AHA antithrombotics in CKD 2012 khotailieu y hoc

Contemporary Reviews in Cardiovascular Medicine
Antithrombotic Therapy in Patients With Chronic
Kidney Disease
Davide Capodanno, MD, PhD; Dominick J. Angiolillo, MD, PhD

C

hronic kidney disease (CKD) is a pandemic public health
problem, with Ͼ500 million people worldwide estimated to have some form of kidney injury.1 Survey data
suggest that the prevalence of CKD in the United States has
increased between 1988 to 1994 and 1999 to 2004 from 10%
to 13%, reaching a rate of 14% in 2010.2,3 Overlapping
conditions such as acute kidney injury play an important role
in the growing epidemiology of CKD, and underlying CKD is
in turn an important risk factor for acute kidney injury and
end-stage renal disease. Key factors contributing to the
increased prevalence of CKD include the aging population
and the growing burden of diabetes mellitus.4 The prevalence
of stage 3 or 4 CKD has been reported to be Ϸ38% for adults
Ն70 years old versus Ϸ1% in adults 20 to 39 years of age.2,5
Patients with diabetes mellitus are found to present with CKD
in about one third of cases, with diabetic nephropathy as the
most common cause of renal impairment.6 Notably, numerous epidemiological studies have shown that patients with all
stages of CKD experience higher rates of atherothrombotic
disease manifestations and processes with thromboembolic
potential such as atrial fibrillation than the general population.7–10 This underscores the importance of antithrombotic
treatment strategies in these patients. However, the risk-tobenefit ratio with antithrombotic therapies may be altered in
CKD. In fact, patients with CKD also have an increased risk
of bleeding complications.11–13 Importantly, bleeding has
emerged as an independent predictor of adverse outcomes,
including mortality.14 –17 Moreover, patients with severe CKD

are less likely to receive medications of proven benefit.18,19
Overall, these findings contribute to explain why patients
with reduced renal function have poorer prognosis compared
with patients with preserved renal function.
Defining the fine balance between safety and efficacy
remains a challenge in patients with CKD treated with
antithrombotic therapy. Unfortunately, dosing errors, which
commonly occur in patients with CKD, accounts for almost
one third of adverse drug events, and more than half of these
errors occur at the prescription stage.20 Therefore, understanding whether a drug should or should not be prescribed
and individualizing dosage regimens are key to balancing the

safety and efficacy profiles of antithrombotic medications in
CKD patients. This article provides an overview of the
currently available evidence on the use of antithrombotic
therapy in patients with CKD. In particular, a description of
thrombosis and hemostatic profiles that characterize CKD
patients, considerations for use of antithrombotic agents,
including antiplatelet and anticoagulant therapies, and a
review of the safety and efficacy data in CKD patients in the
settings of coronary artery disease manifestations and atrial
fibrillation are provided. A discussion of antithrombotic
therapy in patients with acute kidney injury and end-stage
renal disease is beyond the scope of this article.

CKD: Definitions
The Kidney Disease Outcomes Quality Initiative of the
National Kidney Foundation defines CKD as either kidney
damage or a decreased kidney glomerular filtration rate
(GFR) of Ͻ60 mL ⅐ minϪ1 ⅐ 1.73 mϪ2 for Ն3 months.21 The

different stages of CKD are listed in Table 1. While stages 3
through 5 are characterized by a gradient of GFR ranges,
markers of structural or functional kidney damage other than
GFR, including blood, urine, or imaging tests abnormalities,
need to be present to establish a diagnosis of stage 1 and stage
2 CKD. Kidney failure is defined as either a GFR of Ͻ15
mL ⅐ minϪ1 ⅐ 1.73 mϪ2 or a need for initiation of kidney
replacement therapy (dialysis or transplantation). End-stage
renal disease is a US administrative definition that includes
patients treated by dialysis or transplantation regardless of the
GFR level. Many calculators are available to estimate the
GFR. The National Kidney Foundation recommends using
the Modification of Diet in Renal Disease equation.22

Thrombosis and Hemostasis: Biological
Considerations in Patients With CKD
Patients with CKD may present with platelet dysfunction and
abnormalities in the enzymatic coagulation cascade. This may
explain why patients with CKD may experience 2 opposite
hemostatic complications: bleeding diathesis and thrombotic
tendencies.23

From the University of Florida College of Medicine–Jacksonville, Jacksonville (D.C., D.J.A.), and Ferrarotto Hospital, University of Catania, Catania,
Italy (D.C.).
The online-only Data Supplement is available with this article at />111.084996/-/DC1.
Correspondence to Dominick J. Angiolillo, MD, PhD, University of Florida College of Medicine–Jacksonville, 655 W 8th St, Jacksonville, FL 32209.
E-mail
(Circulation. 2012;125:2649-2661.)
© 2012 American Heart Association, Inc.
Circulation is available at

DOI: 10.1161/CIRCULATIONAHA.111.084996

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Table 1.

Stages of Chronic Kidney Disease

Stage

May 29, 2012

GFR,
mL ⅐ minϪ1 ⅐ 1.73 mϪ2

Description

Table 2. Pharmacokinetic Parameters Affected by Chronic
Kidney Disease
Increased bioavailability

1

Kidney damage with normal or
increased GFR

Ͼ90

2

Mild reduction in GFR

60–89

Prolonged half-life

3

Moderate reduction in GFR

30–59

Reduced excretion

4

Severe reduction in GFR

15–29

5

Kidney failure

Ͻ15

Increased distribution
Prolonged time to reach maximum drug concentration

GFR indicates glomerular filtration rate. Adapted from the National Kidney
Federation21 with permission from the publisher. © 2002, Elsevier BV.

