AHA ACS CKD pharmacotherapy statement 2015 khotailieu y hoc

AHA Scientific Statement
Pharmacotherapy in Chronic Kidney Disease Patients
Presenting With Acute Coronary Syndrome
A Scientific Statement From the American Heart Association
Jeffrey B. Washam, PharmD, FAHA, Chair; Charles A. Herzog, MD, FAHA;
Amber L. Beitelshees, PharmD, MPH, FAHA; Mauricio G. Cohen, MD;
Timothy D. Henry, MD; Navin K. Kapur, MD; Jessica L. Mega, MD, MPH, FAHA;
Venu Menon, MD, FAHA; Robert L. Page II, PharmD, MSPH, FAHA;
L. Kristin Newby, MD, MHS, FAHA, Co-Chair; on behalf of the American Heart Association Clinical
Pharmacology Committee of the Council on Clinical Cardiology, Council on Cardiovascular Surgery
and Anesthesia, Council on Functional Genomics and Translational Biology, Council on the Kidney in
Cardiovascular Disease, and Council on Quality of Care and Outcomes Research

C

Background and CKD Staging

hronic kidney disease (CKD) is frequently encountered among patients presenting with acute coronary syndrome (ACS). Recent data from the National
Cardiovascular Data Registry–Acute Coronary Treatment and
Intervention Outcomes Network (NCDR-ACTION) reported
CKD (defined as estimated creatinine clearance [CrCl]
<60 mL·min−1·1.73 m−2) prevalence rates of 30.5% among
patients presenting with ST-segment–elevation myocardial
infarction (STEMI) and 42.9% among patients presenting with non–ST-segment–elevation myocardial infarction
(NSTEMI).1 The presence of CKD among patients presenting
with ACS has been associated with worse outcomes, including
higher rates of mortality and bleeding.2–4 Despite the increased
risk for adverse outcomes, CKD patients presenting with ACS
are less likely to receive evidence-based therapies, including
medications.1 In addition, patients with CKD have been underrepresented in randomized controlled trials of ACS pharmacotherapy.5,6 Thus, the net effect is a relative lack of evidence and
potential for uncertainty in selecting medications in this highrisk population. The purpose of this scientific statement is to

provide a comprehensive review of the published literature
and provide recommendations on the use of evidence-based
pharmacotherapies in CKD patients presenting with ACS.

It has been appreciated now for more than a decade that CKD
is a powerful independent predictor of cardiovascular morbidity, cardiovascular mortality, and all-cause mortality. The
systematic classification of CKD in large part is based on the
efforts of Andrew Levey and colleagues, who published the
K/DOQI (Kidney Disease Outcomes Quality Initiative) clinical practice guidelines for CKD.7 The original schema somewhat arbitrarily defined stages 1 to 5 CKD on the basis of
estimated glomerular filtration rate (eGFR) in the following
manner: Stage 1, eGFR ≥90 mL·min−1·1.73 m−2 (with evidence of kidney damage present, such as albuminuria); stage
2, eGFR <90 but ≥60 (with evidence of kidney damage such
as albuminuria); stage 3, eGFR <60 but ≥30; stage 4, eGFR
<30 but ≥15; and stage 5, eGFR <15 or undergoing dialysis.7
An additional modification was made to create a stage 3a
(eGFR 45–59 mL·min−1·1.73 m−2) and stage 3b (eGFR 30–44
mL·min−1·1.73 m−2). Most recently, based on the stepwise
association of albuminuria with increased rates of CKD
progression, cardiovascular mortality, and total mortality,
the Kidney Disease: Improving Global Outcomes (KDIGO)
group has recommended altering the classification scheme to
include urinary albumin excretion (Figure 1).8

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship
or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete
and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on September 15, 2014. A copy of the
document is available at by selecting either the “By Topic” link or the “By Publication Date” link. To purchase
additional reprints, call 843-216-2533 or e-mail
The American Heart Association requests that this document be cited as follows: Washam JB, Herzog CA, Beitelshees AL, Cohen MG, Henry TD,

Kapur NK, Mega JL, Menon V, Page RL 2nd, Newby LK; on behalf of the American Heart Association Clinical Pharmacology Committee of the Council
on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, Council on Functional Genomics and Translational Biology, Council on the
Kidney in Cardiovascular Disease, and Council on Quality of Care and Outcomes Research. Pharmacotherapy in chronic kidney disease patients presenting
with acute coronary syndrome: a scientific statement from the American Heart Association. Circulation. 2015;131:•••–•••.
Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines
development, visit and select the “Policies and Development” link.
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express
permission of the American Heart Association. Instructions for obtaining permission are located at A link to the “Copyright Permissions Request Form” appears on the right side of the page.
(Circulation. 2015;131:000-000. DOI: 10.1161/CIR.0000000000000183.)
© 2015 American Heart Association, Inc.
Circulation is available at 

