Presented at European Society of Cardiology Scientific Congress, September 2006

1. An Overview of Delayed Stent Thrombosis and Drug-Eluting Stent Mortality Meta-Analysis and Drug-Eluting Stent Late Thrombosis Meta-Analysis Presented at European Society of Cardiology Scientific Congress, September 2006 Presented by Dr. Alain J. Nordmann and Dr. Edoardo Camenzind

2. Initial Reports of the Potential Hazard: Bare Metal and Drug Eluting Stent in Same Pt:DES thrombosis, BMS stays open “We report four cases of angiographically-confirmed stent thrombosis that occurred late after elective implantation of polymer-based paxlitaxel-eluting (343 and 442 days) or sirolimuseluting (335 and 375 days) stents, and resulted in myocardial infarction. All cases arose soon after antiplatelet therapy was interrupted. If confirmed in systematic long-term follow-up studies, our findings have potentially serious clinical implications.” McFadden EP et al, Lancet 2004; 364: 1519–21

3. Wall Street Journal September 7th, 2006 “Previously, Boston Scientific had reported that among some 3,400 patients participating in its clinical trials, there had been eight thrombosis cases in the Taxus group versus one case in the bare-metal group during follow-up from six months to three years.But this summer the company analyzed data that included longer follow-up times -- four years for some of the trials -- and the results for an increased risk of thrombosis, roughly 0.5%, became statistically significant. The increase means that in comparison to bare-metal stents, an added one in every 200 patients gets a stent blood clot between six months and four years after implantation. But stent thrombosis can be deadly about 30% of the time, estimates suggest, and with more than a million people getting the devices every year, some experts believe the issue has become a public-health matter.” Wall Street Journal, By SYLVIA PAGÁN WESTPHAL and RON WINSLOW, September 7, 2006

4. Wall Street Journal September 7th, 2006 “According to figures provided by J&J, based on an analysis of the company's four key stent trials, there were five cases of thrombosis between one and four years in Cypher patients, compared to no cases of thrombosis in bare-metal patients, an increased risk of 0.6% for the Cypher.” “In the analysis, which included about 1,800 patients, this difference didn't reach statistical significance.” “The company's position for now, said Dr. Donohoe, is that there seems to be no "safety signal" about late thrombosis in Cypher stents.” Wall Street Journal, By SYLVIA PAGÁN WESTPHAL and RON WINSLOW, September 7, 2006

5. Drug-Eluting Stent Mortality Meta-Analysis: Background • Compare mortality rates of patients treated with drug-eluting stents (DES) versus bare-metal stents (BMS) among randomized DES trials • Compare mortality rates of different specific drug-eluting stents: sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) Presented at ESC 2006

6. Drug-Eluting Stent Late Thrombosis Meta-Analysis: Background • Compare death or Q-wave myocardial infarction (MI) rates among patients treated with DES versus BMS in randomized trials of DES • Compare death or Q-wave MI rates for treatment with SES and PES versus BMS Presented at ESC 2006

7. Drug-Eluting Stent Mortality Meta-Analysis: Study Design Meta-analysis of 17 randomized trials of treatment with DES versus BMS in patients undergoing percutaneous coronary intervention (PCI) for de novo coronary lesions Treatment with DES: SES or PES Treatment with BMS Follow-up > 1 year post PCI (Mean follow-up = 3-4 years) • Primary Endpoint: Mortality (total, cardiac, and noncardiac) Presented at ESC 2006

8. Drug-Eluting Stent Late Thrombosis Meta-Analysis: Study Design Meta-analysis of first-generation DES versus BMS in patients undergoing percutaneous coronary intervention (PCI) for de novo coronary lesions (n = 5,108). Studies used in meta-analysis: RAVEL, SIRIUS, ESIRIUS and SIRIUS for SES and TAXUS I, II, IV, V and VI for PES Treatment with BMS (n = 870 for SES trials, n = 1,675 for PES trials) Treatment with DES: SES (n = 878) or PES (n = 1,685) Mean follow-up = 3 years • Primary Endpoint: Death or Q-Wave MI (surrogate for late thrombosis) Presented at ESC 2006

9. Drug-Eluting Stent Mortality Meta-Analysis: Total Mortality • Total mortality at 1 year did not differ for BMS vs DES (OR 0.94, 95% CI 0.66-1.34) or for individual type of stents: SES (OR 0.86, 95% CI 0.49-1.51) and PES (OR 0.98, 95% CI 0.64-1.48). • Total mortality at 3 years trended toward higher, but non-significant, rates for DES vs BMS (OR 1.25, 95% CI 0.91-1.73) as well as for SES vs BMS (OR 1.48, 95% CI 0.91-2.42). Presented at ESC 2006

