SUPPLEMENTARY APPENDIX

Drug-coated balloon angioplasty versus drug-eluting stent implantation in patients with coronary stent restenosis

Daniele Giacoppo, MDa; Fernando Alfonso, MDb; Bo Xu, MBBSc; Bimmer E.P.M. Claessen, PhDd; Tom Adriaenssens, MDe; Christoph Jensen, MDf; María J. Pérez-Vizcayno MDg; Do-Yoon Kang, MDh; Ralf Degenhardt, PhDi; Leos Pleva, MDj; Jan Baan, MDk; Javier Cuesta, MDb; Duk-Woo Park, MDh; Pavel Kukla, MDj; Pilar Jiménez-Quevedo, MDg; Martin Unverdorben, MDi,l; Runlin Gao, MDc; Christoph K. Naber, MDf; Seung-Jung Park, MDh; José P.S. Henriques, MDk; Adnan Kastrati, MDa,m; Robert A. Byrne, PhDa,n,o

a Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germanyb Department of Cardiology, Hospital Universitario de La Princesa Madrid, Madrid, Spainc Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, Chinad Mount Sinai Heart, the Zena and Michael Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United Statese Department of Cardiology, University Hospitals Leuven, Leuven, Belgiumf Department of Cardiology, Contilia Heart and Vascular Center, Elisabeth Krankenhaus, Essen, Germanyg Department of Cardiology, Hospital Clinico San Carlos, Madrid, Spainh Department of Cardiology, Asan Medical Center, University of Ulsan, Seoul, South Koreaj Department of Cardiology, University Hospital Ostrava, Ostrava, Czech Republici Department of Cardiology, Herz- und Kreislaufzentrum, Rotenburg an der Fulda, Germanyk Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlandsl Daiichi Sankyo, Basking Ridge, New Jersey, United Statesm DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germanyn Dublin Cardiovascular Research Institute, Mater Private Hospital, Dublin, Irelando School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland

Corresponding author:Daniele Giacoppo, MD, MScDeutsches Herzzentrum München,Lazarettstrasse 36, 80636, Munich, GermanyPhone: +49-89-1218-4578; Fax:+49-89-1218-4053email: giacoppo@dhm.mhn.de

List of trials included in the DAEDALUS study

1. PEPCAD IIThe Paclitaxel-Eluting PTCA-Balloon Catheter in Coronary Artery Disease to Treat In-Stent RestenosesNCT00393315

2. ISAR-DESIRE 3Intracoronary Stenting and Angiographic Results: Drug Eluting Stent In-Stent Restenosis: 3 Treatment ApproachesNCT00987324

3. PEPCAD China ISRA Safety and Efficacy Study of Paclitaxel-eluting Balloon to Paclitaxel-eluting StentNCT01622075

4. RIBS VRestenosis Intra-stent of Bare Metal Stents: Paclitaxel-eluting Balloon vs Everolimus-eluting StentNCT01239953

5. SEDUCESafety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosisNCT01065532

6. RIBS IVRestenosis Intra-stent of Drug-eluting Stents: Paclitaxel-eluting Balloon vs Everolimus-eluting StentNCT01239940

7. TISTreatment of In-Stent RestenosisNCT01735825

8. DAREDrug-Eluting Balloon for In-Stent RestenosisNCT01127958

9. RESTOREThe Treatment of Drug-Eluting Stent REstenosis Using Drug-Eluting STents versus Drug COated Balloon for Preventing REcurrent In-Stent RestenosisNCT01967199

10. BIOLUX-RCTBIOtronik – Clinical performance of the Pantera LUX paclitaxel coated balloon versus the drug eluting Orsiro hybrid stent system in patients with in-stent restenosis – a Randomized Controlled TrialsNCT01651390.

Study search and selection

Studies were eligible for inclusion in the DAEDALUS study when all the following requirements

were satisfied:

1) Random assignment of treatments

2) ISR as target lesion

3) DCB angioplasty alone versus DES alone

4) Clinical follow-up of at least 12 months

Multiple electronic databases (PubMed, Scopus, ScienceDirect, Web of Science) and archives of

major scientific societies and international conferences in the field were searched from 13

November 2006 (date of publication of the first randomized clinical trial on ISR testing PCB) to 15

April 2019. Reports retrieved by literature search were screened for eligibility

After protocol drafting, the primary investigator of each trial eligible for inclusion was invited to

contribute to the DAEDALUS study. Data extraction was managed by the primary investigator of

each trial. Variables of interest were selected at the study protocol stage according to the clinical

relevance and consistency across trials by cross check on original publications. Additional

unpublished data, including extension of follow-up and variable standardization, were provided

when available in the original databases.

All the variables of interest were independently checked for each trial at the German Heart Center

of Munich with satisfactory results before generating the dedicated electronic database of the

DAEDALUS study. The final database was then created and stored at the coordinating center.

Pair-wise comparisons by the log rank test after Bonferroni correction: Efficacy.