DOI: 10.1161/CIR.0000000000000183

1


2  Circulation  March 24, 2015

Persistent albuminuria categories
Description and range
A1

GFR categories (ml/min/ 1.73m2)
Description and range

Prognosis of CKD by GFR
and Albuminuria Categories:
KDIGO 2012

A2

A3

Normal to
mildly
increased

Moderately
increased

Severely
increased

<30 mg/g
<3 mg/mmol

30-300 mg/g
3-30 mg/mmol

>300 mg/g
>30 mg/mmol

≥90

G1

Normal or high

G2

Mildly decreased

60-89

G3a

Mildly to moderately
decreased

45-59

G3b

Moderately to
severely decreased

30-44

G4

Severely decreased

15-29

G5

Kidney failure

Figure 1. Risk for all-cause mortality,

cardiovascular mortality, end-stage
renal disease, progressive chronic
kidney disease (CKD), or acute kidney
injury among CKD patients according
to glomerular filtration rate (GFR) and
albuminuria categories. KDIGO indicates
Kidney Disease: Improving Global
Outcomes. Reprinted from Kidney
Disease: Improving Global Outcomes
(KDIGO) CKD Work Group8 with
permission from Macmillan Publishers
Ltd. Copyright © 2013, International
Society of Nephrology.

<15

As shown in Figure 2, there is a stepwise incremental
age-standardized risk for all-cause mortality, cardiovascular events, and hospitalization associated with diminishing
renal function.9 Compared with patients with eGFR ≥60
mL·min−1·1.73 m−2, the adjusted hazard for death among
patients with eGFR 15 to 29 mL·min−1·1.73 m−2 is more than
3-fold higher, and nearly 6 times higher for patients with
eGFR <15 mL·min−1·1.73 m−2.
It has been suggested that CKD should be regarded as a
“coronary heart disease equivalent.” The publication by
Tonelli and colleagues,10 using the Alberta Kidney Disease
Network database and the National Health and Nutrition
Examination Survey 2003 to 2006, estimated the risk of hospital admissions for myocardial infarction (MI) and all-cause
death among individuals with previous MI, diabetes mellitus, or CKD. Among people without previous MI, the risk of
MI was lower among patients with diabetes mellitus without

CKD than among those with CKD (5.4 per 1000 patient-years
versus 6.9 per 1000 patient-years). The findings in this study
would indicate that CKD should be added to the list of criteria
defining people at high risk for coronary events.

Special Clinical Characteristics
of ACS in CKD Patients
Clinical Presentation of ACS Among CKD Patients
The clinical presentation of ACS among patients with CKD
is distinctly different from that of patients without CKD in
the general population.1,11–15 First, the prevalence of chest
pain among patients with ACS is inversely related to stage of
CKD. As shown in Figure 3, there is a graded reduction in
the frequency of chest pain as eGFR falls.15 For example, in a
collaborative project of the United States Renal Data System
(USRDS) and the National Registry of Myocardial Infarction
(NRMI), the clinical characteristics were compared in a large
population of MI patients that included 2390 dialysis patients,
29 319 patients with advanced CKD (serum creatinine [SCr]

>2.5 mg/dL), and 274 777 non-CKD patients.14 Those with
advanced CKD and dialysis were less likely to have chest
pain on admission (40.4% and 41.1%, respectively) than
those without CKD (61.6%). Similar observations were
made in the SWEDEHEART registry [Swedish Web System
for Enhancement and Development of Evidence-Based Care
in Heart Disease Evaluated According to Recommended
Therapies]; however, up to two thirds of patients with stage
4 and 5 CKD in that registry had chest pain at presentation.15
The USRDS-NRMI study also showed that MI patients with

advanced CKD and those undergoing dialysis more often had
a diagnosis at presentation other than ACS (44% and 47.7%,
respectively) compared with patients without CKD (25.8%).
Compared with patients without CKD, patients with advanced
CKD were also less likely to have ST-segment elevation
(15.9% versus 32.5%, respectively) but more likely to have
heart failure on presentation (52.2% versus 27.2%, respectively) and a higher rate of in-hospital mortality (23% versus
12.6%, respectively).10 Similar differences existed between
those with advanced CKD and those undergoing dialysis.
The distribution of electrocardiographic presentations varies
according to severity of CKD, with fewer STEMIs and more
NSTEMI and left bundle branch block among populations
with increasingly worse renal function (Figure 3).11,15
An additional consideration in the diagnosis of ACS in
patients with CKD is the interpretation of cardiac biomarkers. Chronic troponin elevations in clinically stable patients
with renal failure have been observed and likely represent
nonischemic myocardial injury.16 In spite of these chronic
troponin elevations in a population of patients with CKD,
the National Association of Clinical Biochemistry laboratory medicine practice guidelines recommend the use of
troponins for the diagnosis of MI in patients with CKD presenting with symptoms or electrocardiographic changes suggestive of myocardial ischemia.17 These guidelines, along
with other expert writing groups, advise the importance of a
dynamic change in troponin values after presentation in the