Platelet dysfunction has been suggested to be the main
factor responsible for hemorrhagic tendencies in advanced
CKD and is likely to be multifactorial.11–13 First, a defective
platelet adhesion to subendothelium caused by decreased
membrane expression of glycoprotein (GP) Ib receptors leads
to impaired platelet-vessel interactions.24 –26 Second, platelets
of patients with CKD reveal an aggregation defect at least
partially attributable to decreased GPIIb/IIIa receptor expression with intrinsic dysfunction and the presence of a putative
uremic toxin that inhibits fibrinogen binding to GPIIb/
IIIa.27–29 Finally, several intrinsic platelet abnormalities have
been described, including secretion defects related to impaired arachidonic acid release from platelet phospholipids
and a storage pool defect,30 lower mean content of adenosine
diphosphate and ␤-thromboglobulin,31,32 reduced sensitivity
to platelet agonists,33,34 and decreased thromboxane A2 synthesis.35 Overall, the normal platelet response to vessel wall
injury with platelet activation, recruitment, adhesion, and
aggregation (primary hemostasis) is defective, likely as a
consequence of uremic toxins present in the circulating
blood.36
On the other hand, uremic platelets may also display some
features of procoagulant activity such as increased thrombin
generation, phosphatidylserine exposure, and higher concentrations of von Willebrand factor11–13,37 and platelet-derived

microparticles.38 These microparticles are small vesicles with
procoagulant activity released by activated platelets that are
enriched with membrane receptors for coagulation factor Va
and provide a competent catalytic surface for the prothrombinase reaction, thereby contributing to the acceleration of
thrombin generation.38 These abnormalities, although less
characterized than functional defects contributing to the
bleeding tendency observed in uremic patients, contribute to
explain why patients with CKD may also present with a
greater propensity to platelet aggregation. Importantly, patients with stage 3 to 4 CKD may present with significantly
enhanced platelet activation and aggregation as assessed by
multiple markers compared with those with stage 1 to 2 CKD,
as well as a higher prevalence of high on-aspirin and
on-clopidogrel platelet reactivity.39 – 43
As far as the enzymatic coagulation cascade is concerned,
hemostatic abnormalities consistent with a hypercoagulable
state have been widely described in patients with end-stage
renal disease on hemodialysis. These plasmatic abnormalities
include increased fibrinogen, D-dimer, and prothrombin fragments.44 – 46 Likewise, plasma procoagulant activities of fac-

tors XII, XI, IX, VIII, VII, X, and II are significantly
enhanced,47,48 whereas the anticoagulant activity of protein C,
protein S, and antithrombin III, plasminogen, and tissue type
plasminogen activator is decreased in parallel.49 –52 Dialysis
may partially correct these defects but cannot totally eliminate them.26 The hemodialysis process itself may in fact
contribute to bleeding through the chronic platelet activation
induced by the interaction between blood and artificial
surfaces.26

Pharmacological Issues and Dose Adjustment
in Patients With CKD

Guidelines and summaries of product characteristics drive
guidance of dosing for patients with varying renal function.53–56 The summaries provide the medicolegal reference
for the responsibility of the manufacturer when dosing errors
are investigated. CKD may affect the pharmacokinetic parameters of antithrombotic drugs in several ways (Table 2). A
reduced renal excretion up to 50%, in particular, leads to drug
accumulation in almost two thirds of patients.57 In parallel,
altered pharmacodynamic responses have also been described.58 In this section, the mechanism of action of the most
commonly prescribed antithrombotic agents, including antiplatelet and anticoagulant therapies, and how they are affected by reduced renal function and dosing considerations
are described. A summary of recommendations for dose
adjustment of antithrombotic therapies in patients with CKD
is provided in Tables I and II in the online-only Data
Supplement.

Antiplatelet Therapies
Aspirin
Aspirin selectively and irreversibly acetylates cyclooxygenase-1, thereby blocking the formation of thromboxane A2 in
platelets.59 Aspirin is eliminated mainly by hepatic metabolism but is also excreted unchanged in the urine to an extent
that depends on the dosage and urinary pH. Prostaglandininduced vasodilatation is important in maintaining renal
blood flow in subjects with CKD.60 By inhibiting the synthesis of renal prostaglandins, aspirin makes CKD patients
vulnerable to further deterioration in renal function. For the
above reasons, the package insert recommends that aspirin
should be avoided in patients with severe renal impairment.61
However, although this recommendation is followed for
primary prevention, in patients with coronary artery disease
manifestations, low-dose aspirin (Ͻ100 mg) is still used in
clinical practice even in the presence of severe renal impairment. Nonsteroidal anti-inflammatory drugs other than aspirin and paracetamol are associated with disease progression

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Capodanno and Angiolillo

Antithrombotic Therapy and Chronic Kidney Disease

and should be avoided in patients with CKD owing to further
decrease in volume of renal blood flow resulting from
decreased prostaglandin synthesis and, less frequently, acute
interstitial nephritis.62

P2Y12 Receptor Antagonists
Thienopyridines (ie, clopidogrel, prasugrel) and cyclopentyltriazolopyrimidines (ie, ticagrelor) are irreversible and reversible inhibitors, respectively, of the platelet adenosine diphosphate P2Y12 receptor, which is a key signaling pathway of
platelet activation. Therapeutic experience with P2Y12 receptor antagonists is limited in patients with stage 4 to 5 CKD.
The summary of product characteristics of clopidogrel recommends caution when using clopidogrel in the CKD
population.63
The pharmacokinetics of the active metabolite of prasugrel
is similar in patients with normal and in those with impaired
renal function. In patients with stage 5 CKD, exposure to the
active metabolite of prasugrel is about half that of healthy
control subjects and patients with stage 3 CKD, but this issue
does not translate into significant changes in platelet aggregation after ADP stimuli.64 As a result, the summary of
product characteristics of prasugrel does not recommend dose
adjustment based on renal function while warning that there
is limited experience with prasugrel in patients affected by
stage 5 CKD. The metabolism and excretion of ticagrelor
depend minimally on the kidneys.65 Although the mechanism
has not been elucidated, creatinine levels may increase during
treatment with ticagrelor, especially in patients Ͼ75 years of
age, those with stage 3 to 4 CKD at baseline, and those
receiving concomitant treatment with angiotensin receptor
blockers, warranting that creatinine levels be monitored 1

month after treatment initiation.66 The summary of product
characteristics of ticagrelor does not recommend dose adjustment based on renal function, but like clopidogrel and
prasugrel, use in patients with stage 5 CKD is not recommended because of the lack of data in this specific subpopulation. The pharmacokinetics of cangrelor, the first parenteral P2Y12 receptor antagonist not yet approved for use in
humans, is not affected by renal impairment.67 Elinogrel,
another P2Y12 receptor antagonist available for intravenous
and oral administration, has a balanced renal and hepatic
clearance.68

