Tetra Randomized European Direct Stenting Study (TRENDS) Keith D. Dawkins, M. J. Suttorp, Leif Thuesen, Edouard Benit, Armando Bethencourt, Ursula Morjaria, Susan Veldhof, Bernard Chevalier, on behalf of the TRENDS investigators

Direct Stenting Trials (n=4297) Patients (n) Stent Type BET 338 Tenax CONVERTIBLE 202 BeStent 2 DIRECT 107 Multilink Duet DIRECTO 151 NIR Primo DIRECTOR I + II 520 R-Stent DISCO 416 Various DISTANCE - S7 PREDICT 400 S670 SLIDE 362 SWIBAP NIR TRENDS 1000 Multilink Tetra VELVET II 401 Bx Velocity

Direct Stenting Trials (n=4297) Patients (n) Stent Type BET 338 Tenax CONVERTIBLE 202 BeStent 2 DIRECT 107 Multilink Duet DIRECTO 151 NIR Primo DIRECTOR I + II 520 R-Stent DISCO 416 Various DISTANCE - S7 PREDICT 400 S670 SLIDE 362 SWIBAP NIR TRENDS 1000 Multilink Tetra VELVET II 401 Bx Velocity

TRENDS To define the medium term performance of a no pre-dilatation strategy for elective stent implantation using the Multilink Tetra™ Stent

TRENDS Multicenter, prospective clinical trial 1:1 randomization to stent implantation with or without pre-dilatation 1000 patient enrolment over a period of one year at 46 sites in Europe and South America

Angiographic follow-up TRENDS Trial Design 1000 patients Diagnostic catheter (Randomisation 1:1) Direct Stent (501 pts) Pre-dilatation (499 pts) Angiographic follow-up (6 months)

A Direct stenting strategy Possible Advantages Shorter procedure duration Less radiation Less contrast Reduced resource utilisation Less embolization Less unprotected barotrauma Potential Disadvantages Failure to cross lesion Loss of stent Incomplete stent deployment Increase in guide trauma Undersizing of stent (diameter & length) Poor visualisation Error in stent positioning

TRENDS Total Patients: 1000 Pre-dilatation: 499 Direct stent: 501 117 13 27 2 128 144 75 52 82 133 116 35 41 Total Patients: 1000 Pre-dilatation: 499 Direct stent: 501 35

TRENDS Top Recruiting Centers Country Patients (n) St Antonius Hospital Netherlands 95 Skejby Sygehus Denmark 76 Virga Jesse Ziekenhuis Belgium 59 Hospital Son Dureta Spain 58 CHR Citadelle 56 Wessex Cardiac Unit United Kingdom 52 De Klokkenberg TCI Breda 49 Clinique des Franciscaines France 40 Casa di Cura Montevergine Spa Italy Rigshospitalet

TRENDS Multilink Tetra™ Coronary Stent System Stent diameters: 2.75, 3.0, 3.5, 4.0 mm Stent lengths: 8, 13, 18, 23 mm

TRENDS Primary Endpoint Major Adverse Cardiac Events at 30 days Death Myocardial infarction (Q and non-Q) CABG, or re-PCI (TVR)

TRENDS Secondary Endpoints Use of multiple stents at each target lesion Total procedure time Radiographic screening time Contrast volume Technical success Procedural resource analysis Duration of hospital stay MACE at 6 months Binary angiographic restenosis per lesion at 6 months

TRENDS Inclusion Criteria* Symptomatic angina Planned de novo single lesions, or restenotic lesions (previous POBA) in native coronary arteries MVD may be treated, one lesion per vessel Target vessel diameter ≥2.75 mm to ≤4.25 mm, length ≤18 mm (visual) Target lesion ≥70% stenosis, TIMI flow ≥1 * Selected

TRENDS Exclusion Criteria* Acute MI within the last 24 hours Unprotected left main stem lesion Lesion involving a significant side branch (>2 mm diameter) Evidence of severe calcification Use of IVUS before stenting Chronic total occlusion * Selected

TRENDS Baseline Demographics (I) Pre-dilatation n=499 (%) Direct stent n=501 (%) Age (years) 59.4 (range 32-84) 59.9 (range 31-84) Male 78 Diabetes 18 15 Hypercholesterolemia 58 63 Hypertension 49 53 Family history 36 40 p=ns

TRENDS Baseline Demographics (II) Pre-dilatation n=499 (%) Direct stent n=501 (%) Current smoker 27 25 Previous smoker 46 43 Previous MI 37 38 Previous CABG/PCI 8 History of angina 97 98 p=ns