Washam et al   Pharmacotherapy in CKD Patients With ACS   3
presentation (and thus would not be considered for appropriate therapeutic interventions).

Methods of Estimating Renal
Function for Drug Dosing
Whereas the Modification of Diet in Renal Disease (MDRD)

equation is widely used for CKD diagnosis and staging, the
Cockcroft-Gault (CG) equation has been the most commonly
used equation to estimate renal function for dose adjustment
of medications.22 Although these equations have limitations,
both the CG and MDRD equations have been shown to correlate relatively well with measured glomerular filtration rate
(GFR),22 but differences in medication dose recommendations
have been reported depending on which equation is used.23–25
An analysis of the Can Rapid Risk Stratification of Unstable
Angina Patients Suppress Adverse Outcomes With Early
Implementation of the ACC/AHA Guidelines (CRUSADE)
registry was conducted to compare the CG and MDRD equations with regard to the recommended doses of eptifibatide,
tirofiban, and enoxaparin.23 Results of this analysis showed
a 20% difference in CKD classification between the 2 equations. The proportion of patients classified as having normal/
mild CKD (eGFR ≥60 mL/min), moderate CKD (eGFR 30–
59 mL/min), and severe CKD (eGFR <30 mL/min) by the CG
equation was 41.2%, 39.8%, and 19% compared with 58.9%,
31.5%, and 9.6%, respectively, by the MDRD equation. In
addition, marked differences were seen in the proportion of
patients for whom dose adjustment was recommended by
the CG versus MDRD equation, respectively, for eptifibatide
(45.7% versus 27.3%) and for enoxaparin or tirofiban (19.0%
versus 9.6%). Over the past decade, the CG equation has been
the preferred method used in assessing renal function for dose
adjustment and to determine trial eligibility in randomized
controlled trials of antithrombotic medications. Until further
data validating the MDRD equation as a method for dose
adjustment of cardiovascular medications become available,
current data support the use of the CG equation for cardiovascular drug dosing (Table 1).
Figure 2. Age-standardized rates of death of any cause (A),
cardiovascular events (defined as hospitalization for coronary

heart disease, heart failure, ischemic stroke, or peripheral
arterial disease) (B), and hospitalization (C) according to the
estimated glomerular filtration rate (GFR) among 1 120 295
ambulatory adults. Reprinted from Go et al9 with permission
from Massachusetts Medical Society. Copyright © 2004,
Massachusetts Medical Society.

identification of acute MI (AMI) in patients with end-stage
renal disease (ESRD), who more frequently have chronically
elevated troponin levels.16–18
This striking difference in clinical presentation and electrocardiographic findings has implications for correct diagnosis
and subsequent treatment. It has been a subject of great attention that the use of evidence-based therapy is lower among
patients with CKD.1–3,19–21 Not only are those with ACS and
CKD less likely to receive evidence-based therapies, the
atypical clinical presentation of these patients makes it less
likely that they will be correctly identified as having ACS on

Pharmacotherapy for ACS
Among Patients With CKD
Fibrinolytic Therapy
Current American College of Cardiology Foundation/
American Heart Association guidelines give fibrinolytic therapy a Class I recommendation for STEMI patients presenting within 12 hours of the onset of ischemia symptoms and
without contraindications, when it is anticipated primary percutaneous coronary intervention (PCI) cannot be performed
within 120 minutes.26 Although primary PCI is the preferred
reperfusion strategy for STEMI patients, recent data from the
NCDR-ACTION Registry indicate that fibrinolytic therapy
was the initial reperfusion strategy in ≈10% of patients in the
United States.29 Because initial randomized controlled trials of
fibrinolytic therapy did not assess the treatment effect of the
fibrinolysis in the subgroup of patients with CKD, outcome

data in this population are limited. Clinical trial and observational data on the outcomes of ACS patients with CKD receiving fibrinolytic therapy are summarized in Table 2.


