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Eastern Heart Clinic, Prince of Wales Hospital, Sydney, NSW, AustraliaPrince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
Eastern Heart Clinic, Prince of Wales Hospital, Sydney, NSW, AustraliaPrince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
Eastern Heart Clinic, Prince of Wales Hospital, Sydney, NSW, AustraliaPrince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
In-stent restenosis (ISR) remains a significant mode of stent failure following PCI. The optimal treatment strategy, however, remains undefined and the role of drug-eluting balloons (DEB) in the management of ISR is also unclear.
Methods
A meta-analysis was performed to compare the efficacy of DEB in the treatment of ISR against second generation drug eluting stents (DES).
Results
Seven studies comprised of 1,065 patients were included for analysis. The follow-up period ranged from 12-25 months. The use of DEB was associated with an inferior acute gain in minimal luminal diameter (MLD) (0.36, 95% CI: 0.16-0.57 mm), higher late loss in MLD (0.11, 0.02-0.19 mm) and a higher binary restenosis rate at follow-up (risk ratio: 2.24, 1.49-3.37). No significant differences were noted in the overall incidence of the analysed clinical parameters between the two groups. When only the randomised controlled trials (RCT) were considered however, there was a strong trend towards higher target lesion revascularisation (TLR; 9.9% vs. 3.6%; RR: 2.5, p=0.07) and a significantly higher major adverse cardiovascular event (MACE) rate (15.7% vs. 8.8%; RR 1.78; p=0.02) with DEB.
Conclusion
While equipoise has been demonstrated in selected clinical outcomes between DEB and second generation DES in the treatment of ISR, the suboptimal angiographic outcome at follow-up and the higher TLR and MACE rates associated with DEB observed in the RCT are concerning. The results of the present analysis should be regarded as preliminary, although the generalised adoption of DEB in the treatment of ISR currently cannot be recommended.
], Sigwart et al. reported their experience with coronary stent implantation in 19 patients, demonstrating its efficacy in the prevention of early vessel occlusion and restenosis [
]. Over the ensuing decades, the use of coronary stents experienced an exponential growth, and the dramatic improvement in patients’ clinical and procedural outcomes has resulted in its widespread adoption as a standard part of percutaneous coronary interventions (PCI).
Notwithstanding its overwhelming benefit, the long-term outcome of stent implantation remains significantly constrained by the occurrence of in-stent restenosis (ISR) over time. While many factors such as stent malapposition and stent fracture have been shown to be contributory, the fundamental mechanisms of ISR relate to the progressive increase in cellularity from either neointimal formation, neoatherosclerosis, or a combination of both. The use of bare metal stents (BMS) has been associated with a 16-44% incidence of ISR [
]. This risk was somewhat mitigated by the development of drug eluting stents (DES), although the incidence of ISR remains significant at 5-15% with first generation DES [
]. Furthermore, the increasing off-label use of DES in patients with small arteries, long lesions, complex coronary lesions, diabetes, and history of bypass surgery render ISR an unavoidable legacy of PCI in the long term.
The optimal treatment strategy for ISR however remains undefined. Previous reports have demonstrated clear superiority in the treatment of BMS ISR with DES when compared with Plain Old Balloon Angioplasty (POBA) [
Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: A randomized controlled trial.
Comparison of the very long term (>1 year) outcomes of drug-eluting stents for the treatment of bare-metal and drug-eluting stent restenosis.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology.2009; 5: 448-453
]. Whether the use of second generation DES influences this observation is not clear.
Drug eluting balloon (DEB) therapy has emerged as a potential treatment for ISR due in part to its ability to deliver anti-proliferative agents to a restenotic arterial segment without adding extra layers of metal stents. Its efficacy against other treatment strategies has been demonstrated in both randomised controlled trials [
Comparison Among Drug-Eluting Balloon, Drug-Eluting Stent, and Plain Balloon Angioplasty for the Treatment of In-Stent Restenosis: A Network Meta-Analysis of 11 Randomized, Controlled Trials.
Initial Experience with Drug-Eluting Balloons in the Treatment of In-Stent Restenosis and de novo Coronary Lesions from Two Combined Public and Private Cardiac Catheterisation Laboratories.
Comparison Among Drug-Eluting Balloon, Drug-Eluting Stent, and Plain Balloon Angioplasty for the Treatment of In-Stent Restenosis: A Network Meta-Analysis of 11 Randomized, Controlled Trials.