TRENDS Lesion Characteristics (I) Pre-dilatation Direct stent Procedure: Single vessel 91% 93% Two Vessel 8% 7% Three vessel 1% 0% p=ns

TRENDS Lesion Characteristics (II) Pre-dilatation Direct stent Vessel: LAD 42% 40% LCx 20% 25% RCA 36% 34% p=ns

TRENDS Lesion Characteristics (III) Pre-dilatation Direct stent ACC/AHA Class: Type A 17% Type B1 44% 40% Type B2 38% 42% Type C 1% p=ns

TRENDS Lesion Characteristics (IV) Pre-dilatation Direct stent TIMI Flow: Grade 0 0% Grade 1 2% Grade 2 5% Grade 3 93% p=ns

TRENDS Lesion Characteristics (V) Pre-dilatation Direct stent Thrombus at lesion site 2.1% 1.4% Target site calcification 4.5% 5.3% Lesion angulation >45o 5.0% 4.7% Eccentric 63.5% 64.0% p=ns

TRENDS Quantitative Coronary Arteriography Pre-dilatation mean ± SD (n = 472) Direct stent (n = 469) Pre-procedure DS (%) 63.9 ± 11.2 64.7 ± 10.4 Pre-procedure MLD (mm) 1.07 ± 0.36 1.06 ± 0.36 Pre-procedure reference vessel diameter (mm) 2.99 ± 0.50 3.03 ± 0.56 Lesion length (mm) 12.4 ± 4.87 12.3 ± 4.89 Post-procedure MLD (mm) 2.95 ± 0.44 2.91 ± 0.49 Post-procedure DS (%) 7.95 ± 8.30 8.93 ± 9.73 p=ns

TRENDS Stent Deployment Pressure Percent (%) <10 10-12 13-14 15-16 17-18 19-20 >20 Maximum pressure (Atm)

TRENDS Procedural Data (I) Pre-dilatation Direct stent Maximum pressure 13.0 Atm 13.7 Atm Balloon-Artery Ratio 1.14 ± 0.51 1.14 ± 0.55 Post implant dilatation 13.3% 15.9% Additional stent implant 6.4% 6.7% p=ns

TRENDS Procedural Data (II) Pre-dilatation Direct stent Additional Stent implant: Inflow dissection 13 11 Outflow dissection 8 10 Failure to cover original target lesion 7 Lesion at distant site 6 3 Thrombotic lesion 1 Unknown p=ns

TRENDS Procedural Data (III) Pre-dilatation Direct stent Screening time (mins) 8.7 8.6 Procedure time (mins) 37.5 34.3* Contrast volume (mls) 186 175# Hospital stay (days) 3.6 3.4 *p=0.01, #p=0.05 (Fisher’s Exact Test)

TRENDS Procedural Data (IV) Technical Success: Ability to access the lesion, deploy the stent or remove the delivery system in the event of failure to cross the lesion without stent loss, balloon rupture or general device failure. Pre-dilatation Direct stent Technical Success 100% p=ns

TRENDS Procedural Data (V) Pre-dilatation Direct stent Resource utilization: Guide wires Guiding catheters IVUS catheters PTCA catheters IABP catheters TETRATM stents Other stents 540 554 9 548 1 568 19 543 586* 7 115# 559 22 IIb/IIIa Inhibitor use 19.3% 18.8% *p=0.02, #p=0.001 (Fisher’s Exact Test)

TRENDS Cross-over to pre-dilatation Direct stent (n=541) Cross-over to pre-dilatation: 31 (5.7%) Stent did not cross lesion 25 Guide catheter dissection 1 Ostial location Lesion occluded Fear of dissection Stent placement not feasible Unknown

TRENDS QCA Analysis (6 months) Pre-dilatation (n=395) Direct stent (n=379) Binary Restenosis (≥50%): In-stent 11.4% [95% CI 8.4%, 14.9%] 11.6% [95% CI 8.6%, 15.3%] In-segment (stent ± 5mm) 12.2% [95% CI 9.1%, 15.8%] 13.4% [95% CI 10.1%, 17.2%] Late Loss (In-stent) (mm) 0.88 ± 0.52 [95% CI 0.83, 0.93] 0.83 ± 0.50 [95% CI 0.78, 0.88] p=ns

