TCT 2005: Emerging treatment options

2. LE MANS Acute and late outcome of unprotected left main stenting in comparison with surgical revascularization SENIOR PAMI Senior Primary Angioplasty in myocardial infarction PRASUGREL New agent for platelet inhibition Topics

3. LE MANS Acute and late outcome of unprotected left main stenting in comparison with surgical revascularization

4. LE MANS First modern-day, randomized controlled study to compare unprotected left main stenting with CABG for left main disease 52 patients randomized to PCI and 53 patients randomized to CABG

5. LE MANS end points STUDY OUTCOMES Primary end point was a composite of LVEF, functional capacity, and angina status after 12 months Secondary end points included major adverse cardiac events (MACE), hospital length of stay, survival, and any major adverse events (MAEs), defined as any MACE, procedure-related infection, bleeding, or renal or respiratory insufficiency

6. LE MANS results PRIMARY END POINT Change in LVEF at 12 months was significantly different between the two groups: For PCI patients, LVEF increased from 55% to 60% while LVEF in CABG patients remained unchanged Angina status and treadmill stress test at follow-up were similar between the two groups

7. LE MANS outcomes

8. Where's the long-term safety data? "I think it is a very small study with predictable differences in MACE at one year." Study missing data comparing the long-term safety of stenting with surgery - King

9. Puzzling primary end point Unsure why LVEF was selected as the primary end point Is the change in EF meant to imply the patients were chronically ischemic because of left main disease? Lack of blinding also a concern

10. Small study "MACE is in the eye of the beholder, and it depends how you count it." Higher early MACE with surgery not surprising, but the focus needs to be on longer-term outcomes

11. Patients too selected? Interventional techniques getting better, but more clinical data still required In the right circumstances, treating left main disease percutaneously is possible - Ferguson Question: Were the MACE rates too low? Concerns raised that the patients were too selected. - Cannon

12. What type of left main lesion? "Left main is not a single entity. The critical question as to what kind of trouble you'll get into depends on whether it is all in the shaft of the left main or whether it involves a bifurcation. I don't know that from this study."

13. Other trials coming COMBAT Multicenter, international study randomizing 1000 patients to a sirolimus stent or to surgery for left main disease (will include patients with shaft-only and distal bifurcation lesions) SYNTAX Study evaluating treatment of left main or three-vessel disease with the paclitaxel stent

14. Not all left mains the same "All left mains are not created equal. There are easy, slam-dunk left mains, and then there are much more complicated left mains that get you into bifurcation issues." LE MANS not a blanket endorsement for left main stenting Proceed cautiously

15. New reality "Left main is feasible, and people are less nervous." Unprotected left main stenting is a reality for the interventional cardiologist today. Upcoming trials should provide more answers

16. SENIOR PAMI Senior Primary Angioplasty in Myocardial Infarction

17. SENIOR PAMI Study initiated to compare primary angioplasty with thrombolytic therapy in patients >70 years BACKGROUND Elderly acute MI patients often have decreased PCI success, increased bleeding rates and stroke risks, as well as increased risks of renal failure and death compared with younger patients

18. Study design Approximately 500 patients with acute MI �presenting symptoms between 30 minutes and 12 hours�randomized to PCI or lytic therapy PRIMARY END POINT 30-day death or disabling stroke event rate not significantly different between two study arms

19. SENIOR PAMI: 30-day events

20. Consistent data "I find it very consistent in favoring primary PCI in this very high-risk group. The fact that the p values were not significant is purely data error and not a reflection of lack of benefit."

