BBC ONE David Hildick-Smith Sussex Cardiac Centre Brighton, UK on behalf of the BBC ONE Investigators

BBC ONE The British Bifurcation Coronary study: Old, New and Evolving strategies a randomized comparison of simple versus complex drug-eluting stenting for bifurcation lesions

Techniques Simple – stepwise provisional T-stenting Complex – total lesion coverage: crush or culotte (according to operator preference)

Study organisation Steering Committee: Curzen, Stables, Oldroyd, Hildick-Smith Steering Committee: Curzen, Stables, Oldroyd, Hildick-Smith Initiation visit: Cooter Initiation visit: Cooter Randomisation and data entry: secure e-CRF at www. e-dendrite.com Randomisation and data entry: secure e-CRF at www. e-dendrite.com DSMB: Walsh, Wilcox, Scrase DSMB: Walsh, Wilcox, Scrase CEC: Thomas, MacCarthy CEC: Thomas, MacCarthy Monitoring visit: Cooter, Bennett, Wilson Monitoring visit: Cooter, Bennett, Wilson Data management: Dendrite Clinical Systems Data management: Dendrite Clinical Systems Continous remote monitoring: Cooter, Bennett, Howarth Continous remote monitoring: Cooter, Bennett, Howarth Statistician: Clayton Statistician: Clayton

Inclusion criteria Bifurcation coronary artery disease requiring stenting Bifurcation coronary artery disease requiring stenting Vessel diameters Vessel diameters ≥2.25mm side ≥2.25mm side ≥2.5mm main ≥2.5mm main

Exclusion criteria Unprotected left main stem narrowing ≥50% Unprotected left main stem narrowing ≥50% Primary angioplasty Primary angioplasty Cardiogenic shock Cardiogenic shock CTO of either bifurcation-related vessel CTO of either bifurcation-related vessel Additional Type C or bifurcation lesions requiring PCI Additional Type C or bifurcation lesions requiring PCI Left ventricular ejection fraction ≤20% Left ventricular ejection fraction ≤20%

Statistical hypothesis Assumption: Assumption: Death, MI, TVF (at nine months) Death, MI, TVF (at nine months) 10% vs 20% in the two groups 10% vs 20% in the two groups Sample size of 400 patients would achieve 80% power at a 5% significance level Sample size of 400 patients would achieve 80% power at a 5% significance level To allow for patients lost to follow-up and protocol violations it is proposed to recruit 500 patients to the study. To allow for patients lost to follow-up and protocol violations it is proposed to recruit 500 patients to the study.

Technique (simple) Stage 1 Stage 1 Stent main vessel Stent main vessel

Technique (simple) Following main vessel stenting, the side branch should not be treated further unless there is: Following main vessel stenting, the side branch should not be treated further unless there is: <TIMI 3 flow in the side branch <TIMI 3 flow in the side branch Severe ostial pinching (>90%) of the side branch Severe ostial pinching (>90%) of the side branch Threatened side vessel closure Threatened side vessel closure Side-branch dissection >type A Side-branch dissection >type A if any of these applies, the operator may → Stage 2 if any of these applies, the operator may → Stage 2

Technique (simple) Stage 2 Stage 2 Kissing inflation Kissing inflation

Technique (simple) Following kissing inflations, the side branch should not be treated further unless there is: Following kissing inflations, the side branch should not be treated further unless there is: <TIMI 3 flow in the side branch <TIMI 3 flow in the side branch Severe ostial pinching (>70%) of the side branch Severe ostial pinching (>70%) of the side branch Threatened side vessel closure Threatened side vessel closure Side-branch dissection >type A Side-branch dissection >type A if any of these applies, the operator may → Stage 3 if any of these applies, the operator may → Stage 3

Technique (simple) Stage 3 Stage 3 T-stent T-stent

Technique (simple) Mandatory kissing Mandatory kissing

Technique (complex) Culotte Culotte wire both vessels wire both vessels stent first vessel stent first vessel

