Late Luminal Loss: c linically meaningful surrogate or insignificant angiographic parameter?

1. Late Luminal Loss:clinically meaningful surrogateor insignificant angiographic parameter? Pierfrancesco Agostoni, MD Antwerp Cardiovascular Institute Middelheim Antwerp, Belgium

2. Surrogate end point (eurhma) • A surrogate end point is a biomarker intended to be a substitute for a clinical endpoint • A surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence

3. Late loss: definition Segment 5 mm 5 mm Stent proximaledge distaledge In-stent late loss=post-PCI in-stent MLD – follow up in-stent MLD In-segment late loss=post-PCI in-segment MLD – follow up in segment MLD

4. Late loss: characteristics Angiographic parameter, based on QCA Bi-dimensional parameter (difference between 2 diameters), expressed in mm Prone to the same intrinsic random variability of QCA measurements…QCA resolution is around 0.2 mm… Late loss is a difference of 2 measurements, thus random error is even larger

6. Late loss - MACE relationship MACE (%) 0 Late loss (mm) …to restenosis TLR/TVR From malapposition… stent thrombosis Camendzind E. NEJM 2007

7. 1st thesis:late loss predicts restenosis MACE (%) 0 Late loss (mm) restenosis TLR/TVR

8. SD SD Frequency Mean Mean Value Late loss is not normally distributed…. Mauri L, et al. Circulation Jan 2005

9. IQR IQR Frequency Median Median Value …but it is right-skewed (it has a longer right “tail”) Mauri L, et al. Circulation Jan 2005

10. Transform the skewed curvein the Gaussian curve power transformation Transformed mean LL value==(mean LL value + 1.25) 0.13 [Also the SD was “power transformed” in a similar way] Threshold=post-PCI MLD/2 Also the threshold is “power transformed” in the same way as mean LL The number of lesions that pass the threshold (the “restenotic” lesions) in the new transformed gaussian distribution can be computed Transform the skewed curvein the Gaussian curve power transformation Transformed mean LL value==(mean LL value + 1.25) 0.13 [Also the SD was “power transformed” in a similar way] Threshold=post-PCI MLD/2 Also the threshold is “power transformed” in the same way as mean LL The number of lesions that pass the threshold (the “restenotic” lesions) in the new transformed gaussian distribution can be computed 1. Late loss can predict restenosis, through a mathematical transformation

11. In-stentObs. late loss Obs. BAR Pred. BAR Taxus-IV 0.39mm 5.5% 6.1% Mauri L, et al. Circulation Jan 2005

12. 22 BMS & DES trials Mauri L, et al. Circulation Jun 2005

13. SD SD M M Mauri L, et al. Circulation Jun 2005

14. 2. Late loss is monotonically related to binary restenosis 3.Incremental changes in late loss result in an increased restenosis risk Mauri L, et al. Circulation Jun 2005

15. 1st anti-thesis:does late loss predict restenosis? ? MACE (%) 0 Late loss (mm) restenosis ? TLR/TVR ?

16. SES (n=286): 0.45 mm ± 0.76 Median (IQR) 0.29 (-0.09–0.66) PES (n=306): 0.55 mm ± 0.76 Median (IQR)0.41 (-0.02–0.85) Mann-Whitney U test: p=0.03 Agostoni P, et al. AJC 2007

17. Non restenotic SES lesions: 0.14±0.39 Restenotic SES lesions: 1.75±0.51 Non restenotic PES lesions: 0.27±0.44 Restenotic PES lesions: 1.82±0.62 t test for non restenotic lesions: p=0.002 t test for restenotic lesions: p=0.48 Agostoni P, et al. AJC 2007

18. 1. In DES, late loss can have a ”bimodal” distribution (already shown with POBA and BMS): lesions with an higher tendency to restenose vs. lesions with a lower tendency to restenose Cosgrave J, et al. JACC 2007

19. 2. In 4 out of the 10 predictions performed (40%) the observed restenosis rate was out of the 95% CI of the predicted value (p<0.05 at 1-tail Fisher’s exact test) Agostoni P, et al. AJC 2006

20. Is late loss monotonically related to restenosis? 50 arms of DES (SES, PES, ZES, EES) trials

21. 70 60 R2=0.58 50 40 In-stent binary restenosis (%) 30 20 10 0 -,1 ,1 ,3 ,5 ,7 ,9 1,1 1,3 In-stent mean late loss (mm) 50 arms of DES (SES, PES, ZES, EES) trials R2=0.58 R2=0.20

22. 3. The late loss – binary restenosis – TLR relationship when considering only effective DES is still unclear Agostoni P. Circulation 2005

23. In RCTs of SES vs. PES, late loss was always lower after SES than PES, but binary restenosis not… Could systematic angiographic follow up play a role in this overall “clinical” advantage of SES over PES? The ISAR trials the LONG-DES II and the SIRTAX, all had angio follow up and a 70-80% rate of “conversion” of binary angiographic restenosis in TLR, while in other trials it was only 40-50% Schomig A, et al. JACC 2007

24. In the DES era the angiographic “performance” can be different from the clinical “perfomance” significant difference Late loss DES B Late loss DES A minor (“trivial”) difference Binary restenosis DES A Binary restenosis DES B Revascularization DES A Revascularization DES B No more difference? Substantially all registries (Milan, T-SEARCH/RESEARCH, ORCHID,REWARDS, DEScover, STENT, New York State registry) in more than 32000 patients (respect to “only” 8500 of the meta-analysis) showed similar repeat revascularization rates between SES and PES…

25. Late loss - MACE relationship MACE (%) 0 Late loss (mm) …to restenosis TLR/TVR From malapposition… stent thrombosis Camendzind E. NEJM 2007

26. 2nd thesis:late loss predicts thrombosis MACE (%) 0 Late loss (mm) malapposition Stent thrombosis

27. Lack of endothelium Exposed struts Malapposition Animal and human pathology, angioscopy, IVUS have shown that delayedendothelialization, incomplete strut coverage and lateincompletestent apposition are more common after DES than after BMS These phenomena have been linked to late thrombosis… Someone thought that late loss could “angiographically” represent these phenomena…

28. 2nd anti-thesis:does late loss predict thrombosis? ? MACE (%) 0 Late loss (mm) malapposition ? Stent thrombosis ?

29. 4 30 Trials, 68 Arms 2 0 Stent Thrombosis Difference (%) -1 -0,8 -0,6 -0,4 -0,2 0 0,2 0,4 0,6 -2 R2 = 0.0411 -4 p = 0.229 -6 Late Loss Difference (mm) Mauri L, et al. AHA 2005

30. Despite SES has always and constantly lower late loss value than PES… Schomig A, et al. JACC 2007

31. Conclusion MACE (%) ? ~0.5 0 Late loss (mm)

32. Conclusion The reliability of late loss as effective surrogate end point for MACE prediction is (at least) doubtful • Late loss is a moderate predictor of the restenotic process and its “behavior” can be different according to different DES (in which late loss differences are small, in the order of 0.2-0.4 mm). The possibility of a stepwise relation between late loss and revascularization has not been ruled out. • Even more, the use of late loss as a marker for stent re-endothelialization process is totallymisleading. QCA has a resolution of ~0.2 mm (=~200 micron) and gives 2-D data while the thickness of an endothelial cell is <10 micron and endothelialization is a complex 3-D process.

33. Thank you

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