4  Circulation  March 24, 2015
100%
90%

90%

Frequency (%)

80%
70%

88%

eGFR

≥90

60–89 30–59 15–29 <15/dialysis

76%
67%
65%
58%
56%

60%

66%
60%
60%

46%

50%

38%

40%
31%

30%
20%

41%

37%
29%
25%
22%

15%
10%

10%

3%

15%
12%
11%
6%

0%

Chest pain

Killip ≥ II

STEMI

LBBB

NSTEMI

Figure 3. Relation of renal function to presentation, symptoms, and ECG changes in patients presenting with acute coronary syndrome.
Data from the SWEDEHEART Registry (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart
Disease Evaluated According to Recommended Therapies). eGFR indicates estimated glomerular filtration rate; LBBB, left bundle branch
block; NSTEMI, non–ST-segment–elevation myocardial infarction; and STEMI, ST-segment–elevation myocardial infarction. Reprinted
from Szummer et al15 with permission of the publisher. Copyright © 2010, Blackwell Publishing Ltd.

A pooled analysis of 16 
710 patients enrolled in the
Thrombolysis in Myocardial Infarction (TIMI)-10A, TIMI10B, TIMI-14, and Intravenous NPA for the Treatment of
Infarcting Myocardium Early (InTIME-II) trials was conducted to assess the impact of baseline renal function (SCr and
CrCl) on outcomes in patients receiving fibrinolytic therapy.30
A stepwise increase in mortality was seen with worsening renal

function, and rates of intracranial hemorrhage increased with
worsening renal function (0.6%, 0.8%, 1.8%, and 3.0% for
normal, mildly impaired, moderately impaired, and severely
impaired CrCl, respectively; P<0.0001 for trend).
Several observational analyses have evaluated the association of CKD with outcomes and the treatment effect of fibrinolytic therapy in STEMI patients with various results. Hobbach

Table 1.  Doses of Parenteral Antithrombotic Agents
Medication

Renal
Elimination

Dose in Patients Without CKD

Dose Adjustment in CKD

NS

• PCI: 0.25-mg/kg bolus followed by infusion
of 0.125 μg·kg−1·min−1 (maximum 10 μg/min)
for 12 h after procedure

No adjustment

Bivalirudin26

20%

• PCI: 0.75-mg/kg bolus followed by infusion of
1.75 mg·kg−1·h−1 for duration of the procedure

CrCl <30 mL/min:
• PCI: 0.75-mg/kg bolus followed by infusion of
1 mg·kg−1·h−1 for the duration of the procedure
Dialysis:
• PCI28: 0.75-mg/kg bolus followed by infusion of
0.25 mg·kg−1·h−1

Enoxaparin26,27

40%

•UA/NSTEMI: 1 mg/kg SC every 12 h
• STEMI patients <75 y of age receiving fibrinolytic
therapy: 30-mg single IV bolus plus a 1-mg/kg
SC dose followed by 1 mg/kg SC every 12 h
• STEMI patients ≥75 y of age receiving fibrinolytic
therapy: No bolus, 0.75 mg/kg SC every 12 h

CrCl <30 mL/min:
• UA/NSTEMI: 1 mg/kg SC once daily
• STEMI patients <75 y of age receiving fibrinolytic therapy:
30-mg single IV bolus plus a 1-mg/kg SC dose followed by
1 mg/kg administered SC once daily
• STEMI patients ≥75 y of age receiving fibrinolytic therapy:
No bolus, 1 mg/kg administered SC once daily
Not recommended in dialysis patients

Eptifibatide7,26

50%

• ACS: 180-μg/kg bolus followed by an infusion
of 2 μg·kg−1·min−1 for up to 72 h
• PCI: 180 μg/kg followed by continuous infusion
of 2 μg·kg−1·min−1 for up to 18–24 h. A second
180-μg/kg bolus given 10 min after the first bolus

CrCl < 50 mL/min:
• ACS: 180-μg/kg bolus followed by infusion of
1 μg·kg−1·min−1 for up to 72 h
• PCI: 180-μg/kg bolus followed by infusion of
1 μg·kg−1·min−1 for up to 18–24 h. A second 180-μg/kg
bolus given 10 min after the first bolus
Contraindicated in dialysis patients

Fondaparinux26,27

75%

• STEMI patients receiving fibrinolytic therapy:
2.5 mg IV followed by 2.5 mg SC daily starting
the following day
• UA/NSTEMI: 2.5 mg SC daily

CrCl < 30 mL/min:
• Avoid use

Abciximab26,27

(Continued )


Washam et al   Pharmacotherapy in CKD Patients With ACS   5
Table 1.  Continued
Medication

Renal
Elimination

Unfractionated
heparin26,27

Tirofiban26

Dose in Patients Without CKD

Dose Adjustment in CKD

NS

• UA/NSTEMI (initial dosing): Bolus of 60 U/kg
(maximum 4000 U) followed by an infusion of
12 U·kg−1·h−1 (maximum 1000 U/h) to maintain
aPTT at 1.5–2.0 times control
• STEMI patients receiving fibrinolytic therapy:
Bolus of 60 U/kg (maximum 4000 U/kg) followed
by an infusion of 12 U·kg−1·h−1 (maximum 1000 U)
initially, adjusted to maintain aPTT at 1.5–2.0 times
control for 48 h or until revascularization.