Comparison of paclitaxel-eluting balloons with second-generation drug-eluting stents for treatment of in-stent restenosis: a retrospective analysis of an all-comers cohort.
Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial.
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
]. Herein we present the findings of our meta-analysis examining the efficacy of DEB in the treatment of ISR specifically in comparison to second generation DES.
Materials and Methods
Search Strategy
A systematic literature search was performed by two authors (K.L. and S.P.) in August 2015 using Ovid Medline, Embase, Cochrane Register of Controlled Trials (CCTR), Cochrane Database of Systematic Reviews (CDSR), American College of Physician (ACP) Journal Clubs, and Database of Abstracts of Reviews of Effects (DARE) with no date restriction. Search hedges were created with the assistance of C.C. using the following search terms: (“drug eluting balloon” OR “DEB”), AND (“drug eluting stent”, OR “DES”, OR “everolimus eluting stent”, OR “EES”, OR “Xience”, OR “Promus”, OR “Zotarolimus eluting stent”, OR “ZES”, OR “Resolute”), AND (“in stent restenosis”, OR “ISR”). Further, the reference lists of relevant studies were reviewed for additional citations. Studies were limited to human studies.
Eligibility Criteria
We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines where possible in performing our systematic review. Two co-authors (K.L. and R.L.) reviewed and chose the studies based on the following inclusion criteria: 1) prospective or retrospective studies (randomised controlled trials or observational studies) where DEB is directly compared with a second generation DES in the treatment of ISR; 2) studies including at least 20 adult patients; 3) studies containing raw data for retrieving directly or permitting indirect derivation of outcomes of interest as well as the associated 95% confidence intervals (CI). Abstracts, case reports, editorials and expert opinions were excluded. Review articles were similarly omitted because of potential publication bias and duplication of results. When institutions published duplicated studies with accumulating numbers of patients or increased lengths of follow-up, only the most complete reports were included for assessment.
Outcomes of Interest
The primary outcome of interest is Target Lesion Revascularisation (TLR) as a marker of lesion failure. Secondary clinical outcomes include the incidence of Major Adverse Cardiovascular Events or MACE, myocardial infarction (MI), target vessel revascularisation (TVR), all-cause mortality, and cardiovascular mortality. The acute gain in minimal luminal diameter (MLD), late luminal loss and incidence of binary restenosis at follow-up were also analysed.
Methodological Quality Evaluation and Data Extraction
The quality of the retrieved citations was assessed against pre-specified checklist criteria by K.L. and S.P (Supplementary Figure S1). The data was extracted independently by three of the co-authors (K.L., R.L. and S.P.) and summarised into a standardised extraction sheets. Any disagreements in data collected were resolved by consensus. The study was prospectively registered with the PROSPERO database of systematic reviews (registration number: CRD42015019538).
Statistical Analysis
Heterogeneity among studies was examined with the Cochran's Q and I2 statistic, with p<0.10 indicating the presence of study heterogeneity, and I2 values of 25, 50 and 75% corresponding to low, moderate and high degrees of heterogeneity, respectively. Publication bias is assessed based on study distribution on the funnel plot, and Egger's regression. Due to the anticipated heterogeneous nature of the included studies, we decided a priori to analyse the data with the random effect model. To further reconcile the inter-study heterogeneity, we performed a sensitivity analysis of all outcomes by including results from randomised controlled studies only. Analyses were performed with Review Manager (Version 5.3).
Results
The systematic search yielded a total of 227 records from the four electronic databases as well as from review of the study citations. 201 unique records remained after duplications were excluded. Among these, 194 studies were eliminated after a review of abstracts and/or full text based on the established criteria. Consequently, seven peer-reviewed publications and abstracts were included for quantitative analysis (Figure 1). There was no evidence of publication bias based on the funnel plot (Figure 2) and the Egger's regression intercept (2-sided p=0.63). The studies included however were heterogeneous. There were three multi-centre randomised controlled trials [
Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial.
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
Comparison of paclitaxel-eluting balloons with second-generation drug-eluting stents for treatment of in-stent restenosis: a retrospective analysis of an all-comers cohort.
Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial.
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
Comparison of paclitaxel-eluting balloons with second-generation drug-eluting stents for treatment of in-stent restenosis: a retrospective analysis of an all-comers cohort.
Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial.
