pei a, Feng Zhang b,⁎ a b
Department of Cardiology, Kashgar Prefecture Second People's Hospital, Kashi, Xinjiang 844000, China Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
a r t i c l e
i n f o
Article history: Received 26 April 2014 Received in revised form 25 June 2014 Accepted 16 November 2014 Available online 18 November 2014 Keywords: In-stent restenosis Drug-eluting balloon Drug-eluting stent Coronary artery disease
a b s t r a c t Backgrounds: In-stent restenosis (ISR) remains an important issue even in the current drug-eluting stent (DES) era. We performed a meta-analysis to assess the clinical efficacy and safety of drug-eluting balloon (DEB) as compared with DES for the treatment of ISR. Methods: The published literature was scanned by formal searches of electronic databases from January 2005 to February 2014. All randomized controlled trials were eligible for inclusion if they compared DEB with DES in patients with ISR. Results: Prespecified criteria were met by 4 trials involving 803 patients. There was no significant difference in the primary endpoint (12-month major adverse cardiac events) between the 2 groups (risk ratio [RR] 1.04, P = 0.80). The incidence of death (RR 0.81, P = 0.62), myocardial infarction (RR 0.66, P = 0.29), and target lesion revascularization (RR 1.35, P = 0.12) in the DEB group was also similar to those in the DES group. Conclusions: This meta-analysis showed that DEB was associated with comparable clinical outcomes to DES for the treatment of ISR. DEB might be the preferred interventional strategy for patients with ISR by obviating the need of additional stent layer. © 2014 Published by Elsevier Ireland Ltd.
1. Introduction In-stent restenosis (ISR) remains an important issue even in the current drug-eluting stent (DES) era [1]. As compared with conventional therapeutic strategies, DES had been demonstrated to result in superior angiographic and clinical outcomes in patients suffered from ISR [2–5]. However, repeat metal scaffold implantation may further reduce the flexibility of the coronary artery and limit the repeatability of the interventional procedure. In recent years, drug-eluting balloon (DEB) has emerged as an alternative option for the treatment of ISR. Although the superiority of the DEB over the conventional balloon angioplasty (BA) in treatment of ISR had been widely demonstrated [6–9], the relative safety and efficacy of DEB versus DES remain undetermined. Recently, the results of several randomized controlled trials (RCTs) comparing DEB versus DES for ISR lesions have been reported [10–13]. However, the primary endpoints were angiographic parameters in all of these studies, and none had enough statistical power regarding the clinical outcomes [10–13]. Meta-analysis of randomized trials has the potential to increase the power and improve the precision of treatment
effects and safety [14]. Therefore, we performed a meta-analysis based on all currently available RCTs to assess the clinical efficacy and safety of the DEB angioplasty as compared with the DES implantation for the treatment of ISR. 2. Methods 2.1. Study selection criteria and data extraction We included published RCTs that compared the DEB angioplasty with the DES implantation in patients with ISR. There were no language restrictions. The published literature was scanned by a comprehensive search of electronic databases (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials) to identify relevant articles from January 2005 to February 2014. Search terms included percutaneous coronary intervention, drug-eluting balloon, drug-coated balloon, paclitaxel-eluting balloon, paclitaxelcoated balloon, stent, and restenosis. All review articles, editorials, and Internet-based sources of information on trials of interest were also reviewed. Data abstraction was independently performed by two investigators. In addition to pertinent data on the outcomes of interest, we gathered information on study characteristics, patient characteristics, and treatment information. Disagreements were resolved by consensus. Data were managed according to the intention-to-treat principle. A flow diagram depicting the overall search strategy is demonstrated in Fig. 1. 2.2. Study endpoints
⁎ Corresponding author at: Department of Cardiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. E-mail address: [email protected] (F. Zhang).
http://dx.doi.org/10.1016/j.ijcard.2014.11.114 0167-5273/© 2014 Published by Elsevier Ireland Ltd.
Primary endpoint in the present study was a composite of major adverse cardiac events (MACEs) at 1 year follow-up. The secondary endpoints included all-cause mortality, myocardial infarction (MI), target lesion revascularization (TLR), recurrent binary
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Fig. 1. Flow diagram depicting the selection of studies included in the meta-analysis.
