late luminal loss: c linically meaningful surrogate or insignificant angiographic parameter?
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Late Luminal Loss: c linically meaningful surrogate or insignificant angiographic parameter?. Pierfrancesco Agostoni, MD Antwerp Cardiovascular Institute Middelheim Antwerp, Belgium. Surrogate end point ( eurhma ). - PowerPoint PPT PresentationTRANSCRIPT
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.
For further slides on these topics For further slides on these topics please feel free to visit the please feel free to visit the
metcardio.org website:metcardio.org website:
http://www.metcardio.org/slides.html