Bifurcation Stenting Is a Risk Factor for Stent Thrombosis

1. Bifurcation Stenting Is a Risk Factor for Stent Thrombosis Ioannis Iakovou, MD General Army Hospital of Thessaloniki, Greece Blue Cross Clinic, Euromedica, Thessaloniki, Greece

2. Ever reccuring questions for coronary bifurcations • One or 2 stents? • If 2 stents, which technique? A new question: Are there any thrombotic issues with the treatment of bifurcations with DES?

3. FDA is providing the following information in response to inquiries asking for the agency’s position on adverse events related to coronary drug-eluting stents (DES). September 14, 2006 -- FDA is providing the following information in response to inquiries asking for the agency’s position on adverse events related to coronary drug-eluting stents (DES). This information describes our position at this time and does not represent new agency policy. FDA has been closely monitoring DES since they came to the United States market in 2003 and 2004 – and will continue to do so.We are aware of recent data suggesting a small but significant increase in the rate of death and myocardial infarction (heart attack) possibly due to stent thrombosis (a blood clot in the stent) in patients treated with DES. The specific studies that have prompted recent media inquiries are the BASKET-LATE study (presented at the March 2006 American College of Cardiology Scientific Sessions in Atlanta, Ga.) and more recently, the Camenzind meta-analysis (presented at the September 2006 European Society of Cardiology Annual Meeting/World Congress of Cardiology Meeting in Barcelona, Spain). The small but significant increase in the rate of death and myocardial infarction observed in these studies was noted in patients followed 18 months to 3 years after stent implantation.While the studies presented at the Atlanta and Barcelona meetings have raised important questions, the data we currently have do not allow us to fully characterize the mechanism, risks, and incidence of DES thrombosis. A more formal evaluation of the data in these studies is necessary, and any conclusions are dependent upon a thorough peer review. FDA intends to more formally evaluate the studies presented in Atlanta and Barcelona. Stent thrombosis in patients who receive DES is a primary area of interest for the agency because of the potential for serious adverse outcomes—even though stent thrombosis occurs at low rates. Over the past two months, the agency has met with both manufacturers of the FDA-approved approved DES to discuss any information and perspectives they have that may be pertinent to this issue. In assessing the risk of stent thrombosis, we remain keenly interested in the long-term follow-up of patients enrolled in the original pivotal DES randomized trials as well as those in the more complex patient and lesion subsets (for example, patients with diabetes; acute myocardial infarction or multiple vessel disease; or lesions involving arterial bifurcations, the left main coronary artery, and long arterial segments) who are currently being treated in “real world” randomized and registry studies.  FDA also continues to closely evaluate information related to the duration of treatment with clopidogrel (Plavix), a drug used in combination with aspirin to reduce/prevent clotting in DES patients.    Additional clinical data are likely needed to reach conclusions regarding the optimal antiplatelet therapy regimen for DES patients. We are aware of recent data suggesting a small but significant increase in the rate of death and myocardial infarction (heart attack) possibly due to stent thrombosis (a blood clot in the stent) in patients treated with DES.