65%

• PCI: 25 μg/kg IV over 3 min followed by an infusion
of 0.15 μg·kg−1·min−1 for up to 18 h post-PCI

No adjustment recommended

CrCl ≤60 mL/min:
• P CI: 25 μg/kg IV over 3 min followed by an infusion
of 0.075 μg·kg−1·min−1 for up to 18 h post-PCI

ACS indicates acute coronary syndrome; aPTT, activated partial thromboplastin time; CKD, chronic kidney disease; CrCl, creatinine clearance; IV, intravenous; NS,
not significant; NSTEMI, non–ST-segment–elevation myocardial infarction; PCI, percutaneous coronary intervention; SC, subcutaneous; STEMI, ST-segment–elevation
myocardial infarction; and UA, unstable angina.

and colleagues conducted an observational analysis to assess
the prognostic significance of baseline SCr in a study of 352
STEMI patients receiving fibrinolytic therapy.31 In this study,
there was no association between baseline SCr and TIMI flow
grade after fibrinolytic administration; however, there was a

significant increase in mortality among patients with renal
dysfunction (P<0.001) but no difference in major bleeding
(P=0.363). In 5549 Canadian ACS patients without ESRD who
survived to hospital discharge and were followed up for a mean
of 5.6 years, moderate (eGFR 30–59 mL·min−1·1.73 m−2) and

Table 2.  Summary of Fibrinolytic Studies in STEMI Patients With CKD
Study

Gibson et al30

Hobbach
et al31

Keough-Ryan
et al32

Study Design

Population

Subgroup analysis 16 635 patients received fibrinolytic therapy
of pooled data
in a clinical trial and were divided into 4
from 4 trials
categories according to renal function:
normal (CrCl ≥90 mL/min, n=6062), mildly
impaired (CrCl 60–89 mL/min, n=6795),
moderately impaired (CrCl 30–59 mL/min,
n=3514), and severely impaired (CrCl
<30 mL/min, n=264)

Observational
cohort

Observational
cohort (ICONS
registry)

352 STEMI patients received fibrinolytic
therapy. Patients were divided into groups
based on SCr: normal (SCr <1.2 mg/dL,
n=256) and renal dysfunction (SCr 1.3–2.8
mg/dL, n=87)

5549 consecutive patients with ACS
surviving to hospital discharge. Renal
function classified into normal (>80;
n=1430), mild CRI (60–80; n=2018),
moderate CRI (30–59; n=1795), and severe
CRI (<30; n=306) mL·min−1·1.73 m−2.* ESRD
patients were excluded from this analysis.

End Points
Mortality (30 d)
Angiographic outcomes
(TIMI flow grade, corrected
TIMI frame count)

Results
A stepwise increase in 30-d mortality was seen
in patients with normal, mildly, moderately, and
severely impaired renal function with rates of
2.2%, 5.2%, 13.8%, and 30.7%, respectively
(P<0.0001).
In patients who had angiographic assessment,
the rates of TIMI flow grade 2 or 3 at 90 min
were 80.7%, 80.2%, 85.5%, and 93.3%
(P=0.11 for trend) in the normal, mildly,

moderately, and severely impaired groups,
respectively.

ICH

ICH rates in the 4 renal function categories were
0.6%, 0.8%, 1.8%, and 3.0%, respectively
(P<0.001 for trend)

Mortality (30 d, 6 mo)

30-d mortality rates in patients in the normal
and renal dysfunction groups were 3.4% and
16.1% (P<0.001), respectively. 30-d rates of
reinfarction in the normal and renal dysfunction
groups were 3.4% and 3.6% (P=0.981),
respectively.

Reinfarction (30 d, 6 mo)

Major and minor bleeding

Rates of major bleeding in the normal and
renal dysfunction groups were 2.6% and 4.6%
(P=0.363), respectively, whereas rates of minor
bleeding were 6.4% and 10.3% (P=0.224),
respectively.

