Late loss in the choice of DES: Late loss in the choice of DES: Monty Python or the Holy Grail?Monty Python or the Holy Grail?

Azfar ZamanAzfar Zaman

Freeman Hospital,Freeman Hospital,

Newcastle-upon-TyneNewcastle-upon-Tyne

MY CONFLICTS OF INTEREST ARE:I have been paid for attending Advisory Board meetings:

•Cordis•Boston Scientific•Medtronic

DefinitionDefinition

late losslate loss

The difference between the minimum The difference between the minimum lumen diameter (MLD) immediately lumen diameter (MLD) immediately after stent deployment and the MLD after stent deployment and the MLD at follow-up (within stent)at follow-up (within stent)

Late loss : why use it?Late loss : why use it?

Late loss is a Late loss is a surrogatesurrogate for clinical for clinical eventsevents

How good a surrogate is it for How good a surrogate is it for evaluating clinical outcomes following evaluating clinical outcomes following DES implantation?DES implantation?

Why do we need a surrogate when it Why do we need a surrogate when it is easier to record clinical events?is easier to record clinical events?

Clinical Endpoint Clinical Endpoint

A characteristic or variable that reflects how a patient A characteristic or variable that reflects how a patient

feels, functionsfeels, functions or survivesor survives

Surrogate Endpoint Surrogate Endpoint A biomarker intended to A biomarker intended to substitutesubstitute for a clinical for a clinical

endpoint. endpoint. A surrogate endpoint is expected to predict clinical A surrogate endpoint is expected to predict clinical

benefit (or harm, or lack of benefit) based on benefit (or harm, or lack of benefit) based on epidemiologic, therapeutic, pathophysiologic or other epidemiologic, therapeutic, pathophysiologic or other scientific evidencescientific evidence

A Framework for Biomarker and Surrogate Endpoint Use in Drug Development:A Framework for Biomarker and Surrogate Endpoint Use in Drug Development:Janet Woodcock M.D. Acting Deputy Commissioner for Operations; November 4, 2004Janet Woodcock M.D. Acting Deputy Commissioner for Operations; November 4, 2004

1. Measurement of late loss1. Measurement of late loss

Quantitative coronary angiography Quantitative coronary angiography

Measurement of late lossMeasurement of late loss

Pre-procedure Post-procedure

Measurement of late loss Measurement of late loss

8 Months 0.2 mm

Pre-procedure Post-procedure

Measurement of late lossMeasurement of late loss

8 Months 0.4 mm

Measurement of late lossMeasurement of late loss

Measurement of late lossMeasurement of late loss

a handful of “core” labs worldwidea handful of “core” labs worldwide

different core labs for different studiesdifferent core labs for different studies

accuracy and robustness of QCA data accuracy and robustness of QCA data between labs?between labs?

clinical endpoints more reliable and clinical endpoints more reliable and relevantrelevant

Measurement of late lossMeasurement of late loss

REALITY – head to head trial with REALITY – head to head trial with

all measurements in one core laball measurements in one core lab

2. Can late loss alone predict 2. Can late loss alone predict clinical outcomes?clinical outcomes?

multifactorialmultifactorial

dependent on more than just type of dependent on more than just type of stentstent

Mauri et al Circulation 2005;112:2833

Mauri et al Circulation 2005;2833

Actual TLR by LL and RVD

Analysis Segment Late Loss

Pro

po

rtio

n w

ith

TL

R

Late Loss in small vesselsLate Loss in small vessels

0

0.1

0.2

0.3

0.4

0

0.1

0.2

0.3

0.4

Late L

oss (m

m)

(An

alysis Seg

men

t)

0.31

0.21

0.19

2.5 mm 3.0 mm 3.5 mm

Vessel Diameter

0.17

0.22

0.28

2.5 mm 3.0 mm 3.5 mm

DES 1 DES 2

Whither late loss in LMS?Whither late loss in LMS?

Series of 43 patients Series of 43 patients Mixed LMS lesionsMixed LMS lesions Rapamycin eluting stent Rapamycin eluting stent Overall TVR 23%Overall TVR 23% But 71% in patients with diabetesBut 71% in patients with diabetes

Cheiffo A, et al. Early and mid-term results of Cypher stentsin unprotected left main. J Am Coll Cardiol. 2004;43: 21A-1116-8(abstract)

3. Late loss – the mean3. Late loss – the mean

A two tail tale A two tail tale

0

10

20

30

-1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0

ENDEAVOR I-IIITAXUS IVSIRIUS

% o

f P

ati

en

ts

In-Stent Late Loss (mm)

Comparison of In-stent LLComparison of In-stent LL Relationship at the tailsRelationship at the tails

Left Tail Right Tail

0%

5%

10%

15%

20%

25%

-0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8

In-Stent Late Loss (mm)

% o

f P

ati

en

ts

0%

20%

40%

60%

80%

100%

TL

R P

rob

ab

ilit

y (

%)

The Right tail : relation of LL to Target The Right tail : relation of LL to Target Lesion RevascularisationLesion Revascularisation

*Pts undergoing angiographic follow-up

The Left tail : is there a sting?The Left tail : is there a sting?

