Antiplatelet Therapy in Renal
Dysfunction
Moderator
Panelists
E. Magnus Ohman, MD
Robert F. Storey, MD
Professor of Medicine
Director
Program for Advanced Coronary
Disease
Duke University Medical Center
Durham, North Carolina
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;
http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm
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)
Kidney Disease Improving Global Outcomes initiative recommends adding "T"
to transplant recipients at any stage and "D" for stage 5 treated by dialysis
http://www.kidney.org/professionals/KLS/aboutCKD.cfm
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)-1.154 x (age) -0.203:
• x (0.742 if female)
• x (1.210 if African American)
*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
Bassand JP, et al. Eur Heart J. 2007;28:1598-1660.
http://www.kidney.org/professionals/KLS/aboutCKD.cfm
REACH: MACE by Creatinine Clearance
Patients (%)
P for trend < .01
P for trend < .01
P for trend < .01
Increased risk for significant
bleeding with severe CKD
Adj OR, 1.60 (1.01-2.54; P < .001)
Reprinted from Dumaine RL, et al. Am Heart J. 2009;158:141-148.e1,
with permission from Elsevier.
ACTION: CKD in STEMI and NSTEMI
STEMI
No CKD (N = 13,221) 69.5%
CKD (N = 5808) 30.5%
NSTEMI
No CKD (N = 17,393) 57.1%
CKD (N = 13,609) 42.9%
NSTEMI
STEMI
Fox CS, et al. Circulation. 2010;121:357-365.
In-Hospital Death (%)
ACTION: In-Hospital Mortality by CKD Stage
P < .0001
Adjusted OR
2.5
P < .0001
3.7
4.8
8.0
1.8
P interaction < .0001
From Fox CS, et al. Circulation. 2010;121:357-365.
Republished with permission.
2.4
3.5
4.1
ACTION: Non-CABG Major Bleeding Rates by CKD
P < .0001
Non-CABG Major Bleed ( %)
P < .0001
N = 5808 STEMI patients with CKD and N = 13,069 NSTEMI patients with CKD
Fox CS, et al. Circulation. 2010;121:357-365.
In-Hospital Death (%)
ACTION: Acute Kidney Injury and In-Hospital
Mortality
P < .0001
P < .0001
Adjusted OR
2.4
4.5
12.6
2.1
∆ Admission and peak SCr
AKI = acute kidney injury;
SCr = serum creatinine
No AKI : < 0.3 mg/dL
Mild AKI: 0.3 - < 0.5 mg/dL
Moderate AKI: 0.5- < 1.0 mg/dL
Severe AKI: ≥ 1.0 mg/dL
Fox CS, et al. American Heart Association 2010. Abstract 12592.
3.6
9.5
Clopidogrel → Active Metabolite
O
O
C
CH3
Prodrug
N
S
Intestinal Absorption
Cl
Clopidogrel
Hydrolysis
85% Inactive
Metabolites
O
O
HOOC
* HS
C
N
S
OCH3
O
Active Metabolite
(Esterases)
hCE1
Cl
CYPs:
1A2
2B6
2C19
O
CH3
CYPs:
3A
2B6
2C9
2C19
Hepatic Oxidation
(Cytochrome P450) 2-step
N
Cl
Kurihara A, et al. Drug Metab Rev. 2005;37:99.
Tang M, et al. J Pharmacol Exp Ther. 2006;319:1467-1476.
Reduced Antiplatelet Response in CKD
N = 306 patients with type 2 diabetes mellitus
Reprinted from Angiolillo DJ, et al. J Am Coll Cardiol.
2010;55:1139-1146, with permission from Elsevier.
Clopidogrel Less Effective in Renal
Dysfunction
*Significant RRR or significant
interaction between subgroups
From Montalescot G, et al. Circulation. 2010;122:1049-1052.
Republished with permission.
Prasugrel and Ticagrelor Not Affected
*Significant RRR or significant
interaction between subgroups
From Montalescot G, et al. Circulation. 2010;122:1049-1052.
Republished with permission.
PLATO: Non-CABG TIMI Major Bleeding by CKD
Status
PLATO N = 15,202 ACS patients
(3237 with CKD)
No CKD
TIMI Major Bleeding (%)
CKD
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
James S, et al. Circulation. 2010;122:1056-1067.
Antithrombotic Drug Use in CKD*
Drug
Unfractionated
heparin
Dose reduction based on frequent aPTT measurements to control
therapeutic range
Enoxaparin/lowmolecular-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 measurements
In 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 failure
50% 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
*Corrected text (erratum in original epub).
www.escardio.org/guidelines
Wijns W, et al. Eur Heart J. 2010;31:2501-2555.
Antithrombin Excess Dosing ( %)
ACTION: Excess* Antithrombin Dosing by CKD
P = .45
P < .0003
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.
OASIS 5: Bleeding by Creatinine Clearance
P = .001
Fondaparinux
Major Bleeding (%)
Enoxaparin
P < .001
CrCl < 30 mL/min
CrCl ≥ 30 mL/min
Fondaparinux 2.5 mg daily
Enoxaparin 1 mg/kg twice daily
OASIS 5 Investigators. N Engl J Med. 2006;354:1464-1476.