Table 1 The event definitions used in individual trials. Authors
Trial, published date
MI
TLR
MACE
Unverdorben et al. [10]
–, 2009
Percutaneous reintervention or coronary-artery bypass grafting involving the target lesion
TLR, MI, ST, or all-cause death
Alfonso et al. [11]
RIBS V, 2013
Repeat revascularization by percutaneous coronary intervention or surgery of the target lesion
Death, MI, or TLR
Byrne et al. [12]
ISAR-DESIRE 3, 2009
Any revascularisation procedure involving the target lesion because of luminal renarrowing with symptoms or objective signs of ischemia at 1 year of follow-up
Death, MI, or TLR
Xu et al. [13]
PEPCAD China ISR, 2014
Two of the following 5 criteria were present: chest pain lasting longer than 30 min; substantial changes on ECG that were typical of acute MI; a substantial increase in the level of CK or CK-MB (at least 3 times the ULN); new, clinically significant Q waves; and chest pain leading to angiography up to 6 h after the onset of the pain, with angiographic evidence of a totally occluded vessel Two of the following: prolonged (N30 min) chest pain; rise in CK levels N twice the local ULN (with abnormal MB fraction); and development of persisting ischemic ECG changes Either an increase in CK-MB (or CK) ≥3 ULN and at least 50% over the most recent pre-PCI levels, or the development of new ECG changes consistent with MI and CK-MB (CK) elevation higher than the ULN at two measurements for patients undergoing DES implantation in setting of stable angina pectoris or non-ST-segment elevation acute coronary syndrome and falling or normal CK-MB (CK) levels Non-Q-wave MI was defined as a CK-MB or troponin-T/troponin-I increase to N3 times ULN combined with clinical signs of MI, in the absence of pathological Q waves and not related to an interventional procedure. Q-wave MI was defined as development of new pathological Q waves in 2 or more contiguous leads together with clinical signs of MI
Any repeat percutaneous coronary intervention or aortocoronary bypass surgery because of restenosis ≥ 50% associated with symptoms or
Death, MI, or all-cause revascularization
objective signs of ischemia
MI = myocardial infarction; TLR = target lesion revascularization; MACE = major adverse cardiac event; ST = stent thrombosis; ULN = upper limit of normal; CK = creatine kinase; MB = myocardial band isoform; ECG = electrocardiogram.
12 12 12 12 DEB = drug-eluting balloon; DES = drug-eluting stent; MI = myocardial infarction; NA = not available.
Angiographic
6 6–9 6–8 9 6 12 6 12
DES DEB
3 3 6 12 NA 60 38 37
DES DEB
NA 60 39 53 23 75 11 27
DES DEB
24 59 14 23 26 20 47 35
DES DEB
33 32 41 44 71 66 79 35
DES DEB
75 73 79 38 83 72 77 69 65 64 69 62
DES
10 11 10 9 ± ± ± ± 65 67 68 62
DEB
65 94 131 106
DEB
–, 2009 RIBS V, 2013 ISAR-DESIRE 3, 2009 PEPCAD China ISR, 2014 Unverdorben et al. [10] Alfonso et al. [11] Byrne et al. [12] Xu et al. [13]
DES
Age (years) No. of patients (n) Trial, published date
As shown in Fig. 4, there was no significant difference with regard to the risks of death (2.2% vs. 2.8%; RR 0.81 [0.36–1.85]; P = 0.62), MI (2.46% vs. 3.79%; RR 0.66 [0.31–1.42]; P = 0.29), or TLR (14.0% vs. 10.4%; RR 1.35 [0.93–1.96]; P = 0.12). Data on angiographic follow-up were available in 394 ISR lesions. In the pooled estimate, there were no significant differences in the rate of recurrent binary restenosis between the 2 groups (17.5% for DEB vs.
Authors
3.3. Secondary endpoints
Table 2 Characteristics of randomized controlled trials included in the meta-analysis.
Data on 1 year MACE were available in all 803 patients (100%). As shown in Fig. 2, there were no significant differences in 12-month MACE between the 2 groups (18.4% for DEB vs. 17.7% for DES; RR 1.04 [0.78–1.39]; P = 0.80) by the fixed-effect model. There was no significant heterogeneity between trials (chi2 5.71, P = 0.13, I2 = 47.5%). No evidence of publication bias with respect to this primary endpoint was found using the Begg funnel plot and rank correlation test (P = 1.0, Fig. 3). Omission of individual trials from the analysis did not have any relevant influence on the overall results of the analysis. The RIBS V trial [11] compared PEB with EES, while other 3 trials [10, 12,13] used PES as comparator. By excluding the RIBS V trial, the MACE was numerically lower for PEB as compared with PES, but without statistically significance (20.5% vs. 21.2%, RR 0.97 [0.71 to 1.32], P = 0.83).
