1. Heartbeat – Apr 2003 ACC 2003 ACC 2003: SPORTIF III and ASCOT Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, MA James Ferguson MD Associate Director, Cardiology St Luke's Episcopal Hospital and Texas Heart Institute Houston, TX Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, NY

2. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Trial design Oral thrombin inhibitor in atrial fibrillation 3407 AF patients with at least 1 additional risk factor for stroke Noninferiority, randomized open-label trial of a fixed dose of ximelagatran (36 mg bid) vs adjusted-dose warfarin with a target INR of 2-3 End points: combined rates of all strokes, both ischemic and hemorrhagic, and of systemic embolic events between treatments Primary analysis: intention to treat Secondary analysis: actual treatment received

3. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Primary events ACC 2003 p=0.018p=NS

4. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Bleeding events ACC 2003 End pointXimelagatran (%) Warfarin (%) p Intracerebral hemorrhage 0.20.5NS Major bleeding1.31.8NS Major/minor bleeding 25.529.50.007

5. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Net clinical benefit ACC 2003 Combined end point Ximelagatran (%) Warfarin (%) RRR (%) p Death, major bleeding, primary events 4.6/year6.1/year250.022

6. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Shockwaves "[SPORTIF III] probably will send shock waves through the oral antithrombotic world" Gives us something at least as good as warfarin therapy, without all the downside More studies in different conditions will follow Ferguson

7. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Changing the landscape "This is really going to change the landscape on how we are going to be dealing with atrial fibrillation" Many physicians are not adept at providing warfarin for AF patients A treatment that is: easier to administer needs less monitoring seemingly has better results Weber

8. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Active treatment Cannon "The excitement is that this is an active antithrombotic agent, that it inhibits thrombin directly as opposed to warfarin, which basically depletes the body of clotting factors." Ximelagatran can be initiated early, and the lack of need for INR monitoring eliminates need for very careful follow-up necessary for proper use

9. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Adverse effect ACC 2003 Transanimase liver enzyme Ximelagatran (%) Warfarin (%) p ALT 3x upper limit of normal 6.50.70.001

10. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Drug-drug interactions We need to learn if there will be interactions with other commonly used drugs "…it's really only when you get up to a 5- or 7-fold increase in liver enzymes that you really have to start worrying about any sort of meaningful damage to liver cells. Three-fold doesn't seem to phase anybody." Weber

11. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Liver function enzyme Ferguson The liver function enzyme rise occurred early, mostly in the first 3 months It may be not require continued monitoring out for an extended period of time You should be aware of it and watch out for it in patients in whom you initiate therapy

12. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Analogy with statins Some cases of liver-enzyme rise were out to 18 months "To do LFT monitoring is a pretty routine thing that we're used to with statins so I don't think that will limit [ximelagatran use]." Constant effective anticoagulation is less risky for thrombotic events Cannon

13. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Coronary artery disease In long-term follow-up of patients with CAD we see evidence for chronic treatment with clopidogrel and aspirin CREDO CURE It seems oral anticoagulants and aspirin are doing as well as clopidogrel and aspirin if you can control the INR Fuster

14. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Long-term CAD treatment Recurrent MI in SPORTIF III trended higher (p=0.07) Ximelagatran 1.0% Warfarin.05% Ximelagatran + aspirin may be able to compete with clopidogrel + aspirin due to ease of use High-risk patients may get all 3 Cannon

15. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Effects of the drug Antithrombins affect the clotting system, but the thrombin pathway is also a key pathway of platelet activation "It seems to me the drug in itself, even on a theoretical basis, appears to be quite an interesting drug.... It seems to me that the potential is incredible for the future." Fuster

16. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: The next study Ferguson Data from long-term use of warfarin suggests benefit from prolonged intense antithrombin therapy "My hope would be that we would have the opportunity in the future to do the study that will determine who needs antithrombitic, who needs antiplatelet, and who needs combination therapy."

17. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Bleeding events As we go from double therapy to triple therapy, we must be careful of bleeding events "The potential for long-term secondary prevention is enormous, but we are going to have to be very careful about monitoring safety here." Weber

18. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: History Two problems evolved with hirudin when it was first introduced Bleeding issues Rebound: when you stop the drug, all the events begin to occur We should not forget the history of the field as we move forward Fuster

19. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Bleeding Warfarin's variability in anticoagulation intensity may be a source of bleeding problems and these may be avoided by oral antithrombins Ferguson In the 9 trials with antithrombins in the past 2 years, none were stopped for bleeding, which is good news Fuster

20. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Expenses New drugs are very impressive advances in prevention and therapy ACE inhibitors Statins Clopidogrel Oral antithrombins Is the expense too much for most of the world? Fuster

21. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Cost Ferguson The costs related to oral antithrombin therapy are not just the costs of the drug but of all the monitoring and adjustments that warfarin required "Yes, we're going to have to deal with the cost issues, but I think that the total effect on the healthcare system is going to be beneficial."

22. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Real world use SPORTIF III had superb control of INR that you do not see in real-world practice The benefit may be even greater in the real world because the warfarin is less effectively controlled and more bleeding is likely Cannon

23. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: Trial design aspects Two bold aspects of this trial are worth noting Had a per-protocol analysis in addition to intention to treat Prospective, randomized, open-label blinded end points These trials are easier, safer, and less expensive, and it is good to see them accepted Weber

24. Heartbeat – Apr 2003 ACC 2003 SPORTIF III: SPORTIF V Ferguson SPORTIF V will be a blinded trial in the same sorts of patients "If that turns out to be positive as well, and there's no reason to think that it shouldn't be, that is really going to nail it."

25. Heartbeat – Apr 2003 ACC 2003 ASCOT: Trial design Lipid-lowering arm of ASCOT trial in hypertension patients 10 305 hypertensive patients with at least 3 other cardiovascular risk factors and with total cholesterol below 6.5 mmol/L (250 mg/dL) Randomized to 10-mg atorvastatin or placebo Primary end point: fatal CHD/nonfatal MI with planned 5-year follow-up Secondary end points: fatal and nonfatal stroke, total cardiovascular events, and total coronary events

26. Heartbeat – Apr 2003 ACC 2003 Lancet 2003; 361:1149-1158 ASCOT: Results

27. Heartbeat – Apr 2003 ACC 2003 Lancet 2003; 361:1149-1158 ASCOT: Cholesterol levels

28. Heartbeat – Apr 2003 ACC 2003 ASCOT: Primary prevention Like a primary prevention trial: Original cholesterol levels were fairly normal Patients with multiple risk factors "You put a statin on top of hypertension and other risk factors and you end up with these very significant and positive results." Fuster

29. Heartbeat – Apr 2003 ACC 2003 ASCOT: Beyond the guidelines This provides very strong data that lipid- lowering and statin therapy has use beyond current guidelines "Many of these patients are at lower risk for long-term development of cardiovascular disease than are in the current guidelines. So this is a mega result." Cannon

30. Heartbeat – Apr 2003 ACC 2003 ASCOT: One-size fits all Ferguson There was substantial relative benefit, but the absolute benefit was small in terms of number of primary events 100 in atorvastatin group 154 in the placebo group "This is one-size-fits-all therapy that appears to provide benefit."

31. Heartbeat – Apr 2003 ACC 2003 ASCOT: Absolute vs relative risk Absolute risk reduction in primary event: 3.4/1000 patient years In primary prevention, the number of events will be relatively small Strong relative benefit in these patients will not translate into a strong reduction of absolute events Fuster

32. Heartbeat – Apr 2003 ACC 2003 ASCOT: Ease of statins A strange reluctance for people to use statins despite their proven ease of use Hopefully the demonstrated benefit for lower-risk patients will help convince higher-risk patients to go on statins Risk stratification for these types of patients will have to determined Cannon

33. Heartbeat – Apr 2003 ACC 2003 ASCOT: Extends the application Ferguson All prespecified subgroups benefited from atorvastatin "This extends the potential world of the application of statin therapy. Rather than putting statins in everybody's drinking water right now--that would be great if we could do that but somebody's got to pay for it. "

34. Heartbeat – Apr 2003 ACC 2003 ASCOT: WHO World Health Organization issued a statement in October, 2002 saying the most immediate improvement in CV health would involve getting aspirin and statins to everyone at risk Made possible by generics in statins, bringing cost of the drug combination would cost less than US$14 to treat each person annually Cannon

35. Heartbeat – Apr 2003 ACC 2003 ASCOT: HPS study 20 000 patients at increased risk of CHD death due to prior disease Myocardial infarction or other coronary heart disease Occlusive disease of noncoronary arteries; or Diabetes mellitus or treated hypertension Fuster

36. Heartbeat – Apr 2003 ACC 2003 ASCOT: HPS results Lancet 2002; 360:7-22

37. Heartbeat – Apr 2003 ACC 2003 ASCOT: Global risk These patients were also being aggressively treated for their other risk factors May explain low event rates Interesting that the cholesterol was low enough to justify a placebo Weber

