TAXUS Perseus Core Data Elements Qualitative and Quantitative

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TAXUS Perseus Core Data Elements: Qualitative and Quantitative Angiography Jeffrey J. Popma, MD Alexandra

TAXUS Perseus Core Data Elements: Qualitative and Quantitative Angiography Jeffrey J. Popma, MD Alexandra Almonacid, MD Brigham and Women’s Hospital St. Elizabeth Medical Center Tufts University School of Medicine Boston, MA Angiographic Core Laboratory

Core Lab Lessons: Beyond Late Lumen Loss • After 15 years, substantial observer variabilities

Core Lab Lessons: Beyond Late Lumen Loss • After 15 years, substantial observer variabilities are still found with qualitative angiographic interpretations independent Core Laboratory analyses have become standard for FDA DES studies • Discrepancies noted with Clinical Site Observations: – – – Baseline % diameter stenosis (e. g. , NASCET Carotid) Lesion Length and Reference Vessel Diameter Final Angiographic Result Binary restenosis (? 50 -70% threshold for revascularization) “Oculostenotic reflex”

Core Lab Lessons: Beyond Late Lumen Loss • Our initial focus with QCA was

Core Lab Lessons: Beyond Late Lumen Loss • Our initial focus with QCA was to determine the late term lumen dimensions, and relate them to the early angiographic results and late clinical events – – Balloon angioplasty – less acute gain; less late loss DCA – more acute gain; more lumen loss; better net gain Continuous measures replaced binary criteria Loss index (LL/AG) provided relative benefit --> drugs failed • With stents, LL was attributable to intimal hyperplasia. – Acute gains and late loss was similar (essentially) for all bare metal stents – ? Possible exception related to strut thickness – Late loss replaced loss index as a surrogate

Beyond Late Lumen Loss • Clinical indices were further refined to determine those events

Beyond Late Lumen Loss • Clinical indices were further refined to determine those events that directly related to failure of the stent – TLR replaced “any” revascularization and TVF (in some studies) – Early (< 30 d) stent thrombosis was not included in the criteria for “restenosis” or calculations for late lumen loss but was placed in the early clinical failure category alone – To lower sample sizes, “surrogate” markers were sought to identify was to lower sample sizes required for device approval • In-Lesion (Segment) late lumen loss became the preferred endpoint for many device trials

QCA methodology 5 mm proximal edge stented segment in-stent (all stents used to treat

QCA methodology 5 mm proximal edge stented segment in-stent (all stents used to treat the target lesion) 5 mm distal edge

BMS Restenosis was Near Gaussian allowing expression with mean±SD Example: 3. 0 mm Bare

BMS Restenosis was Near Gaussian allowing expression with mean±SD Example: 3. 0 mm Bare Metal Stent Mean late loss = 1. 0 ± 0. 5 mm Angio Restenosis is any late loss over 1. 5 mm (50% DS) Distribution Density Clinical TLR correlates with late loss over 2. 1 (70% DS) 1. 0 Mean late loss Pts. w/o restenosis 0. 8 Pts. with angio restenosis 0. 6 0. 4 Pts. with clinical restenosis 0. 2 0. 0 -0. 50 -0. 25 0. 00 0. 25 0. 50 0. 75 1. 00 1. 25 1. 50 1. 75 2. 00 2. 25 2. 50 Late loss (mm) Donald Baim, Summer in Seattle, 2006.

DES Have Different Late Loss Distributions Mean late loss = 0. 2 mm 0.

DES Have Different Late Loss Distributions Mean late loss = 0. 2 mm 0. 4 mm 0. 6 mm 1. 0 mm (BMS) Clinical restenosis What % of patients are above that line? Mauri et al. Circulation. 2005; 111: 3435

Angiographic predictors of TLR TAXUS-IV Follow-up % Diameter Stenosis is a Better Predictor ROC

Angiographic predictors of TLR TAXUS-IV Follow-up % Diameter Stenosis is a Better Predictor ROC Analysis combining all patients 1. 0 Late Loss Sensitivity AUC = 0. 918 MLD AUC = 0. 940 0. 5 Diameter Stenosis AUC = 0. 944 0. 0 0. 5 1 - Specificity 1. 0