66 95 137 109
3.2. Primary endpoint
± ± ± ±
9 12 10 9
Male (%)
DES
Hypertension (%)
Hyperlipidemia (%)
Diabetes (%)
Of the 292 potentially relevant articles initially screened, a total of 4 randomized clinical trials were finally included in this meta-analysis, involving 803 patients (407 in the DEB group, 396 in the DES group) [10–13]. The baseline characteristics in the individual trials were shown in Table 2. Before the intervention, all patients received a loading dose of dual antiplatelet regimen (aspirin and ADP receptor antagonist) in all trials. The DEB studied in all 4 trials was the paclitaxel-eluting balloon (PEB, SeQuent Please, B. Braun, Melsungen, Germany) [10–13]. For the control, the paclitaxel-eluting stent (PES, Taxus Liberté, Boston Scientific, Natick, USA) was used in 3 trials [10,12,13] and the everolimus-eluting stent (EES, Xience Prime, Abbott Vascular, Illinois, USA) was used in 1 trial [11]. After the intervention, all patients were treated with aspirin indefinitely [10–13]. Clopidogrel was given for 3 months after DEB angioplasty and for 6–12 months after DES implantation in 2 trials [10,11]. In the PEPCAD China ISR trial, clopidogrel was given for 6 months in both groups [13]. In the ISAR-DESIRE 3 trial, the kind of ADP receptor antagonist was not mentioned, and all patients — irrespective of intervention allocation — were prescribed for 6 months [12].
DES
3.1. Eligible studies
80 72 77 78
Smoking (%)
3. Results
DEB
Previous MI (%)
Thienopyridine (m)
Statistical analysis was performed using Stata software version 9.0 (Stata Corp, College Station, USA). Risk ratios (RRs) with 95% confidence intervals (CI) were calculated as summary statistics. The pooled RR was calculated with the Mantel–Haenszel method for fixed effects and the DerSimonian and Laird method for random effects [15,16]. To assess heterogeneity across trials, we used Cochran's test and means of I2 statistic [17]. We assessed publication bias with respect to the primary outcomes of interest using a funnel plot as well as the adjusted rank correlation test according to the method of Begg and Mazumdar [18]. A sensitivity analysis was performed by assessing the contribution of individual studies to the summary effect estimate with respect to the primary outcomes. This was done by excluding each trial one at a time and computing meta-analysis estimates for the remaining studies. Results were considered statistically significant at P b 0.05.
77 87 67 86
2.3. Statistical analysis
73 86 77 88
Follow-up period (m)
restenosis (≥50% diameter stenosis) and late lumen loss (LLL). As shown in Table 1, the definition of individual endpoints differed slightly among the trials. We accepted these individual protocol definitions as it was impossible to retrospectively recategorize them.
Clinical
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DEB
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Fig. 2. Risk ratios of major adverse cardiac events (primary endpoint) associated with drug-eluting balloon versus drug-eluting stent in patients with in-stent restenosis. The size of the data marker is proportional to the weight of the individual studies, measured as the inverse of the variance in the study by the Mantel–Haenszel procedure.
18.6% for DES; RR 0.93 [0.70–1.26]; P = 0.65). The LLL in the DEB group was also similar to that in the DES group (mean difference −0.06 mm [−0.30–0.18], P = 0.63). 4. Discussion This present meta-analysis showed that DEB was associated with a comparable effectiveness and safety profile as compared with DES in the setting of coronary ISR diseases. Both the clinical outcomes (including 12-month MACE and its individual components) and the angiographic endpoints (including binary restenosis and LLL) were similar between the DEB and the DES groups. ISR lesions have been considered difficult to treat and those patients are at higher risk for recurrent restenosis [1]. Compared with conventional strategies such as BA or cutting balloon angioplasty, DES had been shown to result in superior angiographic and clinical outcomes [2–5]. Dependency on long-term dual antiplatelet therapy, however, has become a major issue for patients receiving DES. Moreover, when an additional stent is deployed to treat coronary ISR, the second strut layer results in excessive stiffening of the coronary artery, and injury to the ostium of side branches may occur.
Fig. 3. Funnel plot of all studies included in the meta-analysis. The standard error of the ln odds ratio was plotted against the odds ratio for 12-month major adverse cardiac events (primary endpoint). No skewed distribution was observed, suggesting no publication bias.
