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 in
Trang 1Antithrombotic Therapy in Patients With Chronic
Kidney Disease
Davide Capodanno, MD, PhD; Dominick J Angiolillo, MD, PhD
Chronic kidney disease (CKD) is a pandemic public health
problem, with ⬎500 million people worldwide
esti-mated 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.4The prevalence
of stage 3 or 4 CKD has been reported to be⬇38% for adults
ⱖ70 years old versus ⬇1% 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.6Notably,
numer-ous 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
popula-tion.7–10 This underscores the importance of antithrombotic
treatment strategies in these patients However, the
risk-to-benefit 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 –17Moreover, 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,
under-standing 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⬍60 mL 䡠 min⫺1䡠 1.73 m⫺2forⱖ3 months.21The 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 ⬍15
mL䡠 min⫺1䡠 1.73 m⫺2 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 http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA 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 dominick.angiolillo@jax.ufl.edu
(Circulation 2012;125:2649-2661.)
© 2012 American Heart Association, Inc.
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Trang 2Platelet dysfunction has been suggested to be the main
factor responsible for hemorrhagic tendencies in advanced
CKD and is likely to be multifactorial.11–13First, a defective
platelet adhesion to subendothelium caused by decreased
membrane expression of glycoprotein (GP) Ib receptors leads
to impaired platelet-vessel interactions.24 –26Second, platelets
of patients with CKD reveal an aggregation defect at least
partially attributable to decreased GPIIb/IIIa receptor
expres-sion with intrinsic dysfunction and the presence of a putative
uremic toxin that inhibits fibrinogen binding to GPIIb/
IIIa.27–29Finally, several intrinsic platelet abnormalities have
been described, including secretion defects related to
im-paired arachidonic acid release from platelet phospholipids
and a storage pool defect,30lower mean content of adenosine
diphosphate and -thromboglobulin,31,32reduced sensitivity
to platelet agonists,33,34and decreased thromboxane A2
syn-thesis.35Overall, 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
concen-trations of von Willebrand factor11–13,37and platelet-derived
microparticles.38These 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
prothrom-binase 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,
pa-tients 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
frag-ments.44 – 46Likewise, plasma procoagulant activities of
fac-tors XII, XI, IX, VIII, VII, X, and II are significantly enhanced,47,48whereas the anticoagulant activity of protein C, protein S, and antithrombin III, plasminogen, and tissue type plasminogen activator is decreased in parallel.49 –52Dialysis may partially correct these defects but cannot totally elimi-nate 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 func-tion.53–56 The summaries provide the medicolegal reference for the responsibility of the manufacturer when dosing errors are investigated CKD may affect the pharmacokinetic pa-rameters 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.57In parallel, altered pharmacodynamic responses have also been de-scribed.58In this section, the mechanism of action of the most commonly prescribed antithrombotic agents, including anti-platelet and anticoagulant therapies, and how they are af-fected 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 cyclooxygen-ase-1, thereby blocking the formation of thromboxane A2in platelets.59Aspirin is eliminated mainly by hepatic metabo-lism but is also excreted unchanged in the urine to an extent that depends on the dosage and urinary pH Prostaglandin-induced vasodilatation is important in maintaining renal blood flow in subjects with CKD.60By inhibiting the synthe-sis 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 (⬍100 mg) is still used in clinical practice even in the presence of severe renal impair-ment Nonsteroidal anti-inflammatory drugs other than aspi-rin and paracetamol are associated with disease progression
Table 1 Stages of Chronic Kidney Disease
Stage Description
GFR,
mL 䡠 min ⫺1 䡠 1.73 m ⫺2
1 Kidney damage with normal or
increased GFR
⬎90
2 Mild reduction in GFR 60–89
3 Moderate reduction in GFR 30–59
4 Severe reduction in GFR 15–29
GFR indicates glomerular filtration rate Adapted from the National Kidney
Federation 21 with permission from the publisher © 2002, Elsevier BV.
