1. Northeast Georgia Heart Center Interventional Pharmacology: Anti-thrombin Therapy J. Jeffrey Marshall, MD, FSCAI Past President SCAI, 2012-2013 Director Cardiac Cath Lab Northeast GA Heart Center SCAI Fellow’s Course Qingdao, CHINA August 22, 2014

2. Northeast Georgia Heart Center Anticoagulation for PCI Heparin LMWH Bivalirudin Fondaparinux Which Agent?

3. Northeast Georgia Heart Center UFH: Clinical Experience, Non-inferiority UFH + GPI: Numerous studies (vs UFH alone) LMWH: ESSENCE, TIMI 11, INTERACT SYNERGY, STEEPLE Bivalirudin: BAT, REPLACE 2, ACUITY, HORIZONS ACS, EuroMax, HEAT- PPCI Fondaparinux: OASIS 5, OASIS 6 Beneficial Agents Interventional Pharmacology

4. Anti-thrombin Platelet Effects UFH Xa / IIa Aggregation GP 2b/3a Inhibition ADP inhibitor Inhibition LMWH Xa / IIa Minimal effect Bivalirudin IIa (direct) Inhibition

5. Northeast Georgia Heart Center Unfractionated Heparin

6. Northeast Georgia Heart Center Unfractionated Heparin  Indirect thrombin inhibitor  Requires AT3 for activation  Does not inhibit clot-bound thrombin  Nonspecific binding to: ― Plasma proteins ― Endothelial cells (variable anticoagulation level)  Inhibited by platelet factor 4 ― reduced effect in ACS  Causes platelet aggregation  Risk of HIT Disadvantages  Multiple sites of action in coagulation cascade (IIa,Xa)  Long history of successful clinical use  Readily monitored by aPTT and ACT  Very inexpensive Advantages Hirsh J, et al: Circulation 2001;103:2994-3018

7. Northeast Georgia Heart Center 2011 PCI Guidelines Administration of IV UFH is useful in patients undergoing PCI. (Level of Evidence: C) Unfractionated Heparin Class I:

8. Northeast Georgia Heart Center LMWH with PCI

9. Northeast Georgia Heart Center Advantages of LMWH vs UFH No platelet activation Inhibits von Willebrand factor release Augments TFPI release Inhibits thrombin generation No rebound hypercoagulability

10. Northeast Georgia Heart Center Enoxaparin and PCI In Cath Lab Transition to Cath Lab NICE 1 NICE 4 ELECT Choussat Carnendran STEEPLE NICE 1 NICE 4 ELECT Choussat Carnendran STEEPLE Collet PEPCI PK study NICE 3 SYNERGY Collet PEPCI PK study NICE 3 SYNERGY

11. Northeast Georgia Heart Center Enoxaparin vs UFH Death or MI at 30 Days* TrialEnoxUFH OR [95% CI]Odds Ratio (95% CI) ESSENCE 5.87.50.76 [0.58, 1.01] TIMI 11B6.47.80.81 [0.60, 1.10] INTERACT4.68.10.55 [0.28, 1.08] A to Z7.36.91.06 [0.68, 1.67] SYNERGY12.614.80.84 [0.68, 1.05] Overall8.09.40.81 [0.70, 0.94] Enox better UFH better Test for heterogeneity: χ 2 = 2.86, df = 4, P =.58 0.21.02.0 Petersen JL: JAMA 2004;292:89-96 * No pre-randomization therapy

12. Northeast Georgia Heart Center LMWH vs UFH in PCI Trials LMWH n=3787 n=3787UFHn=978p Efficacy EP 5.8%7.6%0.03 Major Bleed 0.6%1.8%0.0001 Minor Bleed 3.1%3.1%ns Pooled Results (15 studies) Borentain, Montalescot: ESC 2003

13. Northeast Georgia Heart Center Enoxaparin in PCI Trials Enox 0.5 n=798 Enox 0.75 n=1051 Enox 1.0 n=1226 p Efficacy EP1.8%6.9%6.6%0.0001 All Bleed2.3%4.8%3.9%0.02 Pooled Results Borentain, Montalescot: ESC 2003

