Jeffrey J. Popma, MDAlexandra Almonacid, MD

Brigham and Women’s HospitalSt. Elizabeth Medical Center

Tufts University School of MedicineBoston, MA

TAXUS PerseusCore Data Elements:

Qualitative and Quantitative Angiography

AngiographicCore Laboratory

• 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 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

Core Lab Lessons: 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

Beyond Late Lumen Loss

• In-Lesion (Segment) late lumen loss became the preferred endpoint for many device trials

QCA methodology

stented segment5 mm 5 mmproximal

edgedistaledge

in-stent(all stents used to treat the target lesion)

in-segment

BMS Restenosis was Near Gaussianallowing expression with mean±SD

Pts. w/o restenosis

Example: 3.0 mm Bare Metal StentMean late loss = 1.0 ± 0.5 mm

2.50

Late loss (mm)

Dis

trib

uti

on

Den

sity

-0.50 -0.25 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.250.0

0.2

0.4

0.6

0.8

1.0

Pts. with angio restenosis

Angio Restenosis is any late loss over 1.5 mm (50% DS)

Pts. with clinical restenosis

Clinical TLR correlates with late loss over 2.1 (70% DS)

Donald Baim, Summer in Seattle, 2006.

Mean late loss

0

5

10

15

20

25

30

35

-0.4 0.0 0.4 0.8 1.2 1.6 2.0 2.4 2.8

In-stent Late Loss(mm)

Den

sit

y (

%)

Mean late loss = 0.2 mm

0.4 mm0.6 mm

1.0 mm (BMS)

Clinical restenosis

What % of patients are above that line?

Mauri et al. Circulation. 2005;111:3435

DES Have Different Late Loss Distributions

Angiographic predictors of TLR

1 - Specificity1 - Specificity

1.01.0

0.50.5

0.00.00.00.0 0.50.5 1.01.0

Diameter StenosisAUC = 0.944

Late LossAUC = 0.918

MLDAUC = 0.940

Sen

sitiv

ityS

ensi

tivity

ROC Analysis combining all patientsROC Analysis combining all patients

TAXUS-IV

Follow-up % Diameter Stenosis is a Better Predictor

0.0

0.2

0.4

0.6

0.8

1.0

-1 0 1 2 3

Surrogate Angiographic EndpointsP

rob

abili

ty o

f T

LR

In-stent late loss

Pro

bab

ility

of

TL

R

Pocock S et al ACC 2006Pocock S et al ACC 2006

All patientsRVD <2.5mmRVD 2.5-3.0mmRVD > 3.0mm

In-segment %DS

0.0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40 50 60 70 80 90 100

All patients

LL and % DS vs. TLR - A curvilinear relationshipLL and % DS vs. TLR - A curvilinear relationship

11 RCTs with Cypher, Taxus, Endeavor, and BMS (5381 pts)

Sidebranch Compromise With Overlapping StentsTAXUS 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

TAXUSn=188 pts P value

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

Side Branch Analysis in Multiple Stenting

Sidebranch OcclusionSidebranch Occlusion

TIMI Flow ReductionTIMI Flow Reduction

Side Branch Narrowing Side Branch Narrowing ((ΔΔ ≥ ≥ 70% 70% 100%) 100%)

Impact of the Overlap Region(per side branch)

18.2 16.716.4

27.3

Control TAXUS

Any SidebranchAny Sidebranch

OcclusionOcclusion

37/20337/203 34/20734/207 8/488/48 15/5515/55 51/20351/203 68/20768/207 12/4812/48 26/5526/5556/20356/203 58/20758/207 21/4821/48 24/5524/55

27.6

43.8

28.0

43.6

25.1 25.0

32.9

47.3

Any SidebranchAny Sidebranch

NarrowingNarrowing

Any TIMI FlowAny TIMI Flow

ReductionReduction

Non-overlapNon-overlap

regionregion

OverlapOverlap

regionregion

Non-overlapNon-overlap

regionregion

OverlapOverlap

regionregion

Non-overlapNon-overlap

regionregion

OverlapOverlap

regionregion

p=0.74 p=0.23 p=0.10 p=0.025p=1.00 p=1.00

Definitions Used for Stent Fracture Classification Current Report Allie et al 1 Scheinert et al 2

Type 0 No strut fracture - -

Type I Single strut fracture or gap between struts greater than 2x 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 Allie et al Endovascular Today 2004; July/August: 22-34 2 Scheinert et al J Am Coll Cardiol 2005; 45:312-315

* Type 5 implies spiral fracture of stent

Stent Fractures

Stent Fracture with 3 mm of Stent Overlap

Type 4Stent Fractures

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 2 N=1

- Type 3 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

Incidence of TAXUS-Express Stent FractureIncidence of TAXUS-Express Stent Fracture

* Preliminary Analysis* Preliminary Analysis

Incidence of TAXUS Stent FractureIncidence of TAXUS Stent Fracture

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0.85%0.85%

0.71%0.71%0.81%0.81%

Taxus IVTaxus IV Taxus VITaxus VI OverallOverall

In patients assigned to angiographic FUIn patients assigned to angiographic FU

N=819N=819 N=420N=420 N=1239N=1239

TAXUS-Express Type I Fractures

Taxus IV145-24724.9mm Stented SegmentOverlap >3mm

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

• 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) 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 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 stenosis (50-60%) and say

“I can’t believe that this lesion isn’t causing symptoms, I going to fix it anyway”

Pitfalls in QCA

• 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

Summary

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

SimpleQCARequests

SimpleQCARequests

• Technologist Worksheet or detailed catheterization report with sequential angiographic views

• Dicom3 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