Technique (complex) Culotte Culotte Rewire main vessel Rewire main vessel stent 2 nd vessel stent 2 nd vessel mandatory kissing mandatory kissing

Technique (complex) Crush Crush stent side vessel stent side vessel crush with balloon/stent crush with balloon/stent

Technique (complex) Crush Crush stent main stent main recross side recross side mandatory kissing mandatory kissing

PRIMARY ENDPOINT composite at 9 months of: Death Death Target vessel failure Target vessel failure Myocardial infarction Myocardial infarction

SECONDARY ENDPOINTS Death Death Myocardial infarction Myocardial infarction Target vessel failure Target vessel failure Angina status – CCS and Angina index Angina status – CCS and Angina index Repeat angiography Repeat angiography

Procedural success Procedural success TIMI 3 flow and <30% stenosis main vessel, and TIMI 3 flow and <30% stenosis main vessel, and TIMI 3 flow side branch TIMI 3 flow side branch Kissing balloons success Kissing balloons success In-hospital MACE In-hospital MACE In-hospital serious adverse events (non-MACE) In-hospital serious adverse events (non-MACE) Procedure duration, fluoroscopy, cGy.cm 2, contrast Procedure duration, fluoroscopy, cGy.cm 2, contrast Procedural consumables (wires, balloons, stents) Procedural consumables (wires, balloons, stents) PROCEDURAL ENDPOINTS

Additional details Operators >150 PCI/yr Operators >150 PCI/yr (96% procedures took place at surgical centres) (96% procedures took place at surgical centres) TAXUS stents TAXUS stents Clopidogrel and Aspirin for 9 months Clopidogrel and Aspirin for 9 months

Recruitment

Recruiting centres Brighton, 116

RESULTS

Baseline characteristics Complex (n=250) Simple (n=250) Age (years) mean (SD) Age (years) mean (SD) 64 (11) 64 (10) % male % male77%77% BMI (kg/m 2 ) mean (SD) BMI (kg/m 2 ) mean (SD) 28 (5) Diabetes Diabetes 28 (11%) 31 (13%) Smoking (current) Smoking (current) 43 (17%) 42 (17%) Family history Family history 103 (41%) 104 (42%) Hypertension Hypertension 154 (62%) 142 (57%) Hypercholesterolaemia Hypercholesterolaemia 189 (76%) 188 (76%)

Clinical presentation

Site of bifurcation lesion

Bifurcation types (MEDINA)

Glycoprotein IIb/IIIa use Complex (n=248) Simple (n=249) P value GPI used GPI used 110 (44%) 70 (28%) <0.001

Lesion and stent characteristics Complex (n=250) Simple (n=250) Main vessel Main vessel Stent diameter (mm; SD) Stent diameter (mm; SD) 3.2 (0.3) 3.0 (0.3) Stent length (mm; SD) Stent length (mm; SD) 22 (6) 21 (6) Stenosis pre-procedure (%) Stenosis pre-procedure (%) 85 (11) 87 (10) Stenosis post-procedure (%) Stenosis post-procedure (%) 4 (16) 3 (13)

Lesion and stent characteristics Complex (n=250) Simple (n=250) Side branch Side branch Stent diameter (mm; SD) Stent diameter (mm; SD) 2.6 (0.3) - Stent length (mm; SD) Stent length (mm; SD) 16 (5) - Stenosis pre-procedure (%) Stenosis pre-procedure (%) 68 (29) 63 (31) Stenosis post-procedure (%) Stenosis post-procedure (%) 12 (24) 37 (33)

Lesion and stent characteristics ComplexSimple P value Total stented length (mm; SD) Total stented length (mm; SD) 41 (16) 24 (10) <0.001

500 SIMPLE 250 SIMPLE randomisation delay COMPLEX 250 COMPLEX withdrew consent, 1 no treatment attempted

TOTAL POPULATION n=500 SIMPLE Provisional T n=249 STAGE 1 Stent main vessel n=176 STAGE 2 Stent main vessel plus kiss n=66 STAGE 3 T-stent and kiss (failed n=1) n=7 COMPLEX Total coverage n=248 Crush n=169 Culotte n=75 Simple (operator decision) n=4

