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

Speaker's name: Gerald S. Werner, MD

I do not have any potential conflict of interest to report:

Potential conflicts of interest

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

1) Fefer P et al. J Am Coll Cardiol. 2012;59:991-9972) Råmunddal T. et Al. PLoS One. 2014;9:e1038503) Brilakis E. et al. JACC Cardiovasc Interv. 2015;8:245-53

Study design

• Prospective, open-label, multi-centre randomisedtrial

• 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

PI: G. S. Werner

Steering

Committee:

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)

Statistics: K. Bogaerts (KU Leuven)

DSMB: M Bertrand (Chair); C. Hamm; J-J. Goy

CEC: J. Machecourt (Chair), A. Baumbach, J. Garot

CRO: CERC, Massy, France

(Project Leader M. Carvalho)

e-CRF: Clinigrid

Sponsor: 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/operatorsMassy - 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) 15

Madrid - J. ESCANED (PI) 15

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) 3

Leicester - A. GERSHLICK (PI) 3

Bordeaux - J. LEYMARIE (PI) 2

Salerno - P. GIUDICE (PI) 2

Bad Krozingen - H. BÜTTNER (PI) 1

Catania - A. GALASSI (PI) 1

Rivoli - A. GAGNOR (PI) 1

Wolverhampton - J. COTTON (PI) 10

20

40

60

80

100

120

E F GB D BG LV DK I

Efficacy: Health status @ 12 and 36 months

Safety: Death, non-fatal myocardial infarction (ITT, PP) @ 36 months

Single-vessel disease CTO onlyMultivessel CAD including CTO

Treat non-occlusive disease

by PCI before CTO with DES

Angina or

angina-

equivalent

symptoms

Study flow chart

48%

29%

Efficacy: Health status @ 12 and 36 months

Safety: Death, non-fatal myocardial infarction (ITT, PP) @ 36 months

Single-vessel disease CTO onlyMultivessel CAD including CTO

Treat non-occlusive disease

by PCI before CTO with DES

Angina or

angina-

equivalent

symptoms

Randomisation 2:1

PCI with DES

+ OMT

n=259

2

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.

OMT

n=137

1

Study flow chart

48%

29%

11 pats excluded

Success Failure

Decision as per

usual clinical care

Medical Rx CABG

Efficacy: Health status @ 12 and 36 months

Safety: Death, non-fatal myocardial infarction (ITT, PP) @ 36 months

Repeat Exercise Tolerance Test (ETT) for objective assessment of ischemia @ 12m and 36months

Single-vessel disease CTO onlyMultivessel CAD including CTO

Treat non-occlusive disease

by PCI before CTO with DES

Angina or

angina-

equivalent

symptoms

Randomisation 2:1

PCI with DES

+ OMT

n=259

2

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.

OMT

n=137

1

Study flow chart

48%

29%

Ongoing angina

despite OMT

n=10 (7.3%)

Clinically

indicated

interim PCI

11 pats excluded

Patient characteristics I

OMT(N=137)

PCI(N=259)

Age (years) 64.7 ± 9.9 65.2 ± 9.7Male (%) 86.1 83.0BMI (kg/m²) 28.3 ± 5.2 28.4 ± 4.9Hypertension (%) 71.5 73.0Diabetes mellitus

Insulin-dependent (%) 8.8 8.5Non-Insulin-dependent (%) 20.4 24.3

Hypercholesterolaemia (%) 81.0 81.1History of Smoking (%) 67.2 73.4Family history (%) 26.3 31.3

Patient characteristics II

OMT(N=137)

PCI(N=259)

Previous MI (%) 18.3 22.8Previous CABG (%) 7.3 13.1Previous PCI (%) 51.8 56.0PCI to facilitate study entry (%) 27.0 30.5LVEF (%) 55.7 ± 10.8 54.5± 10.8Myocardial viability (%) 85.4 86.1Number of diseased vessels

Single vessel (%) 45.3 50.2Two vessels (%) 37.2 24.3Three vessels (%) 17.5 25.5

Lesion characteristics

OMT(N=137)