Protease-Activated Receptor Type 1 Antagonists
There were no significant changes in the results of laboratory
tests, including kidney function, in preclinical testing of
vorapaxar and atopaxar, 2 thrombin receptor antagonists
currently under more advanced clinical testing for the treatment and prevention of arterial thrombosis.69

GPIIb/IIIa Inhibitors
No dose adjustment based on renal function is required for
abciximab because of the rapid removal of free drug from the
circulation by the reticuloendothelial system.70 However,
because the potential risk of bleeding is increased in patients
with stage 4 CKD, the use of abciximab in CKD patients
should be considered only after careful appraisal of the risks
and benefits. In patients with stage 3 to 4 CKD, the clearance

2651

of eptifibatide is reduced by Ϸ50%, and steady-state plasma
levels are approximately doubled. The maintenance dose of
eptifibatide should therefore be reduced from 2.0 to 1.0
␮g ⅐ kgϪ1 ⅐ minϪ1 in patients with creatinine clearance Ն30
to Ͻ50 mL/min.71 Use in patients with more severe renal

impairment is contraindicated. Renal excretion also contributes significantly to the elimination of tirofiban.72 As a result,
in patients with stage 4 CKD, the infusion rate of tirofiban
should be adjusted from 0.1 to 0.05 ␮g ⅐ kgϪ1 ⅐ minϪ1.

Anticoagulant Therapies
Indirect Thrombin Inhibitors
Unfractionated heparin is metabolized primarily in the liver
and endothelium, thereby not requiring dose adjustment in
stage 4 to 5 CKD.73 Conversely, enoxaparin, the most
extensively studied low-molecular-weight heparin, is eliminated predominantly via the renal pathway. Although monitoring of anticoagulation activity and dose adjustment of
enoxaparin are not required in patients with stage 2 to 3 CKD,
those with stage 4 CKD experience decreased clearance of
enoxaparin and drug accumulation, leading to increased
half-life, drug exposure, and bleeding risk.74 As a consequence, guidelines recommend extending the dosing interval
of the maintenance dose of enoxaparin (1.0 mg/kg) from 12 to
24 hours in patients with stage 4 CKD presenting with an
acute coronary syndrome (ACS).55 Given the concerns of
overdosing, many clinicians in clinical practice consider this
dose-adjusted regimen even in patients with stage 3 CKD.

Direct Thrombin Inhibitors
Bivalirudin is cleared from plasma by a combination of renal
mechanisms and enzymatic cleavage. Because drug elimination is linearly related to GFR, the infusion dose of bivalirudin may need to be reduced in patients with advanced CKD.
In particular, dose adjustment from 1.75 to 1.0 or 0.25
mg ⅐ kgϪ1 ⅐ hϪ1 should be considered in patients with stage 4
or 5 CKD, respectively.75

Parenteral Anti–Factor Xa Inhibitors
Fondaparinux is eliminated mainly as unchanged drug by the
kidneys in subjects with normal kidney function.76 Conversely, the clearance of fondaparinux decreases with increased renal impairment.73,77 No dose reduction is required

for patients with stage 2 to 3 CKD, whereas fondaparinux
should be avoided in patients with stage 4 CKD.78 Otamixaban, another parenteral factor X inhibitor under advanced
phase clinical testing, exhibits mixed renal and biliary excretion with constant renal clearance.79

Oral Anticoagulants: Vitamin K Antagonists and
Novel Anti–Factor II and Anti–Factor X Antagonists
Warfarin and acenocoumarol (vitamin K antagonists) elimination is not governed primarily by the kidneys. Nonetheless,
careful dosing and more frequent international normalized
ratio monitoring have been recommended in patients with
stage 3 CKD because of the higher baseline risk of bleeding
complications.73 The respective summaries of product characteristics contraindicate vitamin K antagonists in patients
with stages 4 to 5 CKD,80 although they are still often used

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May 29, 2012

judiciously in clinical practice to prevent thromboembolic
recurrences.
Dabigatran is a direct thrombin inhibitor approved for
clinical use in patients with atrial fibrillation but not ACS.
Elimination of dabigatran is predominantly (85%) via the
renal pathway, with Ϸ80% of the administered dose excreted
unchanged in the urine (Figure 1).81 Limited data are available on dabigatran pharmacokinetics in patients with CKD.
However, increased drug exposure, decreased clearance, and

increased coagulation have been reported with decreased
renal function.82 For patients with stage 4 CKD, in whom
exposure is increased by a factor of 6, dose adjustment to 75
mg twice daily is recommended by the Food and Drug
Administration (FDA) on the basis of pharmacokinetic and
pharmacodynamic considerations more than safety or efficacy data.81 However, other regulatory boards, including the
European Medicine Agency, issued a recommendation on the
110 mg twice-daily dose for use on an individual basis and at
the physician’s discretion in patients with low thromboembolic and high bleeding risks.83 Both the FDA and European
Medicine Agency labels of dabigatran have recently been
updated to advise physicians to assess renal function before
starting therapy and to test it annually in patients Ͼ75 years
of age and those with creatinine clearance Ͻ50 mL/min. In
addition, the FDA label now states that physicians should
consider using the 75 mg twice-daily dose in patients with
creatinine clearance of 30 to 50 mL/min who are also taking
dronedarone or systemic ketoconazole. The concomitant use
of dabigatran and GPIIb/IIIa inhibitors should be avoided in
patients with stage 4 CKD.
Different daily doses and regimens (once or twice daily) of
rivaroxaban have been used in pivotal phase II and III trials
of atrial fibrillation (20 mg daily) and ACS (2.5–10 mg twice
daily). The approved dose of rivaroxaban for atrial fibrillation
is 20 mg once daily. A dose modification from 20 to 15 mg
once daily is required in atrial fibrillation patients with
creatinine clearance Ͻ50 mL/min, whereas rivaroxaban is not
recommended in patients with stage 5 CKD.84 Rivaroxaban is
not yet approved for ACS. Other orally active direct factor Xa
inhibitors at advanced stages of clinical development include
apixaban and edoxaban, which have predominantly nonrenal

clearance and thereby represent potentially interesting alternatives to warfarin and other selective coagulation factor
antagonists in CKD patients (Figure 1). Similar to rivaroxaban, a range of different daily doses of apixaban has been
used in pivotal trials of atrial fibrillation (5–10 mg daily) and
ACS (2.5 mg twice daily, 10 mg daily, 10 mg twice daily, 20
mg daily). Apixaban has not yet received approval for clinical
use in atrial fibrillation or ACS. Betrixaban, another factor Xa
inhibitor in the early stages of development, could also be
potentially of increased advantage in CKD patients because it
is metabolized in the liver rather than being excreted by the
kidney. The development of the oral anti–factor X inhibitor
darexaban has recently been discontinued after completion of
phase II clinical testing because of difficulty in finding a
commercial partner for larger phase III testing and intensified
competition in this product area.85

