Antiplatelet Therapy in Renal Dysfunction

Moderator E. Magnus Ohman, MDProfessor of MedicineDirectorProgram for Advanced Coronary DiseaseDuke University Medical CenterDurham, North Carolina

PanelistsRobert F. Storey, MDReader and Honorary Consultant in Cardiology Department of Cardiovascular ScienceUniversity of SheffieldSheffield, United Kingdom

Stephen D. Wiviott, MDAssistant Professor of MedicineTIMI Study GroupCardiovascular DivisionBrigham and Women's HospitalHarvard Medical SchoolBoston, Massachusetts

GFR Calculator

http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm

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

Stages of CKD

Stage Description GFR (mL/min/1.73m2)

1 Kidney damage with normal or ↑ GFR ≥ 90

2 Kidney damage with mild ↓ GFR 60-89

3 Moderate ↓ GFR 30-59

4 Severe↓ GFR 15-29

5 Kidney failure < 15 (or dialysis)

http://www.kidney.org/professionals/KLS/aboutCKD.cfm

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 2007Class I:

• CrCl and/or GFR should be calculated for every patient hospitalized for NSTE-ACS (LoE B)

•MDRD*:• eGFR = 186 x (SCr)-1.154 x (age) -0.203:

• x (0.742 if female) • x (1.210 if African American)

Bassand JP, et al. Eur Heart J. 2007;28:1598-1660.http://www.kidney.org/professionals/KLS/aboutCKD.cfm

*Not validated in:•Age < 18 years or > 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;158:141-148.e1, with permission from Elsevier.

Increased risk for significant bleeding with severe CKD

Adj OR, 1.60 (1.01-2.54; P < .001)

Pati

ents

(%)

P for trend < .01

P for trend < .01

P for trend < .01

ACTION: CKD in STEMI and NSTEMI

Fox CS, et al. Circulation. 2010;121:357-365.

NSTEMISTEMI

NSTEMINo CKD (N = 17,393) 57.1%

CKD (N = 13,609) 42.9%

STEMINo 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;121:357-365. Republished with permission.

In-H

ospi

tal D

eath

(%)

P < .0001

Adjusted OR 2.5 3.7 4.8 8.0 1.8 2.4 3.5 4.1

P < .0001

P interaction < .0001

P < .0001 P < .0001

ACTION: Non-CABG Major Bleeding Rates by CKDN

on-C

ABG

Maj

or B

leed

( %

)

N = 5808 STEMI patients with CKD and N = 13,069 NSTEMI patients with CKD

Fox CS, et al. Circulation. 2010;121:357-365.

ACTION: Acute Kidney Injury and In-Hospital Mortality

Fox CS, et al. American Heart Association 2010. Abstract 12592.

P < .0001 P < .0001

In-H

ospi

tal D

eath

(%)

Adjusted OR 2.4 4.5 12.6 2.1 3.6 9.5

∆ Admission and peak SCrNo AKI : < 0.3 mg/dLMild AKI: 0.3 - < 0.5 mg/dLModerate AKI: 0.5- < 1.0 mg/dLSevere AKI: ≥ 1.0 mg/dL

AKI = acute kidney injury;SCr = serum creatinine

Clopidogrel

Prodrug

Kurihara A, et al. Drug Metab Rev. 2005;37:99. Tang M, et al. J Pharmacol Exp Ther. 2006;319:1467-1476.

Clopidogrel → Active Metabolite

Hydrolysis(Esterases)

85% Inactive Metabolites

hCE1

Active MetaboliteHOOC

* HS

N

O

Cl

OCH3

Hepatic Oxidation(Cytochrome P450) 2-step

CYPs: 1A2 2B6 2C19

CYPs: 3A 2B6 2C9 2C19

ON

S

O

Cl

O CH3C

Intestinal Absorption

Reduced Antiplatelet Response in CKD

N = 306 patients with type 2 diabetes mellitusReprinted from Angiolillo DJ, et al. J Am Coll Cardiol. 2010;55:1139-1146, with permission from Elsevier.

Clopidogrel Less Effective in Renal Dysfunction

From Montalescot G, et al. Circulation. 2010;122:1049-1052.Republished with permission.

*Significant RRR or significantinteraction between subgroups

Prasugrel and Ticagrelor Not Affected

From Montalescot G, et al. Circulation. 2010;122:1049-1052.Republished with permission.

*Significant RRR or significantinteraction between subgroups

PLATO N = 15,202 ACS patients(3237 with CKD)

James S, et al. Circulation. 2010;122:1056-1067.

PLATO: Non-CABG TIMI Major Bleeding by CKD Status

TIM

I Maj

or B

leed

ing

(%)

Clopidogrel = 300- to 600-mg loading dose (LD), 75-mg maintenance doseTicagrelor = 180-mg LD, 90 mg twice dailyTicagrelor is an investigational agent

No CKD

CKD

Antithrombotic Drug Use in CKD*

*Corrected text (erratum in original epub). www.escardio.org/guidelines

Wijns W, et al. Eur Heart J. 2010;31:2501-2555.

DrugUnfractionated 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/1.73m2) avoid or use 50% dose and control of therapeutic levels by factor Xa-activity measurementsIn reduced GFR (30-60 mL/min/1.73m2) use 75% dose

Prasugrel No dosage adjustment is necessary for patients with renal impairment including patients with end-stage renal disease

Ticagrelor No dose reduction required in patients with GFR < 60 mL/min/1.73m2

Clopidogrel No information in patients with renal dysfunction

Abciximab No specific recommendations

Tirofiban Dose adaptation required in patients with renal failure50% dose if GFR < 30 mL/min/1.73m2

Eptifibatide

Dose adaptation in patients with moderate renal impairment(GFR < 60 mL/min/1.73m2) Contraindicated in severe renal dysfunction

P = .45

P < .0003

ACTION: Excess* Antithrombin Dosing by CKDAn

tithr

ombi

n Ex

cess

Dos

ing

( %)

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;121:357-365.

Maj

or B

leed

ing

(%)

CrCl < 30 mL/minCrCl < 30 mL/min CrCl ≥ 30 mL/minCrCl ≥ 30 mL/min

OASIS 5: Bleeding by Creatinine Clearance

Fondaparinux

Enoxaparin

Fondaparinux 2.5 mg dailyEnoxaparin 1 mg/kg twice daily

OASIS 5 Investigators. N Engl J Med. 2006;354:1464-1476.

P = .001

P < .001