2. ACS Management NSTEMI Pro DTI “Hook-ster Hoekstra” Pro Factor Xa “Knockdown Diercks”

3. James W. “Hook-ster” Hoekstra, MD

4. Bivalirudin Use in the ED for NSTEMI: Maximizing Our Choices to Maximize Our Patients’ Benefit James Hoekstra, MD Professor and Chairman Department of Emergency Medicine Wake Forest University

5. 80% Diagnosis Diagnostic catheterization 60% 10% 20% 30% PCI CABG Medical management High risk Low risk CRUSADE Database. Average time to catheterization = 21 hours Current Management of NSTEMI ACS in the United States: Cath Happy!! ACS, acute coronary syndrome; CABG, coronary artery bypass graft.

6. Invasive Strategy Clinical Criteria (Class IA) –Recurrent chest pain –Elevated troponin level –ST depression –Signs of congestive heart failure –Sustained ventricular tachycardia –Hemodynamic instability –PCI in last month –High-risk noninvasive testing results –Prior CABG –TIMI >3 –LVEF <40% –Diabetes 2007 ACC/AHA NSTE ACS Guidelines, available at acc.org.

7. EM Relevance: Medical Management in the Pre-PCI Period Concern Is Recurrent MI/Ischemia ED Presentation Catheterization D/C PCI Pre-PCI Period Post-PCI Period Cardiologists are vulnerable in the PCI and post-PCI period, where bleeding is a major concern

8. The Challenge: Balancing Efficacy and Safety Old guidelines (2002) emphasize reduction of ischemic risk in NSTE ACS—especially for upstream therapy initiated in the ED New guidelines (2007) include data on the harm that bleeding events cause, diminishing ischemic efficacy in some patients, and provide many more options for care upstream Emergency physicians are comfortable with the goal of reducing ischemic risk... and traditionally have left concern over bleeding to “downstream providers”; this paradigm is changing

9. IIa S C Direct antithrombin LMWH AT Xa AT Xa Pentasaccharide Bivalirudin and Fondaparinux = saccharide unit. Konkle BA, Schafer AI. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease. 7th ed. Volume 2. Philadelphia: Elsevier Saunders; 2005:2067–2092. UFH LMWH, low-molecular-weight heparin.

10. Moderate- high risk ACS Study Design: First Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Angiography within 72 hours Aspirin in all Clopidogrel dosing and timing per local practice UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R* *Stratified by preangiography thienopyridine use or administration. ACUITY Design. Stone GW, et al. Am Heart J. 2004;148:764–775. Medical management PCI CABG

11. Primary End Point Measures (Intent to Treat) Heparin* + IIb/IIIa vs Bivalirudin + IIb/IIIa vs Bivalirudin Alone P NI <0.001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.001 P Sup <0.001 *Heparin=unfractionated or enoxaparin. Stone GW, McLaurin BT. N Engl J Med. 2006;355:2203–2216.

12. ACUITY: Primary End Point Measures (Intent to Treat) Bivalirudin Alone Better UFH/Enox + IIb/IIIa Better Risk Ratio ±95% CI Risk Ratio ±95% CI Primary End Point Bival alone UFH/Enox + IIb/IIIa RR (95% CI) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 11.7%10.1%0.86 (0.77-0.97) <0.001 0.015 7.3%7.8%1.08 (0.93-1.24) 0.02 0.32 5.7%3.0%0.53 (0.43-0.65) <0.001 P Value (noninferior) (superior) UFH/Enoxaparin + GPI vs Bivalirudin Alone Stone GW, McLaurin BT. N Engl J Med. 2006;355:2203–2216.

13. UFH/Enoxaparin + IIb/IIIa vs Bivalirudin Alone Yes (n = 3,197) No (n = 6,008) Low (0–2) (n = 1,291) Intermed (3–4) (n = 4,407) High (5–7) (n = 2,449) Elevated (n = 5,368) Normal (n = 3,841) Risk Ratio ±95% CI Risk Ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa 9.2% 11.3% 12.2% 11.1% PP int 0.76 (0.65 – 0.89) 1.02 (0.86 – 1.21) 12.2% 7.1% 13.3% 9.4% 0.92 (0.80 – 1.06) 0.75 (0.61 – 0.93) 0.23 0.01 <0.001 0.83 0.35 0.02 0.18 13.0% 8.6% 13.7% 10.6% 0.96 (0.80 – 1.14) 0.81 (0.69 – 0.95) 0.61 0.01 0.42 Biomarkers (CK/Trop) ST deviation TIMI risk score Prethienopyridine 6.4%10.2%0.63 (0.43 – 0.91)0.01 9.4%10.2%0.92 (0.77 – 1.10) 0.34 13.9%15.2%0.92 (0.76 – 1.11)0.36 Yes (n = 5,192) No (n = 4,023) RR (95% CI) Bivalirudin Alone Better UFH/Enox + IIb/IIIa Better Stone GW, McLaurin BT. N Engl J Med. 2006;355:2203–2216. ACUITY: Net Clinical Outcome Composite

14. Enoxaparin or UFH with antiplatelet agents Fondaparinux or bivalirudin with antiplatelet agents Invasive Therapy: Initial Antithrombin Therapies I I IIa IIb III.