Mortality (mean follow-up
5.6 y)

Moderate and severe CKD were found to be
independent predictors of mortality. Patients
with severe CKD were less likely to receive
fibrinolytic therapy (OR, 0.55; 95% CI, 0.30–
0.98). The adjusted HR (95% CI) for mortality
was 0.885 (0.81–0.97) for the use of fibrinolytic
therapy during hospitalization and 0.846
(0.79–0.91) for cardiac catheterization.
(Continued )


6  Circulation  March 24, 2015
Table 2.  Continued
Study
Medi et al33

Dragu et al34

Study Design
Observational
cohort (GRACE
registry)

Observational
cohort (ACSIS)

Population
12 532 patients with ST-segment
elevation or LBBB. Patients stratified

into groups based on estimated GFR*:
normal, ≥60 mL·min−1·1.73 m−2 (n=9082);
moderate, 30–59 mL·min−1·1.73 m−2
(2982); and severe renal dysfunction,
<30 mL·min−1·1.73 m−2.

132 STEMI patients with renal failure
(defined by a history or SCr >1.5 mg/dL
on admission). 24 (18.2%) received
fibrinolytic therapy, 35 (26.5%) received
primary PCI, and 73 (55.3%) received
no reperfusion.

End Points
Mortality (in-hospital and
6 mo)
Reinfarction

Results
In this analysis, mortality increased as GFR
decreased (P<0.001). The adjusted ORs
(95% CIs) for in-hospital mortality in patients
receiving fibrinolysis vs patients receiving no
reperfusion were as follows: normal, 1.06
(0.78–1.44); moderate, 1.35 (1.01–1.80);
severe renal dysfunction, 1.11 (0.57-2.14).

Major bleeding

Compared with patients receiving no

reperfusion, the rates of major bleed with
fibrinolytic therapy in the moderate and
severe renal dysfunction groups were 2.5% vs
3.4% (P=0.11) and 4.2% vs 8.2% (P=0.12),
respectively

Mortality (7 d, 30 d, 1 y)

The unadjusted mortality rates at 7 d in the
3 groups were as follows: fibrinolytic therapy,
8% (2/24 patients); PCI, 26% (9/35 patients); and
no reperfusion, 15% (11/73 patients; P=0.18).
Unadjusted mortality rates were lower in the
fibrinolytic therapy group at 30 d: 8%, 40%, and
30% (P=0.03), respectively. Bleeding rates were
not reported in this analysis

ACS indicates acute coronary syndrome; ACSIS, Acute Coronary Syndromes Israeli Survey; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine
clearance; CRI, chronic renal insufficiency; ESRD, end-stage renal disease; GFR, glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; HR, hazard
ratio; ICH, intracranial hemorrhage; ICONS, Improved Cardiac Outcomes in Nova Scotia; LBBB, left bundle branch block; OR, odds ratio; PCI, percutaneous coronary
intervention; SCr, serum creatinine; STEMI, ST-segment–elevation myocardial infarction; and TIMI, Thrombolysis in Myocardial Infarction.
*GFR calculated by the modified Modification of Diet in Renal Disease equation.

severe (eGFR <30 mL·min−1·1.73 m−2) CKD were independent
predictors of mortality.32 Factors associated with lower mortality included thrombolysis (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.81–0.97) and cardiac catheterization
(HR, 0.85; 95% CI, 0.79–0.91). Among 12 532 patients with
ST-segment elevation or left bundle branch block enrolled in
the Global Registry of Acute Coronary Events (GRACE), inhospital mortality increased with worsening renal function
(P<0.001), and the use of reperfusion decreased with worsening renal function (P<0.001).33 Compared with no reperfusion,
fibrinolytic therapy was not associated with in-hospital mortality for patients with normal or severe renal dysfunction, but it

was associated with increased mortality among patients with
moderate renal dysfunction (adjusted odds ratio [OR], 1.35;
95% CI, 1.01–1.80). A final observational analysis compared
reperfusion strategies among 132 STEMI patients with renal
failure (defined by history or an SCr ≥1.5 mg/dL on admission) enrolled in the Acute Coronary Syndromes Israeli Survey
(ACSIS).34 In this cohort, 24 patients (18.2%) received fibrinolytic therapy, 35 (26.5%) were treated by primary PCI, and
73 (55.3%) received no reperfusion therapy. There was no significant difference in mortality among the fibrinolytic, primary
PCI, and no reperfusion groups at 7 days; however, at 30 days,
mortality was lower among patients who received the fibrinolytic strategy (8%) than among those with primary PCI (40%)
or no reperfusion (30%; P=0.03).
In summary, although the above data suggest an increase in
adverse outcomes with worsening renal function, assessment
of the treatment effect of fibrinolytic therapy in the subgroup
of patients with CKD is limited and variable. Data from a
pooled analysis of early trials of fibrinolytic therapy in which

all patients received a fibrinolytic agent show increasing rates
of intracranial hemorrhage with worsening renal function.30
This observation is noteworthy because current models for
estimating intracranial hemorrhage risk with fibrinolytic therapy do not include CKD as a risk factor.35,36 In spite of the limitations, taken collectively, the published data would support
that fibrinolytic therapy be considered as a treatment strategy
for CKD patients presenting with STEMI when primary PCI
is not available. However, given the increased rates of intracranial hemorrhage observed with worsening renal function,
careful consideration of the benefits and risk of fibrinolytic
therapy in this population is required.