DEB represents an innovation with a high potential impact in the treatment of patients with coronary artery disease [19]. Currently available DEB is coated with paclitaxel, a highly lipophilic drug, which has rapid uptake and prolonged retention and can exert a sustained effect despite a short contact time with the vessel wall [20]. For ISR lesions, the use of DEB angioplasty offers a simpler option with a shorter procedural time and dual antiplatelet duration. Previous studies have demonstrated that DEB angioplasty, as compared with plain balloon angioplasty, is more effective in treating coronary ISR with long-term clinical benefits up to 5 years [6–9]. However, the control group therapy (BA) in these studies had now been superseded by repeat stenting with DES. Thus, we performed a meta-analysis based on all currently available randomized trials to specifically evaluate the relative safety and efficacy of DEB versus DES. Data from the present study suggest that DEB is similar to DES in terms of both angiographic and clinical outcomes for the treatment of ISR. Both therapeutic strategies were associated with excellent clinical endpoints. Therefore, there is growing evidence that DEB is equally effective and safe as a DES in treating coronary ISR. It is interesting to note that, despite a numerically lower rate of recurrent binary restenosis in the DEB group (17.5% vs. 18.6%, RR 0.93) in our study, the number of patients undergoing TLR was numerically higher in patients treated with DEB angioplasty than with DES implantation (14.0% vs. 10.4%, RR 1.35). The most likely explanation for this finding is that the presence of an existing multiple stent layers in the DES group might have discouraged the operator from repeat intervention. It reflects the significant limitation of use of repeated stenting for treatment of ISR. Once repeated restenosis occurs after DES implantation in the ISR, further management will become more and more challenging. Moreover, both mortality and MI risk were numerically higher in the DES group as compared with the DEB group in our study, although the differences were not statistically significant. Thus, DEB seems to be the ideal treatment of ISR because it eliminates both the stent and the polymer, while at the same time delivering an antiproliferative agent to reduce the risk of recurrent restenosis. Furthermore, promising results with DEB treatment are available from patients with de novo or restenotic lesions in peripheral arteries [21–27] and de novo lesions in small coronary arteries [28,29]. A limitation of our meta-analysis is that all individual trials included were open-label studies given the impossibility of blinding the operator to the stent system used. As the study follow-up was of relatively short
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W. Mamuti et al. / International Journal of Cardiology 179 (2015) 424–429
Fig. 4. Risk ratios of death (A), myocardial infarction (B), target lesion revascularization (C), and recurrent binary restenosis (D) associated with drug-eluting balloon versus drug-eluting stent in patients with in-stent restenosis. The size of the data marker is proportional to the weight of the individual studies, measured as the inverse of the variance in the study by the Mantel–Haenszel procedure.
duration, definitive conclusions will necessitate prolonged clinical followup for several additional years. The clinical outcome of the secondgeneration EES has shown to be better than the first-generation PES in the literature, but most of trials included in this meta-analysis used PES as comparator. Thus, further large, well-conducted randomized trials are needed to provide additional insights into the relative safety and efficacy of the DEB in comparison with the new-generation DES for the treatment of ISR lesions. In conclusion, this meta-analysis showed that DEB was associated with comparable angiographic and clinical outcomes to DES in treatment of ISR. It was suggested that DEB might be the preferred interventional strategy for patients with ISR by obviating the need of additional stent layer. Conflict of interest None declared. Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 81101133) and the Shanghai Outstanding Young Scientist Foundation from the Shanghai Municipal Health Bureau (No. XYQ2011001). References [1] G.D. Dangas, B.E. Claessen, A. Caixeta, E.A. Sanidas, G.S. Mintz, R. Mehran, In-stent restenosis in the drug-eluting stent era, J. Am. Coll. Cardiol. 56 (23) (2010) 1897–1907. [2] A. Kastrati, J. Mehilli, N. von Beckerath, et al., Sirolimus-eluting stent or paclitaxeleluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial, JAMA 293 (2) (2005) 165–171.
