Treatment of Drug-Eluting Stent In-Stent Restenosis With Drug-Eluting Balloons: A Systematic Review and Meta-Analysis

Abstract: Objective. To evaluate the efficacy of drug-coated balloon (DEB) for the treatment of drug-eluting stent (DES) in-stent restenosis (ISR). Methods. A comprehensive literature search was performed. The primary outcome was the composite of death, myocardial infarction (MI), and target-lesion revascularization (TLR) at longest available follow-up (range, 12-36 months). Outcomes for DEB vs balloon angioplasty (BA) and DEB vs DES were analyzed separately using a random-effect Mantel-Haenszel model, as per an a priori protocol. Results. The study cohort comprised 1526 patients (746 DEB, 537 DES, 243 BA). DEB was associated with lower composite outcome compared with BA alone (19% vs 47%; risk ratio [RR], 0.31; 95% confidence interval [CI], 0.11-0.84; P=.02), driven primarily by lower TLR (17% vs 34%; RR, 0.66; 95% CI, 0.46-0.95; P=.03), with no difference in death or MI. There was no difference in the composite outcome between DEB and DES (20% vs 17%; RR, 1.2; 95% CI, 0.82-1.74; P=.35); DEB was associated with higher TLR (17.4% vs 11.3%; RR, 1.48; 95% CI, 1.08-2.03; P=.01), but lower all-cause mortality (2.2% vs 5.7%; RR, 0.43; 95% CI, 0.22-0.82; P=.01), with no difference in MI or stent thrombosis. Conclusions. DEB was associated with a lower TLR rate than BA alone, but associated with a higher TLR rate than implantation of another DES. However, additional DES use was associated with an increase in mortality, a finding that requires further investigation. 

J INVASIVE CARDIOL 2018;30(10):360-366. Epub 2018 August 15.

Key words: drug-eluting balloon, drug-eluting stent, in-stent restenosis, ISR

Drug-eluting stent (DES) implantation has substantially reduced the rates of in-stent restenosis (ISR) and target-lesion revascularization (TLR) compared with bare-metal stent (BMS) implantation.^1-3 However, with the expansion of indications of percutaneous coronary intervention (PCI) to complex coronary lesions in high-risk patients, ISR remains an important issue even with current-generation DES options. Routine angiographic surveillance after unrestricted use of newer-generation DES demonstrated rates of angiographic restenosis of approximately 12% at 6-8 months.² Furthermore, a late catch-up phenomenon of restenosis beyond 1 year after DES implantation is also recognized.^4-6 Clinical presentation of ISR is not always benign and frequently includes an unstable presentation with elevated cardiac markers.^7,8 Despite the clinical and prognostic importance, randomized trials evaluating treatment options for DES-ISR have been limited. The American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) guidelines for PCI recommend DES-ISR to be treated with plain old balloon angioplasty (BA), BMS, or DES.⁹ The European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) guidelines recommend DES or drug-eluting balloon (DEB) for the treatment of ISR.¹⁰ Non-stent based local delivery of an antiproliferative drug using DEB is an attractive emerging option for ISR treatment, with the obvious benefit of not adding additional metal layers to an ISR lesion. Although a few randomized controlled trials (RCTs) have evaluated the efficacy of paclitaxel-coated DEB for DES-ISR, these small studies have focused on angiographic outcomes with limited statistical power for the evaluation of clinical outcomes. Therefore, we performed a systematic review and meta-analysis of these RCTs to determine the efficacy of paclitaxel-coated DEB for the treatment of DES-ISR compared with either BA alone or implantation of another DES.     

Methods

Using an a priori protocol, we conducted our systematic review in accordance with the Methodological Expectations of Cochrane Intervention Reviews guidelines¹¹ and reported our results as per the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines.¹² The authors formulated the research question, reviewed the search strategy and review methods, and provided input throughout the review process.

Research question. Our primary research question was “in patients with DES-ISR, is treatment with DEB, compared with BA or implantation of another DES, associated with significantly lower rates of death, myocardial infarction (MI), and TLR?” We included trials that met the following criteria: (1) RCT; (2) patients ≥18 years; (3) patient population included DES-ISR; and (4) compared treatment with DEB to treatment with BA or DES. The primary outcome was the composite of death, MI, or TLR at longest available follow-up. Secondary outcomes included the individual components of the primary outcome, cardiac mortality, and stent thrombosis (ST). In one study,¹³ TLR was not available; therefore, target-vessel revascularization (TVR) was used interchangeably. 