Antiplatelet Therapy
Aspirin
Current guidelines recommend aspirin should be initiated as
soon as an ACS is suspected and should be continued indefinitely, unless a contraindication develops.26,27 Given that

patients with renal insufficiency have an increased bleeding
risk, there is some trepidation regarding the use of antiplatelet
therapy in these patients. Although patients with CKD were
excluded from most randomized trials of aspirin therapy in
ACS, data on observational studies evaluating aspirin therapy
in patients with renal impairment are shown in Table 3.
The Antithrombotic Trialists’ Collaboration performed
a meta-analysis of 287 randomized trials that included
135 000 patients and compared various antiplatelet therapies versus control.37 Some of those trials included patients
undergoing hemodialysis. Among those undergoing hemodialysis, antiplatelet therapy reduced the risk of serious


Washam et al   Pharmacotherapy in CKD Patients With ACS   7
Table 3.  Summary of Aspirin Studies in Patients With ACS and CKD
Study

Study Design

Population

End Points

Results

Antithrombotic
Trialists’
Collaboration37

Meta-analysis
of randomized

trials

287 studies involving 135 000 patients in
comparisons of antiplatelet therapy versus
control and 77 000 in comparisons of
different antiplatelet regimens. The number
of hemodialysis patients who received
antiplatelet treatment was 1333, whereas
the number of hemodialysis patients who
received control was 1371.

Serious vascular event
(nonfatal MI, nonfatal
stroke, or vascular death

Absolute reduction in the risk of serious vascular
event in patients with previous MI was 36 (SE 5)
per 1000 treated for 2 y and 38 (SE 5) per 1000
treated for 1 mo with AMI. Among individuals
undergoing hemodialysis, antiplatelet therapy
produced a 41% (SE 16%) proportional reduction
in serious vascular events and no significant
increase in extracranial bleeds (2% in antiplatelet
vs 2.3% in control).

Keough-Ryan
et al32

Observational
cohort

5549 consecutive patients with ACS
surviving to hospital discharge. Renal
function classified into normal, >80
mL·min−1·1.73 m−2) n=1430; mild CRI,
60–80 mL·min−1·1.73 m−2 (n=2018);
moderate CRI, 30–59 mL·min−1·1.73 m−2
(n=1795); and severe CRI, <30 (n=306)
mL·min−1·1.73 m−2 *

Mortality (mean follow-up
5.6 y)

A significant interaction was found between
kidney function and discharge aspirin therapy
with regard to mortality. The protective effect of
aspirin was attenuated with increasing degrees
of renal dysfunction. The adjusted HR (95% CI)
for aspirin overall was 0.904 (0.843–0.969);
in mild CRI, it was 0.851 (0.921–1.128); in
moderate CRI, 1.029 (0.988–1.081); and in
severe CRI, 1.232 (1.024–1.117).

McCullough
et al21

Observational,
prospective
cohort study

1724 patients with STEMI. Renal function
classified by quartile corrected creatinine
clearance >81.5 mL/min (n=524), 63.1
to ≤81.5 (n=421), 46.2 to ≤63.1 (n=421),
≤46.2 not undergoing dialysis (n=310),
and chronic dialysis (n=47)

In-hospital mortality

Adjusted RR reduction for the combination
of in-hospital aspirin and β-blocker was 80%,
74.9%, 69%, 64.3%, and 77.9% across the
quartiles of corrected creatinine clearance,
respectively

Berger et al19

Observational,
retrospective
analysis of CCP
and USRDS

AMI patients: 145 740 patients without
ESRD and 1025 patients with ESRD
receiving dialysis

Mortality (30 d)

Aspirin therapy was associated with a 50%
relative reduction in mortality in those receiving

dialysis (P<0.001) and a 63% relative reduction
among those without ESRD (P<0.001)

Yan et al38

Observational,
prospective
cohort study

3510 patients hospitalized for ACS with
normal renal function (CrCl† ≥90 mL/min;
n=1152), mild renal dysfunction (CrCl
60–89 mL/min; n=1253), moderate
renal dysfunction (CrCl 30–59 mL/min;
n=944), and severe renal dysfunction
(CrCl <30 mL/min; n=161)

