Why Heparin Still Has a Role in Contemporary PCI

1. Why Heparin Still Has a Role in Contemporary PCI James P. Zidar, MD, FACC, FSCAI Associate Professor of Medicine Duke University Medical Center Director, Cardiovascular Services Duke Raleigh Hospital

2. Conflicts / Disclosures • Consultant/Advisory Board member/ DSMB member/ research support: • -Abbott Vascular • -Cordis • -Medtronic • -EV3 • Off label use of products will not be discussed in this presentation.

3. Can we do better than heparin and aspirin?

4. Aspirin Ticlopidine Clopidogrel Enoxaparin DX-9065a UF Heparin Fondaparinux GPIIb/IIIa inhibitors Bivalirudin Hirudin Argatroban Ximelagatran Thrombo- lytics Sites of Anti-thrombotic Drug Action Intrinsic, Extrinsic Pathways Coagulation cascade Platelet cascade Platelet Agonists Plasma clotting cascade ADP Thromboxane A2 Prothrombin Factor Xa Conformational activation of GPIIb/IIIa AT III Thrombin Platelet aggregation Fibrinogen Fibrin Thrombus

5. UFH bound to AT Unfractionated Heparin (UFH) • Referred to as standard or unfractionated heparin (UFH) and discovered in 1916 by a medical student, first clinical trials in 1938 • Named heparin because of its abundance in the liver, but found in highest amounts in highly vascularized tissues such as lung and intestine • A catalytic cofactor for antithrombin III of 5,000 – 30,000 Daltons • Heterogeneous mixture of polysaccharide chains with varying effects on anticoagulant activity • Accelerates the action of circulating antithrombin (AT), a proteolytic enzyme which inactivates factors IIa (thrombin), IXa, Xa • Prevents thrombus propagation, but does not lyse existing thrombi

6. Heparin inactivated by Platelet Factor 4 Heparin Heparin activates platelets directly - GP IIb/IIIa activated - P-selectin expressed + P-selectin Platelet Activated Platelet GP IIb/IIIa 2 P Heparin Thrombin P Heparin cannot bind clot-bound thrombin 1 2 Heparin can induce and immune response such as HIT/TS and lead to thrombocytopenia and thrombosis 2 Thrombin Heparin P + PlateletFactor 4 P P Heparin Thrombin Low concentrations of heparin increase the affinity of thrombin for fibrin. Thrombin 1 Anti- bodies + 1 Thrombin Thrombin Thrombin Fibrin Fibrin Heparin exhibitsa nonlinear dose-response ACT Heparin dose Heparin binds to plasma proteins and cells PP PP Cell Cell PP Heparin’s Limitations

7. Historical Perspective on heparin monitoring • In 1966, Hattersley describes the ACT • In 1975, Bull et al recommended the use of ACTs to guide administration and reversal of heparin during cardiopulmonary bypass. • ACT > 300 sec: No clots in the extracorporeal circuit • In 1977, Verska reported on the use of a new automated ACT machine to guide heparin therapy. • ACT gains widespread use to monitor heparin Rx • ACT quick, easy, and reliable  Standard of care • aPTTs  non-linear, unreliable response at higher heparin doses Bull BS, et al Thorac Cardiovasc Surg. 1975 May;69(5):674–684 Verska JJ. Ann Thorac Surg. 1977 Aug;24(2):170–173.

8. Anticoagulation in POBA Retrospective Analyses - ACT and Outcome Ferguson et al. JACC 1994;23:1061 Narins et al. Circ 1996;93:667

9. Unfractionated HeparinOptimal Efficacy vs Optimal Safety* * ACT vs adverse outcomes in pts treated with UFH - meta-analysis of recent major trials of PCI Hemorrhage vs maximum ACT during procedure Ischemic events vs minimum ACT at device activation Best for low bleeding Best for low ischemia Probability of ischemic event/hemorrhage ACT (sec) Chew et al, Circulation 2001;103:961