15. Upstream Hospital Care: Invasive Rx Antiplatelet Therapy  A Platelet GP IIb/IIIa inhibitor in addition to ASA and heparin upstream for patients in whom PCI is planned OR  Clopidogrel 300 mg load and 75 mg/day upstream for a month up to a year Bivalirudin instead of GPI/antithrombin upstream only if clopidogrel is used as well >6 hours prior to PCI  A Platelet GP IIb/IIIa inhibitor in addition to ASA and heparin upstream for patients in whom PCI is planned OR  Clopidogrel 300 mg load and 75 mg/day upstream for a month up to a year Bivalirudin instead of GPI/antithrombin upstream only if clopidogrel is used as well >6 hours prior to PCI I I IIa IIb III

16. Bleeding Among Patients with ACS Conclusions Antithrombotic therapies are cornerstone Rx –Must balance thrombosis and hemostasis Certain patient and PCI procedure characteristics predict bleeding –Age, female gender, chronic kidney disease, procedure time, sheath dwell time Bivalirudin is a GREAT option in these patients

17. Deborah B. “Knockdown” Diercks, MD

18. Xa Better Living Through Chemistry Deborah Diercks, MD Associate Professor Department of Emergency Medicine University of California, Davis Medical Center

19. My Position Agents providing Xa inhibition are more desirable than UFH or direct thrombin inhibition –Xa inhibition is provided In balance with IIa (thrombin) inhibition –LMWH (enoxaparin) In isolation –Fondaparinux

20. My Position Part I: Enoxaparin and fondaparinux are superior to UFH Part II: ACUITY results do not support the superiority of bivalirudin

21. Part I Enoxaparin and Fondaparinux Are Superior to UFH

22. The Enemy and Our Weapons Weapons to stop the cascade: –Heparin –LMWH –Special forces Xa inhibitors Direct thrombin inhibitors Cascade activation (intrinsic or extrinsic pathway) Factor XFactor Xa Prothrombin (factor II) Thrombin (factor IIa) FibrinogenFibrin

23. Weapons

24. LMWH: Cleaner Dalteparin and enoxaparin –Animal derived –Smaller chains  more selective activity –Anti Xa >> anti IIa –Less PF4 binding Less HIT II

25. At least 2 of 3 required:  Age  60 years  ST  (transient) or   (+) CK-MB or troponin IV Heparin Primary end point: death or MI at 30 days High-Risk ACS Patients Randomize (N = 10,027) Early invasive strategy Other therapy per ACC/AHA guidelines (ASA,  -blocker, ACE-I, clopidogrel, GP IIb/IIIa) 60 U/kg  12 U/kg/hr (aPTT 50–70 seconds) 1 mg/kg SC every 12 hours SYNERGY: Study Design Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45–54. Enoxaparin aPTT, activated partial thromboplastin time.

26. SYNERGY: Primary End Point 051015202530 0.8 0.85 0.9 0.95 1.0 Freedom from Death / MI Days from Randomization UFH Enoxaparin HR 0.96 (0.87-1.06) 30-Day Death/MI 0.8 1 1 1.2 Hazard Ratio (95% CI) Enoxaparin Better UFH Better Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45–54.

27. Death or MI to 30 Days Cumulative % of Patients Days from Randomization 051015202530 UFH Enoxaparin HR = 0.82 95% CI: 0.72, 0.94 15.9 13.3 P = 0.004 RRR = 16.4 20 15 10 5 0 J Am Coll Cardiol. 2006;48:1346–1354. SYNERGY: Consistent Therapy