PCI(N=259)

Target vesselRCA (%) 57.4 63.7LAD (%) 27.0 25.5LCX (%) 15.6 10.8

Reference diameter (mm) 3.0 ± 0.41 2.9 ± 0.44Length of occlusion (mm) 26.5 ± 16.0 31.4 ± 20.5Lesion calcifications (%) 36.1 37.3Lesion tortuosity (%) 12.8 21.3J-CTO score 1.67 ± 0.91 1.82 ± 1.07

PCI procedure in PCI group (n=255)

Radial approach for PCI (%) 34.3Bilateral approach (%) 81.2Retrograde approach (%) 35.8Revascularisation successful (%) 86.3Stents used

Biomatrix (%) 91.1Other DES (%) 8.9

Total length of stent used (mm) 65.9 ± 28.9Width of largest stent (mm) 3.3 ± 2.49Number of stents used 2.0 ± 1.32Procedure duration (min) 118.1 ± 67.2Fluoroscopy time (min) 48.8 ± 34.5

Procedural complications

Any complication N(%) 8 (2.9)Death (%) 0Q-wave MI (%) 0Acute TVR/ emergency CABG (%) 0Pericardial tamponade (%) 4 (1.5)Vascular repair (%) 2 (0.7)Blood transfusion (%) 2 (0.7)

• 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) 0.52All cause Death 0 2 (0.8) 0.55

Cardiac death 0 2 (0.8)Myocardial infarction 0 5 (1.9) 0.17

Non-Q-wave 0 4 (1.6)Q-wave 0 1 (0.4)

Ischemia-driven revascularization 9 (6.7) 7 (2.9) 0.10Cerebrovascular event 1 (0.7) 2 (0.8) 0.99Stent thrombosis 0 1 (0.4) 0.99

Number of patients (%)

0

10

20

30

40

50

60

70

80

90

100

BL FU

Physical limitation

Anginalfrequency

Anginalstability

Treatmentsatisfaction

Quality oflife

Primary endpoint: SAQ health status (ITT)

For multiple testing the significance level is 0.01

BL FU BL FU BL FU BL FU BL FU BL FU BL FU BL FU BL FU BL FU

P=0.022

P=0.009P=0.049

P=0.89

P=0.47

Significant change in SAQ subscale scores *)

0

10

20

30

40

50

60

70

80

90

100

Physical limitation ≥8

Anginal frequency ≥20

Freedom ofangina (100%)

Quality of life ≥16

OMT PCI

P=0.003 P=0.013 P=0.008 P=0.005

*) Spertus et al. JACC 1995;25:333-41

Sco

re

Higher score, better health status

Changes in CCS class during follow-up

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Baseline Follow-up Baseline Follow-up

CCS 1 CCS 2 CCS 3 CCS 4OMT PCI

P<0.001

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)

BACKUP SLIDES

EUROCTO Trial

CAD specific medication

0

10

20

30

40

50

60

70

80

90

100

BL FU BL FU BL FU BL FU BL FU BL FU BL FU

OMT PCI

Aspirin ADP ß-blocker ACEI/ARB

Statin Nitrate Ranolazineetc

P=0.04

P<0.001

P=0.006

P=0.14 P=0.009

P=0.16

EQ-5D changes during follow-up

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

BL FU BL FU BL FU BL FU BL FU BL FU

No Moderate Severe

Mobility Activity Pain/discomfort

OMT PCI OMT PCI OMT PCI

P=0.001P<0.001P=0.005

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 limitationBaseline 71.2 ± 24.7 67.1 ± 24.9Follow-up 76.7 ± 23.2 80.2 ± 22.4 0.04Angina frequencyBaseline 80.6 ± 24.2 77.2 ± 23.8Follow-up 87.5 ± 18.8 91.4 ± 16.6 0.02Quality of lifeBaseline 59.8 ± 26.2 55.3 ± 24.9Follow-up 72.1 ± 25.7 76.5 ± 23.1 0.06

Statistics: Analysis of covariance for changes in subscales between groups