Why Heparin Still Has a Role in Contemporary

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

Conflicts / Disclosures §Consultant/Advisory Board member/ DSMB member/ research support: -Abbott Vascular -Cordis -Medtronic -EV 3 Off label use of products will not be discussed in this presentation.

Can we do better than heparin and aspirin?

Sites of Anti-thrombotic Drug Action Intrinsic, Extrinsic Pathways Coagulation cascade Platelet Agonists Aspirin Plasma clotting cascade Enoxaparin DX-9065 a UF Heparin Fondaparinux ADP Thromboxane A 2 Prothrombin Factor Xa Conformational activation of GPIIb/IIIa AT III Thrombin Bivalirudin Hirudin Argatroban Ximelagatran Platelet aggregation Fibrinogen Thrombolytics Platelet cascade Fibrin Thrombus Ticlopidine Clopidogrel GPIIb/IIIa inhibitors

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 UFH bound to AT

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

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 • a. PTTs 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.

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

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

Heparin During PCI: Overview of 6 RCTs ACT and Clinical Outcome among pts on UFH alone: Best target 350 -375 s? 10. 1 N = 5216 11. 1 16. 9 16. 3 9. 8 8. 6 8. 9 6. 6 7. 5 7. 7 n=5, 216; 1992 -1998 13. 7 12. 4 8. 6 9. 9 Chew DP. Circulation 2001; 103: 961

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

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

Overview of 4 PCI Trials Universal Stenting & Aggressive Platelet Inhibition 48 hr Outcomes According to Max ACT (Covariate Adj. ) No interaction with ACS, diabetes 0. 10 0. 05 0. 08 0. 04 0. 06 0. 03 0. 04 0. 02 0. 00 0. 01 100 200 300 400 500 600 Maximum ACT (Sec) 700 Death, MI, TVR 0. 00 100 200 300 400 500 600 Maximum ACT (Sec) 700 Major + Minor Bleed n=9974, 1999 -2002 Brener SJ. Circulation 2004; 110: 994 -998

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

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

ISAR-REACT: Bleeding 30 day Events % TIMI Major Bleed TIMI Minor Bleed p=NS Transfusion p<0. 05 p=0. 82 Abciximab Placebo Kastrati: NEJM 2004; 350: 232

ISAR-REACT 2: Outcomes and Troponin Status Abciximab + Clopidogrel in ACS Undergoing PCI Troponin positive (>0. 03 µg/L, n=1049) p=0. 02 Troponin negative ( <0. 03µg/L, n=973) Primary Events p=0. 98 Similar to ISAR-REACT 1 Heparin 140 u/kg Kastrati A, Mehilli J , et al. JAMA. 2006 Apr 5; 295(13): 1531 -8.

REPLACE-2 Trial Design Bivalirudin vs Heparin + GP IIb/IIIa During PCI N = 6010 Patients: Urgent or Elective PCI Randomization - double blind, triple dummy Heparin 65 U/kg initial bolus Planned GP IIb/IIIa (abciximab or eptifibatide) target ACT > 225 sec Bivalirudin 0. 75 mg/kg initial bolus, 1. 75 mg/kg-hr during PCI Provisional GP IIb/IIIa (abciximab or eptifibatide) 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 ·

Quadruple Endpoint 30 Day Primary Endpoint Components p <0. 001

Triple Ischemic Endpoint • Triple ischemic endpoint actually favored the haparin = GP 2 b 3 a group Odds Ratio = 1. 088 (0. 895 - 1. 322) p = 0. 40

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.

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

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

Lack of Impact of Randomized Trials on Percutaneous Coronary Intervention Practice: Data from the 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

NCDR Cath. PCI Current Antithrombotic Strategies Q 2 2007 – Q 1 2008 • Unfractionated Heparin 53% • Thrombin Inhibitors (any) • LMWH (any) 43% 15% • GP IIb. IIIa inhibitors (any) 39%

Cost comparison of anti-coagulant approaches Abx/hep Eftifib/hep Bival Hep/clop Dose Bolus? Infusion 12 h yes 18 h yes 2 h Yes ? 1 hr Yes No Vial $120(2) 376 $691 - $3 Infusion costs $747 Hospital Costs (US$) $1490 $616 -1232 $3 Duke Raleigh Hospital Pharmacy costs: 2009

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

Heparin Dosing (Zidar algorithm) • Dose varies for applications • Bolus 40 -75 u/kg and monitor ACT q 30 minutes Pts pretreated with clopidogrel • Elective case without 2 b 3 a – ACT >250. • Elective case with 2 b 3 a - ACT >200 • Acute case without 2 b 3 a – ACT>300 • Acute case with 2 b 3 a – ACT > 250.

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