World Congress of Cardiology 2006

1. World Congress of Cardiology 2006 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center, New York, NY Christopher Cannon MD Staff Cardiologist Brigham and Women's Hospital,Boston, MA James Ferguson MD Associate Director, Cardiology Texas Heart Institute, Houston, TX

2. Fuster History of stents • Early 1990s: Bare-metal stents were first used • 2003: Cypher (sirolimus-eluting) stent introduced in the US • 2004: Taxus (paclitaxel) stent introduced • There are currently ~6 million people with drug-eluting stents • Average costs: • Drug-eluting stent: >$2000 • Bare-metal stent: $800

3. Fuster Risk of thrombosis • Some studies have found that thrombosis can occur with drug-eluting stents at one year, at two years, at three years . . . • Are the data supporting this strong?

4. Cannon Stents and thrombosis Stent thrombosis is a pretty catastrophic event • Associated with Q-wave MI in about two thirds of patients • Associated with a 30% to 40% mortality risk Stenting in patients with stable or unstable angina can create worse problems

5. Ferguson Issues surrounding drug-eluting stents • The interventional cardiology community has enthusiastically embraced drug-eluting stents because they deal with restenosis • In the US, probably in excess of 80% of stents used are drug-eluting stents • Two controversies have brought this issue to a head • The long-term implications of drug-eluting stents • The use of drug-eluting stents in thestable angina population

6. Fuster Stent thrombosis • Total rate of stent thrombosis with coated stents over a period of six months is ~1.3% • Not much different from bare-metal stents • Mortality and MI at 36 months • Not much difference between drug-eluting and bare-metal stents

7. Fuster SIRIUS: 5-year follow-up • 533 patients received sirolimus-eluting stents, 525 patients received bare-metal stents • Incidence rate of stent thrombosis: 0.8% in each group at five years

8. Fuster RAVEL: 5-year follow-up • Incidence of thrombosis was practically zero • Freedom from death and MI • 81.1% with sirolimus-eluting stents vs 89.5% with bare-metal stents • One of the critical questions was how long these patients actually took clopidogrel SerruysPW. World Congress of Cardiology 2006; September 6, 2006; Barcelona, Spain.

9. Fuster TAXUS II: 4-year follow-up • No significant difference in terms of events • Not much thrombosis ColomboAA. World Congress of Cardiology 2006; September 6, 2006; Barcelona, Spain. Presentation 4864.

10. Ferguson Reason to worry? • These are relatively small numbers of patients and selected clinical trials • Drug-eluting stents are being widely used outside the confines of the rigid inclusion criteria that applied in clinical trials • Reports of isolated cases of subacute stent thrombosis late in patients is worrisome

11. Fuster Looking for answers • Are mega-studies—the meta-analyses and the registries—going to provide the answers?

12. Cannon More use, more risk • "As things have progressed, we've gotten more and more adventurous and have been able to do interventions in sicker and sicker patients." • With more use, the absolute risk of stent thrombosis rises

13. Fuster BASKET-LATE • Patients were randomized on a 111 strategy • Compared bare-metal stents with sirolimus-eluting and paclitaxel-eluting stents • After six months, all the patients who were free of any events were followed for 18 months Pfisterer ME. American College of Cardiology Annual Scientific Session 2006; March 14, 2006; Atlanta GA.

14. Fuster BASKET-LATE: Troublesome results • The composite of death and MI at 18 months was significantly different • 4.9% for both drug-eluting stents combined vs 1.3% for metal-stent group • Incidence of stent thrombosis • 2.6% for drug-eluting stents vs 1.3% for metal stents

15. Fuster BASKET-LATE: Entire population • The entire BASKET population (826 patients) was followed for 18 months • No significant difference in death and MI • 7.5% for bare-metal stents and 8.4% for drug-eluting stents • In the original BASKET trial, clopidogrel was not given beyond a few months

16. Cannon Strength of BASKET • "The strength of this study was that they had a very strict timing of clopidogrel, where everyone got exactly six months." • In other trials, a duration was recommended but not necessarily followed • That made it a very clean experiment of what stopping clopidogrel does to the early thrombosis risk

17. Ferguson BASKET-LATE: Not a clopidogrel trial • In BASKET-LATE, people had to be event free at six months, excluding those who develop restenosis in the first six months • BASKET-LATE compared drug-eluting stents with bare-metal stents, not six-month clopidogrel vs clopidogrel of longer duration • The results have been interpreted by some to mean that clopidogrel should be given for a year or forever