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W. Mamuti et al. / International Journal of Cardiology 179 (2015) 424–429 [16] R. DerSimonian, N. Laird, Meta-analysis in clinical trials, Control. Clin. Trials 7 (1986) 177–188. [17] J.P. Higgins, S.G. Thompson, J.J. Deeks, D.G. Altman, Measuring inconsistency in meta-analyses, BMJ 327 (2003) 557–560. [18] C.B. Begg, M. Mazumdar, Operating characteristics of a rank correlation test for publication bias, Biometrics 50 (1994) 1088–1101. [19] S. Sharma, N. Kukreja, C. Christopoulos, D.A. Gorog, Drug-eluting balloon: new tool in the box, Expert Rev. Med. Devices 7 (3) (2010) 381–388. [20] A. De Labriolle, R. Pakala, L. Bonello, G. Lemesle, M. Scheinowitz, R. Waksman, Paclitaxel-eluting balloon: from bench to bed, Catheter. Cardiovasc. Interv. 73 (5) (2009) 643–652. [21] E. Stabile, V. Virga, L. Salemme, et al., Drug-eluting balloon for treatment of superficial femoral artery in-stent restenosis, J. Am. Coll. Cardiol. 60 (18) (2012) 1739–1742. [22] F. Liistro, I. Porto, P. Angioli, et al., Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia, Circulation 128 (6) (2013) 615–621. [23] M. Fusaro, S. Cassese, G. Ndrepepa, et al., Paclitaxel-coated balloon or primary bare nitinol stent for revascularization of femoropopliteal artery: a meta-analysis of randomized trials versus uncoated balloon and an adjusted indirect comparison, Int. J. Cardiol. 168 (4) (2013) 4002–4009. [24] F. Liistro, S. Grotti, I. Porto, et al., Drug-eluting balloon in peripheral intervention for the superficial femoral artery: the DEBATE-SFA randomized trial (drug eluting
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Comparison of drug-eluting balloon versus drug-eluting stent in patients with in-stent restenosis: Insight from randomized controlled trials Wahafu Mamuti a, Alimjan Ablimit a, Wumaierjiang Kelimu a, Fang Rao a, Abulimiti Jiamali a, Wei Zhang a, Xiaoli Pei a, Feng Zhang b,⁎ a b
Department of Cardiology, Kashgar Prefecture Second People's Hospital, Kashi, Xinjiang 844000, China Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
a r t i c l e
i n f o
Article history: Received 26 April 2014 Received in revised form 25 June 2014 Accepted 16 November 2014 Available online 18 November 2014 Keywords: In-stent restenosis Drug-eluting balloon Drug-eluting stent Coronary artery disease
a b s t r a c t Backgrounds: In-stent restenosis (ISR) remains an important issue even in the current drug-eluting stent (DES) era. We performed a meta-analysis to assess the clinical efficacy and safety of drug-eluting balloon (DEB) as compared with DES for the treatment of ISR. Methods: The published literature was scanned by formal searches of electronic databases from January 2005 to February 2014. All randomized controlled trials were eligible for inclusion if they compared DEB with DES in patients with ISR. Results: Prespecified criteria were met by 4 trials involving 803 patients. There was no significant difference in the primary endpoint (12-month major adverse cardiac events) between the 2 groups (risk ratio [RR] 1.04, P = 0.80). The incidence of death (RR 0.81, P = 0.62), myocardial infarction (RR 0.66, P = 0.29), and target lesion revascularization (RR 1.35, P = 0.12) in the DEB group was also similar to those in the DES group. Conclusions: This meta-analysis showed that DEB was associated with comparable clinical outcomes to DES for the treatment of ISR. DEB might be the preferred interventional strategy for patients with ISR by obviating the need of additional stent layer. © 2014 Published by Elsevier Ireland Ltd.
1. Introduction In-stent restenosis (ISR) remains an important issue even in the current drug-eluting stent (DES) era [1]. As compared with conventional therapeutic strategies, DES had been demonstrated to result in superior angiographic and clinical outcomes in patients suffered from ISR [2–5]. However, repeat metal scaffold implantation may further reduce the flexibility of the coronary artery and limit the repeatability of the interventional procedure. In recent years, drug-eluting balloon (DEB) has emerged as an alternative option for the treatment of ISR. Although the superiority of the DEB over the conventional balloon angioplasty (BA) in treatment of ISR had been widely demonstrated [6–9], the relative safety and efficacy of DEB versus DES remain undetermined. Recently, the results of several randomized controlled trials (RCTs) comparing DEB versus DES for ISR lesions have been reported [10–13]. However, the primary endpoints were angiographic parameters in all of these studies, and none had enough statistical power regarding the clinical outcomes [10–13]. Meta-analysis of randomized trials has the potential to increase the power and improve the precision of treatment
effects and safety [14]. Therefore, we performed a meta-analysis based on all currently available RCTs to assess the clinical efficacy and safety of the DEB angioplasty as compared with the DES implantation for the treatment of ISR. 2. Methods 2.1. Study selection criteria and data extraction We included published RCTs that compared the DEB angioplasty with the DES implantation in patients with ISR. There were no language restrictions. The published literature was scanned by a comprehensive search of electronic databases (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials) to identify relevant articles from January 2005 to February 2014. Search terms included percutaneous coronary intervention, drug-eluting balloon, drug-coated balloon, paclitaxel-eluting balloon, paclitaxelcoated balloon, stent, and restenosis. All review articles, editorials, and Internet-based sources of information on trials of interest were also reviewed. Data abstraction was independently performed by two investigators. In addition to pertinent data on the outcomes of interest, we gathered information on study characteristics, patient characteristics, and treatment information. Disagreements were resolved by consensus. Data were managed according to the intention-to-treat principle. A flow diagram depicting the overall search strategy is demonstrated in Fig. 1. 2.2. Study endpoints
⁎ Corresponding author at: Department of Cardiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. E-mail address: [email protected] (F. Zhang).
http://dx.doi.org/10.1016/j.ijcard.2014.11.114 0167-5273/© 2014 Published by Elsevier Ireland Ltd.
