1. Heartbeat – ACC 2006 Antithrombotic therapies Christopher Cannon MD Staff cardiologist Brigham and Women's Hospital,Boston, MA Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center, New York, NY James Ferguson MD Associate Director, Cardiology Texas Heart Institute, Houston, TX Harlan Krumholz MD Professor of Medicine Yale University, New Haven, CT

2. Heartbeat – ACC 2006 CHARISMA Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance EXTRACT-TIMI 25 Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment— Thrombolysis in Myocardial Infarction 25 OASIS-6 Sixth Organization to Assess Strategies in Acute Ischemic Syndromes Topics

3. Heartbeat – ACC 2006 Four large trials showed clopidogrel + stenting to be beneficial CAPRIE trial: Clopidogrel alone "borderline better" in CVD than aspirin alone The question remained: What about patients with chronic CVD—are clopidogrel + aspirin better than aspirin alone? Clopidogrel: Historical background

4. Heartbeat – ACC 2006 CHARISMA Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance

5. Heartbeat – ACC 2006 CHARISMA: Trial design Over 15 000 patients worldwide Patients with evidence of CVD or multiple risk factors 75-mg clopidogrel daily + low-dose aspirin vs placebo + aspirin Median 28 months of follow-up Primary efficacy end point: MI, stroke, or cardiac death

6. Heartbeat – ACC 2006 No significant differences in primary efficacy end point (6.8% vs 7.3%, p=NS) Second efficacy end point, adding hospitalization for ischemic events: borderline significance favoring clopidogrel + aspirin Severe bleeding: 1.7% in clopidogrel + aspirin vs 1.3% in aspirin + placebo group (p=0.09) A negative trial overall; some positivity in terms of secondary end point, but counterbalanced by bleeding CHARISMA: Results

7. Heartbeat – ACC 2006 "We can say that clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of MI, stroke, or death from CV causes in patients with very high risk for cardiovascular disease or patients with [early] manifestations of CVD." Fuster CHARISMA: Messages

8. Heartbeat – ACC 2006 Expanding the patient population using aspirin + clopidogrel is appealing, but we've seen we can't broaden too far No benefit and some harm in patients with no previous clinical events Higher-risk coronary patients, including prior MI/stroke, had a more robust benefit Cannon CHARISMA: Messages

9. Heartbeat – ACC 2006 "To me it shows that for longer-term use, higher-risk patients benefit from higher-intensive therapy, and we simply have to integrate that into the decisions on who continues on clopidogrel for longer than one year." CHARISMA: Messages Cannon

10. Heartbeat – ACC 2006 "There were some things that were very surprising and... some things that weren't necessarily quite such a big surprise." Can we extend this into a higher-risk primary-prevention group? Is there benefit over a longer period of time? What is the risk that one pays? Ferguson CHARISMA: Messages

11. Heartbeat – ACC 2006 "It really, in my mind, sharpens the distinction that one has to make between primary prevention in people at risk for the disease and secondary prevention in people who already have the disease." Ferguson CHARISMA: Messages

12. Heartbeat – ACC 2006 The results were negative overall, with some concerns about GI bleeding Two groups of patients:  Those with manifestations of disease showed some favorable trends with clopidogrel + aspirin  Primary-prevention patients with high-risk profile showed opposite results Fuster CHARISMA: Messages

13. Heartbeat – ACC 2006 CHARISMA: Subgroup hazards Krumholz Clopidogrel not effective? Or "suggestive" of benefit in certain groups? Secondary outcomes/subgroup analyses often promoted to the point that studies seem positive when they're not

14. Heartbeat – ACC 2006 CHARISMA: Subgroup hazards Krumholz But aspects of subgroups in CHARISMA make sense clinically; help explain results Clinicians must decide whether to treat patients on the basis of CHARISMA subgroups

15. Heartbeat – ACC 2006 CHARISMA: Results in practice Are there patients in whom we should start new treatment? No But we should still use this information to treat patients who are on clopidogrel for other reasons Cannon

16. Heartbeat – ACC 2006 "I would prefer the term neutral, rather than negative." CHARISMA: Results in practice Ferguson No long-term extended clopidogrel + aspirin in people at risk In patients on clopidogrel + aspirin for ACS indication: no push to extend use beyond one year New risk of people stopping clopidogrel for the wrong reasons, leading to possible explosion of subacute stent thrombosis.

