A Randomized Multicentre Trial to Evaluate the Utilization of Revascularization or Optimal Medical Therapy for the Treatment of Chronic Total Coronary Occlusions Gerald S. Werner, MD PhD on behalf of the EURO CTO trial investigators

Potential conflicts of interest Speaker's name: Gerald S. Werner, MD I do not have any potential conflict of interest to report:

Background 16-18% of all coronary lesions in stable coronary artery disease are chronic total occlusions (CTO)1,2 Only 5% of PCI is performed in CTOs, many patients remain untreated3 Fefer P et al. J Am Coll Cardiol. 2012;59:991-997 Råmunddal T. et Al. PLoS One. 2014;9:e103850 Brilakis E. et al. JACC Cardiovasc Interv. 2015;8:245-53

Study design Prospective, open-label, multi-centre randomised trial Primary efficacy endpoint: the effect of PCI as compared to OMT on the health status at 12 months follow-up as assessed by the Seattle Angina Questionnaire (SAQ) Primary safety endpoint: the safety of performing PCI as compared to OMT for a CTO in stable coronary artery disease during 3 years of follow- up. www.clinicaltrials.gov. NCT01760083

TRIAL ORGANIZATION G. S. Werner PI: Steering Committee: Statistics: DSMB: CEC: CRO: e-CRF: Sponsor: G. S. Werner E. Christiansen; I. Durand Zaleski; J. Escaned; A. Galassi A.H. Gershlick; G. Heyndrickx ; D. Hildick-Smith ; Y. Louvard; G. Olivecrona; G. Sianos; G. S. Werner (Chairperson) K. Bogaerts (KU Leuven) M Bertrand (Chair); C. Hamm; J-J. Goy J. Machecourt (Chair), A. Baumbach, J. Garot CERC, Massy, France (Project Leader M. Carvalho) Clinigrid Euro-CTO Club (grant from Biosensors and Asahi)

Major inclusion/exclusion criteria Patients with stable coronary artery disease and at least one CTO (TIMI 0, >3 months duration) with symptoms and/or ischemia and viability CTO location in a major artery (AHA 1-3, 6-7, 11) with a reference diameter ≥2.5mm Patients with multi-vessel disease should receive PCI to significant non-CTO lesions before randomisation; if the CTO needed treatment first, the patient was excluded

Statistical design 1200 patients were planned to be enrolled to achieve a 90 % power for the safety endpoint at 36 months follow-up 600 patients were calculated as required for the primary efficacy endpoint The study inclusion started in March 2012 and was extended to May 2015, but the intended patient number to assess the primary endpoint was not reached, and the study concluded enrolment with 407 patients

26 Participating centres/operators Massy - Y. LOUVARD (PI) 50 Darmstadt - G. WERNER/H. MOEHLIS (PI) 44 Barcelona - V. MARTIN YUSTE (PI) 43 Brighton - D. HILDICK-SMITH (PI) 40 Toulouse Cedex 9 - N. BOUDOU (PI) 29 Sofia – G. SIANOS/V. GELEV (PI) 28 GALDAKAO - R. RUMOROSO (PI) 27 Riga - A. ERGLIS (PI) 24 Aarhus N, - E. CHRISTIANSEN (PI) 19 Barcelona - L. TERUEL (PI) 15 London - C. DI MARIO (PI) Madrid - J. ESCANED (PI) Krefeld - A. BUFE (PI) 14 Bad Berka, - B. LAUER (PI) 10 Majadahonda - J. GOICOLEA (PI) 9 Edinburgh - J. SPRATT (PI) 8 Toulouse - D. TCHÉTCHÉ (PI) 4 Bad Soden/Taunus - N. REIFART (PI) 3 Barcelona - B. VAQUERIZO (PI) Leicester - A. GERSHLICK (PI) Bordeaux - J. LEYMARIE (PI) 2 Salerno - P. GIUDICE (PI) Bad Krozingen - H. BÜTTNER (PI) 1 Catania - A. GALASSI (PI) Rivoli - A. GAGNOR (PI) Wolverhampton - J. COTTON (PI) 120 100 80 60 40 20 E F GB D BG LV DK I

