1. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis Nordic–Baltic–British left main revascularisation study (NOBLE) A prospective, randomised, open-label, non-inferiority trial
NOBLE
Evald Høj Christiansen
Timo Mäkikallio, Niels R Holm, Mitchell Lindsay, Mark S Spence, Andrejs Erglis, Ian B A Menown, Thor Trovik, Markku Eskola, Hannu Romppanen, Thomas Kellerth, Jan Ravkilde, Lisette O Jensen, Gintaras Kalinauskas, Rikard B A Linder, Markku Pentikainen, Anders Hervold, Adrian Banning, Azfar Zaman, Jamen Cotton, Erlend Eriksen, Sulev Margus, Henrik T Sørensen, Per H Nielsen, Matti Niemelä, Kari Kervinen, Jens F Lassen, Michael Maeng, Keith Oldroyd, Geoff Berg, Simon J Walsh, Colm G Hanratty, Indulis Kumsars, Peteris Stradins, Terje K Steigen, Ole Fröbert, Alastair NJ Graham, Petter C Endresen, Matthias Corbascio, Olli A Kajander, Uday Trivedi, Juha Hartikainen, Vesa Anttila, David Hildick–Smith, Leif Thuesen, and Evald H Christiansen
On behalf of the NOBLE investigators

2. Disclosure Statement of Financial Interest
Within the past 12 months, I have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship
Company
Grant/Research Support
Biosensors

3. Background
PCI is increasingly used in the treatment of left main coronary artery (LMCA) stenosis
Evidence suggest that PCI provides clinical outcomes comparable to CABG in patients with less complex coronary artery disease
Dedicated, adequately powered trials are required to confirm that PCI is a valid alternative

4. Hypothesis
PCI with drug-eluting stents produce non-inferior clinical results compared with CABG in revascularization of patients with unprotected left main coronary artery stenosis

5. Inclusion criteria
Stable angina, unstable angina, or acute coronary syndrome
A significant left main lesion
Visually assessed stenosis diameter >50% or fractional flow reserve ≤0.80
Located in the ostium, mid-shaft, or bifurcation
No more than three additional non-complex lesions
Local interventional cardiologists and cardiac surgeons determined that equivalent revascularization could be achieved with CABG or PCI

6. Exclusion criteria Additional non left main complex lesions
Chronic total occlusions
Bifurcation lesions requiring two stent techniques
Calcified or tortuous vessel morphology
ST-elevation infarction within 24 h
Being considered too high-risk for CABG or PCI
Expected survival of less than 1 year

7. Design
A prospective, randomized, open-label, non-inferiority trial, carried out at 36 hospitals in Latvia, Estonia, Lithuania, Germany, Norway, Sweden, Finland, United Kingdom, and Denmark Enrollment: December 2008 to January 2015

8. Primary endpoint
A composite of major adverse cardiac and cerebrovascular events (MACCE)
Death from any cause
Non-procedural myocardial infarction
Repeat revascularization
Stroke

9. Sample size SYNTAX trial MACCE after 2 years*(30% of PCI,23% of CABG)
A HR of 1·35 was defined accordingly as the clinically acceptable non-inferiority limit not to be exceeded by the one-sided 95% CI
1- β (power) = 80%
275 events, with 1200 patients, 600 in each group needed
The primary endpoint assessment was January 2015 changed to include MACCE endpoints occurring between 2 and 5 years to reach a total of 275 events
September 2015 it was estimated that 275 events could not be reached within full 5 years (January 2020), and the primary endpoint assessment was changed to median 3 years
*Predicted from preliminary 1-year results in the SYNTAX trial

10. Secondary endpoints The individual components of the primary endpoint
Definite stent thrombosis
Symptomatic graft occlusion
Procedural myocardial infarction (post hoc)
Repeat revascularization
Target lesion
Left main coronary artery target lesion
De novo lesion

11. Did not receive PCI (n=13) Died before PCI (n=1)
Randomized (n= 1201)
Allocated to PCI (n=598)
Received PCI (n=585)
Did not receive PCI (n=13)
Died before PCI (n=1)
Patient declined PCI (n=4)
PCI operator declined (n=4)
LMCA lesion not significant (n=4)
Allocated to CABG (n=603)
Received CABG (n=570 )
Did not receive CABG (n=33)
Died before CABG (n=1)
Patient declined CABG (n=15)
Not eligible for CABG (n=15)
Cross over by mistake (n=2)
Lost to follow-up (n=6)
Emigration (n=1)
Contact lost (n=2)
Withdrawal (n=3)
Lost to follow-up (n=11)
Emigration (n=0)
Contact lost (n=0)
Withdrawal (n=11)
Patients allocated to PCI in analysis (n=592)
580 received PCI
7 received CABG
Patients allocated to CABG in analysis (n=592)
567 received CABG
23 received PCI

12. Baseline characteristics
PCI
CABG
P–value
Age (yrs)
66·2±9·9
66·2±9·4
0·91
Gender (female)
116 (20%)
140 (24%)
0·09
BMI (kg/m2)
27·9±4·5
28·1±4·4
0·53
Diabetes type I or type II
86 (15%)
90 (15%)
0·94
Family history of IHD
321 (58%)
307 (56%)
0·45
Statin treatment
482 (82%)
464 (78%)
0·17
Hypertension
386 (65%)
389 (66%)
Active smoking
108 (19%)
127 (22%)
0·18