Impact of Antithrombotic Therapies in CKD
Patients With Coronary Artery Disease
Antiplatelet Therapy
Aspirin
Low-dose aspirin is as effective as higher doses in preventing
ischemic events but is also associated with a lower rate of
major bleeding and an improved net efficacy-to-safety balance.86,87 However, even low-dose aspirin may affect renal
function in elderly patients.88 –90 Few primary or secondary
prevention trials specifically addressed the aspirin benefit-torisk ratio in CKD patients. In the primary prevention Hypertension Optimal Treatment (HOT) study, low-dose aspirin
therapy was associated with greater absolute reduction in
major cardiovascular events and mortality in hypertensive
patients with CKD than in those with normal kidney function.
This finding can be explained in part by the high baseline risk
of CKD patients, thereby translating a similar relative benefit
into a greater absolute benefit. Importantly, an increased risk

of major bleeding was outweighed by the substantial benefits,
and aspirin therapy had no detrimental effect on renal
function.91 Among 2539 patients with type 2 diabetes mellitus
and coexisting renal dysfunction enrolled in the Japanese
Primary Prevention of Atherosclerosis With Aspirin for
Diabetes (JPAD) trial, low-dose aspirin therapy did not
reduce the primary ischemic end point in patients with stage
1 to 2 CKD compared with those with stage 3 to 4 CKD,
suggesting the potential for a differential effect of low-dose
aspirin therapy in diabetic patients with mild renal impairment.92 In an individual patient meta-analysis from the
Antithrombotic Trialists’ Collaborative Group that included
105 cardiovascular events in 2704 patients with stage 5 CKD,
a 41% odds reduction in the risk of vascular death, myocardial infarction (MI), and stroke with antiplatelet therapy
among hemodialysis patients was found compared with a
22% odds reduction seen in the overall study population,
although this difference was not statistically significant.93
Overall, these findings from subgroup analyses support the
design of prospective randomized clinical trials of aspirin use
for the primary prevention of cardiovascular events in patients with different stages of CKD.
P2Y12 Receptor Antagonists
In the Clopidogrel in Unstable Angina to Prevent Recurrent
Events (CURE) study, the beneficial effect of adding clopidogrel to standard treatment was observed in all 3 tertiles of
renal function (lower tertile, Ͻ64 mL/min; intermediate
tertile, 64 – 81.2 mL/min; upper tertile, Ͼ81.2 mL/min), with
a modest absolute and relative reduction in the primary
ischemic end point with clopidogrel versus placebo among
patients with renal dysfunction compared with those with
normal renal function, although without any significant interaction (lower third: relative risk [RR], 0.89; 95% confidence
interval [CI], 0.76 –1.05]; medium third: RR, 0.68; 95% CI,
0.56 – 0.84; upper third: RR, 0.74; 95% CI, 0.60 – 0.93; P for

interactionϭ0.11)94 (Figure 2). Clopidogrel treatment significantly increased the risk of minor bleeding in all tertiles of
renal function. The risk of major or life-threatening bleeding
increased moderately with the addition of clopidogrel to

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Capodanno and Angiolillo

Antithrombotic Therapy and Chronic Kidney Disease

2653

Figure 1. Pharmacokinetics of novel
selective oral anticoagulants. Schematic
overview of target, hours to Cmax, halflife, and metabolism for betrixaban, rivaroxaban, edoxaban, apixaban, and
dabigatran.

standard treatment (lower third: RR, 1.12; 95% CI, 0.83–
1.51; medium third: RRϭ1.4; 95% CI, 0.97–2.02; upper
third: RR, 1.83; 95% CI, 1.23–2.73), but this did not appear
to be greatest in those with the lowest renal function. In the
Clopidogrel for Reduction of Events During Observation
(CREDO) trial, clopidogrel versus placebo reduced the composite end point of death, MI, and stroke in patients with
normal renal function, but a trend in the opposite direction
was noted in patients with stage 2 to 4 CKD.96 Similarly, a
post hoc analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and
Avoidance (CHARISMA) trial suggested that clopidogrel
Hazard Ratio for Efficacy
(95% CI)

Total No. of
Patients

may even be harmful in patients with diabetic nephropathy.97
This finding could be attributable to a higher likelihood of
clopidogrel resistance among patients with stage 3 to 4
CKD.38 – 42 Even in CKD patients, the presence of low platelet
response to clopidogrel is associated with worse outcomes,98
thus emphasizing the need for novel antiplatelet strategies
with a favorable risk-to-benefit profile.
Prasugrel is a new-generation thienopyridine that, because
of higher bioavailability, achieves more potent antiplatelet
effects than clopidogrel. The Trial to Assess Improvement in
Therapeutic Outcomes by Optimizing Platelet Inhibition
With Prasugrel–Thrombolysis in Myocardial Infarction 38

Primary Endpoint
Comparator-Ref
(%)

Reduction
in Risk
(%)

Clopidogrel
CREDO
CURE

<60 mL/min

999

17.8

13.1

60-90 mL/min

672

10.3

12.8

+44
-20

>90 mL/min

331

4.4

10.4

-58*

<64 mL/min

4087

13.4

14.9

-11

64-81.2 mL/min

4075

7.5

10.8

-32*

≥81.2 mL/min

4091

6.6

8.8

-26*

<60 mL/min

1490

15.1

17.5

-14

≥60 mL/min

11,890

9.0

11.1

-20*

<60 mL/min

3237

17.3

22.0

-23*

≥60 mL/min

11,965

7.9

8.9

-10

<60 mL/min†

2562

16.4

22.4

-29*

≥60 mL/min†

12,640

8.5

9.6

-10

Prasugrel
TRITON

Ticagrelor
PLATO

†MDRD

Estimation.