18. Ferguson BASKET-LATE: Sorting out the data • How do the clopidogrel issues relate to drug-eluting stents? • Are there differences between the drug-eluting stents? • A subanalysis of BASKET-LATE looking at bypass grafts and small vessels suggested that, in that population, there was demonstrable benefit of drug-eluting stents

19. Fuster A registry study • Of 8146 patients registered, there were 152 instances of stent thrombosis • Incidence rate of 1.3 per 100 patient-years • Rates of stent thrombosis • 1.2% at 30 days • 1.7% at 1 year • 2.3% at 2 years • 2.9% at 3 years • A cumulative increase of 0.6% per year Wenaweser P. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. Presentation 1012.

20. Fuster Questions about the registry • Did all the patients have angiography? • Is this a selective group? • What was the rate for bare-metal stents?

21. Cannon Ongoing and constant risk • "The demonstration of an ongoing and pretty constant risk is the sobering component of this." • With drug-eluting stents, we need to worry about the long term, not just the first six months after placement

22. Fuster The question of clopidogrel • In this registry study, 51% of patients were taking only aspirin; 23% were taking neither aspirin nor clopidogrel • Incident rate of thromboembolism with a mechanical heart valve • Without anticoagulants: ~3% per year • With anticoagulants: 1% per year

23. Ferguson Stent thrombosis: A new problem? • We don't have the data from bare-metal stents to know whether this is a problem that we just didn't recognize before • After stenting, three to six months of combination therapy (aspirin+clopidogrel) is just not enough • The data suggest an ongoing risk of stent thrombosis; however, the rate is relatively low

24. Ferguson Evaluating stent thrombosis • We don't often have angiographic confirmation of an occlusive thrombus • A lot of trials have had to infer, from clinical events or higher rates of mortality or death/MI, that there might be a thrombotic problem • We don't yet understand the physiology of what is going on

25. Cannon Drug-eluting stents and thrombosis • Stent thrombosis is more likely to happen with drug-eluting stents • The coating and potentially the polymers are designed to prevent healing, so the stent is exposed for a much longer period of time • As interventionalists and cardiologists, we need to make it very clear to primary-care physicians that longer-duration dual-antiplatelet therapy is needed

26. Fuster CHARISMA • High-risk patients, the majority with coronary artery disease • The incidence of stroke and major hemorrhage were exactly the same with aspirin alone and aspirin+clopidogrel • The incidence of the medium type of hemorrhage was slightly different between aspirin alone and aspirin+clopidogrel • If I were going to get a drug-eluting stent tomorrow, I would take aspirin+clopidogrel forever

27. Cannon Risk of long-term clopidogrel • I would also take aspirin+clopidogrel forever • In the broader set of patients, the risk of longer-term antiplatelet therapy has to be considered • We must recognize that long-term antiplatelet therapy goes along with drug-eluting stents

28. Ferguson Ongoing clopidogrel: The down side • I would take clopidogrel for an absolute minimum of one year and, if I could afford it, would continue to take it • The difficulty is that you cannot infinitely defer elective surgical procedures • Some of the procedures that really should be done might be deferred or might not be done at all because of concerns about continued aspirin+clopidogrel therapy

29. Fuster Elective surgery and ongoing therapy • When patients with mechanical heart valves undergo elective surgery, they might be off Coumadin for 10 days • The overall incidence of events in that window is very low • The only thing we don't know is whether this is a rebound phenomenon

30. Ferguson Reality vs perception • The risk associated with discontinuing clopidogrel for some brief finite period of time is very small • The perception in the practicing world is that if clopidogrel is stopped, the patient is going to subacutely thrombose the next day • We have to better define what the risks are • If we really think there is a risk, maybe we can develop some sort of bridging strategy with shorter-acting agents • A risk of 0.6% per year is not very high; one has to balance the reality of caring for patients in the real world

31. Ferguson Understanding the biology • For me, right now, the minimum duration for clopidogrel after a drug-eluting stent is one year • After that, the pluses and minuses of continuing therapy can be examined • We need to better define which patients are at risk • We need to identify the patients in whom endothelialization is inadequate • When we better understand the biology,we might be able to develop markers to identify these patients

32. Fuster Safety of drug-eluting stents: A meta-analysis • A meta-analysis of randomized trials of sirolimus- and paclitaxel-eluting stents • With sirolimus-eluting stents, overall adverse events were significant • 6.3% with sirolimus-eluting stents vs 3.9% with bare-metal stents • Difference between paclitaxel-eluting stents and bare-metal stents was not quite significant Camenzind E. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. Hotline I.