10. 16.9 11.1 16.3 10.1 9.8 13.7 8.9 8.6 12.4 12.4 12.4 7.7 7.5 9.9 6.6 8.6 Heparin During PCI:Overview of 6 RCTs ACT and Clinical Outcome among pts on UFH alone: Best target 350-375 s? N = 5216 n=5,216; 1992-1998 Chew DP. Circulation 2001;103:961

11. Heparin During PCI:Overview of 6 RCTsGP IIb/IIIa blunt events with lower ACT Death, MI, Revasc Heparin Abcix and Heparin Chew DP. Circulation 2001;103:961

12. event rate Overview of 4 PCI Trials Death, MI, TVR • History of 7 trials over 10yrs • Both thrombotic and bleeding complications have decreased • ACTs have decreased • No difference in ACT between pts with (dark) and without (lighter) events event rate Major + Minor Bleed Brener SJ. Circulation 2004;110:994-998

13. 0.10 0.08 0.06 0.04 0.02 0.00 0.05 0.04 0.03 0.02 0.01 0.00 100 200 300 400 500 600 700 100 200 300 400 500 600 700 Maximum ACT (Sec) Maximum ACT (Sec) Overview of 4 PCI TrialsUniversal Stenting & Aggressive Platelet Inhibition 48 hr Outcomes According to Max ACT (Covariate Adj.) No interaction with ACS, diabetes Death, MI, TVR Major + Minor Bleed n=9974, 1999-2002 Brener SJ. Circulation 2004;110:994-998

14. ISAR-REACT Trial 2159 low-risk patients having elective PCI Exclusions: • Acute coronary syndrome • Acute MI <14 days • ST segment depression • Positive biomarkers • Insulin dependent diabetes • Chronic total coclusions • EF < 30% • Thrombus present • Lesions in bypass grafts Clopidogrel (600 mg load dose, 2 x 75 mg/day through discharge, 75 mg/day for 4 wks) Abciximab n=1079 Placebo n=1080 Endpoints: Primary : 30 day Death / MI / Urgent TVR Secondary: 30 day bleeding complications Kastrati: NEJM 2004; 350:232

15. ISAR-REACT: Results to 30 Days • 2159 stent pts • No ACS/MI • No IDDM • Clopidogrel • 600 mg > 2hrs pre-PCI • 75 mg bid until discharge • 75 mg qd (mo) • Abciximab or placebo • UFH —Kastrati A, et al. NEJM 350;2004

16. ISAR-REACT: Bleeding 30 day Events % TIMI Major Bleed TIMI Minor Bleed Transfusion p<0.05 p=NS p=0.82 Abciximab Abciximab Abciximab Placebo Placebo Placebo Kastrati: NEJM 2004; 350:232

17. Primary Events ISAR-REACT 2: Outcomes and Troponin StatusAbciximab + Clopidogrel in ACS Undergoing PCI Troponin positive (>0.03 µg/L, n=1049) Troponin negative ( <0.03µg/L, n=973) p=0.02 p=0.98 Similar to ISAR-REACT 1 Heparin 140 u/kg Heparin 140 u/kg Kastrati A, Mehilli J , et al. JAMA. 2006 Apr 5;295(13):1531-8.

18. Heparin 65 U/kg initial bolus Planned GP IIb/IIIa (abciximab or eptifibatide) Bivalirudin 0.75 mg/kg initial bolus, 1.75 mg/kg-hr during PCI Provisional GP IIb/IIIa (abciximab or eptifibatide) target ACT > 225 sec REPLACE-2 Trial Design Bivalirudin vs Heparin + GP IIb/IIIa During PCI N = 6010 Patients: Urgent or Elective PCI Randomization - double blind, triple dummy abciximab: 0.25 mg/kg bolus, 0.125 mg/kg-min (max 10 mg/min) x 12 hrs eptifibatide: 180 mg/kg double bolus, 2.0 mg/kg-min x 18-24 hrs ·“Quadruple Endpoint” at 30 Days·