0.5

0.6 0.7 0.8 0.91.0

P2Y12 Inhibitor BeƩer

Figure 2. Effect of P2Y12 receptor antagonists stratified by creatinine clearance.
Hazard ratio for efficacy (95% confidence
interval [CI]) evaluated as the composite
end point of cardiovascular death, myocardial infarction, or stroke in the Clopidogrel in Unstable Angina to Prevent
Recurrent Events (CURE), Clopidogrel for
Reduction of Events During Observation
(CREDO), Trial to Assess Improvement in
Therapeutic Outcomes by Optimizing
Platelet Inhibition With Prasugrel (TRITON),
and Platelet Inhibition and Patient Outcomes (PLATO) trials according to renal
function calculated with the CockcroftGault equation when not specified or the
Modification of Diet in Renal Disease
(MDRD) equation when indicated. *A significant relative risk reduction with the
study criteria or a significant P value for
interaction between subgroups. NA indicates not available. Adapted from Montalescot et al.95

1.2

Placebo BeƩer

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(TRITON-TIMI 38) randomized study documented that,
compared with clopidogrel, prasugrel results in a 19% reduction of ischemic events in moderate to high risk ACS patients
undergoing percutaneous coronary intervention (PCI).99 Although in the TRITON-TIMI 38 trial this benefit was partially offset by the increased risk of bleeding, the net clinical
benefit (defined as death resulting from any cause, nonfatal
MI, nonfatal stroke, and TIMI major hemorrhages) remained
in favor of prasugrel. In subjects with stage 3 to 4 CKD,
prasugrel was associated with a higher absolute (2.4% versus
2.1%) and a lower relative (14% versus 20%) reduction of the
primary end point compared with subjects with normal renal
function or stage 1 to 2 CKD. However, in patients with stage
3 to 4 CKD (nϭ1490), the incidence of ischemic events was
not significantly different between those taking prasugrel and
those taking clopidogrel (15.1% versus 17.5%), unlike patients with stage 1 to 2 CKD or normal renal function
(nϭ11 890; 9.0% versus 11.1%), which is likely a reflection
of the smaller number of patients with stage 3 to 4 CKD
enrolled in the trial (Figure 2).
Ticagrelor is a novel antiplatelet drug belonging to the

family of cyclopentyltriazolopyrimidines that, unlike clopidogrel and prasugrel, requires a dual daily administration and
reversibly binds to the P2Y12 receptor. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, conducted in
patients with ACS, ticagrelor reduced the primary composite
end point of cardiovascular death, MI, and stroke at 12
months compared with clopidogrel, with similar PLATOdefined major bleedings and higher non– coronary artery
bypass grafting–related major bleedings.100 About 25% of the
study population met the general definition of CKD. In
subjects with stage 3 to 4 CKD (nϭ3237), ticagrelor was
associated with a higher absolute (4.7% versus 1.0%) and
relative (23% versus 10%) reduction of the primary end point
than clopidogrel compared with subjects with normal renal
function or stage 1 to 2 CKD (nϭ11 965). Consistently with
the overall PLATO population, patients with CKD experienced a reduction in mortality (10.0% versus 14.0%; hazard
ratio, 0.72; 95% CI, 0.58 – 0.89).101 Major bleeding rates, fatal
bleedings, and non– coronary bypass–related major bleedings
were not significantly relatively increased with ticagrelor
compared with clopidogrel in patients with stage 3 to 4 CKD.
Importantly, none of the above efficacy and safety outcomes
was associated with significant interaction between CKD and
treatment, which suggests that the size effect of ticagrelor
remains of the same magnitude with or without renal insufficiency (Figure 2). However, when the more contemporary
Modification of Diet in Renal Disease formula replaces the
Cockcroft-Gault equation for the definition of CKD, a significant P value for interaction arises for the primary end
point and mortality.101 If confirmed, these findings would
target patients with stage 3 to 4 CKD as a preferred group for
ticagrelor and conversely suggest limited added value of
ticagrelor over clopidogrel in patients without stage 3 to 4
CKD. The reasons for a presumptive benefit in CKD are
puzzling because they lack physiological explanation. In fact,
the clearance of ticagrelor depends minimally on renal

function; therefore, other factors (ie, play of chance, inhibition of adenosine reuptake by erythrocytes, differential ben-

efits of intensified platelet inhibition in patients with different
risk profiles) may have played a role. In view of the
above-mentioned uncertainties, whether a causal and specific
effect of ticagrelor exists in patients with stage 3 to 4 CKD
needs to be further elucidated.95

GPIIb/IIIa Inhibitors
CKD would seem to identify a population of high-risk
patients undergoing PCI who could be considered candidates
for selective use of GPIIb/IIIa receptor inhibitors. Although
abciximab increases the risk of bleeding in all patients
submitted to revascularization, there have been some inconsistencies among studies concerning whether the increase in
relative risk is significantly greater in patients with CKD.102–104
In pooled data from abciximab trials, however, there was no
difference in the rates of all major bleeding and the 30-day
primary end point of death, MI, or urgent intervention in
patients with CKD between the abciximab and placebo
groups.105 With tirofiban, the pivotal trials evaluating efficacy
and safety excluded patients with serum creatinine Ͼ2.5
mg/dL. Among patients with stage 2 to 3 CKD in the Platelet
Receptor Inhibition in Ischemic Syndrome Management in
Patients Limited by Unstable Signs and Symptoms (PRISMPLUS), tirofiban was well tolerated and effective in reducing
ischemic ACS complications, with no evidence of treatmentby– creatinine-clearance interaction.106 With eptifibatide, no
clinical data are available for patients with serum creatinine
Ͼ4.0 mg/dL. In the Enhanced Suppression of the Platelet
IIb/IIIa Receptor With Integrilin Therapy (ESPRIT) trial, a
treatment effect of eptifibatide was noted regardless of renal
function and trended toward being greater in patients with