Table 2 Pharmacokinetic Parameters Affected by Chronic Kidney Disease
Increased bioavailability Increased distribution Prolonged time to reach maximum drug concentration Prolonged half-life
Reduced excretion
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Trang 3and 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
P2Y 12 Receptor Antagonists
Thienopyridines (ie, clopidogrel, prasugrel) and
cyclopentyl-triazolopyrimidines (ie, ticagrelor) are irreversible and
revers-ible inhibitors, respectively, of the platelet adenosine
diphos-phate P2Y12receptor, which is a key signaling pathway of
platelet activation Therapeutic experience with P2Y12
recep-tor antagonists is limited in patients with stage 4 to 5 CKD
The summary of product characteristics of clopidogrel
rec-ommends 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
aggre-gation 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.65Although the mechanism
has not been elucidated, creatinine levels may increase during
treatment with ticagrelor, especially in patients⬎75 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.66The summary of product
characteristics of ticagrelor does not recommend dose
adjust-ment based on renal function, but like clopidogrel and
prasugrel, use in patients with stage 5 CKD is not
recom-mended because of the lack of data in this specific
subpop-ulation The pharmacokinetics of cangrelor, the first
paren-teral P2Y12receptor antagonist not yet approved for use in
humans, is not affected by renal impairment.67 Elinogrel,
another P2Y12receptor 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
treat-ment 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
of eptifibatide is reduced by⬇50%, and steady-state plasma levels are approximately doubled The maintenance dose of eptifibatide should therefore be reduced from 2.0 to 1.0
g 䡠 kg⫺1䡠 min⫺1 in patients with creatinine clearance ⱖ30
to ⬍50 mL/min.71 Use in patients with more severe renal impairment is contraindicated Renal excretion also contrib-utes significantly to the elimination of tirofiban.72As a result,
in patients with stage 4 CKD, the infusion rate of tirofiban should be adjusted from 0.1 to 0.05g 䡠 kg⫺1䡠 min⫺1
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 elimi-nated predominantly via the renal pathway Although moni-toring 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 conse-quence, 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 elimina-tion is linearly related to GFR, the infusion dose of bivaliru-din may need to be reduced in patients with advanced CKD
In particular, dose adjustment from 1.75 to 1.0 or 0.25
mg䡠 kg⫺1䡠 h⫺1should 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 Con-versely, the clearance of fondaparinux decreases with in-creased renal impairment.73,77No dose reduction is required for patients with stage 2 to 3 CKD, whereas fondaparinux should be avoided in patients with stage 4 CKD.78 Otamixa-ban, another parenteral factor X inhibitor under advanced phase clinical testing, exhibits mixed renal and biliary excre-tion 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) elimi-nation 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.73The respective summaries of product char-acteristics contraindicate vitamin K antagonists in patients with stages 4 to 5 CKD,80although they are still often used
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Trang 4judiciously 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⬇80% of the administered dose excreted
unchanged in the urine (Figure 1).81Limited data are
avail-able 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
effi-cacy data.81However, 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
thromboem-bolic and high bleeding risks.83Both 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⬎75 years
of age and those with creatinine clearance⬍50 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⬍50 mL/min, whereas rivaroxaban is not
recommended in patients with stage 5 CKD.84Rivaroxaban 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
alter-natives to warfarin and other selective coagulation factor
antagonists in CKD patients (Figure 1) Similar to
rivaroxa-ban, 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 bal-ance.86,87 However, even low-dose aspirin may affect renal function in elderly patients.88 –90Few primary or secondary prevention trials specifically addressed the aspirin benefit-to-risk ratio in CKD patients In the primary prevention Hyper-tension 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.91Among 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 impair-ment.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, myocar-dial 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 pa-tients 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 clopi-dogrel to standard treatment was observed in all 3 tertiles of renal function (lower tertile, ⬍64 mL/min; intermediate tertile, 64 – 81.2 mL/min; upper tertile,⬎81.2 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 inter-action (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
interaction⫽0.11)94(Figure 2) Clopidogrel treatment signif-icantly 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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Trang 5standard treatment (lower third: RR, 1.12; 95% CI, 0.83–
1.51; medium third: RR⫽1.4; 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
com-posite 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.96Similarly, a
post hoc analysis of the Clopidogrel for High
Atherothrom-botic Risk and Ischemic Stabilization, Management, and
Avoidance (CHARISMA) trial suggested that clopidogrel
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 – 42Even 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
Figure 1 Pharmacokinetics of novel
selective oral anticoagulants Schematic overview of target, hours to Cmax, half-life, and metabolism for betrixaban, rivar-oxaban, edrivar-oxaban, apixaban, and dabigatran.