21. Study setting I agree, there is a benefit in the setting where this study was conducted� hospitals with primary angioplasty capabilities What about hospitals not equipped to do primary angioplasty? - King

22. Reassuring data Data suggest if you can't get thrombolysis done, the elderly not unlike younger patients Early infarction can be treated with thrombolysis if unable to get patient to cath lab Data also reassuring that despite patients being sicker, thrombolysis not that much worse, even in hospitals equipped for primary angioplasty

23. Half-full vs half-empty The message that emerges for me is sort of like a glass that is half-full and half-empty Study less a win for primary PCI: suggests thrombolysis might be just as good in the elderly Elderly benefit from any form of reperfusion therapy

24. Improving thrombolysis Thrombolysis is getting better, especially with lower doses of heparin Adding clopidogrel shown to improve outcomes in thrombolysis "Many refinements are ongoing." - Cannon

25. What about heparin? Is heparin absolutely necessary today? - Fuster Not much heparin is necessary. It seems we get better results the more we crank heparin down. - King

26. Role of heparin Heparin won't be completely eliminated In acute MI, reperfusion exposes thrombin, and because of this, some degree of thrombin inhibition is necessary Might be less than previously used, in light of adjunctive therapies

27. Trial results TIMI 14 Fall-off in vessel patency with ultra-ultra-low doses of heparin OASIS 5 Evidence of catheter thrombus (1%), possibly due to an absence of thrombin inhibition in the cath lab

28. Prasugrel New agent for platelet inhibition

29. New agent Prasugrel Developed by Lilly and Sankyo Drug belongs to the same class as clopidogrel�thienopyridine P2Y12 receptor antagonists Acts directly on the receptor

30. Study design Data reported from a pooled analysis of three early-phase studies In total, 112 healthy volunteers were randomized to receive either a 60-mg loading dose of prasugrel or a 300-mg loading dose of clopidogrel in a two-way crossover design ADP-induced platelet aggregation was measured in blood samples at four to five hours and 24 hours after the medications were administered

31. Results All subjects responded effectively to prasugrel, but when the same subjects were given clopidogrel, between 22% and 43% were classed as nonresponders, depending on the definition of nonresponder used

32. Insights into prasugrel Agent metabolized differently, and more rapidly, than clopidogrel Issue of no-response or low response shifted upward with prasugrel "Is more platelet inhibition better for improving outcomes, as we've seen with clopidogrel vs just aspirin alone?" - Cannon

33. Big studies coming TRITON TIMI 38 Prasugrel is currently being studied in a phase 3 trial in 13 000 ACS patients undergoing PCI Study is comparing prasugrel and clopidogrel and incorporates a loading dose before PCI, followed by once-daily maintenance dosing starting after the PCI procedure� The study is expected to be completed in early 2007

34. Many unknowns What is known . . . New agent, more potent on mg-per-mg basis, metabolized differently, and with faster onset of action What is not known . . . Dose effect with the thienopyridines, ie, giving more drug gets more platelet inhibition Overcoming resistance may have nothing to do with the drug and everything to do with the dose

35. Many unknowns There is a real unknown as to how much of the difference relates to the onset of action, how much relates to metabolism, how much just relates to the dose of drug that you're giving. . . . There are a lot of unknowns right now."

36. Balancing the risks TRITON TIMI 38 Trial will attempt to determine the balance between increased efficacy and bleeding risks Mean follow-up of one year OASIS 7 study also under way (comparing the 300-mg and 600-mg loading doses of clopidogrel)

37. Summary "I'm not hugely surprised, and my degree of excitement goes along with my degree of being surprised." - Ferguson High-risk left main patients and the very elderly are still high risk, but there are different options Prasugrel an open question

38. Pushing known pathways "I'm a glass half-full kind of guy." - Cannon Data on prasugrel is exciting�the concept of pushing a pathway that works well is analogous to statin trials SENIOR PAMI supports primary PCI in the elderly, where it can be done Left main stenting still in the realm of easy lesions

39. Getting up to speed "One of the major problems is how to get up to speed to do unprotected left mains." - King What is the safe way to stent left main? Surgeons are polished at left mains, but we have a whole learning curve in front of us

40. Other thoughts Among the elderly, PCI is safe and effective, but early lytic therapy is also reasonable where primary angioplasty not available Bringing a second thienopyridine to market should hopefully bring the price down� cost is still one of the limiting factors of adequate, double-antiplatelet therapy - King