stage 2 CKD.107

Anticoagulant Therapy
Currently approved anticoagulants for treatment of patients
with coronary artery disease manifestations include unfractionated heparin, low-molecular-weight heparins, bivalirudin,
and fondaparinux. Other agents in advanced stages of clinical
development include oral (dabigatran, rivaroxaban and apixaban) and parenteral (otamixiban) anticoagulant agents. The
kidneys eliminate most of these drugs. Therefore, assessment
of renal function before administration in patients receiving
anticoagulants is of primary importance.
A total of 11 881 patients with ACS from the Global
Registry of Acute Coronary Events (GRACE) were divided
into 3 groups according to creatinine clearance strata. Lowmolecular-weight heparin alone was more beneficial than
unfractionated heparin alone, regardless of renal status.
Bleeding rates were significantly lower with low-molecularweight heparin plus GPIIb/IIIa inhibitors than with unfractionated heparin plus GPIIb/IIIa inhibitors.108
Bivalirudin provides comparable suppression of ischemic
events with a decrease in bleeding events compared with
heparin and GPIIb/IIIa inhibition.109 –111 Among 5710 patients referred to PCI from the Second Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events
(REPLACE-2) study, stage 3 to 4 CKD was associated with
increased ischemic events, bleeding complications, and
1-year mortality.112 There was no interaction between treat-

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Antithrombotic Therapy and Chronic Kidney Disease

ment assignment, bleeding, or ischemic complications and

stage 3 to 4 CKD. In a meta-analysis of 3 randomized trials
(nϭ5035) comparing bivalirudin with heparin during PCI, the
relative benefit of bivalirudin with respect to ischemic and
bleeding events was maintained regardless of renal function.
The absolute benefit in terms of ischemic and bleeding
complications increased with increasing CKD stage (normal
renal function or stage 1 CKD, 2.2%; stage 2 CKD, 5.8%;
stage 3 CKD, 7.7%; stage 4 CKD, 14.4%; P for trend Ͻ0.001,
P for interactionϭ0.044).113 The authors concluded that
bivalirudin provides greater absolute benefit in patients with
impaired renal function. In the Acute Catheterization and
Urgent Intervention Triage Strategy (ACUITY) trial, stage 3
to 4 CKD was present in 2469 of 12 939 randomized ACS
patients (19.1%) with baseline creatinine clearance data.114
Similar to the overall population, the use of bivalirudin
monotherapy in patients with stage 3 to 4 CKD resulted in
nonstatistically different ischemic outcomes but significantly
less 30-day major bleeding compared with heparin plus a
GPIIb/IIa inhibitor. No significant interaction between treatment (bivalirudin or abciximab plus heparin) and renal
function (GFRϾ83 or Յ83 mL/min) was found in another
trial specifically focusing on patients with non–ST-segment–
elevation MI undergoing PCI with regard to the primary net
clinical outcome of death, large recurrent MI, urgent target
vessel revascularization, or major bleeding at 30 days.111 In
the Harmonizing Outcomes With Revascularization and
Stents in Acute Myocardial Infarction (HORIZONS-AMI),
stage 3 to 4 CKD was present at baseline in 554 of 3397
patients (16.3%) undergoing primary PCI.115 Patients with
stage 3 to 4 CKD randomized to bivalirudin monotherapy
versus heparin plus GPIIb/IIa inhibitors had no significant

difference in major bleeding or death compared with those
without stage 3 to 4 CKD.
The Fifth Organization to Assess Strategies in Acute
Ischemic Syndromes (OASIS-5) trial showed similar efficacy
of fondaparinux and enoxaparin in reducing the risk of
ischemic events at 9 days. However, fondaparinux substantially reduced major bleeding (2.2% versus 4.1%; odds ratio,
0.52; PϽ0.001) and 30-day mortality (2.9% versus 3.5%;
odds ratio, 0.83; Pϭ0.02).116 A post hoc analysis focusing on
patients with measured baseline creatinine showed that, in
patients with stage 3 to 4 CKD, the benefit of fondaparinux
compared with enoxaparin was more marked as a consequence of lower bleeding rates.117
Novel anticoagulants are under clinical testing in the
setting of ACS as an adjunct to dual antiplatelet therapy. In
the phase II Study of Otamixaban Versus Unfractionated
Heparin and Eptifibatide in Non-ST Elevation Acute Coronary Syndrome (SEPIA-ACS-1), intermediate doses of the
new intravenous direct factor Xa inhibitor otamixaban
showed a trend toward lower ischemic end points with a
similar rate of bleeding complications compared with unfractionated heparin plus eptifibatide118; however, patients with
stage 4 to 5 CKD were excluded from this study. Further
testing with otamixaban (0.08-mg/kg bolus plus infusion at
0.10 or 0.14 mg ⅐ kgϪ1 ⅐ hϪ1) in a phase III clinical trial is
ongoing (NCT01076764). In the phase II Dose Finding Study
for Dabigatran Etexilate in Patients With Acute Coronary

2655

Syndrome (RE-DEEM) trial, dabigatran was associated with
a dose-dependent (ranging from 50 to 150 mg twice daily)
increase in bleeding events and significantly reduced coagulation activity in patients with a recent MI.119 No significant
interaction with subgroups based on creatinine clearance was

