1. Why Bleeding Matters in ACS Importance of Multi-specialty ED and IC Therapeutic (EDICT) Alignment of Upstream Care for ACS Sunil Rao, MD, FACC Director of Interventional Cardiology Veterans Administration Medical Center Assistant Professor Division of Cardiovascular Medicine Duke University Medical Center Why Bleeding Matters in ACS Importance of Multi-specialty ED and IC Therapeutic (EDICT) Alignment of Upstream Care for ACS Sunil Rao, MD, FACC Director of Interventional Cardiology Veterans Administration Medical Center Assistant Professor Division of Cardiovascular Medicine Duke University Medical Center Getting in the (Up)Stream of Things

2. Program Faculty and COI COI Disclosures Sunil V. Rao, MD, FACC Grant/Research Support: Cordis, The Medicines Company Consultant: sanofi-aventis, Bristol-Myers Squibb, The Medicines Company Speaker’s Bureau: sanofi-aventis, Bristol-Myers Squibb, Cordis, The Medicines Company

3. AcuteCoronarySyndrome What Do The Guidelines Mean for ED Physicians and Cardiologists?

4. AcuteControversySyndrome

5. AcuteConfoundedSyndrome NSTE GLs: “The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. What Do The Guidelines Mean for ED Physicians and Cardiologists?

6. AcuteContentiousnessSyndrome

7. AcuteCollaborationSyndrome

8. Opportunities for Collaboration between Emergency Medicine and Cardiology ► Improve D2R times ► More consistency in anticoagulation and antiplatelet therapy in transition from ED to cath ● Familiarity and consistency result in fewer dosing errors, omissions and delays in therapy ► Improve compliance with evidence-driven best practice ● CRUSADE and ACTION indicate better patient outcomes; new studies suggest further improvement is possible

9. ACS Case Presentation ► 77 year old female presents to ED with 2 weeks of progressive angina, one episode lasting 90 minutes ● History of Type 2 DM, HTN, cigarette smoking ● Weight 65 kg ► ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl ► Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTG ► Continued chest pain ● Anticoagulation options in the ED? ● Risk stratification strategy? ● Which upstream strategy makes most sense? ● Collaboration with cardiology colleagues? ► 77 year old female presents to ED with 2 weeks of progressive angina, one episode lasting 90 minutes ● History of Type 2 DM, HTN, cigarette smoking ● Weight 65 kg ► ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl ► Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTG ► Continued chest pain ● Anticoagulation options in the ED? ● Risk stratification strategy? ● Which upstream strategy makes most sense? ● Collaboration with cardiology colleagues?

10. Medical Rx (cath) Time AdmissionCathDischarge No Cath Cath PCI Surgery Medical Rx (no cath) Medical Rx No disease (82 % of total) (18 % of total) (52% of total, 63% of those undergoing cath) 40 % < 48 hrs 12 % > 48 hrs (12% of total, 15% of those undergoing cath) 63 % < 48 hrs 19 % > 48 hrs CRUSADE Registry 10/04-9/05 n=35,897 Patient X ACS Management Pathways Cath Medical Rx

11. Ischemic Complications Hemorrhage HIT ► Death ► MI ► Urgent TVR ► Death ► MI ► Urgent TVR ► Major Bleeding ► Minor Bleeding ► Thrombocytopenia ► Major Bleeding ► Minor Bleeding ► Thrombocytopenia Composite Adverse Event Endpoints Evolving Paradigm for Evaluating ACS Management Strategies Although these complications usually are not seen in the ED, choices made in the ED influence the likelihood of these adverse events! Although these complications usually are not seen in the ED, choices made in the ED influence the likelihood of these adverse events!

12. SYNERGY LMWH ESSENCE 1994199519961997199819992000200220032004200520062001 CURE Clopidogrel GP IIb/IIIa blockers PRISM-PLUS PURSUIT ACUITY TACTICS TIMI-18 Early invasive PCI ~ 5% stents ~85% stents Drug-eluting stents ISAR-REACT 2 Milestones in ACS Management OASIS-5 [ Fondaparinux ] Anti-Thrombin Rx Anti-Platelet Rx Anti-Platelet Rx Treatment Strategy Heparin Aspirin Conservative ICTUSBivalirudin REPLACE 2 Bleeding risk Ischemic risk Adapted from and with the courtesy of Steven Manoukian, MD. 20072008 ISAR-REACT 3 OASIS-6 HORIZONS AMI TRITON TIMI-38

13. Options for NSTE-ACS Therapy in 2009 ► Antiplatelet therapies ● ASA, Clopidogrel ● Glycoprotein IIb/IIIa inhibitors ► Antithrombin therapy ● UFH ● Enoxaparin ● Fondaparinux ● Bivalirudin ► Risk stratification ● Conservative ● Invasive ► Antiplatelet therapies ● ASA, Clopidogrel ● Glycoprotein IIb/IIIa inhibitors ► Antithrombin therapy ● UFH ● Enoxaparin ● Fondaparinux ● Bivalirudin ► Risk stratification ● Conservative ● Invasive