13. Clinical characteristics
PCI
CABG
P–value
Ejection fraction (% [IQR])
60 [55;65]
60 [52;64]
0·27
Stable angina pectoris
466 (79%)
476 (81%)
0·61
Acute coronary syndrome
106 (18%)
100 (17%)
0·65
NYHA class I
244 (53%)
195 (43%) II
135 (30%)
150 (33%)
III
57 (13%)
77 (17%) IV
23 (5%)
33 (7%)
0·012
EUROSCORE
2 [2:4]
0·18

14. Lesion characteristics
PCI
CABG
P–value
SYNTAX score
22·5±7·5
22·4±8·0
0·74
Distal LMCA lesion
477 (81%)
482 (81%)
0·77

15. Treatment PCI LMCA stenting involving ostium and not the bifurcation
59 (10%)
Shaft LMCA stenting only
11 (2%)
LMCA bifurcation lesion stenting
508 (88%)
IVUS pre–evaluation
270 (47%)
IVUS post–evaluation
430 (74%)
Complete revascularization
543 (94%)

16. Treatment CABG Off–pump technique 88 (16%) Arterial graft 532 (95%)
Arterial graft to LAD
526 (93%)

17. Results Primary endpoint: MACCE
28·9%
HR 1·48 (1·11–1·96); p=0·0066
19·1%
PCI did not show non-inferiority
and CABG was superior to PCI

18. Results All-cause mortality
11.5%
HR 1·07 (0·67–1·72); p=0·77
11·6%
9.5%
9·5%

19. Results Non-procedural myocardial infarction
HR 2·88 (1·40–5·90); p=0·004
6·9%
1·9%

20. Results Total repeat revascularization
HR 1·50 (1·04–2·17); p=0·03
16·2%
10·4%

21. Results Stroke
HR 2·25 (0·92–5·48); p=0·07
4·9%
1·7%

22. Results Secondary endpoints
PCI
CABG
P–value
Definite ST or
symptomatic graft occlusion*
3%(9)
4%(15)
0·22
Procedural myocardial infarction (post hoc)
 5%(16/296)
7%(16/238)
0·52 
*Kaplan-Meier 5 year estimates by intention-to-treat

23. Results Secondary endpoints
PCI
CABG
P–value
Repeat revascularization
16%(71)
10%(47)
0·032
Target lesion revascularization
12%(50)
8%(36)
0·14
De novo lesion revascularization
6%(24)
3%(11)
0·018
Target LMCA revascularization
10%(41)
9%(33)
0·37
Kaplan-Meier 5 year estimates by intention-to-treat

24. Results SYNTAX score subgroups
K-M estimates
4.9%
1.9%
HR 1·88 (1·23–2·89); p=0·0031
HR 1·16 (0·76–1·78); p=0·48
HR 1·41 (0·62–3·20); p=0·41
SYNTAX score assessed by independent corelab (CERC)

25. Conclusions
PCI did not meet non-inferiority for the primary endpoint of 5- year MACCE compared to CABG
CABG was superior to PCI
PCI resulted in higher rates of non-procedural myocardial infarctions
Repeat revascularization was higher after PCI, primarily due to de novo lesions and non LMCA target lesion revascularization
All-cause mortality was similar for PCI and CABG

27. Backup slides

28. MACCE: Death, MI, stroke
HR 1.33 ( ); p=0.13
12.7%
8.8%

29. MACCE: Death, MI, stroke
HR % CI ( ) p=0.02

30. Kaplan-Meier 5 year estimates by intention-to-treat
K-M estimates
4.9%
1.9%

31. Outcomes between index procedure and 30 days of follow-up by treatment group
K-M estimates
4.9%
1.9%
(*assessable in 296 [50%] of 592 and 238 [40%] of 592 patients)

32. 1-year clinical outcome by treatment group
K-M estimates
4.9%
1.9%

33. 1-year clinical outcome by treatment group
K-M estimates
4.9%
1.9%

34. Completed follow-up

35. Treatment PCI LMCA stenting involving ostium and not bifurcation
59 (10·2%)
Shaft LMCA stenting only
11 (1·8%)
LMCA bifurcation lesion stenting
508 (87·7%)
IVUS pre–evaluation
270 (46·8%)
IVUS post–evaluation
430 (74·9%)
Total stent length in LMCA lesion (mm)
24 [IQR 15:35]
Number of treated lesions
312 (53·4%) 2
191 (32·5%) 3
55 (9·6%) 4
14 (2·4%) 5
3 (0·5%)
Complete revascularisation
543 (94·1%)

36. Treatment PCI: LMCA bifurcation
Angulation less than 70 degrees
110 (22·3%)
Visible calcification
213 (42·5%)
Severe tortuosity
55 (10·8%)
Stenting of LMCA–LAD only
300 (59·4%)
Stenting of LMCA–Cx only
21 (4·2%)
Culotte
119 (23·9%)
Crush
20 (4·0%)
T–stenting
41 (8·4%)
V–stenting
1 (0·2%)
Other technique
4 (0·8%)
Kissing balloon post inflation
277 (54·5%)

37. Treatment CABG Off–pump technique 88 (15·6%) Arterial graft
532 (94·5%)
Arterial graft to LAD
526 (93·4%)
LIMA + RIMA grafts
44 (7·9%)
LIMA + venous graft
480 (85·7%)
Radial artery graft
26 (4·8%)
Venous grafts only
27 (5·0%)
Grafts per patient
23 (4·1%) 2
294 (52·0%) 3
220 (39·0%) 4
25 (4·4%) 5
3 (0·6%)