4. September 14, 2006 -- FDA is providing the following information in response to inquiries asking for the agency’s position on adverse events related to coronary drug-eluting stents (DES). FDA will convene a public meeting of the Circulatory System Devices Advisory Panel by the end of the year in an effort to improve our knowledge regarding the incidence and timing of stent thrombosis as well as the appropriate duration of clopidogrel use in patients who receive DES. This Panel of outside experts will assist the agency in the review and analysis of the available scientific data and provide recommendations for appropriate actions to address this issue, such as possible changes to device labeling or the need for additional clinical studies. An announcement of this meeting will appear on FDA’s web site, www.fda.gov/cdrh. • At this time, FDA believes that coronary DES remain safe and effective when used in patients having clinical and coronary anatomic features similar to those treated in the pivotal trials conducted by the manufacturers for FDA approval. The approved indications are: • The CYPHER Sirolimus-eluting Coronary Stent is indicated for improving coronary luminal diameter in patients with symptomatic ischemic disease due to discrete de novo lesions of length ≤ 30 mm in native coronary arteries with reference vessel diameter of ≥2.5 mm to ≤3.5 mm. • The TAXUS Express Paclitaxel-Eluting Coronary Stent System is indicated for improving luminal diameter for the treatment of de novo lesions ≤28 mm in length in native coronary arteries ≥2.5 to ≤3.75 mm in diameter. • For more information, see http://www.fda.gov/cdrh/pdf2/P020026.html and http://www.fda.gov/cdrh/pdf3/P030025.html. • For thousands of patients each year, these devices have resulted in a significant reduction in the need of second procedures to treat restenosis. The FDA will continue to carefully evaluate all DES data in an attempt to maximize the benefits and minimize the risks for patients undergoing this therapy for treatment of their coronary artery disease. • To summarize: • FDA has been monitoring coronary drug-eluting stents closely since they came on the U.S. market in 2003 and 2004, and will continue to do so. • New data were released recently that suggest a small but significant increased risk of stent thrombosis in patients who have drug-eluting stents. The agency is keenly interested in this issue because of the potential for serious harm to patients—even though stent thrombosis occurs at low rates. • While the new data are of interest to FDA and raise important questions, we do not have enough information yet to draw conclusions. It’s unclear, for example, what causes drug-eluting stent thrombosis, how often it occurs, under what circumstances it occurs, or what the risk of occurrence is in a given patient. • At this time, FDA believes that coronary DES remain safe and effective when used in patients havingclinical and coronary anatomic features similar to those treated in the pivotal trials conducted by the manufacturers for FDA approval. The approved indications are: • The CYPHER Sirolimus-eluting Coronary Stent is indicated for improving coronary luminal diameter in patients with symptomatic ischemic disease due to discrete de novo lesions of length ≤ 30 mm in native coronary arteries with reference vessel diameter of ≥2.5 mm to ≤3.5 mm. • The TAXUS Express Paclitaxel-Eluting Coronary Stent System is indicated for improving luminal diameter for the treatment of de novo lesions ≤28 mm in length in native coronary arteries ≥2.5 to ≤3.75 mm in diameter. What about bifurcations?

5. Bifurcation Stenting NHLBI Dynamic Registry J.Al Suwaidi et al, AJC 2001

6. Bifurcation lesions: 1 stent versus 2 stents March 1993 and April 1999: 92 patients Angio. FU rate 77% 68% 6-month total MACE (51% vs. 38%, p=NS) 100 (%) Main Branch 38 53pts 39pts 33 100 (%) 62 Restenosis rates 48 100 (%) Global restenosis rate 51 Side Branch 33 Yamashita et al. JACC 2000; 35: 929-36

7. Event-Free Survival: (MI, CABG, rePTCA and Severe Angina) Bifurcation lesions: 1 stent versus 2 stents MACE at 6 months (Y vs. T): 86.3% vs. 30.4%, p = 0.004 October 1993 and November 1998: 131 patients T stenting n= 33 1 stent n= 77 2 stents n= 54 « Y » stenting n= 19 Al Suwaidi et al. JACC 2000; 35, 4: 929-936

8. Randomized Study of Bifurcation Lesions with SES Restenosis and Major Adverse Cardiac Events at 6-month P=NS for all comparisons stent thrombosis: 3.5% Colombo A, et al. Circulation. 2004; 109: 1244-1249.

9. Bifurcations in RESEARCH Registry At six months follow-up: • Death 1.2% • TLR 8.2% • TVF 17.6% • Thrombosis 3.5%

10. Stent Thrombosis After DES implantation Iakovou et al. JAMA 2005

11. Stent Thrombosis After DES 2229 patients after successful DES implantation PES 1167 pts 2223 stents SES 1062 pts 2272 stents SAT 4 (0.4%) SAT 10 (0.9%) P=0.5 LST 10 (0.9%) LST 5 (0.5%) P=0.3 9months Total DES 29/2229 (1.3%) Total SES 9 (0.9%) Total PES 20 (1.7%) P=0.09 Iakovou I. et al. JAMA 2005

12. Thrombosis rates according to selected patient characteristics % ULM Bifurcations UA Antiplatelet Therapy disc Prior Brachy Renal failure Diabetes *Iakovou et al TCT 2005

13. Correlates of DES Thrombosis Moreno et al, JACC 45:954, 2005 N=5030 (10 RCT) Iakovouet al, JAMA 293:2126, 2005 N=2229 (3 Centers) Kuchulakantiet al, Circulation 113:1108, 2006 N=2974 • Number of stents/patient • Total stent length • Premature antiplatelet rx d/c • Renal failure • Bifurcation lesion • Diabetes • low LVEF •Discontinuation of clopidogrel •Renal failure •Bifurcation lesion

14. DES thrombosis and bifurcations Flow patterns at bifurcations may alter drug release and deposition Richter et al, JCI, 2004

15. DES thrombosis and bifurcations Inhomogeneous strut placement dramatically affected local concentrations without changing mean concentrations Hwang et al, Circulation, 2001

16. DES thrombosis and bifurcations « … cause of stent thrombosis: stent underexpension, crush technique … » Courtesy of Renu Virmani