DCB for BMS-ISR vs. DCB for DES-ISR, p<0.0001; DCB for BMS-ISR vs. DES for BMS-ISR, p>0.999;

DCB for BMS-ISR vs. DES for DES-ISR, p=0.431; DCB for DES-ISR vs. DES for BMS-ISR, p=0.002; DCB

for DES-ISR vs. DES for DES-ISR, p=0.001; DES for BMS-ISR vs DES for DES-ISR, p>0.999.

Pair-wise comparisons by the log rank test after Bonferroni correction: Safety.

DCB for BMS-ISR vs. DCB for DES-ISR, p>0.999; DCB for BMS-ISR vs. DES for BMS-ISR, p>0.999; DCB

for BMS-ISR vs. DES for DES-ISR, p=0.478; DCB for DES-ISR vs. DES for BMS-ISR, p>0.999; DCB for

DES-ISR vs. DES for DES-ISR, p=0.346; DES for BMS-ISR vs DES for DES-ISR, p=0.196.

Supplementary Tables

Table 1. Search strategy

Database Search strategy Results

PubMed Restenosis[All Fields] AND "humans"[MeSH Terms] 10083

Scopus

TITLE-ABS-KEY (restenosis)

AND (LIMIT-TO (PUBYEAR 2019) OR LIMIT-TO (PUBYEAR 2018) OR LIMIT-TO (PUBYEAR 2017) OR LIMIT-TO (PUBYEAR 2016) OR LIMIT-TO (PUBYEAR 2015) OR LIMIT-TO (PUBYEAR 2014) OR LIMIT-TO (PUBYEAR 2013) OR LIMIT-TO (PUBYEAR 2012) OR LIMIT-TO (PUBYEAR 2011) OR LIMIT-TO (PUBYEAR 2010) OR LIMIT-TO (PUBYEAR 2009) OR LIMIT-TO (PUBYEAR 2008) OR LIMIT-TO (PUBYEAR 2007) OR LIMIT-TO (PUBYEAR 2006)

OR LIMIT-TO (PUBYEAR 2005))

AND (LIMIT-TO (DOCTYPE "ar") OR LIMIT-TO (DOCTYPE "re") OR LIMIT-TO (DOCTYPE "le") OR LIMIT-TO (DOCTYPE "cp") OR

LIMIT-TO (DOCTYPE "ch") OR LIMIT-TO (DOCTYPE "ip")

AND (LIMIT-TO (SUBJAREA "MEDI")

16992

ScienceDirect

“Restenosis”

Review articles, Research articles, Book chapters, Conference abstracts, Data articles

Timespan: 2006-2019

12890

Web of Science

TI=(restenosis) OR TS=(restenosis)

(Article OR Abstract of Published Item OR Book Chapter OR Data Paper OR Early Access OR Meeting Abstract OR Proceedings

Paper OR Review)

Timespan: 2006-2019.Indexes: SCI-EXPANDEDSSCIA&HCICPCI-SCPCI-SSHESCI.

15862

Results refer to the time range from November 13th, 2006 to April 15th, 2019.

Table 2. Two-stage analysis of clinical outcomes at 3-year follow-up between DCB and DES according to BMS- and DES-ISR.

Bare-Metal Stent In-Stent RestenosisFixed-Effect Random-Effects Heterogeneity

HR [95% CI] pW HR [95% CI] pW Q I2 τ2 pAll-Cause Death 1.33 [0.62-2.88] 0.464 1.33 [0.62-2.88] 0.464 2.259 0% 0 0.812Cardiac Death 0.98 [0.31-3.12] 0.975 0.98 [0.31-3.12] 0.975 1.143 0% 0 0.950Non-Cardiac Death 1.45 [0.50-4.21] 0.490 1.45 [0.50-4.21] 0.490 2.137 0% 0 0.711Myocardial Infarction 0.92 [0.58-1.46] 0.727 0.92 [0.58-1.46] 0.727 0.765 0% 0 0.932Target Lesion Thrombosis 1.06 [0.17-6.55] 0.954 1.06 [0.17-6.55] 0.954 1.442 0% 0 0.696Ischemia-Driven Target Lesion Revascularization 0.80 [0.44-1.44] 0.457 0.86 [0.43-1.75] 0.683 7.382 32.3% 0.191 0.194

Target Vessel Revascularization 0.74 [0.46-1.18] 0.208 0.76 [0.44-1.34] 0.351 7.706 35.1% 0.131 0.173All-Cause Death, Myocardial Infarction, Target Lesion Thrombosis, or Target Lesion Revascularization

0.89 [0.59-1.33] 0.564 0.91 [0.57-1.45] 0.687 6.579 24.0% 0.073 0.254

All-Cause Death, Myocardial Infarction, Target Lesion Thrombosis, or Target Vessel Revascularization