Primary endpoint in the present study was a composite of major adverse cardiac events (MACEs) at 1 year follow-up. The secondary endpoints included all-cause mortality, myocardial infarction (MI), target lesion revascularization (TLR), recurrent binary
W. Mamuti et al. / International Journal of Cardiology 179 (2015) 424–429
425
Fig. 1. Flow diagram depicting the selection of studies included in the meta-analysis.
Table 1 The event definitions used in individual trials. Authors
Trial, published date
MI
TLR
MACE
Unverdorben et al. [10]
–, 2009
Percutaneous reintervention or coronary-artery bypass grafting involving the target lesion
TLR, MI, ST, or all-cause death
Alfonso et al. [11]
RIBS V, 2013
Repeat revascularization by percutaneous coronary intervention or surgery of the target lesion
Death, MI, or TLR
Byrne et al. [12]
ISAR-DESIRE 3, 2009
Any revascularisation procedure involving the target lesion because of luminal renarrowing with symptoms or objective signs of ischemia at 1 year of follow-up
Death, MI, or TLR
Xu et al. [13]
PEPCAD China ISR, 2014
Two of the following 5 criteria were present: chest pain lasting longer than 30 min; substantial changes on ECG that were typical of acute MI; a substantial increase in the level of CK or CK-MB (at least 3 times the ULN); new, clinically significant Q waves; and chest pain leading to angiography up to 6 h after the onset of the pain, with angiographic evidence of a totally occluded vessel Two of the following: prolonged (N30 min) chest pain; rise in CK levels N twice the local ULN (with abnormal MB fraction); and development of persisting ischemic ECG changes Either an increase in CK-MB (or CK) ≥3 ULN and at least 50% over the most recent pre-PCI levels, or the development of new ECG changes consistent with MI and CK-MB (CK) elevation higher than the ULN at two measurements for patients undergoing DES implantation in setting of stable angina pectoris or non-ST-segment elevation acute coronary syndrome and falling or normal CK-MB (CK) levels Non-Q-wave MI was defined as a CK-MB or troponin-T/troponin-I increase to N3 times ULN combined with clinical signs of MI, in the absence of pathological Q waves and not related to an interventional procedure. Q-wave MI was defined as development of new pathological Q waves in 2 or more contiguous leads together with clinical signs of MI
Any repeat percutaneous coronary intervention or aortocoronary bypass surgery because of restenosis ≥ 50% associated with symptoms or
Death, MI, or all-cause revascularization
objective signs of ischemia
MI = myocardial infarction; TLR = target lesion revascularization; MACE = major adverse cardiac event; ST = stent thrombosis; ULN = upper limit of normal; CK = creatine kinase; MB = myocardial band isoform; ECG = electrocardiogram.
12 12 12 12 DEB = drug-eluting balloon; DES = drug-eluting stent; MI = myocardial infarction; NA = not available.
Angiographic
6 6–9 6–8 9 6 12 6 12
DES DEB
3 3 6 12 NA 60 38 37
DES DEB
NA 60 39 53 23 75 11 27
DES DEB
24 59 14 23 26 20 47 35
DES DEB
33 32 41 44 71 66 79 35
DES DEB
75 73 79 38 83 72 77 69 65 64 69 62
DES
10 11 10 9 ± ± ± ± 65 67 68 62
DEB
65 94 131 106
DEB
–, 2009 RIBS V, 2013 ISAR-DESIRE 3, 2009 PEPCAD China ISR, 2014 Unverdorben et al. [10] Alfonso et al. [11] Byrne et al. [12] Xu et al. [13]
DES
Age (years) No. of patients (n) Trial, published date
As shown in Fig. 4, there was no significant difference with regard to the risks of death (2.2% vs. 2.8%; RR 0.81 [0.36–1.85]; P = 0.62), MI (2.46% vs. 3.79%; RR 0.66 [0.31–1.42]; P = 0.29), or TLR (14.0% vs. 10.4%; RR 1.35 [0.93–1.96]; P = 0.12). Data on angiographic follow-up were available in 394 ISR lesions. In the pooled estimate, there were no significant differences in the rate of recurrent binary restenosis between the 2 groups (17.5% for DEB vs.