38. Heartbeat – Apr 2003 ACC 2003 ASCOT: ALLHAT Trial design 10 355 patients age >55 with hypertension and 1 additional risk factor and moderate hypercholesterolemia Randomized to:  pravastatin (40 mg/day, n=15 255)  usual care Primary end point: all-cause mortality

39. Heartbeat – Apr 2003 ACC 2003 ASCOT: ALLHAT Primary results JAMA 2002; 288:2998-3007

40. Heartbeat – Apr 2003 ACC 2003 ASCOT: Hypertension plus Ferguson ASCOT is hypertension plus additional risk factors while ALLHAT-LLT was not "There is your risk stratification right there." If there had been more patients in ALLHAT maybe you would have seen a result teased out

41. Heartbeat – Apr 2003 ACC 2003 ALLHAT-LLT: Statin use JAMA 2002; 288:2998-3007

42. Heartbeat – Apr 2003 ACC 2003 ASCOT: Diverging curves The Kaplan-Meier curves separate almost immediately in this study Previously, the curves in long-term populations studies of statins separated after a year "I don't know what the explanation for that very early separation is, but it's encouraging that we're getting an essentially immediate effect." Cannon

43. Heartbeat – Apr 2003 ACC 2003 ASCOT: All-cause mortality Ferguson The all cause mortality curves don't separate throughout the trial The stroke curves diverge over time "To make the leap and say that there's something unique about this population where we get instantaneous benefit, I think you need to look at the endpoints that you're looking at."

44. Heartbeat – Apr 2003 ACC 2003 Summary: SPORTIF III Oral antithrombins at a fixed dose are of at least equal benefit as warfarin, with possibly fewer side effects There may be a liver enzyme issue; so far it seems transient and reversible Must wait for SPORTIF V Fuster

45. Heartbeat – Apr 2003 ACC 2003 Summary: ASCOT Hypertension patients with other risk factors randomized to atorvastatin or placebo Strikingly positive results favoring the statin group The use of statin appears to be meaningful in patients with multiple risk factors without an event Similar to HPS Fuster

46. Heartbeat – Apr 2003 ACC 2003 EPHESUS N Engl J Med 2003; 348:1309-1321

47. Heartbeat – Apr 2003 ACC 2003 Coated stents: TAXUS II Ferguson Long-term results with the paclitaxel stents in TAXUS II were very good % MACE at 12 months Bare stent--21.7 Slow-release coated stent--10.9 Moderate-release coated stent--9.9 "We may have another player emerging into the marketplace in the not-too-distant future."

48. Heartbeat – Apr 2003 ACC 2003 Coated stents:SIRIUS cost analysis CostSirolimus ($) Control ($) Difference ($) p Index procedure 725243952856<0.001 Initial hospital costs 11 34584642880<0.001 Discharge to 1 year 54688040-2571<0.001 Total 1 year16 81316 504309NS Cohen DJ. ACC 2003

49. Heartbeat – Apr 2003 ACC 2003 Coated stents: Cost effectiveness Coated stents seem essentially cost- neutral, you pay more up front but you recoup that by avoiding expensive hospitalizations down the line This should be very reassuring to all of us that this is a therapy whose early costs are offset by the lack of late costs Cannon

50. Heartbeat – Apr 2003 ACC 2003 Final word: Weber I'll be a lot more aggressive in the use of statins Is it worth measuring cholesterol now in high-risk patients? Antithrombins will become a dominant force We need to explain to our administrators the wisdom of an up-front investment in drug- eluting stents Weber

51. Heartbeat – Apr 2003 ACC 2003 Final word: Cannon We didn't discuss higher-dose clopidogrel loading that seemed to obviate the need for GP IIb/IIIa inhibition in low-risk patients "We thought we had maxed out on [antithrombotic] treatment but we're still making advances." Cannon

52. Heartbeat – Apr 2003 ACC 2003 Final word: Ferguson We have better ways of doing things and easier ways of doing them "What you're watching in the meetings is the relentless progress of medical care as we're ultimately targeting improving patient outcomes." Ferguson

53. Heartbeat – Apr 2003 ACC 2003 Final word: Fuster "When you go back even 5 years, I don't see any other area in medicine where so many advances have been made in respect to therapies and prevention." Fuster

54. Heartbeat – Apr 2003 ACC 2003 Next program ACC 2003 Part 2 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, MA Robert Harrington MD Professor, Cardiology Duke University Medical Center Durham, NC Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, NY