Surrogate Angiographic Endpoints LL and % DS vs. TLR - A curvilinear relationship All

Surrogate Angiographic Endpoints LL and % DS vs. TLR - A curvilinear relationship All patients RVD <2. 5 mm RVD 2. 5 -3. 0 mm RVD > 3. 0 mm In-stent late loss Probability of TLR 11 RCTs with Cypher, Taxus, Endeavor, and BMS (5381 pts) All patients In-segment %DS Pocock S et al ACC 2006

Sidebranch Compromise With Overlapping Stents TAXUS V Multiple Stent Analysis Blinded core lab analysis

Sidebranch Compromise With Overlapping Stents TAXUS V Multiple Stent Analysis Blinded core lab analysis of all multiple stent patients • Main Vessel Analysis: – Main vessel No Reflow, TIMI flow, Dissection, Distal Embolization, Abrupt Closure • Side Branch Analysis (for branches >1 mm): – Branch occlusion (total occlusion) – Branch narrowing (Δ≥ 70% 100%) – Branch TIMI flow

TAXUS V: SB Analysis With Multiple Stents Control n=184 pts TAXUS n=188 pts Total

TAXUS V: SB Analysis With Multiple Stents Control n=184 pts TAXUS n=188 pts Total Sidebranches (n) 268 289 % pts with Sidebranch 87. 5 89. 1 0. 74 # Branches (per pt. ) 1. 60± 1. 01 1. 66± 0. 99 0. 55 Sidebranch RVD (mm) 1. 40± 0. 36 1. 42± 0. 37 0. 45 P value

Side Branch Analysis in Multiple Stenting Sidebranch Occlusion Side Branch Narrowing (Δ ≥ 70%

Side Branch Analysis in Multiple Stenting Sidebranch Occlusion Side Branch Narrowing (Δ ≥ 70% 100%) TIMI Flow Reduction

Impact of the Overlap Region (per side branch) Control Any Sidebranch Occlusion p=0. 74

Impact of the Overlap Region (per side branch) Control Any Sidebranch Occlusion p=0. 74 37/203 34/207 Non-overlap region p=0. 23 8/48 15/55 Overlap region TAXUS Any Sidebranch Narrowing p=1. 00 56/203 58/207 Non-overlap region p=1. 00 21/48 24/55 Overlap region Any TIMI Flow Reduction p=0. 10 51/203 68/207 Non-overlap region p=0. 025 12/48 26/55 Overlap region

Definitions Used for Stent Fracture Classification Current Report Type 0 No strut fracture Type

Definitions Used for Stent Fracture Classification Current Report Type 0 No strut fracture Type I Single strut fracture or gap between struts greater than 2 x normal Single strut fracture only Minor – single strut facture Type II Multiple strut fractures with V-form division of the stent Multiple single stent fractures occurring at different sites Moderate – facture >1 strut Type III Complete transverse stent fracture without displacement of fractured fragments more than 1 mm during the cardiac cycle Multiple single stent fractures resulting in complete transverse linear fracture but without stent displacement Severe – complete separation of stent segments Type IV Complete transverse stent fracture with abundant movement and displacement of fractured fragments of more than 1 mm during the cardiac cycle Complete transverse linear type III fracture with stent displacement 1 2 Allie et al 1 Scheinert et al 2 - Allie et al Endovascular Today 2004; July/August: 22 -34 Scheinert et al J Am Coll Cardiol 2005; 45: 312 -315 - - * Type 5 implies spiral fracture of stent

Stent Fractures Type 4 Stent Fractures Stent Fracture with 3 mm of Stent Overlap

Stent Fractures Type 4 Stent Fractures Stent Fracture with 3 mm of Stent Overlap

Incidence of TAXUS-Express Stent Fracture Detailed angiographic review of TAXUS IV and VI Core

Incidence of TAXUS-Express Stent Fracture Detailed angiographic review of TAXUS IV and VI Core Lab remains blinded due to ongoing adjudication Taxus IV: 7 Fractures TAXUS VI: 3 Factures - Type 1 N=3 Type 1 N=1 - Type 2 N=1 - Type 3 N=1 - Type 4 N=2 - Of the 10 fractures, 5 cases had overlapping stents (all overlaps were longer thatn 3 mm). In 4 of 5 cases, the stent fracture was within 5 mm of the overlap * Preliminary Analysis

Incidence of TAXUS Stent Fracture In patients assigned to angiographic FU 0. 85% 0.