Authors
3.3. Secondary endpoints
Table 2 Characteristics of randomized controlled trials included in the meta-analysis.
Data on 1 year MACE were available in all 803 patients (100%). As shown in Fig. 2, there were no significant differences in 12-month MACE between the 2 groups (18.4% for DEB vs. 17.7% for DES; RR 1.04 [0.78–1.39]; P = 0.80) by the fixed-effect model. There was no significant heterogeneity between trials (chi2 5.71, P = 0.13, I2 = 47.5%). No evidence of publication bias with respect to this primary endpoint was found using the Begg funnel plot and rank correlation test (P = 1.0, Fig. 3). Omission of individual trials from the analysis did not have any relevant influence on the overall results of the analysis. The RIBS V trial [11] compared PEB with EES, while other 3 trials [10, 12,13] used PES as comparator. By excluding the RIBS V trial, the MACE was numerically lower for PEB as compared with PES, but without statistically significance (20.5% vs. 21.2%, RR 0.97 [0.71 to 1.32], P = 0.83).
66 95 137 109
3.2. Primary endpoint
± ± ± ±
9 12 10 9
Male (%)
DES
Hypertension (%)
Hyperlipidemia (%)
Diabetes (%)
Of the 292 potentially relevant articles initially screened, a total of 4 randomized clinical trials were finally included in this meta-analysis, involving 803 patients (407 in the DEB group, 396 in the DES group) [10–13]. The baseline characteristics in the individual trials were shown in Table 2. Before the intervention, all patients received a loading dose of dual antiplatelet regimen (aspirin and ADP receptor antagonist) in all trials. The DEB studied in all 4 trials was the paclitaxel-eluting balloon (PEB, SeQuent Please, B. Braun, Melsungen, Germany) [10–13]. For the control, the paclitaxel-eluting stent (PES, Taxus Liberté, Boston Scientific, Natick, USA) was used in 3 trials [10,12,13] and the everolimus-eluting stent (EES, Xience Prime, Abbott Vascular, Illinois, USA) was used in 1 trial [11]. After the intervention, all patients were treated with aspirin indefinitely [10–13]. Clopidogrel was given for 3 months after DEB angioplasty and for 6–12 months after DES implantation in 2 trials [10,11]. In the PEPCAD China ISR trial, clopidogrel was given for 6 months in both groups [13]. In the ISAR-DESIRE 3 trial, the kind of ADP receptor antagonist was not mentioned, and all patients — irrespective of intervention allocation — were prescribed for 6 months [12].
DES
3.1. Eligible studies
80 72 77 78
Smoking (%)
3. Results
DEB
Previous MI (%)
Thienopyridine (m)
Statistical analysis was performed using Stata software version 9.0 (Stata Corp, College Station, USA). Risk ratios (RRs) with 95% confidence intervals (CI) were calculated as summary statistics. The pooled RR was calculated with the Mantel–Haenszel method for fixed effects and the DerSimonian and Laird method for random effects [15,16]. To assess heterogeneity across trials, we used Cochran's test and means of I2 statistic [17]. We assessed publication bias with respect to the primary outcomes of interest using a funnel plot as well as the adjusted rank correlation test according to the method of Begg and Mazumdar [18]. A sensitivity analysis was performed by assessing the contribution of individual studies to the summary effect estimate with respect to the primary outcomes. This was done by excluding each trial one at a time and computing meta-analysis estimates for the remaining studies. Results were considered statistically significant at P b 0.05.
77 87 67 86
2.3. Statistical analysis
73 86 77 88
Follow-up period (m)
restenosis (≥50% diameter stenosis) and late lumen loss (LLL). As shown in Table 1, the definition of individual endpoints differed slightly among the trials. We accepted these individual protocol definitions as it was impossible to retrospectively recategorize them.
Clinical
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DEB
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Fig. 2. Risk ratios of major adverse cardiac events (primary endpoint) associated with drug-eluting balloon versus drug-eluting stent in patients with in-stent restenosis. The size of the data marker is proportional to the weight of the individual studies, measured as the inverse of the variance in the study by the Mantel–Haenszel procedure.
18.6% for DES; RR 0.93 [0.70–1.26]; P = 0.65). The LLL in the DEB group was also similar to that in the DES group (mean difference −0.06 mm [−0.30–0.18], P = 0.63). 4. Discussion This present meta-analysis showed that DEB was associated with a comparable effectiveness and safety profile as compared with DES in the setting of coronary ISR diseases. Both the clinical outcomes (including 12-month MACE and its individual components) and the angiographic endpoints (including binary restenosis and LLL) were similar between the DEB and the DES groups. ISR lesions have been considered difficult to treat and those patients are at higher risk for recurrent restenosis [1]. Compared with conventional strategies such as BA or cutting balloon angioplasty, DES had been shown to result in superior angiographic and clinical outcomes [2–5]. Dependency on long-term dual antiplatelet therapy, however, has become a major issue for patients receiving DES. Moreover, when an additional stent is deployed to treat coronary ISR, the second strut layer results in excessive stiffening of the coronary artery, and injury to the ostium of side branches may occur.