10. Drug-Eluting Stent Mortality Meta-Analysis: Cardiac and Noncardiac Mortality • Cardiac mortality at 3 years did not differ with DES treatment vs BMS treatment (OR 1.00, 95% CI 0.62-1.60). • Non-cardiac mortality at 3 years was directionally, but not significantly, higher for treatment with DES vs BMS (OR 1.45, 95% Cl 0.93-2.25). • Treatment with SES was associated with significantly higher rates of non-cardiac mortality at 2 years (OR 2.74, 95% CI 1.22-6.13, p < 0.05) and 3 years (OR 2.04, 95% CI 1.00-4.15, p < 0.05) compared with BMS. Presented at ESC 2006

11. Drug-Eluting Stent Late Thrombosis Meta-Analysis: Mortality/MI Death or Q-wave MI (%) in patients treated with BMS (n=870) versus SES (n=878) • Death or Q-wave MI was significantly higher in patients treated with SES versus BMS at last available follow-up (6.3% vs 3.9%, p = 0.03). p=0.03 p=0.06 p=0.09 p=0.30 p=0.21 Presented at ESC 2006

12. Drug-Eluting Stent Late Thrombosis Meta-Analysis: Mortality/MI Death or Q-wave MI (%) in patients treated with BMS (n=1,675) versus PES (n=1,685) • Death or Q-wave MI did not differ significantly in patients treated with PES versus BMS at last available follow-up (2.6% vs 2.3%, p = 0.68). p=0.60 p=0.78 p=0.68 p=0.80 p=0.88 Presented at ESC 2006

13. Drug-Eluting Stent Mortality and Late Thrombosis Meta-Analysis: Limitations • The scope of these meta-analyses was limited in that none of the randomized trials were powered to investigate harder endpoints of death or Q-wave MI. • Longer-term follow-up and greater insight into the specific causes of death will be useful. Presented at ESC 2006

14. Drug-Eluting Stent Mortality and Late Thrombosis Meta-Analysis: Summary • From Late Thrombosis Meta-Analysis: • Treatment with SES was associated with significant increase in late death or Q-wave MI at 3 years versus treatment with BMS. • Treatment with PES has no significant difference on incidence of death or Q-wave MI compared with BMS treatment. • From Mortality Meta-Analysis: • Treatment with DES was not associated with a significant difference in total mortality compared to treatment with BMS at 3 years • Higher rates of noncardiac death at both 2 and 3 years with SES compared with BMS • Present meta-analysis suggests a potential, but nonsignificant hazard in late mortality with DES compared with BMS Presented at ESC 2006

15. 6 Month angiographic follow-up is when most target lesion revasc occurs; this may overestimate clinical need for revasc

16. Potential Magnitude of the Problem from a Public Health Perspective: Liberal Estimate • 1,000,000 stents placed per year • Assume meta analysis figure of 2.4% increase in the risk of death or MI with use of drug eluting stent vs bare metal stent (6.3% vs 3.9%) • 2.4% of 1,000,000 would be 24,000 death or MIs per year associated with drug eluting stent use over bare metal stent use.

17. Potential Magnitude of the Problem from a Public Health Perspective: Conservative Estimate • 1,000,000 stents placed per year • Assume a conservative figure of 0.5% incremental risk of stent thrombosis with use of drug eluting stent vs bare metal stent (Boston Scientific estimate) • Assume 30% of stent thromboses are fatal • Then 30% of 0.5% = 0.15% more patients would die if a drug eluting stent was placed • 0.15% of 1,000,000 would be 1,500 deaths per year associated with drug eluting stent use over bare metal stent use

18. Potential Magnitude of the Problem from a Public Health Perspective: Vioxx Risk vs DES Risk Incremental risk of MI with Vioxx in the VIGOR Trial: 0.3% (increased from 0.1% to 0.4%) Incremental risk of MI with Taxus stent according to Boston Scientific: 0.5%* Incremental risk of MI with Cypher stent according to J and J: 0.6%* 0.6% Absolute Increase in Risk of MI 0.5% 0.3% * Wall Street Journal, By SYLVIA PAGÁN WESTPHAL and RON WINSLOW, September 7, 2006 Vioxx Taxus Cypher

19. Challenges in Evaluating Late Stent Thrombosis • Event rates are low, hard to be certain of risk • Larger randomized trials needed with longer duration of follow-up • Devices have traditionally not had to demonstrate a durable benefit in hard endpoints such as death or MI • A non fatal surrogate endpoint (restenosis) has been accepted over death or MI • Registries are not going to be adequate given the differences in the types of patients and lesions that DES and BMS are placed in (lesion length, vessel diameter, presence of thrombus, crush technique, bifurcation location are all confounders)

20. Challenges in Evaluating Late Stent Thrombosis • It will be critical to know if thrombosis was in target vessel, target lesion, or uninstrumented artery (may not be clear if an angio is not performed) • The role of prothrombotic events must be identified (i.e. did discontinuation of antiplatelet therapy before surgery lead to stent thrombosis?) • Optimal duration of thienopyridines is unclear (unclear if longer duration may permit greater intimal hyperplasia to form) • Optimal dose of ASA is unclear • Role of clopidogrel and ASA resistance is unclear • Role of ticlid (not a pro drug, little resistance, rapid acting) is unclear