Antiplatelet Therapy in Renal Dysfunction Moderator E. Magnus Ohman, MD Professor of Medicine Director Program for Advanced Coronary Disease Duke University Medical Center Durham, North Carolina Panelists Robert F. Storey, MD Reader and Honorary Consultant in Cardiology Department of Cardiovascular Science University of Sheffield Sheffield, United Kingdom Stephen D. Wiviott, MD Assistant Professor of Medicine TIMI Study Group Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston, Massachusetts

GFR Calculator IDMS = isotope dilution mass spectrometry; KDOQI = Kidney Disease Outcomes Quality Initiative;

Stages of CKD StageDescriptionGFR (mL/min/1.73m 2 ) 1 Kidney damage with normal or ↑ GFR ≥ 90 2 Kidney damage with mild ↓ GFR Moderate ↓ GFR Severe↓ GFR Kidney failure< 15 (or dialysis) Kidney Disease Improving Global Outcomes initiative recommends adding "T" to transplant recipients at any stage and "D" for stage 5 treated by dialysis

European Society of Cardiology UA/NSTEMI Guidelines 2007 Class I: CrCl and/or GFR should be calculated for every patient hospitalized for NSTE-ACS (LoE B) MDRD*: eGFR = 186 x (SCr) x (age) : x (0.742 if female) x (1.210 if African American) Bassand JP, et al. Eur Heart J. 2007;28: * Not validated in: Age 70 years Pregnant women Racial/ethnic groups other than Caucasian and African American Individuals with normal kidney function

REACH: MACE by Creatinine Clearance Reprinted from Dumaine RL, et al. Am Heart J. 2009;158: e1, with permission from Elsevier. Increased risk for significant bleeding with severe CKD Adj OR, 1.60 ( ; P <.001) Patients (%) P for trend <.01

ACTION: CKD in STEMI and NSTEMI Fox CS, et al. Circulation. 2010;121: NSTEMI STEMI NSTEMI No CKD (N = 17,393) 57.1% CKD (N = 13,609) 42.9% STEMI No CKD (N = 13,221) 69.5% CKD (N = 5808) 30.5%

ACTION: In-Hospital Mortality by CKD Stage From Fox CS, et al. Circulation. 2010;121: Republished with permission. In-Hospital Death (%) P <.0001 Adjusted OR P <.0001 P interaction <.0001

P <.0001 ACTION: Non-CABG Major Bleeding Rates by CKD Non-CABG Major Bleed ( %) N = 5808 STEMI patients with CKD and N = 13,069 NSTEMI patients with CKD Fox CS, et al. Circulation. 2010;121:

ACTION: Acute Kidney Injury and In-Hospital Mortality Fox CS, et al. American Heart Association Abstract P <.0001 In-Hospital Death (%) Adjusted OR ∆ Admission and peak SCr No AKI : < 0.3 mg/dL Mild AKI: < 0.5 mg/dL Moderate AKI: 0.5- < 1.0 mg/dL Severe AKI: ≥ 1.0 mg/dL AKI = acute kidney injury; SCr = serum creatinine

N S O Cl O CH 3 C Clopidogrel Prodrug Kurihara A, et al. Drug Metab Rev. 2005;37:99. Tang M, et al. J Pharmacol Exp Ther. 2006;319: Clopidogrel → Active Metabolite Hydrolysis (Esterases) 85% Inactive Metabolites hCE1 Active Metabolite HOOC * HS N O Cl OCH 3 Hepatic Oxidation (Cytochrome P450) 2-step CYPs: 1A2 2B6 2C19 CYPs: 3A 2B6 2C9 2C19 O N S O Cl O CH 3 C Intestinal Absorption

Reduced Antiplatelet Response in CKD N = 306 patients with type 2 diabetes mellitus Reprinted from Angiolillo DJ, et al. J Am Coll Cardiol. 2010;55: , with permission from Elsevier.

Clopidogrel Less Effective in Renal Dysfunction From Montalescot G, et al. Circulation. 2010;122: Republished with permission. * Significant RRR or significant interaction between subgroups

Prasugrel and Ticagrelor Not Affected From Montalescot G, et al. Circulation. 2010;122: Republished with permission. * Significant RRR or significant interaction between subgroups

PLATO N = 15,202 ACS patients (3237 with CKD) James S, et al. Circulation. 2010;122: PLATO: Non-CABG TIMI Major Bleeding by CKD Status TIMI Major Bleeding (%) Clopidogrel = 300- to 600-mg loading dose (LD), 75-mg maintenance dose Ticagrelor = 180-mg LD, 90 mg twice daily Ticagrelor is an investigational agent No CKD CKD

Antithrombotic Drug Use in CKD* *Corrected text (erratum in original epub). Wijns W, et al. Eur Heart J. 2010;31: Drug Unfractionated heparin Dose reduction based on frequent aPTT measurements to control therapeutic range Enoxaparin/low- molecular-weight heparin In severe renal failure (GFR < 30 mL/min/1.73m 2 ) avoid or use 50% dose and control of therapeutic levels by factor Xa-activity measurements In reduced GFR (30-60 mL/min/1.73m 2 ) use 75% dose Prasugrel No dosage adjustment is necessary for patients with renal impairment including patients with end-stage renal disease TicagrelorNo dose reduction required in patients with GFR < 60 mL/min/1.73m 2 ClopidogrelNo information in patients with renal dysfunction AbciximabNo specific recommendations Tirofiban Dose adaptation required in patients with renal failure 50% dose if GFR < 30 mL/min/1.73m 2 Eptifibatide Dose adaptation in patients with moderate renal impairment (GFR < 60 mL/min/1.73m 2 ) Contraindicated in severe renal dysfunction

P =.45 P <.0003 ACTION: Excess* Antithrombin Dosing by CKD Antithrombin Excess Dosing ( %) N = 5808 STEMI patients with CKD and N = 13,069 NSTEMI patients with CKD *Above guideline recommendations for UFH, LMWH, and /or lytics. Fox CS, et al. Circulation. 2010;121:

Major Bleeding (%) CrCl < 30 mL/minCrCl ≥ 30 mL/min OASIS 5: Bleeding by Creatinine Clearance Fondaparinux Enoxaparin Fondaparinux 2.5 mg daily Enoxaparin 1 mg/kg twice daily OASIS 5 Investigators. N Engl J Med. 2006;354: P =.001 P <.001