17. Heartbeat – ACC 2006 Patients at "high risk" only should not get aspirin + clopidogrel, just aspirin alone ACS or stent patients should get drug combination for one year Only patients to get combination beyond one year would be very high-risk patients, with CAD and/or stroke recurrences, but only those with no history of bleeding Fuster CHARISMA: Results in practice

18. Heartbeat – ACC 2006 Dangers of stopping clopidogrel—will public/press misinterpret results? Compounded by results from BASKET- LATE study, showing high rates of clinical events possibly related to stent thrombosis after stopping clopidogrel Need to get the message out about not prematurely stopping clopidogrel in DES patients CHARISMA: Disaster pending? Cannon

19. Heartbeat – ACC 2006 "It's really more of a lesson in not who you can stop it in but who you should not be starting it in as long-term therapy." CHARISMA: Lessons Ferguson

20. Heartbeat – ACC 2006 Anybody who is within one year of stenting should continue to use clopidogrel + aspirin Individual with CVD with previous manifestations/recurrences, possibly affecting multiple systems, may need combination therapy A class IIa or IIb recommendation? Fuster CHARISMA: Concerns

21. Heartbeat – ACC 2006 EXTRACT-TIMI 25 Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment—Thrombolysis in Myocardial Infarction 25

22. Heartbeat – ACC 2006 Enrolled >20 000 patients with ST- elevation AMI scheduled for fibrinolysis Randomized to either enoxaparin throughout hospitalization or weight- based UFH for at least 48 hours Primary efficacy end point: death or repeat MI within 30 days Fuster EXTRACT TIMI-25: Enoxaparin in STEMI

23. Heartbeat – ACC 2006 A positive result with LMW heparin in terms of efficacy, but a concern about bleeding, although composite still favored enoxaparin EXTRACT TIMI-25: Results OutcomeUFHEnoxaparin p Primary end point (%) 129.9<0.001 Nonfatal MI (%) Major bleeding (%) 4.5 1.4 3 2.1 <0.001

24. Heartbeat – ACC 2006 "In patients with STEMI undergoing fibrinolytic therapy, enoxaparin appeared to be superior to UFH.... Despite increased bleeding, the net clinical benefit was there." Fuster EXTRACT TIMI-25: Results

25. Heartbeat – ACC 2006 Past studies suggested that LMWH provides more reliable anticoagulation at a small but real bleeding price Larger questions raised about event curves at 48 hours, when heparin was discontinued—possible benefits of prolonging antithrombotic duration following fibrinolysis Also notable that LMWH dose was adjusted in elderly EXTRACT TIMI-25: Implications Ferguson

26. Heartbeat – ACC 2006 "The real question for any clinician is: How do I do the math to figure out if this is the right strategy?" EXTRACT TIMI-25: Benefits vs bleeding risks Krumholz

27. Heartbeat – ACC 2006 A 2.2% absolute difference in death/MI/nonfatal disabling stroke favoring enoxaparin Factor in major bleeding, favoring UFH at 1.7% absolute difference Composite score=1.5% absolute fewer patients having any one of those events with enoxaparin: a net clinical benefit EXTRACT TIMI-25: Benefits vs bleeding risks Cannon

28. Heartbeat – ACC 2006 Does the fact that UFH was given for only two days and enoxaparin for seven days explain the differences in efficacy and bleeding? EXTRACT TIMI-25: Benefits vs bleeding risks Fuster

29. Heartbeat – ACC 2006 Direct comparison at 48 hours favors enoxaparin Added advantage of continuing longer "Compared with what we're doing now, longer duration of antithrombin therapy... was better than the shorter duration." EXTRACT TIMI-25: Benefits vs bleeding risks Cannon

30. Heartbeat – ACC 2006 Longer-duration UFH not possible in this setting Extended duration is an advantage of other compounds Discontinuing UFH may have been problematic EXTRACT TIMI-25: Duration of treatment Ferguson

31. Heartbeat – ACC 2006 Patients who went on to PCI stayed on enoxaparin and did well, with fewer bleeding complications—a useful finding Enoxaparin easier to use than UFH In the guidelines, use of enoxaparin would be a class I indication for STEMI Costs: $50–$60 per day, but fewer lab tests—relatively inexpensive EXTRACT TIMI-25: Other benefits