14. IV enoxaparin 0.5 mg/kg n=1070 IV enoxaparin 0.5 mg/kg n=1070 STEEPLE Trial IV enoxaparin 0.75 mg/kg n=1228 IV enoxaparin 0.75 mg/kg n=1228 3528 pts undergoing non-emergent single or multi-vessel PCI Primary Endpoint: Major / minor bleeding (non-CABG) at 48 hrs post-PCI Secondary Endpoints: - Percent reaching target anticoagulation levels at start and end of PCI - Percent reaching target anticoagulation levels at start and end of PCI - Composite of major bleed (48 hrs), mortality; MI, urgent TVR at 30 days - Composite of major bleed (48 hrs), mortality; MI, urgent TVR at 30 days Primary Endpoint: Major / minor bleeding (non-CABG) at 48 hrs post-PCI Secondary Endpoints: - Percent reaching target anticoagulation levels at start and end of PCI - Percent reaching target anticoagulation levels at start and end of PCI - Composite of major bleed (48 hrs), mortality; MI, urgent TVR at 30 days - Composite of major bleed (48 hrs), mortality; MI, urgent TVR at 30 days UFH (ACT – adjusted) Target ACT 200-300 With GP IIb/IIIa Target ACT 300-350 if no GP IIb/IIIa n=1230 UFH (ACT – adjusted) Target ACT 200-300 With GP IIb/IIIa Target ACT 300-350 if no GP IIb/IIIa n=1230 Montalescot: NEJM 2006;355:1006-1017

15. Northeast Georgia Heart Center STEEPLE Primary Endpoint % Non-CABG Major or Minor bleeding at 48 hrs p=0.014 vs UFH p=0.052 vs UFH Lower bleeding seen overall and in the GPI subgroup Montalescot: NEJM 2006;355:1006-1017

16. Northeast Georgia Heart Center STEEPLE Primary Endpoint % p=0.005 vs UFH p=0.007 vs UFH Major Bleeding Montalescot: NEJM 2006;355:1006-1017

17. Northeast Georgia Heart Center % p=ns Major Bleed at 48 hrs and 30 day Death, MI, or urgent TVR STEEPLE: Secondary Composite Endpoint Montalescot: NEJM 2006;355:1006-1017 No difference in Death or MI among groups

18. Northeast Georgia Heart Center 2011 PCI Guidelines PCI with enoxaparin may be reasonable in pts either treated with “upstream” SQ enoxaparin for UA/NSTEMI or who have not received prior anti- thrombin therapy and are administered IV enoxaparin at the time of PCI (Level of Evidence: B) LMWH Class IIb:

19. Northeast Georgia Heart Center Bivalirudin

20. Northeast Georgia Heart Center Direct Thrombin Inhibitors  Predictable anticoagulant response  Inhibits soluble and fibrin-bound thrombin  Inhibits thrombin-induced platelet aggregation  No HIT  Needs continuous infusion  No antidote  Short t 1/2 (20 min)  Cost DisadvantagesAdvantages

21. Northeast Georgia Heart Center Direct Thrombin Inhibitors REPLACE – 2 ACUITY HORIZONS ACS EuroMax HEAT PPCI Bivalirudin

22. Northeast Georgia Heart Center Moderate- to high- risk ACS ACUITY Study Design: First Randomization Angiography within 72 h Aspirin in all; Clopidogrel dosing and timing per local practice UFH or enox + GP IIb/IIIa n=4603 Bivalirudin + GP IIb/IIIa n=4604 Bivalirudin alone n=4,612 R* Moderate- to high-risk patients with UA or NSTEMI undergoing an invasive strategy (N = 13,819) Medical management PCI CABG Stone GW, et al: Am Heart J 2004; 148:764–775 *Stratified by pre-angiography thienopyridine treatment

23. Northeast Georgia Heart Center 11.7%11.8%1.01 (0.90-1.12) <.001.93 Risk ratio ±95% CI Risk ratio ±95% CI Primary EP ACUITY: Primary End Point Measures* UFH/Enox + GPI vs Bivalirudin + GPI Net clinical outcome Ischemic composite Major bleeding Bivalirudin + GPI better GPI better Bivalirudin + GPI better GPI better UFH/Enox + GPI better GPI better UFH/Enox + GPI better GPI better Bival + GPI UFH/Enox + GPI RR (95% CI) p value (noninferior) (superior) 7.3%7.7%1.07 (0.92-1.23).015.39 5.7%5.3%0.93 (0.78-1.10) <.001.38 Upper boundary non-inferiority Stone GW, et al: Presented at: 55 th ACC Annual Meeting March 2006 *ITT population

