late luminal loss: c linically meaningful surrogate or insignificant angiographic parameter?

Late Luminal Loss:Late Luminal Loss:

cclinically meaningful surrogatelinically meaningful surrogateor or

insignificant angiographic parameter?insignificant angiographic parameter?

Pierfrancesco Agostoni, MDPierfrancesco Agostoni, MD

Antwerp Cardiovascular Institute MiddelheimAntwerp Cardiovascular Institute Middelheim

Antwerp, BelgiumAntwerp, Belgium

Surrogate end pointSurrogate end point ( ())

I.I. A surrogate end point is a A surrogate end point is a biomarker intended to be a biomarker intended to be a substitutesubstitute for a clinical endpoint for a clinical endpoint

II.II. A surrogate endpoint is expected A surrogate endpoint is expected to to predictpredict clinical benefit (or clinical benefit (or harm, or lack of benefit) based on harm, or lack of benefit) based on epidemiologic, therapeutic, epidemiologic, therapeutic, pathophysiologic or other pathophysiologic or other scientific evidencescientific evidence

SegmentSegment

StentStent

proximalproximaledgeedge

distaldistaledgeedge

5 mm5 mm 5 mm5 mm

Late loss: definitionLate loss: definition

In-stent late lossIn-stent late loss==

post-PCI in-stent MLD – follow up in-stent MLDpost-PCI in-stent MLD – follow up in-stent MLD

In-segment late lossIn-segment late loss==

post-PCI in-segment MLD – follow up in segment MLDpost-PCI in-segment MLD – follow up in segment MLD

Late loss: characteristicsLate loss: characteristics

Angiographic parameter, based on QCAAngiographic parameter, based on QCA

Bi-dimensional parameter (difference between Bi-dimensional parameter (difference between 2 diameters), expressed in mm2 diameters), expressed in mm

Prone to the same intrinsic random variability Prone to the same intrinsic random variability of QCA measurements…of QCA measurements…QCA resolution is around 0.2 mm… QCA resolution is around 0.2 mm… Late loss is a difference of 2 measurements, Late loss is a difference of 2 measurements, thus random error is thus random error is even largereven larger

From malapposition…From malapposition… stent thrombosisstent thrombosis

……to restenosisto restenosis TLR/TVRTLR/TVR

Late loss (mm)

MA

CE (

%)

0

Late loss - MACE relationshipLate loss - MACE relationship

Camendzind E. NEJM 2007

restenosisrestenosis TLR/TVRTLR/TVR

Late loss (mm)

MA

CE (

%)

0

11stst thesis: thesis:late loss predicts restenosislate loss predicts restenosis

Mauri L, et al. Circulation Jan 2005Value

Fre

qu

en

cy

MeanMean MeanMean

SDSD SDSD

Late loss is Late loss is not normally not normally distributed….distributed….

Mauri L, et al. Circulation Jan 2005

MedianMedian

IQRIQR

MedianMedian

IQRIQR

Fre

qu

en

cy

Value

……but it is but it is right-skewedright-skewed

(it has a longer right “tail”)(it has a longer right “tail”)

Transform the Transform the skewed curveskewed curvein the in the Gaussian curveGaussian curve

power transformationpower transformation

Transformed mean LL value=Transformed mean LL value==(mean LL value =(mean LL value ++ 1.25) 1.25) 0.130.13

[Also the SD was “power transformed” [Also the SD was “power transformed” in a similar way]in a similar way]

Threshold=post-PCI MLD/2Threshold=post-PCI MLD/2

Also the threshold is “power Also the threshold is “power transformed” in the same way as transformed” in the same way as

mean LLmean LL

The number of lesions that pass the The number of lesions that pass the threshold (the “restenotic” lesions) in threshold (the “restenotic” lesions) in

the new transformed gaussian the new transformed gaussian distribution can be computed distribution can be computed

1.1. Late loss can Late loss can predictpredict restenosis, through a restenosis, through a

mathematical mathematical transformationtransformation

Transform the skewed curveTransform the skewed curvein the Gaussian curvein the Gaussian curve

power transformationpower transformation

Transformed mean LL value=Transformed mean LL value==(mean LL value + 1.25) =(mean LL value + 1.25) 0.130.13

[Also the SD was “power transformed” [Also the SD was “power transformed” in a similar way]in a similar way]

Threshold=post-PCI MLD/2Threshold=post-PCI MLD/2

Also the threshold is “power Also the threshold is “power transformed” in the same way as transformed” in the same way as

mean LLmean LL

The number of lesions that pass the The number of lesions that pass the threshold (the “restenotic” lesions) in threshold (the “restenotic” lesions) in

the new transformed gaussian the new transformed gaussian distribution can be computed distribution can be computed