Fig. 3. Funnel plot of all studies included in the meta-analysis. The standard error of the ln odds ratio was plotted against the odds ratio for 12-month major adverse cardiac events (primary endpoint). No skewed distribution was observed, suggesting no publication bias.
DEB represents an innovation with a high potential impact in the treatment of patients with coronary artery disease [19]. Currently available DEB is coated with paclitaxel, a highly lipophilic drug, which has rapid uptake and prolonged retention and can exert a sustained effect despite a short contact time with the vessel wall [20]. For ISR lesions, the use of DEB angioplasty offers a simpler option with a shorter procedural time and dual antiplatelet duration. Previous studies have demonstrated that DEB angioplasty, as compared with plain balloon angioplasty, is more effective in treating coronary ISR with long-term clinical benefits up to 5 years [6–9]. However, the control group therapy (BA) in these studies had now been superseded by repeat stenting with DES. Thus, we performed a meta-analysis based on all currently available randomized trials to specifically evaluate the relative safety and efficacy of DEB versus DES. Data from the present study suggest that DEB is similar to DES in terms of both angiographic and clinical outcomes for the treatment of ISR. Both therapeutic strategies were associated with excellent clinical endpoints. Therefore, there is growing evidence that DEB is equally effective and safe as a DES in treating coronary ISR. It is interesting to note that, despite a numerically lower rate of recurrent binary restenosis in the DEB group (17.5% vs. 18.6%, RR 0.93) in our study, the number of patients undergoing TLR was numerically higher in patients treated with DEB angioplasty than with DES implantation (14.0% vs. 10.4%, RR 1.35). The most likely explanation for this finding is that the presence of an existing multiple stent layers in the DES group might have discouraged the operator from repeat intervention. It reflects the significant limitation of use of repeated stenting for treatment of ISR. Once repeated restenosis occurs after DES implantation in the ISR, further management will become more and more challenging. Moreover, both mortality and MI risk were numerically higher in the DES group as compared with the DEB group in our study, although the differences were not statistically significant. Thus, DEB seems to be the ideal treatment of ISR because it eliminates both the stent and the polymer, while at the same time delivering an antiproliferative agent to reduce the risk of recurrent restenosis. Furthermore, promising results with DEB treatment are available from patients with de novo or restenotic lesions in peripheral arteries [21–27] and de novo lesions in small coronary arteries [28,29]. A limitation of our meta-analysis is that all individual trials included were open-label studies given the impossibility of blinding the operator to the stent system used. As the study follow-up was of relatively short
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Fig. 4. Risk ratios of death (A), myocardial infarction (B), target lesion revascularization (C), and recurrent binary restenosis (D) associated with drug-eluting balloon versus drug-eluting stent in patients with in-stent restenosis. The size of the data marker is proportional to the weight of the individual studies, measured as the inverse of the variance in the study by the Mantel–Haenszel procedure.
duration, definitive conclusions will necessitate prolonged clinical followup for several additional years. The clinical outcome of the secondgeneration EES has shown to be better than the first-generation PES in the literature, but most of trials included in this meta-analysis used PES as comparator. Thus, further large, well-conducted randomized trials are needed to provide additional insights into the relative safety and efficacy of the DEB in comparison with the new-generation DES for the treatment of ISR lesions. In conclusion, this meta-analysis showed that DEB was associated with comparable angiographic and clinical outcomes to DES in treatment of ISR. It was suggested that DEB might be the preferred interventional strategy for patients with ISR by obviating the need of additional stent layer. Conflict of interest None declared. Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 81101133) and the Shanghai Outstanding Young Scientist Foundation from the Shanghai Municipal Health Bureau (No. XYQ2011001). References [1] G.D. Dangas, B.E. Claessen, A. Caixeta, E.A. Sanidas, G.S. Mintz, R. Mehran, In-stent restenosis in the drug-eluting stent era, J. Am. Coll. Cardiol. 56 (23) (2010) 1897–1907. [2] A. Kastrati, J. Mehilli, N. von Beckerath, et al., Sirolimus-eluting stent or paclitaxeleluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial, JAMA 293 (2) (2005) 165–171.
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