19. p <0.001 Quadruple Endpoint 30 Day Primary Endpoint Components

20. Heparin superiority boundary Heparin + GP IIb/IIIa non-inferiority boundary = 0.84 Odds Ratio = 1.088 (0.895 - 1.322) p = 0.40 Heparin Better 0.83 Bivalirudin Better Odds Ratio & 95% CI Triple Ischemic Endpoint • Triple ischemic endpoint actually favored the haparin = GP2b3a group

21. Do we need any anti-thrombin in elective PCI? • Prospective, consecutive 500 pt registry with abciximab and minimal dose UFH (< 1000 U)* • Median ACT 168 sec • Non Q MI 1.6% • Major bleeding 0.2%, minor bleeding 3.6% • Thrombocytopenia 2.2% • 30 day events 0.2% *Denardo, AJC 2003; 91: 1-5.

22. 700 chronic CAD patients with low-risk lesions enrolled between 6/06 – 1/07 ASA 75-160 mg/day Clopidogrel 75 mg for 7d or 300 mg 24 h prior GPI at operator’s discretion All p values=NS R Heparin 70-100 U/KgTarget ACT<250 sec Placebo ACT=125±25 sec ACT=201±34 sec PCI/Stent (5F System) Sheath Removed in Holding AreaIndependent of ACT 30-day F/U Death/MI/urgent TVR Ciao Study: PCI without Heparin? Stabile E. et al, JACC 2008;52:1293-8

23. Protamine • Can reverse effects of heparin • Test dose – 10 mg, wait 10 minutes give 10-30 mg to reduce ACT as required. • Adverse affects- incidence 0.06-10.6% • catastrophic events - rare • major adverse responses occur during 2.6% of cardiac surgical procedures • “Risk factors” in 39% of CABG surgery patients, including: • fish allergy or previous exposure to protamine • diabetics treated with protamine zinc insulin • previous drug reaction • Hemodynamic changes • transient systemic hypotension and pulmonary hypertension observed • complement activation and inflammatory mediators • Drug reactions • related to rapid drug administration

24. Lack of Impact of Randomized Trials on Percutaneous Coronary Intervention Practice: Data fromthe National Cardiovascular Data Registry Sunil V. Rao MD, Dadi Dai MS, Sameer K. Mehta MD, Steven Marso MD, Eric D. Peterson MD MPH, Timothy Sanborn MD, Lloyd W. Klein MD on behalf of the NCDR

25. NCDR CathPCICurrent Antithrombotic Strategies Q2 2007 – Q1 2008 • Unfractionated Heparin 53% • Thrombin Inhibitors (any) 43% • LMWH (any) 15% • GP IIbIIIa inhibitors (any) 39%

26. Cost comparison of anti-coagulant approaches Duke Raleigh Hospital Pharmacy costs: 2009

27. Heparin Monotherapy: Dose Bolus 70-100 u/kg Additional 2000-5000u ACT Target HemoTec 250-300s Hemochron 300-350s Unfractionated Heparin and ACT Hemochron usually exceeds HemoTec by 30-50s (variable) • Varies substantially after fixed dose heparin • Weight-adjusted dose generally preferred • Controversy regarding ACT and ischemic/bleeding complications Heparin + GPI: • Dose • Bolus 50-70 u/kg • Additional 2000-5000u • ACT Target • HemoTec >200s • Hemochron >200s ACC/AHA 2005 PCI Guidelines.

28. Heparin Dosing(Zidar algorithm) • Dose varies for applications • Bolus 40-75u/kg and monitor ACT q30 minutes Pts pretreated with clopidogrel • Elective case without 2b3a – ACT >250. • Elective case with 2b3a - ACT >200 • Acute case without 2b3a – ACT>300 • Acute case with 2b3a – ACT > 250.

29. Conclusions • Heparin is safe and effective with very low event rates in contemporary practice, especially stable elective patients who are pretreated with clopidogrel • Positive and linear bleeding response with increasing levels of anticoagulation • Heparin is easily reversible with protamine • It is clearly the cheapest strategy in the cath lab • Heparin remains the most popular choice in US labs