Mauri L, et al. Circulation Jan 2005

In-stentIn-stent Obs. late lossObs. late loss Obs. BARObs. BAR Pred. BARPred. BARTaxus-IVTaxus-IV 0.39mm0.39mm 5.5%5.5% 6.1%6.1%

Mauri L, et al. Circulation Jun 2005

22 BMS & DES trials

Mauri L, et al. Circulation Jun 2005

SDSD

SDSD

MM MM

Mauri L, et al. Circulation Jun 2005

2.2. Late loss is Late loss is monotonicallymonotonically related related to binary restenosisto binary restenosis

3.3. IncrementalIncremental changes in late loss changes in late loss

result in an result in an increasedincreased restenosis riskrestenosis risk

restenosis ?restenosis ? TLR/TVR ?TLR/TVR ?

Late loss (mm)

MA

CE (

%)

0

11stst anti-thesis: anti-thesis:does late loss predict restenosis?does late loss predict restenosis?

?

late loss (mm)

3,22,41,6,8-,0-,8

A

Fre

quen

cy

50

40

30

20

10

0

late loss (mm)

3,22,41,6,8-,0-,8

B

Fre

quen

cy

50

40

30

20

10

0

SES (n=286): SES (n=286): 0.45 mm ± 0.760.45 mm ± 0.76Median (IQR) 0.29 (-0.09–0.66Median (IQR) 0.29 (-0.09–0.66)

PES (n=306): 0PES (n=306): 0.55 mm ± 0.76.55 mm ± 0.76Median (IQR)0.41 (-0.02–0.85)Median (IQR)0.41 (-0.02–0.85)

Mann-Whitney U test: p=0.03Mann-Whitney U test: p=0.03Agostoni P, et al. AJC 2007

tt test for restenotic lesions: test for restenotic lesions: p=0.48p=0.48

tt test for non restenotic lesions: test for non restenotic lesions: p=0.002 p=0.002

Non restenotic SES lesions: 0.14±0.39

Non restenotic PES lesions:0.27±0.44

Restenotic SES lesions:1.75±0.51

Restenotic PES lesions:1.82±0.62

Agostoni P, et al. AJC 2007

Cosgrave J, et al. JACC 2007

1.1. In DES, late loss can have a In DES, late loss can have a ”bimodal” distribution”bimodal” distribution (already (already shown with shown with POBAPOBA and and BMSBMS): lesions with an higher tendency to ): lesions with an higher tendency to

restenose vs. lesions with a lower tendency to restenoserestenose vs. lesions with a lower tendency to restenose

2. 2. In 4 out of the In 4 out of the 10 predictions 10 predictions

performed (performed (40%40%) ) the observed the observed

restenosis rate restenosis rate was out of the 95% was out of the 95% CI of the predicted CI of the predicted value (value (p<0.05p<0.05 at 1- at 1-tail Fisher’s exact tail Fisher’s exact

test)test)

Agostoni P, et al. AJC 2006

In- stent mean late loss (mm)

,8,6,4,20,0

In-s

tent

bin

ary

rest

enosi

s (%

)

30

25

20

15

10

5

0

50 arms of DES (SES, PES, ZES, EES) trials50 arms of DES (SES, PES, ZES, EES) trials

Is late loss monotonically related to restenosis?Is late loss monotonically related to restenosis?

In- segment late loss (mm)

,8,6,4,20,0

In-s

egm

ent

bin

ary

rest

enosi

s (%

)

30

25

20

15

10

5

0

RR2=2=0.580.58

In-stent mean late loss (mm)

1,31,1,9,7,5,3,1-,1

In-s

tent

bin

ary

rest

enos

is (

%)

70

60

50

40

30

20

10

0

R2=0.58

Mean late loss (mm)

1,4,9,4-,1

Sta

nd

ard

De

via

tion

(m

m)

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

R2=0.20

50 arms of DES (SES, PES, ZES, EES) trials50 arms of DES (SES, PES, ZES, EES) trials

Agostoni P. Circulation 2005

3.3. The The late losslate loss – – binary restenosisbinary restenosis – – TLRTLR relationship relationship when considering when considering onlyonly effective DES is still effective DES is still unclearunclear

Schomig A, et al. JACC 2007

Could Could systematic angiographic follow upsystematic angiographic follow up play a role in play a role in this overall “clinical” advantage of SES over PES? this overall “clinical” advantage of SES over PES? The The ISARISAR trials the trials the LONG-DES IILONG-DES II and the and the SIRTAXSIRTAX, all had , all had angio follow up and a 70-80% rate of “conversion” of angio follow up and a 70-80% rate of “conversion” of binary angiographic restenosis in TLR, while in other binary angiographic restenosis in TLR, while in other trials it was only 40-50%trials it was only 40-50%

In In RCTsRCTs of of SESSES vs. vs. PESPES, , late loss was late loss was alwaysalways lower lower after SES than PES, but after SES than PES, but binary restenosis binary restenosis notnot……

Late loss Late loss DES ADES A

Late loss Late loss DES BDES B

Binary restenosis Binary restenosis DES ADES A

Binary restenosis Binary restenosis DES BDES B

Revascularization Revascularization DES ADES A

Revascularization Revascularization DES BDES B

significantsignificant

differencedifference

minorminor(“trivial”)(“trivial”)

differencedifference

No more difference?No more difference?