17. Contemporary stent treatment of coronary bifurcations J. Ormiston

18. Stent Underexpansion After Stent Crush Postprocedure IVUS in the SB “Optimal” angiographic result SB distal stent Ostium of the SB stent Main Vessel Costa et al. JACC 2005

19. “Incomplete Crush” - found in >60% of non-left main bifurcation lesions treated by crush stenting - associated with SB stent underexpansion (77.1±7.6% in lesions with incomplete crush vs. 89.4±13.1% in lesions with “complete” crush, p=0.04) Costa et al. JACC 2005

20. Postprocedure IVUS Measurements of Bifurcation Lesions* Treated with Crush Stenting *Non-Left Main lesions †65% at the ostium location Costa et al. JACC 2005

21. Combined Crush experience: Milan and Rotterdam 231 pts, 241 de novo bifurcations possible postprocedural stent thrombosis = 4.3%. Hoye A, Iakovou I, et al. JACC 2006

22. 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Predictors of stent thrombosis OR=4.18; 95%CI, 0.70-24.67, p=0.1 OR=11.48;95%CI, 4.27-30.83, p<0.0001 OR=2.96; 95%CI, 0.80-10.97, p=0.1 OR=1.23; 95%CI, 0.42-3.60, p=0.7 OR=1.49; 95%CI, 0.81-2.73, p=0.2 OR=7.19; 95%CI, 2.36-21.82, p<0.0001 OR=3.36; 95%CI, 1.53-7.37, p=0.02 OR=1.09; 95%CI, 1.05-1.13, p<0.0001 Prior Brachytherapy Renal Failure Unprotected Left Main 2 stents per bifurcation Stents per lesion Bifurcation Diabetes Ejection Fraction Iakovou et al AHA 2005

23. Group 2S Group 1S SES in Bifurcation Lesions Thrombosis 174 consecutive patients 3 (2.6%) 2 (1.7%) 1 (0.9%) 0 0 0 Subacute Intra-procedure Total Ge, Tsagalou, Iakovou et al AJC 2005

24. DES thrombosis and bifurcations • Are dedicated stents the answer to the problem of bifurcation treatment (including thrombosis)? • Very promising but with little evidence We don’t know yet!!!

25. Dedicated bifurcation stents • Four alternatives: conceptual approaches • Provisional main branch: Guidant Frontier • Side branch stent: Sidekick Ymed, • Tryton NDC, Nile Minvasys • Proximal main branch cone: Devax • True bifurcation stent: Cordis DBS, • AST Petal

26. Stent thrombosis in bifurcations treated with DES: Potential Influencing Factors… • More complex patients (CRF, diabetes, multivessel disease) and lesions (ISR, CTO) • DEScharacteristics (open vs. close cell design, cell diameter, etc)? • Lack of meticulous attention to DES operator technique issues (I.e. full lesion coverage, high pressure post-dilation?) • Stent sizing errors and stent shortages (diameters and lengths) resulting in under-sizing and under-deployment

27. DES thrombosis and bifurcations Conclusions • It appears that bifurcation compared to non-bifurcation treatment with DES is associated with a higher thrombosis rate. • There is no proven difference between rates of thrombosis after DES vs. BMS treatment of bifurcations. • The dedicated stents may impact on the rates of stent thrombosis but we have no evidence yet.

28. DES thrombosis and bifurcations Future Implications • Up to now there is no clear demonstration that the one stent techniques are better than the two. • .(..when you cannot do provisional T stenting…) the battle of the techniques continues. Finding the technique with the less thrombogenic and more antirestenotic effect has to be studied in adequately powered and well designed studies.

29. Thank you!!! iako@hol.gr

30. Second Meeting of the (EBC) European Bifurcation ClubFriday 29 – Saturday 30 September 2006 Torre Rossa Park Hotel, Via di Torre Rossa 94, 00165  Roma, Italia

31. RAVEL: Five-year outcomes Serruys P. World Congress of Cardiology 2006; September 2-6, 2006; Barcelona, Spain. *Fischer's exact test

33. 35 30 25 20 15 10 5 0 Comparison between T-stent and Crushing technique T-Stent Group (n=61) Crush-Stenting Group (n=121) 32.8% 31.1% 31.1% 28.9% 16.5% 14.1% 14.0% 11.3% P=0.09 P=0.053 P=0.03 P=0.04 P=0.01 P=0.04 P=0.02 P=0.03 TLR TVR TLR TVR KISSING BALLOON ENTIRE COHORT Ge L, Iakovou I, Cosgrave J et al Heart 2005