0.81 [0.56-1.18] 0.270 0.83 [0.53-1.27] 0.386 7.010 28.7% 0.063 0.220

Drug-Eluting Stent In-Stent RestenosisFixed-Effect Random-Effects Heterogeneity

HR [95% CI] pW HR [95% CI] pW Q I2 τ2 pAll-Cause Death 0.65 [0.38-1.13] 0.130 0.65 [0.33-1.28] 0.214 5.842 31.5% 0.097 0.211Cardiac Death 0.50 [0.22-1.14] 0.100 0.50 [0.22-1.14] 0.100 2.064 0% 0 0.559Non-Cardiac Death 0.80 [0.39-1.66] 0.553 0.80 [0.39-1.66] 0.553 3.111 0% 0 0.539Myocardial Infarction 0.96 [0.54-1.70] 0.892 0.96 [0.54-1.70] 0.892 3.948 0% 0 0.557Target Lesion Thrombosis 1.02 [0.31-3.37] 0.974 1.02 [0.31-3.37] 0.974 1.658 0% 0 0.646Ischemia-Driven Target Lesion Revascularization 1.60 [1.16-2.22] 0.005 1.60 [1.16-2.22] 0.005 3.079 0% 0 0.688

Target Vessel Revascularization 1.43 [1.06-1.92] 0.018 1.43 [1.06-1.92] 0.018 5.432 7.9% < 0.0001 0.366All-Cause Death, Myocardial Infarction, Target Lesion Thrombosis, or Target Lesion Revascularization

1.15 [0.90-1.47] 0.271 1.15 [0.90-1.47] 0.271 4.205 0% 0 0.520

All-Cause Death, Myocardial Infarction, Target Lesion Thrombosis, or Target Vessel Revascularization

1.06 [0.83-1.34] 0.656 1.06 [0.82-1.37] 0.671 5.315 5.9% 0.010 0.379

CI=Confidence Interval; HR=Hazard Ratio, PW=P value of the Wald-type test.

Table 3. Clinical characteristics by ISR type.

BMS-ISR(n=710)

DES-ISR(n=1248) p

Age (years) 66.5 [58.7-74.1] 66.2 [59.0-73.6] 0.976Female 161 (22.7) 283 (22.7) 0.999Diabetes 187 (26.3) 515 (41.3) <0.001

Insulin-requiring 67 (35.5) 175 (34.0) 0.728Hypertension 549 (77.3) 941 (75.4) 0.338Hypercholesterolemia 543 (76.5) 833 (66.7) <0.001Ever-Smoked 374 (52.8) 597 (47.8) 0.037Prior Myocardial Infarction 401 (56.6) 538 (43.1) <0.001

Clinical Presentation   <0.001

Silent Ischemia/Stable Angina 455 (65.1) 720 (58.0)

Unstable Angina 160 (22.9) 505 (40.7)

NSTEMI 75 (10.7) 16 (1.3)

STEMI 9 (1.3) 0

LVEF (%) 60 [50-62] 60 [53-65] <0.001Multivessel Disease 316 (53.6) 567 (51.2) 0.358

BMS=Bare-Metal Stent; DES=Drug-Eluting Stent; ISR=In-Stent Restenosis; LVEF=Left Ventricular Ejection Fraction; NSTEMI=Non-ST-Segment Elevation Myocardial Infarction; STEMI=ST-Segment Elevation Myocardial Infarction.

Table 4. Angiographic and procedural characteristics by ISR-type.

BMS-ISR(n=724)

DES-ISR(n=1338) p

Target Lesion Site 0.898

Left Main 1 (0.1) 4 (0.3)

Left Anterior Descending 300 (41.6) 576 (43.1)

Left Circumflex 166 (23.0) 296 (22.1)

Right Coronary Artery 244 (33.8) 443 (33.1)

Saphenous Vein Graft 11 (1.5) 18 (1.3)

In-Stent Restenosis Morphology <0.001

Focal 290 (41.2) 837 (65.8)

Diffuse 295 (41.9) 326 (25.6)

Proliferative 93 (13.2) 62 (4.9)

Occlusive 26 (3.7) 47 (3.7)

Focal In-Stent Restenosis Morphology 0.983

Edge or Gap 67 (27.8) 210 (27.3)

Body 157 (65.1) 504 (65.5)

Multifocal 17 (7.1) 56 (7.3)

Restenosis Length (mm) 12.4 [8.1-18.6] 9.5 [6.6-14.7] <0.001Diameter Stenosis (%) 68.0 [58.5-76.3] 68.8 [58.7-78.9] 0.081Minimum Lumen Diameter (mm) 0.84 [0.63-1.13] 0.81 [0.55-1.12] 0.072Reference Vessel Diameter (mm) 2.73 [2.41-3.06] 2.71 [2.40-3.04] 0.694Predilation 666 (92.2) 1218 (92.3) 0.981Maximum Balloon Pressure 16 [12-18] 16 [12-19] 0.534

Treatment Assigned 0.810

Drug-Coated Balloon 379 (52.3) 693 (51.8)

Drug-Eluting Stent 345 (47.7) 645 (48.2)

BMS=Bare-Metal Stent; DES=Drug-Eluting Stent; ISR=In-Stent Restenosis.

Supplementary Figures

Figure 1. Selection process

Figure 2. Qualitative assessment of trials