24. Northeast Georgia Heart Center ACUITY: Primary End Point Measures* BivalirudinbetterBivalirudinbetter UFH/Enox + GPI better UFH/Enox + GPI better Risk ratio ±95% CI Risk ratio ±95% CI Primary EP Bival alone UFH/Enox + GPI RR (95% CI) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 11.7%10.1%0.86 (0.77-0.97) <.001.015 7.3%7.8%1.08 (0.93-1.24).02.32 5.7%3.0%0.53 (0.43-0.65) <.001 p value (noninferior) (superior) UFH/Enox + GPI vs Bivalirudin alone Stone GW et al: Presented at: 55 th ACC Annual Meeting March 2006 *ITT population

25. Northeast Georgia Heart Center ACUITY-PCI 0 5 10 15 05101520253035 Days from Randomization Estimate p (log rank) 13.5% Heparin* + GPI (N=2561) Bivalirudin + GPI (N=2609) 0.10 15.1% Bivalirudin alone (N=2619) 0.049 11.7% p=0.001 Stone GW: Presented at TCT; October 2006 % n=7789 (56%) Net Clinical Outcomes

26. Northeast Georgia Heart Center 3,602 pts with STEMI with symptom onset ≤12 hours Primary PCI Strategy UFH + GPI (abciximab or eptifibatide) Bivalirudin (± provisional GP IIb/IIIa) Aspirin, thienopyridine R 1:1 3,000 pts eligible for stent randomization R 1:3 Bare metal stentTAXUS ® stent Clinical FU at 30 days, 1 yr, then yearly through 5 yrs HORIZONS AMI Trial Design Open-label, randomized, prospective, multicenter trial

27. RR = 0.99 P sup = 1.00 HORIZONS Outcomes (30 day events) RR = RR = 0.60 P sup ≤ 0.0001 RR = RR = 0.76 P sup = 0.006 1  endpoint ** MACE = Death, re-MI, TVR or stroke * Non-CABG Stone GW et al: NEJM 2008; 358: 2218-2230 %

28. 30 Day Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin 1800175817511746174217291666 Heparin + GPIIb/IIIa 1802176417481736172817071630 Death (%) Time in Days 2.9% 1.8% Heparin + GPI (n=1802) Bivalirudin (n=1800) 0.3% 0.2% Cardiac Non-cardiac HR = 0.62 p=0.029

29. 1-Year Net Adverse Clinical Events* *MACE or major bleeding (non CABG) 18.3% 15.7% HR = 0.84 [0.71, 0.98] p=0.03 Bivalirudin (n=1800) Heparin + GPI (n=1802)

30. 1-Year Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin (n=1800) Heparin + GPI (n=1802) 18001705168416691520 18021678166316461486 Cardiac Non Cardiac Mortality (%) 0 1 2 3 4 5 Time in Months 0123456789101112 3.8% 2.1% 1.3% 1.1% p=0.005 2.9% 1.8% Δ = 1.1% p=0.03 Δ = 1.7%

31. HORIZONS: 3-Year Mortality or Re-MI Landmark Analysis 5 4 3 2 1 0 0369121518212427303336 Heparin + GPI (n=1802) Bivalirudin (n=1800) 3-year HR (95% CI) 0.72 (0.58 – 0.91) p=0.005 30-day HR (95% CI) 0.84 (0.61 – 1.16) p=0.30 10.6% 7.8% % 3.8% 4.5% Months Stone GW : Lancet 2011; Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

32. HORIZONS Acute Stent Thrombosis (ARC Def or Prob) 0.3% 1.5% HR (95%CI) = 5.93 [2.06,17.04] p = 0.0002 16111583158015781577 15911587158415831583 Number at risk Bivalirudin UFH+GPIIb/IIIa 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Time in Hours 06121824Bivalirudin UFH + GPI %

33. Acute Stent Thrombosis: Impact of Pre-Randomization Heparin 10661052105110501049 545531529528528 Number at risk P-R Heparin No P-R Heparin Def/Prob Stent Thrombosis (%) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Time in Hours 06121824 Pre-Randomization Heparin No Pre-Randomization Heparin UFH+GPI 12111208120712071207 378377375374374 P-R Heparin No P-R Heparin Bivalirudin 0.1% 0.8% HR = 9.64 p = 0.02 0.9% 2.6% HR = 3.07 p = 0.006 P int antithrombin x pre-rand hep = 0.39