14. Antiplatelet Tx: 2007 I I IIa IIb III ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: add IIb/IIIa upstream EIS: it is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: can omit IIb/IIIa if bivalirudin is anticoagulant + at least 300mg clopidogrel given > 6h prior to cath ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: add IIb/IIIa upstream EIS: it is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: can omit IIb/IIIa if bivalirudin is anticoagulant + at least 300mg clopidogrel given > 6h prior to cath

15. New Guidance on Thienopyridines I I IIa IIb III Clopidogrel 75mg/d should be added to ASA in STEMI patients if lysed or if not reperfused If < 75y/o and lysed or if not reperfused, add oral load of 300mg clopidogrel In PPCI, give 600mg clopidogrel as soon as possible Clopidogrel 75mg/d should be added to ASA in STEMI patients if lysed or if not reperfused If < 75y/o and lysed or if not reperfused, add oral load of 300mg clopidogrel In PPCI, give 600mg clopidogrel as soon as possible Antman et al, 2007 Focused Update to 2004 ACC/AHA STEMI GLs King et al, 2008 Focused Update to 2005 ACC/AHA/SCAI PCI GLs Antman et al, 2007 Focused Update to 2004 ACC/AHA STEMI GLs King et al, 2008 Focused Update to 2005 ACC/AHA/SCAI PCI GLs

16. Risk of events Risk of bleeding Thrombosis Hemostasis Two sides of the same coin Degree of Anticoagulation Risk Balancing Ischemic Events and Bleeding Risk

17. CRUSADE In-Hospital Outcomes: 2006 * Excluding CABG-related transfusions CRUSADE DATA: January 1, 2006 – December 31, 2006 (n= 29,825) Death3.6% (Re)-Infarction1.8% CHF6.6% Cardiogenic Shock 2.2% Stroke0.7% RBC Transfusion* 9.1%

18. ACS-related Bleeding —Relevant Questions for the Emergency Medicine Specialist ► Who bleeds? Can we risk stratify? ► Should bleeding risk affect upstream antithrombotic care? If so, how? ► Is bleeding bad or a necessary evil? ► Can blood transfusion “correct” risks associated with bleeding? ► Does bleeding affect resource use? ► What options do we have to balance efficacy (reduced risk for ischemic outcomes) and safety (reduced bleeding)? ► Who bleeds? Can we risk stratify? ► Should bleeding risk affect upstream antithrombotic care? If so, how? ► Is bleeding bad or a necessary evil? ► Can blood transfusion “correct” risks associated with bleeding? ► Does bleeding affect resource use? ► What options do we have to balance efficacy (reduced risk for ischemic outcomes) and safety (reduced bleeding)?

19. Bleeding in ACS—Identification Questions to be answered — 1.Who bleeds? 2.What risk factors are predictive of bleeding? 3.How should initial choices for upstream care be influenced by bleeding risk? Questions to be answered — 1.Who bleeds? 2.What risk factors are predictive of bleeding? 3.How should initial choices for upstream care be influenced by bleeding risk?

20. Independent predictors of major bleeding in marker- positive acute coronary syndromes Moscucci, GRACE Registry, Eur Heart J. 2003 Oct;24(20):1815-23. Predictors of Major Bleeding in ACS ► Older Age ► Female Gender ► Renal Failure ► History of Bleeding ► Right Heart Catheterization ► GPIIb-IIIa Antagonists ► Older Age ► Female Gender ► Renal Failure ► History of Bleeding ► Right Heart Catheterization ► GPIIb-IIIa Antagonists

21. P-value RR (95% CI) Risk ratio ± 95% CI Predictors of Major Bleeding Age >75 (vs. 55-75) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension No prior PCI Prior antithrombotic therapy Heparin(s) + GPI (vs. Bivalirudin) 1.56 (1.19-2.04) 0.0009 1.89 (1.48-2.41) <0.0001 1.68 (1.29-2.18) <0.0001 1.30 (1.03-1.63) 0.0248 2.08 (1.68-2.57) <0.0001 1.42 (1.06-1.90) 0.0178 1.33 (1.03-1.70) 0.0287 1.47 (1.15-1.88) 0.0019 1.23 (0.98-1.55) 0.0768 2.08 (1.56-2.76) <0.0001 Manoukian SV, Voeltz MD, Feit F et al. TCT 2006; Manoukian, Feit, Mehran et al., JACC; 2007; 49(12); 1362-68. Results: The ACUITY Trial — PCI Population