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
] had both clinical and angiographic follow-up while the remainder provided information on clinical outcomes only. While all studies used paclitaxel eluting DEB, five studies examined it specifically against everolimus eluting stents [
Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial.
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
Comparison of paclitaxel-eluting balloons with second-generation drug-eluting stents for treatment of in-stent restenosis: a retrospective analysis of an all-comers cohort.
Overall, 1,065 patients were included in the final analyses. 526 of these received a DEB for the treatment of ISR. The study, patient, angiographic and procedural characteristics for the included studies are listed in Table 1, Table 2, Table 3, and Supplementary Tables 1 and 2.
Overall, there was no significant difference in the incidence of TLR between DEB (12.7%) and second generation DES (9.3%). There was moderate heterogeneity in the results however (I2=71%, p=0.002).
When only the RCT were considered, the result was far more homogenous (I2=22%, p=0.28) in showing a strong trend towards higher incidence of TLR with DEB (9.9% vs. 3.6%; RR: 2.5, p=0.07).
Comparison of paclitaxel-eluting balloons with second-generation drug-eluting stents for treatment of in-stent restenosis: a retrospective analysis of an all-comers cohort.
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
] reported the MACE rate at follow-up. There was moderate heterogeneity in the results presented (I2=54%, p=0.07). No significant differences were noted between DEB and second generation DES (p=0.52). The overall MACE rate was 19.6% in those treated with DEB, and 16.7% with DES.
Among the two RCT with extractable data, MACE rate was consistently (I2=0%, p=0.96) and significantly higher in the DEB cohort (15.7% vs. 8.8%; RR 1.78; p=0.02).
Myocardial Infarction (Supplementary Figure S2)
All studies reported incidence of MI at follow-up. The data was highly consistent among studies included (I2=0%, p=0.63) in showing no differences between those treated with DEB and second generation DES (p=0.71). The overall MI rate in the DEB and DES cohorts were 3.4% and 3.5%, respectively. No significant difference was noted between the RCT and observational studies (p=0.58).
All but one study reported the incidence of all-cause mortality. There was no heterogeneity in the data reported (I2=0%, p=0.69). There is a numerical trend towards higher all-cause mortality in the DEB cohort (6.2%) as compared with the DES cohort (3.3%; RR 1.73, p=0.09). The increased mortality rate however was predominantly observed in observational studies (11.2% vs. 5.6%; RR 1.99, p=0.07).
Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial.
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
] reported the incidence of cardiovascular mortality. There was a trend towards higher cardiovascular death in the DEB cohort (2.3% vs. 1.2%) although statistical significance was not reached (RR: 1.81, p=0.25). There was again very little heterogeneity in the data presented (I2=0%, p=0.96) and no significant difference could be observed between the RCT and observational studies (p=0.82).
Target Vessel Revascularisation (Figure S4)
The incidence of target vessel revascularisation (TVR) was reported by five studies. The results were moderately heterogeneous across the board (I2=58%, p=0.05). There was no significant difference in the incidence of TVR between the two groups (13.5% with DEB vs. 12.1% with DES). In keeping with observations made with TLR however, there is a numerical trend towards higher TVR with DEB in the RCT (12% vs. 7.2%, RR 1.6, p=0.23) as compared with the observational studies.
Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial.
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
], those treated with DES had 0.36 mm more in acute luminal gain following PCI compared to those treated with DEB (p<0.001). There was also a significant overall trend towards a more significant late luminal loss with DEB compared to those treated with second generation DES (0.11 mm, p=0.02). As a consequence, the binary restenosis rate at follow-up was much higher in the DEB cohort (17.9%) as compared with the DES cohort (8.7%, RR: 2.24, p<0.001). This result was highly consistent among the studies included in the analyses (I2=0%, p=0.89).
Figure 6Angiographic outcomes, DEB vs. DES; A. Acute gain; B. Late loss; C. Binary Restenosis.
This is the first meta-analysis that specifically compares the efficacy of DEB in the treatment of DES or BMS ISR with that of second generation DES. Despite the heterogeneous nature of the studies included, there was a consistent equipoise in the overall incidence of MACE, MI, TVR and cardiovascular death between the DEB and DES cohorts at 12-25 months following ISR PCI. The incidence of TLR was also similar between the two groups, although the result was less compelling due to its heterogeneity and the higher late luminal loss and binary restenosis rate observed with DEB. When only RCTs were considered however, the TLR rate was considerably higher in the DEB cohort resulting in a higher rate of MACE. Finally, there was a strong trend towards higher incidence of all-cause mortality with DEB, although this was not evident when only RCTs were analysed.