33. Fuster Different meta-analysis, different findings • A meta-analysis with 17 randomized controlled trials with the sirolimus- and paclitaxel-eluting stents • There was no significant difference at all, except there might have been a slight increase in mortality with the sirolimus-eluting stent that was not cardiac in origin Nordmann AJ. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. Hotline I.

34. Fuster The value of meta-analyses • Original studies are often too small, but here we have two meta-analysis with the same type of patients coming up with different results

35. Cannon The value of peer review • Anything presented and not published is preliminary • "The key to a meta-analysis, other than doing the statistics properly, is making sure that you've identified all appropriate studies to be included and then keeping them in the analysis." • The peer-review process ensures that appropriate studies weren't excluded, so that you have the totality of the evidence

36. Cannon Larger newer studies needed • A lot of issues are arising now because we're using these devices in higher-risk lesions

37. Fuster The mechanisms • Across the board, the chance of developing thrombosis is less with clopidogrel • If the diameter of the vessel stented is more than 2.5 to 3 mm, the chance of thrombosis is higher • Surfaces tend to endothelialize much later, and not completely, with drug-eluting than with bare-metal stents • Maybe we were much more conservative with bare-metal stents

38. Ferguson Endothelialization • It seems unlikely, in very late stent thrombosis (two and three years out), that the stents still have not endothelialized

39. Ferguson Vessel size • All things being equal, larger vessels should be less likely to clot • Could it be exposure to the compound, or could it be that there's a larger area that has to endothelialize? • Quality vs quantity • The endothelium might be in place but it might not be functioning as well as it should be

40. Ferguson Higher-risk patients • The early clinical trials, for which we have long-term follow-up data, did not include very-high-risk patients • In the real world, drug-eluting stents have been used in increasingly high-risk patients • Maybe we are now seeing some selection bias in terms of how these stents are being used • If the endothelium is part of the problem, then the problem may be worse in diabetics, who have the equivalent of endotheliopathy • The problems are going to become more evident as drug-eluting stents are used in higher-risk patients

41. Fuster Theoretically . . . • Is the endothelium really a problem?

42. Cannon Assessing endothelialization • In patients who've died, there's no endothelium • Stents are designed to prevent healing, so that's not that much of a surprise • How can we figure out who has endothelialized and who has not? • With advanced and targeted imaging, we might be able to develop tests for this • Patients could be imaged after 18 to 24 months to determine whether the stent has endothelialized and whether it is safe to discontinue antiplatelet therapy

43. Fuster Progenitor cells • It is becoming clear that bone-marrow cells are critical in healing the endothelial surfaces • In the future, maybe we'll be able to stimulate bone-marrow cells to encourage healing

44. Cannon Bioabsorbable stents • This is part of the impetus that has sparked interest in bioabsorbable stents • If there is a long-term thrombotic issue, we need to be smarter about how we deliver the drugs and over what period of time • Maybe a device that disappears after some period of time is the answer

45. Fuster FREEDOM • Patients with multivessel coronary disease are randomized to coronary artery bypass surgery or drug-eluting stents • Close to 3000 patients enrolled • Currently, the recommendation is to use clopidogrel across the board for at least one year • We are waiting to hear from the FDA and other groups that are looking at this before we make any changes to this recommendation

46. Fuster Collecting data • Is it difficult to get data from industry to complete meta-analyses?

47. Cannon Collaboration: To everyone's benefit • In general, it's the same whether it's an academic group or industry • The stent makers probably recognize that it will improve the safety of their devices • It's in their interest to help sort out what the issues are and how to fix them • Collaboration wasn't an issue in the Cholesterol Treatment Trial or with COX-2 inhibitors (a contentious area)

48. Fuster Going backward? • Are we going back to bypass surgery for the stable angina patient or to bare-metal stents (with all the restenosis issues)?

49. Ferguson A legitimate question • "We have embraced enthusiastically (and in some circumstances unquestioningly) the benefits associated with aggressive revascularization strategies, particularly in so-called stable patients." • In the interventional world, it's very hard to overcome the oculostenotic reflex of "see a lesion, treat a lesion" • We have aggressive revascularization strategies and conservative revascularization strategies • For stable angina, the best course of action remains unresolved

50. Ferguson Not black and white • There are good reasons for revascularization • When large amounts of territory are at risk • When silent angina or other risk factors are present • When someone absolutely has to have their coronaries fixed • There are a lot of other cases that fall in the gray area