Search strategy and study selection. We searched PubMed/Medline (National Library of Medicine), EMBASE (Ovid), and CENTRAL (the Cochrane Library-Wiley) from inception to November 4, 2017. The Cochrane highly sensitive search strategy was used as a model for searching.¹⁴ The following search terms and its variants were used: “in-stent restenosis,” “drug-eluting balloon,” and “drug-eluting stent.” In addition to electronic database searching, we searched abstracts and conference proceedings. Lastly, the reference lists of relevant narrative and systematic reviews and included trials were hand-searched for possible relevant citations. Two reviewers (SL and MW) independently reviewed the title and abstract of each citation to determine whether a study generally met the inclusion criteria. The full text of all citations listed as “include” or “unsure” by either reviewer at this stage was retrieved for formal review. The full text of each potentially relevant citation was then independently assessed to determine whether the trial met the predetermined inclusion and exclusion criteria. 

Data abstraction and management. Two reviewers (SL and MW) independently extracted data from the included trials using standardized and piloted data extraction forms. Discrepancies were resolved through consensus. The following data were extracted from each study: (1) study characteristics (author, year of publication, language of publication, source of funding, duration of follow-up, publication status, and country); (2) methodological quality criteria (using the Cochrane Collaboration risk of bias tool^15,16); (3) patient characteristics (age, sex, diabetes, hypertension, dyslipidemia, smoking, prior MI, previous PCI, prior coronary artery bypass graft surgery, multivessel disease, clinical presentation, ejection fraction, culprit vessel); and (4) results reported for the outcomes of interest. The data were entered into a Microsoft Excel database (Microsoft Corporation). 

Quality assessment. The internal validity of each trial was assessed using the Cochrane Collaboration risk of bias tool,^15,16 which consists of six domains (sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias) and an overall risk of bias assessment. Each separate domain was determined to be low, unclear, or high risk. The overall risk of bias will be considered low only if all components were rated as low risk. 

Data analysis. The data from included studies were analyzed using the Cochrane Review Manager (RevMan, version 5.3.5, 2014; The Cochrane Collaboration). For dichotomous data, a summary measure of effect was expressed as risk ratios (RRs) and absolute risk (AR) difference with 95% confidence intervals (CIs) using the Mantel-Haenszel method. A random-effects model was used for all analyses. Statistical heterogeneity of the data was explored and quantified using the I² test.¹⁷ Publication bias was assessed using funnel plot

techniques.

Results

Study and patient characteristics. Of the 601 records identified through electronic and hand searches, we included six unique RCTs (with three companion articles) enrolling a total of 1526 patients (Figure 1 and Table 1).^13,18-25 The mean patient age in the trials ranged from 62-70 years and 67%-88% were male. Prevalence of diabetes mellitus was 40%. Four studies only included patients with DES-ISR,^18,19,21,25 while two studies included patients with both BMS-ISR and DES-ISR.^13,23 BMS-ISR (243 patients) comprised a total of 16% of the analysis population. Information regarding the original DES type was available in five studies (Table 1).^{13,18,19,21,25} Two studies compared DEB vs BA,^23,25 three studies compared DEB vs DES (two with everolimus DES and one with paclitaxel DES),^13,18,21 and one study compared DEB vs paclitaxel DES and BA.¹⁹ The duration of longest follow-up ranged between 6 months and 3 years. All trials ranged from unclear to high risk of performance bias (Figure 2), as all included studies were prospective randomized open-label blinded end-point (PROBE) design. 