Study flow chart 48% 29% Efficacy: Health status @ 12 and 36 months Multivessel CAD including CTO Angina or angina- equivalent symptoms Single-vessel disease CTO only 48% 29% Treat non-occlusive disease by PCI before CTO with DES Efficacy: Health status @ 12 and 36 months Safety: Death, non-fatal myocardial infarction (ITT, PP) @ 36 months

Study flow chart 48% 29% 11 pats exclude d n=259 n=137 Multivessel CAD including CTO Angina or angina- equivalent symptoms Single-vessel disease CTO only 48% 29% Treat non-occlusive disease by PCI before CTO with DES OMT to include: Aspirin, Statin, ACE-inhibitor where tolerated - + at least 2 anti-anginal agents at max tolerated dose including rate- limiting agent where appropriate. Ischaemic symptoms should be confirmed with non-invasive test. Randomisation 2:1 11 pats exclude d PCI with DES 2 1 + OMT OMT n=259 n=137 Efficacy: Health status @ 12 and 36 months Safety: Death, non-fatal myocardial infarction (ITT, PP) @ 36 months

Study flow chart 48% 29% n=259 11 pats exclude d n=137 n=10 (7.3%) Multivessel CAD including CTO Angina or angina- equivalent symptoms Single-vessel disease CTO only 48% 29% Treat non-occlusive disease by PCI before CTO with DES OMT to include: Aspirin, Statin, ACE-inhibitor where tolerated - + at least 2 anti-anginal agents at max tolerated dose including rate- limiting agent where appropriate. Ischaemic symptoms should be confirmed with non-invasive test. Randomisation 2:1 PCI with DES + OMT n=259 Success Failure 11 pats exclude d 2 1 OMT n=137 Clinically indicated interim PCI Decision as per usual clinical care Medical Rx CABG Ongoing angina despite OMT n=10 (7.3%) Repeat Exercise Tolerance Test (ETT) for objective assessment of ischemia @ 12m and 36months Efficacy: Health status @ 12 and 36 months Safety: Death, non-fatal myocardial infarction (ITT, PP) @ 36 months

Patient characteristics I OMT (N=137) PCI (N=259) Age (years) 64.7 ± 9.9 65.2 ± 9.7 Male (%) 86.1 83.0 BMI (kg/m²) 28.3 ± 5.2 28.4 ± 4.9 Hypertension (%) 71.5 73.0 Diabetes mellitus Insulin-dependent (%) 8.8 8.5 Non-Insulin-dependent (%) 20.4 24.3 Hypercholesterolaemia (%) 81.0 81.1 History of Smoking (%) 67.2 73.4 Family history (%) 26.3 31.3

Patient characteristics II OMT (N=137) PCI (N=259) Previous MI (%) 18.3 22.8 Previous CABG (%) 7.3 13.1 Previous PCI (%) 51.8 56.0 PCI to facilitate study entry (%) 27.0 30.5 LVEF (%) 55.7 ± 10.8 54.5± 10.8 Myocardial viability (%) 85.4 86.1 Number of diseased vessels Single vessel (%) 45.3 50.2 Two vessels (%) 37.2 24.3 Three vessels (%) 17.5 25.5

Lesion characteristics OMT (N=137) PCI (N=259) Target vessel RCA (%) 57.4 63.7 LAD (%) 27.0 25.5 LCX (%) 15.6 10.8 Reference diameter (mm) 3.0 ± 0.41 2.9 ± 0.44 Length of occlusion (mm) 26.5 ± 16.0 31.4 ± 20.5 Lesion calcifications (%) 36.1 37.3 Lesion tortuosity (%) 12.8 21.3 J-CTO score 1.67 ± 0.91 1.82 ± 1.07