TRENDS MACE at 180 days* TVF (Death, MI, TLR, TVR) 11.4% 10.8% Pre-Dilatation Direct stent Difference [95% CI] TVF (Death, MI, TLR, TVR) 11.4% 10.8% 0.64% [0.25%, 1.04%] MACE (Death, MI, TLR) 9.8% 1.04% [0.66%, 1.43%] Death 1.0% 0.00% [-0.12%, 0.13%] Q-wave MI 0.4% 0.00% [-0.08%, 0.08%] Non-Q wave MI 3.0% 2.0% 1.01% [0.80%, 1.22%] * Hierarchical Ranking

TRENDS MACE at 180 days* TLR CABG 0.6% 0.2% TLR PCI 5.8% 6.2% TVR CABG Pre-Dilatation Direct stent Difference [95% CI] TLR CABG 0.6% 0.2% 0.40% [0.31%, 0.50%] TLR PCI 5.8% 6.2% -0.38% [-0.67%, -0.09%] TVR CABG 0.0% 0.00% [0.00%, 0.00%] TVR PCI 1.0% -0.04% [-0.49%, -0.30%] Stent thrombosis 0.00% [-0.05%, 0.06%] Bleeding Complication Vascular Complication 2.8% 0.4% 2.0% 0.81% [0.60%, 1.01%] 0.00% [-0.08%, 0.08%] * Hierarchical Ranking

TRENDS Survival Days Percent Surviving 99.0% 99.0% Difference [95% CI] = 0.00% [-0.12%, 0.13%] Days

TRENDS Major Adverse Cardiac Events* Freedom from MACE (%) 92.94% 91.21% Difference [95% CI] = 1.04% [0.66%, 1.43%] Days *MACE: Death, MI, TLR

TRENDS Diabetic status Non-Diabetic (n=872) Diabetic (n=128)

TRENDS Diabetic subgroup (n=128) 19% Target Vessel Failure (%) Pre-Dilatation Direct Stent TVF = Death, MI, TLR, TVR *95% CI 3.92 [2.52, 5.33]

TRENDS Diabetic subgroup (n=128) 27% MACE (%) Pre-Dilatation Direct Stent MACE = Death, MI, TLR *95% CI 5.59 [4.18, 6.99]

TRENDS Diabetic subgroup (n=128) 53% Target Lesion Revascularisation (%) TLR = CABG, Re-PCI *95% CI 9.31 [7.99, 10.64]

TRENDS Diabetic subgroup (n=128) 27% MACE (%) Pre-Dilatation Direct Stent MACE = Death, MI, TLR *95% CI 5.59 [4.18, 6.99]

J Am Coll Cardiol 2002;39:15-21

Direct Stenting in AMI (n=206) p=0.01 Composite Angiographic Endpoint* (%) Pre-Dilatation Direct Stent *Composite angiographic endpoint = distal embolization, slow flow, no reflow J Am Coll Cardiol 2002;39:15-21

Direct Stenting in AMI (n=206) p=0.01 ST-segment Resolution (%) Pre-Dilatation Direct Stent J Am Coll Cardiol 2002;39:15-21

Restenosis Rates Selected Trials (uncoated stents) Sirius 30 Taxus I 25 20 15 10 5 Taxus I Ravel Benestent I Elutes Finesse II Taxus II Binary Restenosis Rate (%)* Trends West II Benestent II Music Taxus II *QCA at six month angiographic follow-up

TRENDS Conclusions Direct stenting, without balloon pre-dilatation, is technically feasible in the majority of patients Failure to deploy the Multilink Tetra™ stent using a direct stenting strategy in a wide variety of lesions is uncommon, occurring in only 5.8% of patients in this study Resource utilization is significantly less with a direct stent approach Six month QCA results were comparable between groups with a low (11.5%) in-stent binary restenosis rate At six month follow-up, a direct stenting strategy resulted in a lower target vessel failure (TVF) rate, and a lower major adverse cardiac event (MACE) rate than in the balloon pre-dilatation group Direct stenting may have a significant impact on the late results when using a drug eluting stent

A Direct stenting strategy Possible Advantages Shorter procedure duration Less radiation Less contrast Reduced resource utilisation Less embolization Less unprotected barotrauma Potential Disadvantages Failure to cross lesion Loss of stent Incomplete stent deployment Increase in guide trauma Undersizing of stent (diameter & length) Poor visualisation Error in stent positioning

A Direct stenting strategy Possible Advantages Shorter procedure duration Less contrast Reduced resource utilisation Less embolization Less unprotected barotrauma Potential Disadvantages Failure to cross lesion 5.8%