Incidence of TAXUS Stent Fracture In patients assigned to angiographic FU 0. 85% 0. 81% 0. 71% N=819 N=420 N=1239 Taxus IV Taxus VI Overall

TAXUS-Express Type I Fractures Taxus IV 145 -247 24. 9 mm Stented Segment Overlap

TAXUS-Express Type I Fractures Taxus IV 145 -247 24. 9 mm Stented Segment Overlap >3 mm

Fundamental “Pitfalls” for the Seasoned Professional Interventionalist - Forget the angiographic inclusion and exclusion

Fundamental “Pitfalls” for the Seasoned Professional Interventionalist - Forget the angiographic inclusion and exclusion criteria, the patient really needs the Taxus Perseus stent “I don’t really see a stenosis, but it must be tight behind that diagonal branch” or “Who needs two views, it looks pretty tight in this one” I’m sure the Core Lab can measure that tip of the injection catheter Who needs documentation, I’ll remember all the views I took when the patient comes back for at follow-up I can’t believe that this lesion isn’t causing symptoms, I going to fix it anyway

Pitfalls in QCA • Make certain that all patients meet the angiographic inclusion and

Pitfalls in QCA • Make certain that all patients meet the angiographic inclusion and exclusion criteria with respect to lesion length, vessel size, and lesion complexity • A “Friendly Feedback” sheet will give you a 20 point score for the film quality • Dr. Almonacid and I will provide “personal” feedback if we disagree with the patient being enrolled in the study. Remember, we’re colleagues and friends, but. .

Pitfalls in QCA • An accurate calibration source (the injection catheter filled with contrast)

Pitfalls in QCA • An accurate calibration source (the injection catheter filled with contrast) is the only way that we can identify the absolute changes in the MLD, edges, and within the stent between the final and the follow-up - We need to see the very distal, nontapered portion of the catheter and document the size of the catheters on the Technician’s - Nitroglycerin with the final stent placement and at FU is essential to control vasomotor tone for the calculations of late lumen loss

Pitfalls in QCA - “Who needs the documentation, I will remember the views I

Pitfalls in QCA - “Who needs the documentation, I will remember the views I took when the patient comes back for follow-up” Please Use the Worksheet

Pitfalls in QCA - At the time of follow-up angiography, you see and intermediate

Pitfalls in QCA - At the time of follow-up angiography, you see and intermediate stenosis (50 -60%) and say “I can’t believe that this lesion isn’t causing symptoms, I going to fix it anyway”

Summary • Core QCA data elements should include conventional morphologic and quantitative angiographic parameters

Summary • Core QCA data elements should include conventional morphologic and quantitative angiographic parameters in order to classify “tested” and “untested” therapies - Newer analysis methods are needed for bifurcations • Late lumen loss is a reason index (% diameter stenosis may be better) for the late angiographic outcome but its ability to predict TLR (and MACE) may be limited in DES v. DES studies • Core QCA elements should add sidebranch patency (for overlapping stents), stent fracture, aneurysms, and stent thrombosis to assess long-term safety

Slides posted on http: //www. clinicaltrialresults. org

Slides posted on http: //www. clinicaltrialresults. org

Simple QCA Requests • Technologist Worksheet or detailed catheterization report with sequential angiographic views

Simple QCA Requests • Technologist Worksheet or detailed catheterization report with sequential angiographic views • Dicom 3 Compatible CDs or 35 mm film • Please don’t forget the nitroglycerin • Follow Image Acquisition Guidelines • Match 2 Pre, Final, and Follow-up • Document everything on cine, particularly in the radiation studies • Near 100% angiographic follow-up is essential