1. Anticoagulation to the max A Michael Lincoff MD Cardiologist Division of Cardiology Cleveland Clinic Cleveland, OH

2. Bivalirudin (Angiomax) Anticoagulation to the max A synthetic molecule Structure based on study of the saliva of the medicinal leech Directly and reversibly binds to thrombin molecule at 2 sites

3. Bivalirudin vs heparin Anticoagulation to the max Heparin: has difficulty penetrating clot, indirect binding, indirect thrombin inhibitor, neutralized by circulating inhibitors, depends on a circulating antithrombin Bivalirudin: easy penetration, direct binding, direct thrombin inhibitor, not neutralized by circulating inhibitors, acts independently of a circulating antithrombin

4. 3 of 4 Anticoagulation to the max Hirulog angioplasty trial N Engl J Med 1995;333(12):764-9 1993-4 (balloon angioplasty era). 4000-patients. Efficacy: bivalirudin is as effective as heparin in reducing ischemic complications, & in high-risk patients, is more effective. Safety:a marked reduction in rate of bleeding in patients who received bivalirudin instead of heparin.

5. CACHET: a pilot study of how bivalirudin interacts with IIb/IIIa inhibitors (Hirulog angioplasty trial was carried out before the stenting & IIb/IIIa era) Compared bivalirudin in various doses with abciximab, and without abciximab (bail-out approach) vs heparin + abciximab Results: treatments with bivalirudin are at least equivalent in efficacy and safety as treatments with heparin. 2 of 4 Anticoagulation to the max CACHET trial

6. Low-molecular-weight heparin Anticoagulation to the max We lack data from large-scale, randomized trials showing low-molecular weight heparin is better than unfractionated heparin in coronary intervention. Limited data in the current era of coronary interventions support the superiority of bivalirudin to heparin. We need the large-scale REPLACE trial.

7. Bivalirudin vs lepirudin Anticoagulation to the max Lepirudin (Refludan), a hirudin, is approved for treatment of heparin-induced thrombocytopenia. Hirudin: irreversible inhibition of thrombin, dependence on renal function, significantly increased bleeding Bivalirudin: reversible inhibition of thrombin, independent of renal function, no increased bleeding

8. Cost effectiveness? Anticoagulation to the max There is planned economic component to the REPLACE trial. Savings with bivalirudin relative to heparin expected: 1) by allowing physicians to direct use of IIb/IIIa to patients at high risk 2) by reducing bleeding complications. (Expense of a major bleeding event equals that of angioplasty or bypass surgery)

9. Summary Anticoagulation to the max Bivalirudin appears to be a safe and suitable replacement for heparin. How bivalirudin works with IIb/IIIa inhibitors, and with setting, remains to be determined.