28. Patients with NSTE ACS, chest discomfort <24 hours 2 of 3: Age >60 years, ST segment Δ,  cardiac markers Patients with NSTE ACS, chest discomfort <24 hours 2 of 3: Age >60 years, ST segment Δ,  cardiac markers Fondaparinux 2.5 mg SC once daily Fondaparinux 2.5 mg SC once daily OASIS-5: Study Overview ASA, clopidogrel, GP IIb/IIIa, planned cath/PCI as per local practice Randomize Enoxaparin 1 mg/kg SC twice daily Enoxaparin 1 mg/kg SC twice daily Primary: Efficacy: Death, MI, refractory ischemiaat 9 days Safety: Major bleeding at 9 days Risk benefit: Death, MI, refractory ischemia, major bleeds at 9 days Secondary: Above & each component separately at day 30 and 6 months Hypothesis: First test noninferiority, then test superiority Primary: Efficacy: Death, MI, refractory ischemiaat 9 days Safety: Major bleeding at 9 days Risk benefit: Death, MI, refractory ischemia, major bleeds at 9 days Secondary: Above & each component separately at day 30 and 6 months Hypothesis: First test noninferiority, then test superiority Outcomes PCI <6 hours: No additional UFH PCI >6 hours: IV UFH With IIb/IIIa 65 U/kg Without IIb/IIIa 100 U/kg PCI <6 hours: IV fondaparinux 2.5 mg without IIb/IIIa, 0 with IIb/IIIa PCI >6 hours: IV fondaparinux 2.5 mg with and 5.0 mg without IIb/IIIa Exclude Age <21 years Any contraindication to enoxaparin Hem stroke <12 months Cr >3 mg/dL/265 umol/L N = 20,000

29. OASIS-5: Efficacy Outcomes at Day 9 EnoxFonda Death/MI/RI5.8%5.9% Death/MI4.1% Death1.9%1.8% MI2.7% Refractory ischemia 1.9%2.05% 0.811.2 Noninferiority Margin = 1.185 Hazard Ratio Fondaparinux Better Enoxaparin Better

30. OASIS-5: Bleeding Rates at Day 9 OutcomeEnox (%) Fonda (%) HR (95% CI)P value No. randomized10,02110,057 Total bleed7.03.20.44 (0.39-0.51)<<0.0001 Major bleed4.02.10.53 (0.45-0.62)<<0.0001 TIMI major bleed1.30.70.54 (0.41-0.73)<<0.0001 Minor bleed3.11.10.35 (0.28-0.43)<<0.0001

31. OASIS-5: Mortality at 6 Months Days Cumulative Hazard 0.0 0.02 0.04 0.06 020406080100120140160180 HR = 0.89 95% CI: 0.79, 0.99 P = 0.037 Enoxaparin Fondaparinux

32. Oasis-5 Summary of Oasis-5 –Fondaparinux has similar efficacy to enoxaparin –Fondaparinux (as used in this study) has less bleeding than enoxaparin (as used in this study) –This lower bleeding rate translated into fewer adverse outcomes at 6 months Critique –Enoxaparin was not used appropriately?

33. Part II ACUITY Results Do Not Support the Superiority of Bivalirudin

34. Moderate- high risk ACS ACUITY Study Design Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Angiography within 72 hours Aspirin in all Clopidogrel dosing and timing per local practice UFH or enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin alone R* *Stratified by preangiography thienopyridine use or administration. ACUITY Design. Stone GW, et al. Am Heart J. 2004;148:764–775. Medical management PCI CABG

35. ACUITY Major Entry Criteria ACUITY Design. Stone GW, et al. Am Heart J. 2004;148:764–775. Inclusion Criteria  Age ≥18 years  Chest pain ≥10 minutes within 24 hours  At least one of: New ST depression or transient ST elevation ≥1 mm Troponin I, T, or CKMB  Documented coronary artery disease All other 4 TIMI risk criteria - Age ≥65 years - Aspirin within 7 days - ≥2 angina episodes within 24 hours - ≥3 cardiac risk factors  Written informed consent Exclusion Criteria  No angiography within 72 hours  Acute STEMI or shock  Bleeding diathesis or major bleed within 2 weeks  Platelet count ≤100,000/mm 3  International normalized ratio >1.5 control  CrCl level ≤30 mL/min  Abciximab or ≥2 prior LMWH doses Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed  Allergy to drugs, contrast

36. Primary Results by Treatment Arm (30 Day) Heparin* + IIb/IIIa vs Bivalirudin + IIb/IIIa vs Bivalirudin Alone P NI <0.001 P Sup = 0.015 P NI = 0.01 P Sup = 0.32 P NI <0.001 P Sup <0.001 *Heparin=unfractionated or enoxaparin. Stone GW, et al. N Engl J Med. 2006;335:2203–2216.

37. Non–CABG-related bleeding – Intracranial bleeding or intraocular bleeding – Retroperitoneal bleeding – Access site bleed requiring intervention/surgery – Hematoma ≥5 cm – Hemoglobin  ≥3 g/dL with an overt source or  ≥4 g/dL without overt source – Blood product transfusion – Reoperation for bleeding 1. Superiority was driven by decreased bleeding –Trend toward higher ischemic events –Hematoma does not equal death *Heparin=unfractionated or enoxaparin. Stone GW, et al. N Engl J Med. 2006;335:2203–2216.