22. P-value RR (95% CI) Age >75 (vs. 55-75) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension Heparin(s) + GPI (vs. Bivalirudin) 1.420 (1.055-1.910) 0.0060 3.764 (2.919-4.855) <0.0001 2.097 (1.568-2.803) <0.0001 1.560 (1.209-2.014) 0.0060 2.233 (1.739-2.867) <0.0001 1.754 (1.297-2.372) 0.0003 1.457 (1.051-2.020) 0.0241 1.728 (1.256-2.379) 0.0007 Predictors of Transfusion Risk ratio ± 95% CI Results: The ACUITY Trial Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

23. ► Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion ► Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia ► These risk factors can readily be identified during the ED evaluation of a patient with ACS ► Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion ► Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia ► These risk factors can readily be identified during the ED evaluation of a patient with ACS Bleeding Predictors — Conclusions

24. Questions to be answered 1.Is bleeding bad or a necessary evil? 2.What is the relationship between bleeding and patient outcomes in ACS? 3.What initial choices can the ED physician make that are compatible with guidelines and that will reduce bleeding? Questions to be answered 1.Is bleeding bad or a necessary evil? 2.What is the relationship between bleeding and patient outcomes in ACS? 3.What initial choices can the ED physician make that are compatible with guidelines and that will reduce bleeding? Bleeding in ACS — Consequences

25. Moscucci M et al. Eur Heart J 2003;24:1815-23. P<0.001 Overall Unstable NSTEMI STEMI ACS Angina Patients (%) Major Bleeding Predicts Mortality in ACS 24,045 ACS patients in the GRACE registry, in-hospital death

26. log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Bleeding and Outcomes in ACS Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12. Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT

27. 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST Bleeding severity and adjusted hazard of death *p<0.0001 Bleeding and Outcomes in NSTE-ACS Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12. Bleeding Severity 30d Death 30d Death/MI 6 mo. Death Mild*1.61.31.4 Moderate*2.73.32.1 Severe*10.65.67.5 *Bleeding as a time-dependent covariate

28. Mortality (%) Days from Randomization 0306090120150180210240270300330360390 0 5 15 30 10 25 20 1 year Estimate Major Bleed only (without MI) (N=551)12.5% 28.9%Both MI and Major Bleed (N=94) 3.4%No MI or Major Bleed (N=12,557) MI only (without Major Bleed) (N=611)8.6% Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 28.9% 12.5% 8.6% 3.4% ACUITY Stone GW, et al. JAMA 2007; 298:2497-2506

29. Day 0 – 2 after MI 12.6 (7.8-20.4) 29 (37.6) <0.0001 Day 3 – 7 after MI 5.3 (2.7-10.4) 11 (14.3) <0.0001 Day 8 – 35 after MI 1.6 (0.8-3.1) 12 (15.6) 0.18 Day > 35 after MI 1.2 (0.8-1.9) 25 (32.5) 0.34 Day 0 – 2 after Major Bleed 3.0 (1.6-5.6) 12 (12.9) 0.0009 Day 3 – 7 after Major Bleed 4.0 (2.1-7.5) 15 (16.1) <0.0001 Day 8 – 35 after Major Bleed 4.5 (2.8-7.4) 25 (26.9) <0.0001 Day > 35 after Major Bleed 2.2 (1.5-3.2) 41 (44.1) <0.0001 P-valueP-value Deaths (n/%) HR ± 95% CI 0.5 1 2 4 8 16 HR (CI) Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year ACUITY TRIAL—Cox model adjusted for baseline predictors: Bleeding and MI as time updated covariates Stone, ACC 2007

30. In-Hospital Bleeding and Discharge Therapies N=2498 pts in PREMIER Registry Less likely More likely Wang TY, et.al. Circulation (in press) Discharge 1 Month 6 Months 1 Year Discharge 1 Month 6 Months 1 Year Discharge 1 Month 6 Months 1 Year Aspirin Thienopyridine Beta-Blocker 0 0.5 1.0 1.5

31. ► Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those undergoing PCI ● Mortality rates are higher among those who bleed ● MI rates are higher among those who bleed ► The risk is at least similar to that conferred by MI (maybe higher) ► The risk is persistent out to 1 year while the risk from recurrent ischemia appears limited to 30 days ► Decisions made in the ED may affect subsequent bleeding risk, and in turn, evidence-based therapy and clinical outcomes ► Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those undergoing PCI ● Mortality rates are higher among those who bleed ● MI rates are higher among those who bleed ► The risk is at least similar to that conferred by MI (maybe higher) ► The risk is persistent out to 1 year while the risk from recurrent ischemia appears limited to 30 days ► Decisions made in the ED may affect subsequent bleeding risk, and in turn, evidence-based therapy and clinical outcomes Bleeding and Outcomes — Conclusions

