Late loss in the choice of DES: Monty Python or the Holy Grail? Azfar Zaman Freeman Hospital, Newcastle-upon-Tyne

MY CONFLICTS OF INTEREST ARE: I have been paid for attending Advisory Board meetings: Cordis Boston Scientific Medtronic

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

Late loss : why use it? Late loss is a surrogate for clinical events Late loss is a surrogate for clinical events How good a surrogate is it for evaluating clinical outcomes following DES implantation? How good a surrogate is it for evaluating clinical outcomes following DES implantation? Why do we need a surrogate when it is easier to record clinical events? Why do we need a surrogate when it is easier to record clinical events?

Clinical Endpoint A characteristic or variable that reflects how a patient feels, functions or survives A characteristic or variable that reflects how a patient feels, functions or survives Surrogate Endpoint A biomarker intended to substitute for a clinical endpoint. A biomarker intended to 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 A surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence A Framework for Biomarker and Surrogate Endpoint Use in Drug Development: Janet Woodcock M.D. Acting Deputy Commissioner for Operations; November 4, 2004

1. Measurement of late loss Quantitative coronary angiography Quantitative coronary angiography

Measurement of late loss Pre-procedure Post-procedure

Measurement of late loss 8 Months0.2 mm

Pre-procedure Post-procedure Measurement of late loss

8 Months0.4 mm Measurement of late loss

a handful of “core” labs worldwide a handful of “core” labs worldwide different core labs for different studies different core labs for different studies accuracy and robustness of QCA data between labs? accuracy and robustness of QCA data between labs? clinical endpoints more reliable and relevant clinical endpoints more reliable and relevant

Measurement of late loss REALITY – head to head trial with REALITY – head to head trial with all measurements in one core lab all measurements in one core lab

2. Can late loss alone predict clinical outcomes? multifactorial multifactorial dependent on more than just type of stent dependent on more than just type of stent

Mauri et al Circulation 2005;112:2833

Mauri et al Circulation 2005;2833

Actual TLR by LL and RVD Analysis Segment Late Loss Proportion with TLR

Late Loss in small vessels Late Loss (mm) (Analysis Segment) mm 3.0 mm 3.5 mm Vessel Diameter mm 3.0 mm 3.5 mm DES 1 DES 2

Whither late loss in LMS? Series of 43 patients Series of 43 patients Mixed LMS lesions Mixed LMS lesions Rapamycin eluting stent Rapamycin eluting stent Overall TVR 23% Overall TVR 23% But 71% in patients with diabetes But 71% in patients with diabetes Cheiffo A, et al. Early and mid-term results of Cypher stents in unprotected left main. J Am Coll Cardiol. 2004;43: 21A (abstract)

3. Late loss – the mean A two tail tale

ENDEAVOR I-III TAXUS IV SIRIUS % of Patients In-Stent Late Loss (mm) Comparison of In-stent LL Relationship at the tails Left Tail Right Tail

0% 5% 10% 15% 20% 25% In-Stent Late Loss (mm) % of Patients 0% 20% 40% 60% 80% 100% TLR Probability (%) The Right tail : relation of LL to Target Lesion Revascularisation *Pts undergoing angiographic follow-up

The Left tail : is there a sting? MACE after DES insertion not linear MACE after DES insertion not linear a negative LL may be consequence of late incomplete apposition of DES a negative LL may be consequence of late incomplete apposition of DES need late loss of 0.15 to cover stent struts need 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 not linear In stent late loss, mm MACE, % From malapposition? ? restenosis! To 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 is non linear DELIVER DELIVER ENDEAVOR II: ENDEAVOR II: TAXUS IV: TAXUS IV: SIRIUS: SIRIUS: In stent late loss TLR Stepwise or curvilinear relationship at best between LL and 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: 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: ESC 2005 Lansky 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: )

In diabetic subsets : relationship also non-linear ENDEAVOR II (n=107): ENDEAVOR II (n=107): TAXUS IV (n=155): * TAXUS IV (n=155): * SIRIUS (n=131): SIRIUS (n=131): In stent late loss TLR Diabetic subset All QCA measurements done at Brigham & Women’s * 12 month result ACC 2005 Hermiller 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;45:1172–9 Moussa I, Leon M, Baim D, et al. Impact of Sirolimus-Eluting Stents on Outcome in Diabetic Patients A SIRIUS Substudy Circulation. 2004;109:

MACE shows even less relation to LLL DES Arms ENDEAVOR IITAXUS IVSIRIUS TLR TVR TVF MACE In-stent LL In-segment LL In-stent ABR In-segment ABR % 13.3% % 7.9% % 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: 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:

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 : Conclusion is a surrogate marker (not validated) is a surrogate marker (not validated) is measured using QCA is measured using QCA independently cannot predict restenosis independently cannot predict restenosis cannot accurately discriminate between available DES across all patient sub groups cannot accurately discriminate between available DES across all patient sub groups

Late Loss : Monty Python or Holy Grail ?

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