SIMPLE Procedure n=249 No stent to main vessel n=4 2% Stent to main vessel No kiss n=172 68% Stent to main vessel Kissing balloons n=66 27% Stent to main vessel T-stent to side Kissing balloons n=7 3%

COMPLEX (Culotte) Procedure n=75 ≥1 vessel not stented n=5 7% Stent to both vessels Failed kiss n=3 4% Stent to both vessels Kissing balloons n=67 89%

COMPLEX (Crush) Procedure n=169 ≥1 vessel not stented n=16 9% Stent to both vessels Failed kiss n=31 18% Stent to both vessels Kissing balloons n=122 72%

PRIMARY ENDPOINT Composite (9months) Death, MI, TVF PRIMARY ENDPOINT Composite (9months) Death, MI, TVFComplexSimple P value Death Death 2 (0.8%) 1 (0.4%) - Myocardial infarction Myocardial infarction 28 (11.2%) 9 (3.6%) - Target vessel failure Target vessel failure 18 (7.2%) 14 (5.6%) - Primary endpoint Primary endpoint 38 (15.2%) 20 (8.0%) HR 2.0 (1.2 to 3.5)

0% 5% 10% 15% 20% Cumulative % death, MI, TVF 0369 Follow-up time (months) Complex Simple PRIMARY ENDPOINT Death, MI, TVF Complex Simple p=0.009

MYOCARDIAL INFARCTION p=0.001

Biomarker data Complex (n=248) Simple (n=249) CK CK 231 (93%) 233 (94%) Troponin Troponin 222 (90%) 233 (94%) CK or Troponin CK or Troponin 240 (97%) 244 (98%)

TARGET VESSEL FAILURE 0% 5% 10% 15% 20% Cumulative percentage 0369 Follow-up time (months) Complex Simple p=ns

Target vessel failure ComplexSimple No. patients 18 (7.2%) 14 (5.6%) Immediate CABG2 (0.8%) 0 Inpatient CABG1 (0.4%) 0 Stent thrombosis (ARC definite) 5 (2.0%) 1 (0.4%) Revascularisation (restenosis) Revascularisation (restenosis)912 Revascularisation (distant lesion) Revascularisation (distant lesion)11

In-hospital MACE ComplexSimple P value No. patients 20 (8.0%) 5 (2.0%) RR 4.0 (1.5 to 10.5) Death Death 10 Myocardial infarction Myocardial infarction 185 CABG CABG 30

In-hospital serious adverse events (non-MACE) ComplexSimple No. patients 104 Bleed (TIMI major)31 Stroke10 Cardiac tamponade21 Perforation without tamponade31 Transfusion61 Left main stem dissection11 Vascular surgery01

Procedural endpoints ComplexSimple P value Procedure time (mins; mean, SE) 78 (1.9) 57 (1.6) <0.001 mean, SE) Fluoroscopy time (min; mean, SE) 22 (0.8)15 (0.7)<0.001 mean, SE) Diamentor (cGy.cm 2 ; mean, SE) 7900 (350)6140 (300)<0.001 No. guidewires used (mean, SE) 3.11 (0.08) 2.21 (0.06) <0.001 (mean, SE) No. balloons used (mean, SE) 3.97 (0.11)2.26 (0.09)<0.001 (mean, SE) No. stents used (mean, SE) 2.21 (0.07)1.17 (0.04)<0.001

CONCLUSIONS For unselected bifurcation lesions, a stepwise provisional T stent strategy is superior to a systematic dual stenting strategy in all domains: For unselected bifurcation lesions, a stepwise provisional T stent strategy is superior to a systematic dual stenting strategy in all domains: procedural success procedural success procedural complications procedural complications in-hospital and 9-month MACE in-hospital and 9-month MACE

CONCLUSIONS Further studies will examine whether there are bifurcation subsets in which total lesion coverage may be advantageous Further studies will examine whether there are bifurcation subsets in which total lesion coverage may be advantageous