34. Northeast Georgia Heart Center Days Bivalirudin UFH with optional GPI 8.4% Log-rank p = 0.002 Euromax: Primary Endpoint Death or Major Bleed, 30 day 5.1% 10 8 6 4 2 0 25 30 20 15 10 5 0 % Steg PG: Am Heart J 2013

35. Northeast Georgia Heart Center HEAT PPCI: Primary EP (MACE) n=1812 Shahzad A, Stables R: ACC LBCT March 2014

36. Northeast Georgia Heart Center BivalirudinHeparinp Definite / Prob3.4 %0.9 %0.001 Acute2.9 %0.9 %0.001 Subacute0.6%0%ns ARC definite / prob ST events Heat PPCI: Stent Thrombosis Shahzad A, Stables R: ACC LBCT March 2014

37. % Acute Stent Thrombosis (within 24 hrs) p=0.006 p=0.001 Bivalirudin for Primary PCI p=0.02 p=0.007 UFH Pre; BV d/c Immed No UFH; BV d/c Immed BV cont 2-4 hrNo UFH; BV d/c Immed

38. % Acute Stent Thrombosis vs Duration of Bivalirudin p=0.006 p=0.001 Bivalirudin for Primary PCI: Euromax p=0.02 p=0.007 UFH Pre; BV d/c Immed No UFH; BV d/c Immed BV cont 2-4 hrNo UFH; BV d/c Immed

39. Northeast Georgia Heart Center % Acute Stent Thrombosis vs Bival Duration & Dose p=0.006 p=0.001 Bivalirudin for Primary PCI: Euromax p=0.02 p=0.007 N = 249 N = 659 N = 1,109N = 191 Clemmensen P: JACC 2014; 63: A27

40. Northeast Georgia Heart Center 2011 ACC/AHA/SCAI PCI Guidelines Class I: For pts having PCI, bivalirudin is useful as an anticoagulant with or without prior treatment with UFH). (Level of Evidence: B) For pts with HIT, it is recommended that bivalirudin or argatroban be used to replace UFH. (Level of Evidence: B) Bivalirudin

41. Northeast Georgia Heart Center Fondaparinux

42. Northeast Georgia Heart Center Fondaparinux Difficult to monitor (no aPTT or ACT) Long half-life Catheter thrombosis during PCI DisadvantagesAdvantages SC administration Once-daily Fixed dose Predictable response No antigenicity Simoons ML: J Am Coll Cardiol 2004;43:2183-2190 Yusuf S: N Engl J Med 2066; 354:1464-1476

43. Northeast Georgia Heart Center Fondaparinux OASIS 6 STEMI Superior to placebo Similar to heparin Catheter thrombus with PCI OASIS 5 High risk ACS (vs enoxaparin) Similar efficacy; less bleeding Supplemental UFH for PCI

44. Northeast Georgia Heart Center OASIS-5: Results Death, MI, or Refractory Ischemia Major Bleeding 6 5 4 3 2 1 0 Days HR: 1.01 (95% CI, 0.90-1.13) Enoxaparin Fondaparinux Days HR: 0.52 (95% CI, 0.44-1.61) p<0.001 Enoxaparin Fondaparinux Adapted from Yusuf S: et al: N Engl J Med 2006:354:1464-1476 EventFondaparinuxEnoxaparinp value Mortality (30 day)2.9%3.5%0.02 Mortality (6 mo)5.8%6.5%0.05 30 Day and 6 Month Results *1.5% thrombus on catheter (in fondaparixux group) if no UFH given % 4 3 2 1 0 % 0 1 2 3 4 5 6 7 8 9

45. Northeast Georgia Heart Center Interventional Pharmacology UFH is effective for PCI, particularly when used with a GPI LMWH (enox) is safe and effective with PCI but is infrequently used in US Bivalirudin has superior outcomes (  NACE and bleeding) for ACS and STEMI pts Acute stent thrombosis is issue with bivalirudin for pPCI which requires adjunctive Rx Fondaparinux is effective for ACS but problematic and generally avoided with PCI – catheter thrombosis Summary