Numerous treatment strategies have been developed for patients with ISR. These include POBA, cutting or scoring balloon, rotational atherectomy and intravascular brachytherapy. These techniques, however, have been largely superseded by DES due to their profound inhibitory effect on neointimal formation. To this end, DES has become the standard of care in the treatment of ISR in many parts of the world, particularly ISR within a previous DES. Further, evidence seems to suggest that second generation DES out-performs its first generation counterpart [
Implantation of a drug-eluting stent with a different drug (switch strategy) in patients with drug-eluting stent restenosis. Results from a prospective multicenter study (RIBS III [Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent]).
], although no direct comparison to date has been or is likely to be performed.
The treatment of ISR with DES however is not without challenges, as the clinical consequences of an increased intra-coronary metallic burden can be considerable [
]. Accordingly, DEB has been increasingly adopted as an alternative treatment strategy, particularly to first generation DES, in the treatment of ISR. Paclitaxel eluting balloon (PEB), the most common DEB currently available in clinical practice, relies upon the lipophilic property of paclitaxel, which facilitates its rapid transfer from the balloon to the tissue. It is then retained in the smooth muscle for a prolonged period of time, resulting in a sustained anti-proliferative effect despite the absence of a constant drug releasing mechanism [
Comparison Among Drug-Eluting Balloon, Drug-Eluting Stent, and Plain Balloon Angioplasty for the Treatment of In-Stent Restenosis: A Network Meta-Analysis of 11 Randomized, Controlled Trials.
]. The ISAR-DESIRE 3 study demonstrated non-inferiority in the diameter restenosis between PEB and paclitaxel eluting stents (38.0% vs. 37.4%) in the treatment of DES-ISR [
Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial.
Drug eluting balloon offers a number of advantages over DES in the treatment of ISR. Drug eluting balloon obviates the need for additional stents, avoids strut overlap and therefore eliminates the potential complications associated with an increased intra-coronary metallic burden. It has been shown with OCT that more stent struts remained exposed at follow-up following DES treatment of an ISR as compared with DEB [
Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial.
], acting as a potential substrate for late stent thrombosis. Drug eluting balloon is also less likely to compromise side branch where ISR involves a bifurcation, and may be more suited to complex anatomy such as a tortuous or calcified vessel where stent implantation and therefore drug delivery may be suboptimal [
]. Furthermore, the use of DEB does not lead to dependency on prolonged antiplatelet therapies, which is obligatory with DES. The absence of polymers in DEB also eliminates the risk of late stent thrombosis due to chronic inflammation.
In our analysis, treatment of ISR with DEB and second generation DES yielded similar clinical outcomes at intermediate term follow-up. However, when only the RCT were considered, there was an increased incidence of TLR and therefore MACE in the DEB cohort. This is not surprising though, given that both the acute and late angiographic results were inferior, and the binary restenosis rate was significantly higher with DEB. The higher acute luminal gain with DES is anticipated in the presence of mechanical scaffolding, and contributes partially to the superior late angiographic findings with DES. The disparity in late angiographic appearance however could also be attributed to the greater late luminal loss with DEB. There is evidence that an intrinsic difference exists in the vessel healing response following exposure to both paclitaxel and everolimus, where paclitaxel appears to induce a higher degree of inflammation in the short term and a greater neointimal thickness in the long term [
Differences in vessel healing following delivery of everolimus or paclitaxel: a comparative experimental study using identical stent and biodegradable polymer platforms.
]. The different pharmacology between the two strategies therefore may be contributory to the differences observed in patients’ TLR rate. The thinner strut design and reduced polymer burden associated with second generation DES have also shown significant anti-restenotic efficacy particularly against their predecessors, which further enhances its superior angiographic performance in the long term. Late luminal loss following PCI is associated with a worse clinical outcome [
]. The equipoise in the clinical endpoints observed in our analysis therefore may simply reflect the short follow-up duration. Significant separation in clinical outcome such as MI, cardiac mortality, and TVR may become apparent over time, although a large registry or a well-designed RCT with adequate mechanisms for long-term follow-up may be required to provide some clarification in this regard.