32. Heartbeat – ACC 2006 Enoxaparin compares favorably with UFH in STEMI Some questions/caution about bleeding Enoxaparin appears to be a class I indication for STEMI, as compared with UFH EXTRACT TIMI-25: Conclusions Fuster

33. Heartbeat – ACC 2006 OASIS-6 Sixth Organization to Assess Strategies in Acute Ischemic Syndromes

34. Heartbeat – ACC 2006 A synthetic pentasaccharide A selective factor Xa inhibitor Not a direct antithrombin Does not affect platelet adhesion Penetrates into factor Xa in the clot Fondaparinux: Theoretical advantages Fuster

35. Heartbeat – ACC 2006 20 000 patients with NSTE-ACS randomized to fondaparinux 2.5 mg daily or enoxaparin for a mean of six days Fondaparinux noninferior for primary outcome of death, MI, or refractory ischemia at nine days Significantly lower rate of secondary outcome—major bleeding at nine days Less bleeding translated into superior performance of fondaparinux at 30 days and six months OASIS 5: Published in NEJM

36. Heartbeat – ACC 2006 OASIS 5 reminds us of need to avoid bleeding, potentially improving efficacy and reducing mortality -Cannon Questions remain re: bleeding definitions, dosing, and problems related to PCI in OASIS 5 -Ferguson Fondaparinux concept has always "made sense" and looks promising -Krumholz OASIS 5: Published in NEJM

37. Heartbeat – ACC 2006 "The good news is, there's a lot of things that work; the bad news is, there's a lot of things that work. And now we've got to make some decisions." Anticoagulants: A multitude of choices Ferguson

38. Heartbeat – ACC 2006 "We may need to get a lot of people together to update the guidelines soon, because the confusion is going to lead to paralysis: people aren't going to know what to do." Krumholz Anticoagulants: A multitude of choices

39. Heartbeat – ACC 2006 "In OASIS 6, my enthusiasm dial is not quite as high." An overall benefit, but clear subsets didn't benefit:  Patients heading to PCI  Patients in whom UFH, not placebo, was the control "I have real questions as to what exactly this has really shown us." OASIS 6: Fondaparinux in STEMI Ferguson

40. Heartbeat – ACC 2006 Vast majority of patients got no antithrombin as control Very different from EXTRACT, which compared therapy with guideline- recommended treatment More evidence that longer therapy may be beneficial OASIS 6: Fondaparinux in STEMI

41. Heartbeat – ACC 2006 OASIS 6 will not have major impact on MI world -Ferguson Our enthusiasm should be circumspect -Krumholz You need some type of antithrombin in the cath lab -Cannon OASIS 6: Fondaparinux in STEMI

42. Heartbeat – ACC 2006 Recommendations: CHARISMA Clopidogrel + aspirin for one year is "a must" poststenting and for AMI patients: a class I indication Beyond one year, or in nonstented patients/non-ACS patients, evidence is less clear for clopidogrel + aspirin

43. Heartbeat – ACC 2006 Recommendations: EXTRACT-TIMI 25 and OASIS 5, 6 EXTRACT-TIMI 25: Enoxaparin moving toward a class I indication in STEMI OASIS 5: Fondaparinux in NSTE-ACS: likely a class I indication OASIS 6: Fondaparinux in STEMI appeared to be superior, but the trial was complex: possibly a IIa or IIb level of evidence Fuster

44. Heartbeat – ACC 2006 Many exciting new options for antithrombotic therapy in various types of ACS "We all need to revisit our pathways to sort out: do we have the mix right for what's available and what our practice is in our hospitals?" Conclusions Cannon

45. Heartbeat – ACC 2006 Concerns about fondaparinux in NSTE-ACS due to invasive management pathway and catheter thrombosis in OASIS 5 CHARISMA: Don't use combination therapy on the basis of individual risk, or beyond one year except in rare circumstances Conclusions Ferguson

46. Heartbeat – ACC 2006 EXTRACT TIMI 25: Rethink LMWH as fibrinolytic therapy in STEMI; possible need for longer-duration fibrinolysis OASIS 5, 6: How can we integrate fondaparinux into guidelines, practice? Conclusions Ferguson

47. Heartbeat – ACC 2006 " The avalanche of information that's coming out of these meetings is a challenge. [We have] to try to help doctors sort through this and to figure out how we're going to create faster ways to adapt the right technology." Krumholz Conclusions