Ticagrelor
Prasugrel
15.1 17.5 -14
0.7 0.6 0.5 0.8 0.91.0 1.2
P2Y 12 Inhibitor Beer Placebo Beer
Clopidogrel
Hazard Ratio for Efficacy (95% CI) Total No of Patients
Primary Endpoint Comparator-Ref (%)
Reduction
in Risk (%)
Figure 2 Effect of P2Y12receptor antag-onists stratified by creatinine clearance Hazard ratio for efficacy (95% confidence interval [CI]) evaluated as the composite end point of cardiovascular death, myo-cardial infarction, or stroke in the Clopi-dogrel 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 Out-comes (PLATO) trials according to renal function calculated with the Cockcroft-Gault equation when not specified or the Modification of Diet in Renal Disease (MDRD) equation when indicated *A sig-nificant relative risk reduction with the
study criteria or a significant P value for
interaction between subgroups NA indi-cates not available Adapted from Mon-talescot et al 95
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compared with clopidogrel, prasugrel results in a 19%
reduc-tion of ischemic events in moderate to high risk ACS patients
undergoing percutaneous coronary intervention (PCI).99
Al-though in the TRITON-TIMI 38 trial this benefit was
par-tially 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 (n⫽1490), the incidence of ischemic events was
not significantly different between those taking prasugrel and
those taking clopidogrel (15.1% versus 17.5%), unlike
pa-tients with stage 1 to 2 CKD or normal renal function
(n⫽11 890; 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
clopi-dogrel and prasugrel, requires a dual daily administration and
reversibly binds to the P2Y12receptor In the Platelet
Inhibi-tion 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
PLATO-defined major bleedings and higher non– coronary artery
bypass grafting–related major bleedings.100About 25% of the
study population met the general definition of CKD In
subjects with stage 3 to 4 CKD (n⫽3237), 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 (n⫽11 965) Consistently with
the overall PLATO population, patients with CKD
experi-enced a reduction in mortality (10.0% versus 14.0%; hazard
ratio, 0.72; 95% CI, 0.58 – 0.89).101Major 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
insuf-ficiency (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
sig-nificant 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,
inhibi-tion 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 incon-sistencies 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.105With tirofiban, the pivotal trials evaluating efficacy and safety excluded patients with serum creatinine ⬎2.5 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 (PRISM-PLUS), tirofiban was well tolerated and effective in reducing ischemic ACS complications, with no evidence of treatment-by– creatinine-clearance interaction.106With eptifibatide, no clinical data are available for patients with serum creatinine
⬎4.0 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 unfrac-tionated heparin, low-molecular-weight heparins, bivalirudin, and fondaparinux Other agents in advanced stages of clinical development include oral (dabigatran, rivaroxaban and apixa-ban) and parenteral (otamixiapixa-ban) 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 Low-molecular-weight heparin alone was more beneficial than unfractionated heparin alone, regardless of renal status Bleeding rates were significantly lower with low-molecular-weight heparin plus GPIIb/IIIa inhibitors than with unfrac-tionated 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 pa-tients referred to PCI from the Second Randomized Evalua-tion 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.112There was no interaction between
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stage 3 to 4 CKD In a meta-analysis of 3 randomized trials
(n⫽5035) 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⬍0.001,
P for interaction⫽0.044).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
treat-ment (bivalirudin or abciximab plus heparin) and renal
function (GFR⬎83 or ⱕ83 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.111In
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
substan-tially reduced major bleeding (2.2% versus 4.1%; odds ratio,
0.52; P⬍0.001) and 30-day mortality (2.9% versus 3.5%;
odds ratio, 0.83; P⫽0.02).116A 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
conse-quence 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
Coro-nary 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
unfrac-tionated 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䡠 kg⫺1䡠 h⫺1) in a phase III clinical trial is
ongoing (NCT01076764) In the phase II Dose Finding Study
for Dabigatran Etexilate in Patients With Acute Coronary