32. Bleeding in ACS Question To Be Answered Can blood transfusion “correct” adverse outcomes associate with bleeding?

33. 30-Day Survival By Transfusion Group Rao SV, et. al., JAMA 2004;292:1555–1562. Transfusion in ACS N=24,111

34. *Transfusion as a time-dependent covariate Cox Model for 30-day Death N=24,111N=24,111 Rao SV, et. al., JAMA 2004;292:1555–1562. PRBC Transfusion Among NSTE ACS Patients PRBC Transfusion Among NSTE ACS Patients Adjusted for transfusion propensity Adjusted for baseline characteristics Adjusted for baseline characteristics, bleeding propensity, transfusion propensity, and nadir HCT Adjusted for transfusion propensity Adjusted for baseline characteristics Adjusted for baseline characteristics, bleeding propensity, transfusion propensity, and nadir HCT 3.77 (3.13, 4.52 3.54 (2.96, 4.23) 3.94 (3.26, 4.75) -4.01.0 10.0

35. Adjusted Risk of In-Hospital Outcomes By Transfusion Status* Adjusted Risk of In-Hospital Outcomes By Transfusion Status* *Non-CABG patients only Yang X, J Am Coll Cardiol 2005;46:1490–5. N=74,271 ACS patients from CRUSADE Death Death or Re-MI 1.0 2.0

36. Transfusion, Ischemic Endpoints, and Mortality in ACUITY Trial P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial (N=13,819)

37. Increased 1-year mortality in transfused patients Adjusted Odds Ratio 4.26 (2.25–8.08) Transfusion Post PCI — REPLACE 2 One Year Mortality P<0.0001 Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT 2005. Abstract.

38. ► Blood transfusion is independently associated with death and re-MI ► Transfusion does not correct the adverse impact bleeding and is not an “insurance policy” for choices made in the ED ► Blood transfusion is best avoided in ACS patients whenever possible ► Decisions regarding bleeding risk should be part of ED decision-making process ► Blood transfusion is independently associated with death and re-MI ► Transfusion does not correct the adverse impact bleeding and is not an “insurance policy” for choices made in the ED ► Blood transfusion is best avoided in ACS patients whenever possible ► Decisions regarding bleeding risk should be part of ED decision-making process Blood Transfusion — Conclusions

39. Bleeding in ACS Question To Be Answered Does bleeding impact resource use? Does bleeding impact resource use? Question To Be Answered Does bleeding impact resource use? Does bleeding impact resource use?

40. Bleeding and Resource Use Predictors of Total Costs Moderate/severe bleed Per patient cost - $530 Transfusion - $2,080, P < 0.01 Per patient cost - $287 Moderate/severe bleed Per patient cost - $530 Transfusion - $2,080, P < 0.01 Per patient cost - $287 Model C-index=0.87 Adjusted for patient characteristics Model C-index=0.87 Adjusted for patient characteristics Rao SV, et. al. AHJ 2008. N=1235 pts from GUSTO IIb

41. ► The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding ● Both ischemic complications and bleeding are associated with increased costs such that any cost savings realized by reducing one is offset by cost increases associated with the other ► Although these costs are not realized in the ED, the choices made there impact costs downstream ► The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding ● Both ischemic complications and bleeding are associated with increased costs such that any cost savings realized by reducing one is offset by cost increases associated with the other ► Although these costs are not realized in the ED, the choices made there impact costs downstream Bleeding and Costs — Conclusions

42. Risk versus Benefit ThrombosisThrombosis BleedingBleeding

43. ► Decision made to pursue rapid invasive risk stratification ● High-risk features Elevated troponin Elevated troponin Ongoing chest pain despite medical therapy Ongoing chest pain despite medical therapy ► Antithrombin therapy choices ● Risk for bleeding Age, Female sex, renal insufficiency, anemia Age, Female sex, renal insufficiency, anemia ● Bivalirudin bolus and gtt initiated ► Angiography ► Decision made to pursue rapid invasive risk stratification ● High-risk features Elevated troponin Elevated troponin Ongoing chest pain despite medical therapy Ongoing chest pain despite medical therapy ► Antithrombin therapy choices ● Risk for bleeding Age, Female sex, renal insufficiency, anemia Age, Female sex, renal insufficiency, anemia ● Bivalirudin bolus and gtt initiated ► Angiography Case Presentation

44. Addressing the Challenges of Selecting an Anticoagulation Strategy Bleeding Risk Ischemic Risk Renal function AgeAge Time to cath CostCost Ease of use PCI vs CABG vs Med Rx

45. UPSTREAM ACS CARE Collaborations, Models, and Protocols UPSTREAM ACS CARE Collaborations, Models, and Protocols The Mandate to Cooperate and Collaborate ED EmergencyDepartment IC InterventionalCardiology + + T TherapeuticTeams + + ACS for