MACE after DES insertion not linearMACE after DES insertion not linear

a negative LL may be consequence of late a negative LL may be consequence of late incomplete apposition of DESincomplete apposition of DES

need late loss of 0.15 to cover stent strutsneed late loss of 0.15 to cover stent struts

what does a negative LL mean ? what does a negative LL mean ?

The relationship of LL vs MACE is The relationship of LL vs MACE is not linearnot linear

In stent late loss, mmIn stent late loss, mm

MA

CE,

%M

AC

E,

%

From From malapposition?malapposition?

?

To restenosis! restenosis!

* Quevedo P, et al. Sirolimus-eluting stent to prevent restenosis in diabetic patients with de novo coronary stenoses: the diabetes trial. Nine-month intravascular ultrasound results. Abstract at ESC 205.

DIABETES trial: Late acquired stent malapposition was observed in 15 patients (19.5%) in the SES group*

The relationship between LL and TLR The relationship between LL and TLR

is non linearis non linear

DELIVERDELIVER 0.810.81 8.18.1

ENDEAVOR II: ENDEAVOR II: 0.61 0.61 4.6 4.6 TAXUS IV: TAXUS IV: 0.39 0.39 3.0 3.0 SIRIUS: SIRIUS: 0.17 0.17 4.1 4.1

In stent late loss TLRTLR

Stepwise or Stepwise or curvilinear curvilinear relationship relationship at best at best between LL between LL and TLRand TLR

Moses J, Leon M, Popma M, Fitzgerald P, et al. Sirolimus-Eluting Stents versus Standard Stents in Patients with Stenosis in a Native Coronary Artery. Engl J Med 2003;349:1315-23.Stone G, Ellis S, Cox D, et al. A Polymer-Based, Paclitaxel-Eluting Stent in Patients with Coronary Artery Disease. N Engl J Med 2004;350:221-31.

ESC 2005Lansky A, Costa R, Mintz G, et al. Non–Polymer-Based Paclitaxel-Coated Coronary Stents for the Treatment of Patients With De Novo Coronary Lesions Angiographic Follow-Up of the DELIVER Clinical Trial Circulation. 2004;109:1948-1954.)

In diabetic subsets : relationship also In diabetic subsets : relationship also non-linearnon-linear

ENDEAVOR II (n=107):ENDEAVOR II (n=107): 0.680.68 7.67.6 TAXUS IV (n=155):TAXUS IV (n=155): 0.370.37 7.4*7.4* SIRIUS (n=131): SIRIUS (n=131): 0.290.29 6.96.9

In stent In stent late losslate loss TLRTLR

Diabetic subsetAll QCA measurements done at Brigham & Women’s

* 12 month result* 12 month result

ACC 2005Hermiller J, Raizner A, Cannon L, et al. Outcomes With the Polymer-Based Paclitaxel-Eluting TAXUS Stent in Patients With Diabetes Mellitus The TAXUS-IV Trial. J Am Coll Cardiol 2005;45:1172–9Moussa I, Leon M, Baim D, et al. Impact of Sirolimus-Eluting Stents on Outcome in Diabetic Patients A SIRIUS Substudy Circulation. 2004;109:2273-2278.

MACE shows even less relation to LLL

DES Arms

4.63 4.1

6.1 4.77.38.0 7.6 8.6

7.3 8.57.1

ENDEAVOR II TAXUS IV SIRIUS

TLRTVRTVFMACE

In-stent LLIn-segment LLIn-stent ABRIn-segment ABR

0.610.369.5%13.3%

0.390.235.5%7.9%

0.170.243.2%8.9%

ACC 2005 Moses J, Leon M, Popma M, Fitzgerald P, et al. Sirolimus-Eluting Stents versus Standard Stents in Patients with Stenosis in a Native Coronary Artery. Engl J Med 2003;349:1315-23.Stone G, Ellis S, Cox D, et al. A Polymer-Based, Paclitaxel-Eluting Stent in Patients with Coronary Artery Disease. N Engl J Med 2004;350:221-31.

•For modern DES, does the LL mean have any meaning?

•Or is the marketing “tail” wagging the clinical dog?

Questions to ponder?

Mauri et al Circulation 2005:112;2833

Late Lumen Loss : ConclusionLate Lumen Loss : Conclusion

is a surrogate marker (is a surrogate marker (not validatednot validated)) is measured using QCAis measured using QCA independentlyindependently cannot predict cannot predict

restenosis restenosis cannot accurately discriminate cannot accurately discriminate

between available DES across all between available DES across all patient sub groups patient sub groups

Late Loss : Monty Python or Holy Late Loss : Monty Python or Holy Grail ?Grail ?

Thank youThank you