In general, the outcome of DES-ISR treatment appeared worse than BMS-ISR, irrespective of the choice of treatment strategy. We showed that among the RCT, the use of DEB led to a late loss of 0.14-0.16 mm in the treatment of BMS-ISR compared with 0.3 mm for DES-ISR. Similarly, the use of second generation DES resulted in a late loss of 0.04-0.08 mm and 0.18 mm respectively in the treatment of BMS-ISR and DES-ISR. A recent study further demonstrates a close to seven-fold difference in the rate of late restenosis following DEB treatment of DES-ISR as compared with BMS-ISR [
]. Furthermore, while the advantage of DES in terms of MLD achieved at follow-up is sustained in BMS-ISR even in high risk patients (diabetes, restenosis <6 months, diffuse disease ≥ 10 mm) [
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
]. In the latter group the presence of these high risk features, perhaps suggesting the presence of a more aggressive substrate, nullifies the performance of DES in comparison to DEB [
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
]. As the DES failure rate secondary to ISR remains significant at 5-10% and results in close to 200,000 repeat revascularisations a year in the United States [
], the development of an optimal treatment strategy for DES-ISR is critical. While this remains the subject of ongoing clinical investigations, careful patient selection is likely to be the key to long-term clinical and angiographic success.
The mechanism underlying the increased all-cause mortality amongst the DEB cohort is unclear, although selection bias may have a significant role to play given the trend was generally more pronounced in the observational studies. As the choice of treatment strategy in these studies was often at the discretion of the physicians involved, it is possible that patients who received DEB may be those with recurrent restenosis previously treated with multiple stents, patients with complex lesions not amenable to stenting, and those with multiple co-morbidities precluding prolonged DAPT and thus stent implantation. The mortality for these patients may be high at baseline, and introduces significant bias into our analysis. This is however likely to be a reflection of the real-world practice. The results, while potentially skewed, may therefore still carry clinical relevance. Whether this observation represents a genuine safety signal beyond the anticipated patient attrition rate in these observational studies remains unclear, and requires further elucidation by larger scale studies.
Limitations
Several key factors merit considerations. First, the studies included in this analysis are diverse in their designs, definitions and patient cohort, and therefore may undermine the generalisability of the results. Second, not every study consistently reported the outcomes of interest (mortality, MI, TVR and angiographic results) thus limiting the scope of our analysis. Third, patient level data is lacking and it is difficult to exclude the influence of confounders that could not be accounted for by study level analysis. Lastly, while there is a fundamental difference between the ISR substrate (BMS v.s. DES) [
Differential relative efficacy between drug-eluting stents in patients with bare metal and drug-eluting stent restenosis; evidence in support of drug resistance: insights from the ISAR-DESIRE and ISAR-DESIRE 2 trials.
], its interaction with the treatment strategies cannot be reliably explored by the present review due to the modest sample size.
Conclusion
Our results demonstrate that judicious use of DEB, at least in the intermediate term, may be a reasonable alternative to second generation DES in the treatment of ISR. The suboptimal late angiographic results and the higher TLR and MACE rate associated with DEB however are concerning and require further clarification. As a result, the widespread adoption of DEB over second generation DES in the treatment of ISR at present remains premature and demands caution.
Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: A randomized controlled trial.
Comparison of the very long term (>1 year) outcomes of drug-eluting stents for the treatment of bare-metal and drug-eluting stent restenosis.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology.2009; 5: 448-453
Comparison Among Drug-Eluting Balloon, Drug-Eluting Stent, and Plain Balloon Angioplasty for the Treatment of In-Stent Restenosis: A Network Meta-Analysis of 11 Randomized, Controlled Trials.
Initial Experience with Drug-Eluting Balloons in the Treatment of In-Stent Restenosis and de novo Coronary Lesions from Two Combined Public and Private Cardiac Catheterisation Laboratories.
Comparison of paclitaxel-eluting balloons with second-generation drug-eluting stents for treatment of in-stent restenosis: a retrospective analysis of an all-comers cohort.
Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial.
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial.
Implantation of a drug-eluting stent with a different drug (switch strategy) in patients with drug-eluting stent restenosis. Results from a prospective multicenter study (RIBS III [Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent]).
Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial.
Differences in vessel healing following delivery of everolimus or paclitaxel: a comparative experimental study using identical stent and biodegradable polymer platforms.
Differential relative efficacy between drug-eluting stents in patients with bare metal and drug-eluting stent restenosis; evidence in support of drug resistance: insights from the ISAR-DESIRE and ISAR-DESIRE 2 trials.
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