Eptifibatide plus Heparin Increases the Risk of Major and Minor Hemorrhagic Complications Compared to Bivalirudin in Patients with Normal Renal Function Undergoing Percutaneous Coronary Intervention Michael C. McDaniel 1, Reza Fazel 1, Michele D. Voeltz 1, Frederick Feit 2, A. Michael Lincoff 3, Steven V. Manoukian 1 1 Emory University School of Medicine, Atlanta, GA 2 New York University School of Medicine, New York, NY 3 The Cleveland Clinic, Cleveland, OH

I have no financial interests/arrangement to disclose. I have no financial interests/arrangement to disclose. Relevant Conflict of Interest Statement

Hemorrhagic Complications with Normal Renal Function in PCI: Background Excess dosing of eptifibatide and heparin –occurs more frequently with impaired renal function –increases the risk of hemorrhagic complications Bivalirudin reduces hemorrhagic complications –compared to eptifibatide plus heparin –whether this benefit is attenuated with normal renal function, where excess dosing is less likely, is unknown We assessed the risk of bleeding complications in patients with normal renal function undergoing PCI.

Alexander KP et al. JAMA 2005;294: Background: The CRUSADE ACS Registry Excess Dosing of Anticoagulants and Major Bleeding

Background: The REPLACE-2 Trial Predictors of One-Year Mortality in PCI Feit F, Voeltz MD, Attubato MA, et al. Unpublished. VariableOR (95%CI) p- value CHF3.58 (2.27, 5.65)< Day Revascularization3.30 (1.36, 8.00)0.008 Major Bleeding2.66 (1.44, 4.92) Day MI2.46 (1.44, 4.20)0.001 Age > (1.51, 3.46) Prior Angina2.16 (1.25, 3.75)0.006 Pre-procedure LVEF ≤ 50%2.15 (1.44, 3.21) Pre-procedural Anemia2.12 (1.49, 3.13) BMI > 25 (vs )0.61 (0.40, 0.99)0.007

Background: The REPLACE-2 Trial Major Bleeding is Increased with Eptifibatide or Abciximab vs. Bivalirudin in PCI p= p= % 2.5% 2.2% 4.1% Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-737.

Hemorrhagic Complications with Normal Renal Function in PCI: Hypothesis In patients with normal renal function undergoing PCI, in whom excess dosing is less likely, bivalirudin plus provisional eptifibatide is associated with lower rates of hemorrhagic complications compared to eptifibatide plus heparin.

Hemorrhagic Complications with Normal Renal Function in PCI: Methods: REPLACE-2 Bivalirudin + Provisional GPIIb/IIIa inhibitor Eptifibatide or Abciximab + Heparin Lincoff AM et al. JAMA 2003;289: N=6002 Urgent or Elective PCI patients N=3317 Eptifibatide Cohort N=1648 Eptifibatide Cohort With CrCl >90 mL/min N=812 Bivalirudin + provisional Eptifibatide N=836 Eptifibatide + Heparin Endpoints: 30-day Death MI Revasc Hemorrhage 6, 12m follow up Endpoints: 30-day Death MI Revasc Hemorrhage 6, 12m follow up N=2994 N=3008

Hemorrhagic Complications with Normal Renal Function in PCI: Bleeding Definitions: REPLACE-2 Major Bleeding –Intracranial, intraocular, or retroperitoneal –Overt bleed with fall in Hgb >3g/dL –Any decrease in Hgb >4g/dL –Transfusion  2 units PRBC or whole blood Minor Bleeding –Overt bleeding that did not meet major bleeding criteria

Hemorrhagic Complications with Normal Renal Function in PCI: Results: Baseline Characteristics of the Eptifibatide Cohort with CrCl >90 mL/min Eptifibatide + Heparin (n=836) Bivalirudin + provisional Eptifibatide (n=812) P-value Age (yrs)5756ns Women16.9% ns BMI ns Weight (kg) ns Smoking29.3%33.5%ns Prior MI37.1%41%ns Prior CABG16%14%ns Prior CVA1.8%1.7%ns DM26.7%29.7%ns HTN64.6%62.5%ns CHF3.9%5.2%ns CrCl (mL/min)122124ns

Results: Ischemic Event Rates Hemorrhagic Complications with Normal Renal Function in PCI: Results: Ischemic Event Rates in the Eptifibatide Cohort with CrCl >90 mL/min P=NS for all 6.6% 5.7% 6.1% 4.6% 0.9% 1.7%

Results: Mortality Hemorrhagic Complications with Normal Renal Function in PCI: Results: Mortality in the Eptifibatide Cohort with CrCl >90 mL/min P=NS for all 0% 0.4% 0.2% 0.6% 0.7%

Hemorrhagic Complications with Normal Renal Function in PCI: Results: Minor Bleeding in the Eptifibatide Cohort with CrCl >90 mL/min 11.0% 23.7% p<0.0001

Hemorrhagic Complications with Normal Renal Function in PCI: Results: Major Bleeding in the Eptifibatide Cohort with CrCl >90 mL/min 1.0% 2.9% p=0.0056

Hemorrhagic Complications with Normal Renal Function in PCI: Results: Major Bleeding with Age % 2.9% p=0.0025

Hemorrhagic Complications with Normal Renal Function in PCI: Results: Major Bleeding by CrCl in the Overall Eptifibatide Cohort 2.2% 4.1% 1.0% 2.9% 3.5% 5.2% 46% Reduction 66% Reduction 33% Reduction Overall Cohort P= CrCl >90 P= CrCl <90 P=0.099

Hemorrhagic Complications with Normal Renal Function in PCI: Conclusions Hemorrhagic complications are more frequent with eptifibatide plus heparin compared to bivalirudin plus provisional eptifibatide in patients with normal renal function undergoing PCI. These findings imply that the increase in hemorrhagic risk with eptifibatide plus heparin cannot be attributed to excess dosing.