PCI procedure in PCI group (n=255) Radial approach for PCI (%) 34.3 Bilateral approach (%) 81.2 Retrograde approach (%) 35.8 Revascularisation successful (%) 86.3 Stents used Biomatrix (%) 91.1 Other DES (%) 8.9 Total length of stent used (mm) 65.9 ± 28.9 Width of largest stent (mm) 3.3 ± 2.49 Number of stents used 2.0 ± 1.32 Procedure duration (min) 118.1 ± 67.2 Fluoroscopy time (min) 48.8 ± 34.5

Procedural complications Any complication N(%) 8 (2.9) Death (%) Q-wave MI (%) Acute TVR/ emergency CABG (%) Pericardial tamponade (%) 4 (1.5) Vascular repair (%) 2 (0.7) Blood transfusion (%) 6 post procedural CK >3 times ULN, including 2 CK > 5 times ULN, 4 troponine increase. None of the patients experienced pain or changes of the ECG and CEC did not adjudicate any of them as 4aMI ( Universal definition)

MACCE during follow-up OMT (N=137) PCI (N=259) P-value Patients with any adverse event 9 (6.7) 13 (5.2) 0.52 All cause Death 2 (0.8) 0.55 Cardiac death Myocardial infarction 5 (1.9) 0.17 Non-Q-wave 4 (1.6) Q-wave 1 (0.4) Ischemia-driven revascularization 7 (2.9) 0.10 Cerebrovascular event 1 (0.7) 0.99 Stent thrombosis Number of patients (%)

Primary endpoint: SAQ health status (ITT) BL FU P=0.47 P=0.009 P=0.049 P=0.022 100 90 80 P=0.89 70 60 50 40 30 20 10 BL FU BL FU Physical limitation BL FU BL FU Anginal frequency BL FU BL FU Quality of life BL FU BL FU Anginal stability BL FU BL FU Treatment satisfaction For multiple testing the significance level is 0.01

Significant change in SAQ subscale scores *) 100 OMT PCI P=0.003 P=0.013 P=0.008 P=0.005 90 80 70 60 50 40 30 20 10 Score Physical limitation ≥8 Anginal frequency ≥20 Freedom of angina (100%) Quality of life ≥16 Higher score, better health status *) Spertus et al. JACC 1995;25:333-41

Changes in CCS class during follow-up 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Baseline Follow-up OMT CCS 1 Baseline Follow-up PCI CCS 2 CCS 3 CCS 4

Summary of results Due to slow recruitment the number of patients in this study is below the preplanned number However, the results are relevant and demonstrate, that PCI of CTO improved the health status regarding angina frequency, physical limitations, and quality of life as compared to OMT, and improved the functional class In experienced hands, periprocedural risk was low, and the 12 months MACCE rate was comparable to OMT, but the long-term safety remains to be evaluated at 36 months (Primary safety endpoint)

EUROCTO Trial BACKUP SLIDES

CAD specific medication 100 P<0.001 90 80 70 OMT PCI P=0.04 P=0.006 60 P=0.16 50 40 30 P=0.14 P=0.009 20 10 BL FU BL FU BL FU BL FU BL FU BL FU BL FU Aspirin ADP ß-blocker ACEI/ Statin Nitrate Ranolazine ARB etc

EQ-5D changes during follow-up P=0.005 P<0.001 P=0.001 OMT PCI OMT PCI OMT PCI 100% 90% 80% 70% 60% 50% 40% 30% 20% No Moderate Severe 10% 0% BL FU BL FU BL FU BL FU BL FU BL FU Pain/discomfort Mobility Activity

Primary endpoint: SAQ health status (ITT) OMT (N=137) PCI (N=259) P-value Available at baseline 133 (97%) 253 (98%) Available at follow-up 116 (85%) 209 (81%) Physical limitation Baseline 71.2 ± 24.7 67.1 ± 24.9 Follow-up 76.7 ± 23.2 80.2 ± 22.4 0.04 Angina frequency 80.6 ± 24.2 77.2 ± 23.8 87.5 ± 18.8 91.4 ± 16.6 0.02 Quality of life 59.8 ± 26.2 55.3 ± 24.9 72.1 ± 25.7 76.5 ± 23.1 0.06 Statistics: Analysis of covariance for changes in subscales between groups