38. 2. An unusual and unimportant bleeding scale was used –TIMI-major bleeding rates were low in all arms

39. 3. TIMI major bleeding rates in ACUITY are similar to those seen in all other trials –Superiority due to the “innovative” bleeding scale Comparison of major bleeding rates by arm, by study

40. 4. ACUITY does not reflect practice in the United States –Biomarker-negative patients were receiving heparin + GPI

41. 5. Who is the enemy? Cost effectiveness of bivalirudin –GP IIb/IIIa Is this an issue for emergency physicians? –New guidelines suggest not every patient needs one –Registry data says that not every patient is getting one

42. My Position Follow the evidence- based guidelines –Enoxaparin and fondaparinux are indicated regardless of the management strategy –Even in the invasive arm, not all get a GP Anti-Xa is the way!!!

43. BLEEDING IS IMPORTANT ONE SIZE DOES NOT FIT ALL!!! Pro DTI “Hook-ster Hoekstra”

44. Selection of Therapy in the ED Must Include Consideration of Bleeding Risk Age Gender Renal insufficiency Baseline anemia Expectation of prolonged medical therapy

45. P valueRR (95% CI)Risk Ratio ± 95% CI Results: The ACUITY Trial PCI Population Predictors of Major Bleeding Age >75 years (vs 55–75) Anemia CrCl level <60 mL/min Diabetes Female gender High risk (ST/biomarkers) Hypertension 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

46. ACUITY: Impact of 30-Day Events on 1-Year Mortality Stone GW, McLaurin BT. N Engl J Med. 2006;355:2203–2216. Stone et al. American College of Cardiology Annual Scientific Session; March 24–27, 2007; New Orleans, La.

47. 30-Day Outcomes: Renally Impaired (CrCl <60 mL/min) by Treatment Group *Heparin=unfractionated or enoxaparin. RR 0.64 (0.45-0.89) RR 1.21 (0.91-1.61) RR 0.96 (0.77-1.19)

48. Bivalirudin 30-Day Outcomes in Diabetic Patients: ACUITY Substudy P = 0.08 P = 0.42 P < 0.003 30-Day Events (%) Major bleeding (non-CABG) Data on file. The Medicines Company, Parsippany, NJ.

49. Seamless Transition to the Cath Lab: The Ideal Scenario??? Presentation Early Treatment in the ED Catheterization D/C PCI Drug Administration

50. Bivalirudin is a good antithrombin agent It should be used in the patient population that was studied –That is what evidence-based medicine is all about Pro Factor Xa “Knockdown Diercks”

51. Let’s Take a Closer Look

52. 1. Patients were on study drug for a very short time - Patients were on study drug a median of 3.9–4.1 hours prior to PCI 2. Majority of the patients were treated with a UFH or anti-Xa inhibitor prior to randomization 3. All patients were to undergo an invasive management strategy

53. 4. Broad inclusion criteria Inclusion Criteria  Age ≥18 years  Chest pain ≥10 minutes within 24 hours  At least one of: New ST depression or transient ST elevation ≥1 mm Troponin I, T, or CKMB  Documented coronary artery disease All other 4 TIMI risk criteria - Age ≥65 years - Aspirin within 7 days - ≥2 angina episodes within 24 hours - ≥3 cardiac risk factors High risk??? Does this reflect current practice? What is the appropriate treatment for this group?

54. My Final Position In high-risk patients: –Enoxaparin or fondaparinux are recommended agents in patients who will be managed with a conservative or invasive strategy In intermediate-risk patients or patients at higher risk for bleeding, who are rapidly going on to cardiac intervention (no long ED stay), who have been treated with an anti-Xa agent prior to initiating bivalirudin, it is a reasonable agent

55. Why You Should Use Enoxaparin Enoxaparin –Similar rates of bleeding to UFH Improved clinical outcomes –Benefit persists regardless of whether invasive or conservative approach used –Lower resource consumption –Proven

56. Why You Should Use Fondaparinux Fondaparinux –Less bleeding than enoxaparin and bivalirudin (even in a higher-risk population) –Similar clinical outcomes (to enoxaparin) –Low cost –Ease of dosing

57. Why Would You Choose Bivalirudin? Uncertain performance in high-risk patients –What would ACUITY have looked like if it was done in the same patient population as SYNERGY or OASIS-5? Requires continuous infusion $$$$$