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 coagu-lation activity in patients with a recent MI.119No 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 recruit-ing 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 intracra-nial bleeding, was not counterbalanced by the expected decrease in recurrent ischemic events compared with pla-cebo.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.122Clinically significant bleed-ing was increased in the rivaroxaban groups in a dose-dependent manner The primary efficacy end point, a com-posite of death, MI, stroke, or severe recurrent ischemia requiring revascularization, was numerically, albeit nonsig-nificantly, lower in patients treated with rivaroxaban Rivar-oxaban doses of 2.5 and 5 mg twice daily reduced the risk of the composite end point of death resulting from cardiovascu-lar 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⬇35% of patients with atrial fibrilla-tion, with 3.3% of patients presenting with stage 4 to 5 CKD.124,125Although 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.126This underuse is explained by a fear of causing fatal bleedings, but some shortcomings of warfarin use, including the need for international normalized ratio moni-toring and multiple environmental and genetic factors,127play another relevant role and warrant the development of novel alternatives to warfarin Importantly, cost issues are going to
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anticoagulant
In the Randomized Evaluation of Long-Term
Anticoagu-lation Therapy (RE-LY) trial, patients were randomly
as-signed 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 3.0.128Both
dabiga-tran 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
signifi-cantly superior to warfarin and the 110 mg regimen Bleeding
episodes (defined as a reduction in hemoglobin ofⱖ2 g/dL,
need for a transfusion of ⱖ2 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.129However, because dabigatran is
cleared primarily by the kidneys (⬇80%), leading to
accu-mulation and hence potentially to more bleeding
complica-tions,130patients 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 (n⫽3343)
with creatinine clearanceⱖ30 to ⬍50 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
epi-sodes per 100 patient-years).129Therefore, even in a
popula-tion exposed to higher dabigatran concentrapopula-tions, the
benefit-to-risk ratio is in favor of the 150 mg dose Of note, although
no relevant interaction was found between creatinine
clear-ance 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
Pre-vention of Stroke and Embolism Trial in Atrial Fibrillation
(ROCKET-AF),⬎14 000 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
normal-ized 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 rivar-oxaban 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 rivaroxa-ban Compared with patients with creatinine clearance⬎50 mL/min, the 2950 patients (20.7%) with creatinine clearance ⱖ30 to ⬍50 mL/min enrolled in the ROCKET-AF trial were older and had higher event rates regardless of study treat-ment.133 Among patients with creatinine clearance ⱖ30 to
⬍50 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 oc-curred in 17.82% and 18.28% of patients in the rivaroxaban
and warfarin groups (P⫽0.76) After the results from the ROCKET-AF trial became available, rivaroxaban was re-cently 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 embo-lism.135Importantly, 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 interaction⫽0.72) However,
a significant interaction (P⫽0.03) 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 anti-inflammatory 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 (⬍100 mg) Pa-tients requiring a P2Y12receptor 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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the more potent agents prasugrel and ticagrelor are both
contraindicated in patients at high risk of bleeding If
bleed-ing 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
hemor-rhagic 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
mainte-nance dose ⬎100 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
small-molecule 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
man-agement 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
Over-all, 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
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, Sanofi-Aventis, GlaxoSmithKline, Otsuka, Eli Lilly Co, Daiichi Sankyo, Inc, The Medicines Company, Portola, Accumetrics, Schering-Plough, AstraZeneca, and Eisai Dr Capodanno has received hono-raria for lectures from AstraZeneca and Eli Lilly Co.
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