Comparison of DEB vs BA alone. Treatment with DEB was associated with lower risk of the composite of death, MI, or TLR (RR, 0.31; 95% CI, 0.11-0.84; AR, 3.17%; I², 89%; P=.02) compared with BA alone, driven primarily by lower TLR (RR, 0.66; 95% CI, 0.46-0.95; AR, 17.46%; I², 82%; P=.03) (Figure 3). There was no significant difference in all-cause mortality (RR, 0.65; 95% CI, 0.28-1.54; AR,  2.92%; I², N/A; P=.33), MI (RR, 1.09; 95% CI, 0.06-18.43; AR, 0.79%; I², 63%; P=.95), cardiac mortality (RR, 0.33; 95% CI, 0.10-1.08; AR, 2.96%; I², 2%; P=.07), or ST (RR, 0.49; 95% CI, 0.02-10.02; AR, 1.07%; I², 60%; P=.65) between DEB and BA. 

Comparison of DEB vs implantation of DES. There was no difference in risk of the composite of death, MI, or TLR (RR, 1.20; 95% CI, 0.82-1.74; AR, 3.17%; I², 47%; P=.35), MI alone (RR, 1.08; 95% CI, 0.55-2.11; AR, 0.34%; I², 0%; P=.83), or ST (RR, 0.38; 95% CI, 0.07-1.98; AR, 0.81%; I², 0%; P=.25) with DEB compared with implantation of additional DES (Figure 4). However, DEB was associated with lower all-cause mortality (RR, 0.43; 95% CI, 0.22-0.82; AR, 3.43%; I², 0%; P=.02) and cardiac mortality (RR, 0.38; 95% CI, 0.15-0.99; AR, 1.9%; I², 0%; P=.05), but greater TLR (RR 1.48; 95% CI, 1.08-2.03; AR, 6.04%; I², 7%; P=.01). 

Discussion

The major findings of this systematic review and meta-analysis are the following: (1) there is a paucity of RCT data evaluating the efficacy of DEB for the treatment of DES-ISR; (2) treatment with DEB was associated with 55% lower rate of recurrent TLR compared with BA alone; (3) compared with implantation of another DES, use of DEB was associated with 48% greater TLR, yet unexpectedly 57% lower all-cause mortality and 62% lower cardiac mortality.  We detected no difference in rates of MI or ST between treatment with DEB and DES.

Prior pooled analyses compared DEB vs BA alone for treatment of BMS-ISR, and found DEB to be superior.^26,27 Our findings are consistent with and extend these observations to DES-ISR. Although acute lumen enlargement achieved both from tissue extrusion and additional stent expansion with BA would be expected to be similar with or without use of DEB, long-term BA alone results are suboptimal, as observed with a recurrent TLR rate of 34.5% in this meta-analysis. DEB use reduced recurrent TLR by 55%, corresponding to a number needed to treat of approximately 6 patients. Neointimal hyperplasia (NIH) remains an important mechanism of ISR even with current-generation DES options.²⁸ Furthermore, neoatherosclerotic change within the restenotic tissue is seen earlier and more frequently in DES-ISR.²⁹ The addition of drug to the vessel wall with DEB mitigates intimal hyperproliferation associated with BA-induced barotrauma, particularly among patients with NIH or neoatherosclerosis as the etiology of DES-ISR. There was no signal for any adverse effects of using DEB. Thus, with the advent and wider availability of DEB, and the high rate of recurrent ISR with BA alone, the role of BA alone for the treatment of DES-ISR is likely to diminish further. 

We found rates of recurrent TLR to be higher with the use of DEB compared with implantation of another DES. Adjunctive DES implantation prevents recoil, offering more durable preservation of the acute gains. Furthermore, stent fracture, a more prevalent cause of ISR with DES than BMS,³⁰ is treated more optimally with additional stent coverage. Proliferative restenosis of unstented vessel segment is also better treated with additional stenting. On the other hand, the use of additional stents, especially in a previously underexpanded stent(s), renders it vulnerable to ST.^31-33 Use of an additional layer of stent may also jail side branches, and limit future treatment options. We did not observe a greater rate of ST with implantation of an additional layer of DES; however, the small sample size and low number of total ST events (n = 7) precludes a definitive conclusion. Although MI rates were also not higher with the use of DES, all-cause and cardiac mortality were unexpectedly higher with the use of DES. This was also previously observed in a meta-analysis of observational studies and RCTs of DES-ISR.³⁴ Although the point estimate for all-cause mortality favored DEB compared with DES in all four studies, results were driven primarily by findings from the ISAR-DESIRE 3 study, where the comparator DES was the early-generation paclitaxel-eluting stent.¹⁹ Increased events with PES occurred mainly after 1 year, beyond the study-recommended duration of dual-antiplatelet therapy (DAPT). Findings in this study are similar to the 2-year follow-up of the PEPCAD China ISR trial.²¹ Despite known concerns regarding late ST with PES compared with current-generation everolimus-eluting stents,²¹ given no apparent increase in MI or ST in our study cohort, a clear mechanistic link for increased cardiac and all-cause mortality with DES was not deducible from the data. Whether this is a chance finding or a real observation that can be extrapolated to current-generation DES options is unknown and requires further investigation. 