noted, but patients with stage 4 to 5 CKD were not included
in the trial. Phase III testing in the setting of ACS is not being
pursued with dabigatran. In the phase II Apixaban for
Prevention of Acute Ischemic Safety Events (APPRAISE-1)
trial, apixaban (2.5 to 20 mg twice daily) resulted in a
dose-dependent increase in bleeding compared with placebo
in patients with a recent ACS, but a trend toward a reduction
in clinically relevant ischemic events was also noted.120
However, the phase III Apixaban for Prevention of Acute
Ischemic Events 2 (APPRAISE-2) trial did not confirm these
ischemic benefits using apixaban at a 5-mg twice-daily dose.
In particular, the trial was stopped prematurely after recruiting 7392 of the planned 10 800 patients because an interim
analysis showed that the increase in major bleeding with
apixaban, including increases in events of fatal and intracranial bleeding, was not counterbalanced by the expected
decrease in recurrent ischemic events compared with placebo.121 The safety and tolerability of rivaroxaban at total
daily doses ranging from 5 to 20 mg in patients with a recent
ACS have been the objective of the phase II Rivaroxaban in
Combination With Aspirin Alone or With Aspirin and a
Thienopyridine in Patients With Acute Coronary Syndromes
(ATLAS ACS-TIMI 46) trial.122 Clinically significant bleeding was increased in the rivaroxaban groups in a dosedependent manner. The primary efficacy end point, a composite of death, MI, stroke, or severe recurrent ischemia
requiring revascularization, was numerically, albeit nonsignificantly, lower in patients treated with rivaroxaban. Rivaroxaban doses of 2.5 and 5 mg twice daily reduced the risk of
the composite end point of death resulting from cardiovascular causes, MI, or stroke in the ATLAS-2 trial with no
significant interaction based on CKD stage but also increased
the risk of major bleeding and intracranial hemorrhage.123
Unlike APPRAISE-2, in which apixaban was tested at the
same dose used for atrial fibrillation, a lower dose of
rivaroxaban than that used in atrial fibrillation patients was
used in the ATLAS-2, with the best benefit, including
reduced mortality, observed with a 2.5 mg dose.

Impact of Antithrombotic Therapies in CKD
Patients With Atrial Fibrillation

CKD may be found in Ϸ35% of patients with atrial fibrillation, with 3.3% of patients presenting with stage 4 to 5
CKD.124,125 Although the efficacy of vitamin K antagonists is
well established for the prevention of stroke in patients with
atrial fibrillation, warfarin is widely underused, at a cost of a
greater number of unnecessary disabling strokes and systemic
embolisms.126 This underuse is explained by a fear of causing
fatal bleedings, but some shortcomings of warfarin use,
including the need for international normalized ratio monitoring and multiple environmental and genetic factors,127 play
another relevant role and warrant the development of novel
alternatives to warfarin. Importantly, cost issues are going to

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May 29, 2012

factor into the decision-making process with any new
anticoagulant.
In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, patients were randomly assigned to receive 150 mg dabigatran twice daily, 110 mg
dabigatran twice daily, or warfarin titrated to achieve an
international normalized ratio of 2.0 to 3.0.128 Both dabigatran doses were shown to be noninferior to warfarin with
respect to the primary combined end point of stroke or
systemic embolisms, but the 150 mg regimen was significantly superior to warfarin and the 110 mg regimen. Bleeding

episodes (defined as a reduction in hemoglobin of Ն2 g/dL,
need for a transfusion of Ն2 U blood or packed cells, or
symptomatic bleeding in a critical area or organ) were less
common with dabigatran 110 mg than warfarin and were
similar between dabigatran 150 mg and warfarin. Given these
findings, in October 2010, only the higher 150 mg dose
regimen of dabigatran was approved by the FDA for the
reduction of the risk of stroke and systemic embolisms in
patients with nonvalvular atrial fibrillation. This decision was
affected by benefit-to-risk considerations in which disabling
stroke and systemic embolisms are given more weight than
nonfatal bleeding events.129 However, because dabigatran is
cleared primarily by the kidneys (Ϸ80%), leading to accumulation and hence potentially to more bleeding complications,130 patients with CKD could theoretically benefit from a
lower dose. For this reason, the FDA approved a dose of 75
mg twice daily for patients with stage 4 CKD, whereas the
European Medicine Agency currently recommends using the
lower 110 mg dose used in the RE-LY trial in patients with
low thromboembolic risk and high potential for bleeding.
Analyses of the RE-LY trial restricted to patients (nϭ3343)
with creatinine clearance Ն30 to Ͻ50 mL/min showed that
dabigatran concentrations were 2 to 3 times as high as those
in patients with normal renal function but the incidence of
stroke or systemic embolism was approximately half with
150 mg dabigatran (1.3 per 100 patient-years) compared with
110 mg (2.4 per 100 patient-years) with no significant
differences in bleeding (5.3 versus 5.7 major bleeding episodes per 100 patient-years).129 Therefore, even in a population exposed to higher dabigatran concentrations, the benefitto-risk ratio is in favor of the 150 mg dose. Of note, although
no relevant interaction was found between creatinine clearance and the relative risk of the primary outcome with both
doses of dabigatran compared with warfarin in the RE-LY
trial, patients with stage 4 to 5 CKD were excluded.128
However, patients with stage 4 to 5 CKD are known to be at

increased risk for atrial fibrillation owing to structural and
electric atrial remodeling.131,132
In the Rivaroxaban Once-Daily Oral Direct Factor Xa
Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation
(ROCKET-AF), Ͼ14 000 patients with atrial fibrillation were
randomized to 20 mg rivaroxaban once daily (or 15 mg in
patients with moderate renal impairment at screening) or to
dose-adjusted warfarin (titrated to an international normalized ratio of 2.5). Rivaroxaban was found to be noninferior to
warfarin in terms of the combined primary end point of stroke
and systemic embolisms and was superior to warfarin in the

on-treatment but not in the stricter intention-to-treat analysis,
raising concerns about potentially poor adherence with rivaroxaban in real-world practice. In terms of bleeding, the rates
of the composite of major and nonmajor clinically relevant
bleeding were comparable in the rivaroxaban and warfarin
treatment groups, with less fatal bleeding and intracranial
hemorrhage observed among patients treated with rivaroxaban. Compared with patients with creatinine clearance Ͼ50
mL/min, the 2950 patients (20.7%) with creatinine clearance
Ն30 to Ͻ50 mL/min enrolled in the ROCKET-AF trial were
older and had higher event rates regardless of study treatment.133 Among patients with creatinine clearance Ն30 to
Ͻ50 mL/min, the annualized rates of the primary end point
were 2.32% with rivaroxaban 15 mg once daily and 2.77%
with warfarin (hazard ratio, 0.84; 95% CI, 0.57–1.23) in the
per-protocol population. The intention-to-treat analysis
yielded similar results (hazard ratio, 0.86; 95% CI, 0.63–
1.17). Major and clinically relevant nonmajor bleeding occurred in 17.82% and 18.28% of patients in the rivaroxaban
and warfarin groups (Pϭ0.76). After the results from the
ROCKET-AF trial became available, rivaroxaban was recently approved by the FDA for use in the prevention of
stroke and systemic embolism in patients with nonvalvular
atrial fibrillation.134