Substantially all Substantially all registriesregistries ( (MilanMilan, , T-SEARCH/RESEARCHT-SEARCH/RESEARCH, , ORCHIDORCHID,, REWARDSREWARDS, , DEScoverDEScover, , STENTSTENT, , New York State New York State registryregistry) in more than ) in more than 3200032000 patients (respect to “only” patients (respect to “only” 85008500 of the meta-analysis) showed similar repeat of the meta-analysis) showed similar repeat revascularization rates between SES and PES…revascularization rates between SES and PES…

In the DES eraIn the DES era

the the angiographicangiographic “performance”“performance”

can be different fromcan be different from

the the clinicalclinical “perfomance” “perfomance”

From malapposition…From malapposition… stent thrombosisstent thrombosis

……to restenosisto restenosis TLR/TVRTLR/TVR

Late loss (mm)

MA

CE (

%)

0

Late loss - MACE relationshipLate loss - MACE relationship

Camendzind E. NEJM 2007

malappositionmalapposition Stent thrombosisStent thrombosis

Late loss (mm)

MA

CE (

%)

0

22ndnd thesis: thesis:late loss predicts thrombosislate loss predicts thrombosis

Animal Animal andand human pathology human pathology, , angioscopyangioscopy, , IVUSIVUS have have shown that shown that delayeddelayed endothelializationendothelialization, , incomplete strut incomplete strut coveragecoverage and and latelate incompleteincomplete stent appositionstent apposition are more are more common after DES than after BMScommon after DES than after BMS

These phenomena have been linked to These phenomena have been linked to late thrombosislate thrombosis……

Someone thought that late loss could Someone thought that late loss could “angiographically”“angiographically” represent these phenomena…represent these phenomena…

Exposed strutsExposed strutsExposed strutsExposed strutsLack of endotheliumLack of endotheliumLack of endotheliumLack of endothelium MalappositionMalappositionMalappositionMalapposition

malapposition ?malapposition ? Stent thrombosis ?Stent thrombosis ?

Late loss (mm)

MA

CE (

%)

0

22ndnd anti-thesis: anti-thesis:does late loss predict thrombosis?does late loss predict thrombosis?

?

RR22 = 0.0411 = 0.0411

p = 0.229p = 0.229

-6

-4

-2

0

2

4

-1 -0,8 -0,6 -0,4 -0,2 0 0,2 0,4 0,6

Late Loss Difference (mm)Late Loss Difference (mm)

Ste

nt

Th

rom

bosis

Diff

ere

nce (

%)

Ste

nt

Th

rom

bosis

Diff

ere

nce (

%)

Mauri L, et al. AHA 2005

30 Trials, 68 Arms30 Trials, 68 Arms

Schomig A, et al. JACC 2007

Despite Despite SESSES has has alwaysalways and and constantlyconstantly lower late loss value than lower late loss value than PESPES……

Late loss (mm)

MA

CE (

%)

00

ConclusionConclusion

~0.5~0.5

?

ConclusionConclusion

The The reliabilityreliability of late loss as effective surrogate of late loss as effective surrogate

end point for MACE prediction is (at least) end point for MACE prediction is (at least) doubtfuldoubtful

I.I. Late loss is a Late loss is a moderatemoderate predictor of the restenotic predictor of the restenotic process and its process and its “behavior”“behavior” can be different can be different according to different DES (in which late loss according to different DES (in which late loss differences are small, in the order of differences are small, in the order of 0.20.2--0.4 mm0.4 mm). ). The possibility of a The possibility of a stepwisestepwise relation between late relation between late loss and revascularization has not been ruled out.loss and revascularization has not been ruled out.

II.II. Even more, the use of late loss as a marker for stent Even more, the use of late loss as a marker for stent re-endothelialization process is re-endothelialization process is totallytotally misleadingmisleading. . QCA has a resolution of QCA has a resolution of ~0.2 mm~0.2 mm (= (=~200 micron~200 micron) ) and gives and gives 2-D2-D data while the thickness of an data while the thickness of an endothelial cell is endothelial cell is <10 micron<10 micron and endothelialization and endothelialization is a complex is a complex 3-D3-D process. process.

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