Given heterogeneity in DES-ISR etiology and trade-offs in options available for treatment, intravascular imaging has been advocated to assess the etiology of DES-ISR and guide therapy. Although DES implantation is associated with lower recurrent TLR overall, there are circumstances where avoidance of a second layer of stent would be warranted. This includes small vessels, across major side branches, in under-expanded or malapposed stents, where >1 layer of stent is already present, and where use of DAPT must be minimized due to high bleeding risk. In such cases, intravascular-imaging guided optimal predilation with or without high-pressure ballooning followed by DEB treatment may be preferred. In other cases, implantation of another DES would be reasonable. Although Alfonso et al³¹ suggested the implantation of a different type of DES for DES-ISR (eg, paclitaxel-eluting stent after sirolimus-eluting stent ISR), Cosgrave et al³³ found no difference in clinical outcomes when the eluted drug was changed compared with the use of the same drug in the original DES-ISR. In the present analysis, current-generation (everolimus, zotarolimus, and biolimus) DES comprised only 35% of the original DES-ISR population and 32% of the treatment DES population; thus, the issue of whether switching to a different drug type with the current generation of DES options offers an advantage over using DES with the same or similar type of drug cannot be resolved with the available data and requires further investigation. 

Study limitations. Limitations of this systematic review and meta-analysis include significant heterogeneity between and within studies in baseline demographics, indication for stenting (stable vs acute disease), type of original DES used, type of DES-ISR (focal, proliferative, occlusive), and type of treatment DES. The majority of DES-ISR cases pertained to first-generation DESs, and outcomes of these studies may not be directly extrapolated to second-generation DESs. All trials included in this meta-analysis used only the paclitaxel-coated SeQuent DEB (B. Braun). Recently, the first-in-human, single-arm SABRE³⁵ study showed excellent procedural success for the Virtue sirolimus-eluting DEB (Caliber Therapeutics) for the treatment of ISR. However, a class effect for these devices cannot be assumed. Further studies are required to determine the efficacy of different DEB technologies in this setting. Details regarding lesion preparation prior to DEB use are also not reported and likely heterogenous between and within studies. It remains unknown whether the efficacy of the DEB can be further improved with lesion preparation with a scoring or cutting balloon. Finally, the PROBE study design of these studies also introduces risk of performance bias, even with blinded adjudication. 

Conclusion

There is a paucity of randomized data evaluating the efficacy of DEB for the treatment of DES-ISR. Due to the lack of appropriately powered pivotal trials in this field, we are unable to draw a firm conclusion of the overall efficacy or effectiveness of DEB. We did find that use of DEB was associated with lower recurrent TLR compared with BA alone; however, compared with the use of an additional DES, DEB was associated with greater recurrent TLR. Additional DES use was associated with an increase in all-cause and cardiac mortality without an increase in MI or ST, an unexpected finding that requires further investigation. Given heterogeneity in DES-ISR etiology and trade-offs in options available for treatment, individualizing treatment based upon underlying etiology is warranted. 

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From the ¹Terrence Donnelly Heart Centre, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; ²Division of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; and ³Whitby Cardiovascular Institute, Whitby, Ontario, Canada. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bagai reports personal fees from Bayer, AstraZeneca, Beohringer Ingelheim; other income from Soundbite. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted May 5, 2018 and accepted May 22, 2018.

Address for correspondence: Akshay Bagai, MD, MHS, Terrence Donnelly Heart Center, St. Michael’s Hospital, University of Toronto, Ontario, Canada. Email: bagaia@smh.ca