In the Apixaban for the Prevention of Stroke in Subjects
With Atrial Fibrillation (ARISTOTLE) trial, comparing
apixaban 5 mg twice daily with warfarin in subjects with
atrial fibrillation and risk factors for stroke, the oral direct
factor Xa inhibitor apixaban was found to be superior to
warfarin for the prevention of stroke and systemic embolism.135 Importantly, apixaban was also associated with less
bleeding and lower mortality than warfarin. There was no
interaction between treatment type and CKD stage for the
primary efficacy outcome (P for interactionϭ0.72). However,
a significant interaction (Pϭ0.03) was found for the primary
safety outcome. In particular, patients with stage 3 to 4 CKD
appeared to gain a larger risk reduction in major bleeding
with apixaban over warfarin compared with patients with
stage 1 CKD or those with no renal impairment. Apixaban is
currently pending approval by drug-regulating authorities for
clinical use.

Recommendations for Clinical Practice
Patients receiving antithrombotic medications should be
screened for CKD. General measures to prevent progression
of CKD, including control of contributing risk factors (ie,
hypertension, diabetes mellitus) and avoidance of potentially
nephrotoxic medications, such as nonsteroidal antiinflammatory drugs, should be considered. The choice and
dose of antithrombotic drugs need to be carefully evaluated in
patients with CKD. Therefore, patients requiring aspirin
therapy should opt for low-dose regimens (Ͻ100 mg). Patients requiring a P2Y12 receptor antagonist have the option
of choosing clopidogrel (ACS and non-ACS), ticagrelor
(ACS), or prasugrel (only ACS undergoing PCI), none of
which requires renal dosing adjustments. In addition to
defining the clinical setting (ACS versus non-ACS; PCI

versus coronary artery bypass graft surgery versus medically
managed), patients requiring P2Y12-inhibiting therapy with a

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Antithrombotic Therapy and Chronic Kidney Disease

high risk of bleeding should consider using clopidogrel since
the more potent agents prasugrel and ticagrelor are both
contraindicated in patients at high risk of bleeding. If bleeding risk is less of a concern and should patients require more
potent P2Y12 receptor blockade, then the choice between
prasugrel and ticagrelor may depend on the individual patient.
Prasugrel is contraindicated in patients with a prior transient
ischemic attack/stroke, and should be used with caution in
patients with low weight and the elderly, and considered only
if patients underwent PCI in the setting of an ACS.56
Ticagrelor is contraindicated in patients with prior hemorrhagic stroke and severe hepatic impairment, and should be
used with precaution in patients treated with potent inhibitors
or inducers of CYP3A activity due to drug interactions.
Although ticagrelor can be used across the spectrum of ACS,
managed both medically and invasively, its use should be
carefully considered in patients with poor compliance given
its twice-daily administration.56 Also, aspirin at a maintenance dose Ͼ100 mg should be avoided as this has been
associated with reduced effectiveness of ticagrelor.136
Numerous antithrombotic agents available for parenteral
use require dosage adjustments in patients with CKD, which
clinicians should be aware of in order to avoid overdosing,

and include eptifibatide, tirofiban, bivalirudin, enoxaparin,
and fondaparinux. For ACS patients undergoing PCI in whom
potent antithrombotic effects are warranted, recent trial data
are strongly supportive of the use of bivalirudin, which,
compared with GPIIb/IIIa inhibitors, has a similar impact on
ischemic events but with significantly less bleeding, making
bivalirudin a more desirable agent in this setting. However, if
a GPII/IIIa inhibitor is chosen, it is important to ensure that
dosage adjustments occur in CKD patients when smallmolecule GPIIb/IIIa inhibitors (eptifibatide, tirofiban) are
used. Long-term oral anticoagulation with warfarin requires
careful dosing and more frequent international normalized
ratio monitoring in CKD patients. The development of novel
antithrombotic agents with a more favorable safety profile
may have a promising role in this ever-growing population,
but more clinical experience with these agents is warranted
before we will be able to define which of them may have a
better niche for patients with CKD.

Conclusions
CKD is a frequent consequence of diabetes mellitus, renal
disease, or aging. Safety with antithrombotic therapy is a
major concern, especially in patients with renal impairment,
because of the potential for increased risk of bleeding events.
Therefore, understanding strategies of antithrombotic management in patients with CKD is of key importance. The lack
of studies performed specifically in patients with impaired
renal function, particularly those with acute kidney injury or
end-stage renal disease, who are generally excluded from
many large-scale clinical trials, often leads to either no
recommendation on their most appropriate antithrombotic
treatment regimen or sometimes arbitrary assumptions. Overall, the choice and combination of antithrombotic drugs used

should be balanced against the individual risk of thrombotic
and bleeding complications. Clinical experience with newer
agents is still limited, and more data from large-scale clinical

2657

trials or even dedicated studies in patients with CKD are
warranted.

Disclosures
Dr Angiolillo reports receiving honoraria for lectures from Bristol
Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc,
Abbott Vascular, and AstraZeneca; consulting fees from Bristol
Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc,
The Medicines Company, Portola, Novartis, Medicure, Accumetrics,
Arena Pharmaceuticals, Abbott Vascular, AstraZeneca, Merck, and
Evolva; and research grants from Bristol Myers Squibb, SanofiAventis, GlaxoSmithKline, Otsuka, Eli Lilly Co, Daiichi Sankyo,
Inc, The Medicines Company, Portola, Accumetrics, ScheringPlough, AstraZeneca, and Eisai. Dr Capodanno has received honoraria for lectures from AstraZeneca and Eli Lilly Co.

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KEY WORDS: acute coronary syndrome
failure, chronic Ⅲ thrombosis

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Ⅲ

atrial fibrillation

Ⅲ

kidney

Antithrombotic Therapy in Patients With Chronic Kidney Disease
Davide Capodanno and Dominick J. Angiolillo
Circulation. 2012;125:2649-2661
doi: 10.1161/CIRCULATIONAHA.111.084996
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