1-y Survival

Aspirin was associated with improved 1-y
survival to a similar extent among those with
normal and impaired renal function. Discharge
aspirin use adjusted OR 0.43 (95% CI, 0.31–
0.60; P<0.001; P=0.15 for heterogeneity across
CrCl <60 vs ≥60 mL/min)

Wright et al2

Observational,
retrospective

cohort study

3106 patients with AMI with no renal
disease (n=1320), mild CRI (CrCl >50
mL/min but ≤75 mL/min; n=860),
moderate renal dysfunction (CrCl >35
mL/min but ≤50 mL/min; n=491), severe
renal insufficiency (CrCl† <35 mL/min;
n=391), or ESRD (n=44)

Short- and long-term
survival stratified by CrCl

Aspirin within 24 h of admission was
associated with a significant reduction in
in-hospital death adjusted OR 0.4 (95% CI,
0.3–0.6; P<0.001), and discharge aspirin
was associated with improved postdischarge
survival across the spectrum of renal failure
(adjusted HR, 0.7; 95% CI, 0.5–0.8; P<0.001)

Sciahbasi et al39

Retrospective
review

595 patients with AMI, 404 with normal
renal function, and 191 with impaired renal
function (GFR* ≤60 mL·min−1·1.73 m−2)

Ratio of NSTEMI to STEMI
patients

Prior therapy with aspirin or statins was
associated with increased ratio of NSTEMI to
STEMI in the overall population and in those
with impaired renal function. Adjusted OR (95%
CI) for STEMI with prior aspirin or statin therapy
in the overall population was 0.8 (0.65–0.93;
P=0.008) and in those with renal impairment,
0.5 (0.2–1.0; P=0.05)

ACS, acute coronary syndrome; AMI, acute myocardial infarction; CCP, Cooperative Cardiovascular Project; CI, confidence interval; CKD, chronic kidney disease; CrCl,
creatinine clearance; CRI, chronic renal insufficiency; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction; NSTEMI,
non–ST-segment–elevation myocardial infarction; OR, odds ratio; RR, relative risk; SE, standard error; STEMI, ST-segment–elevation myocardial infarction; and USRDS,
United States Renal Data System.
*GFR calculated by the modified Modification of Diet in Renal Disease equation.
†CrCl calculated via Cockcroft-Gault equation.

vascular events (nonfatal MI, nonfatal stroke, or vascular
death) by 41% (standard error, 16%). There was no significant increase in extracranial bleeds, although the absolute
number was small (2% in antiplatelet-treated patients versus
2.3% in control subjects).37

Most of the published observational data show similar benefits of aspirin therapy in ACS patients across the spectrum of
renal function (Table 3). However, one study did find a significant interaction between discharge aspirin therapy and renal
function, with an attenuated benefit with increasing degree of


8  Circulation  March 24, 2015

renal dysfunction.32 Although not conducted in ACS patients
per se, the United Kingdom Heart and Renal Protection Study
and the Dialysis Outcomes and Practice Patterns Study both
showed no increased bleeding risk with aspirin therapy among
patients receiving hemodialysis, which provides further support
for the safety of aspirin in patients with CKD.40,41 Collectively,
the available data suggest that aspirin therapy is safe and effective in ACS patients with CKD and should be used in these
patients to reduce the risk of death and vascular events.
Clopidogrel, Prasugrel, and Ticagrelor
Current guidelines recommend the use of a P2Y12 receptor
inhibitor across the spectrum of ACS presentations.26,42 Data
evaluating P2Y12 receptor inhibitors in patients with ESRD
are limited, and such information is available predominantly
for individuals with moderate or no CKD. Data on the use of
P2Y12 receptor inhibitors in ACS patients with CKD are summarized in Table 4. The Clopidogrel in Unstable Angina to
Prevent Recurrent Events (CURE) trial randomized patients
with an ACS without ST-segment elevation to either a 300mg loading dose of clopidogrel followed by 75 mg per day
or placebo. Based on tertiles of renal function, the relative risks (RR) and 95% CIs for the primary composite outcome associated with clopidogrel versus placebo were 0.74
(0.60–0.93) in the upper third, 0.68 (0.56–0.84) in the middle
third, and 0.89 (0.76–1.05) in the lower third, with a Pinteraction
of 0.11.43,44 In the Clopidogrel for the Reduction of Events
During Observation (CREDO, a trial of patients undergoing
planned PCI or coronary angiogram)45,46 and the Clopidogrel
as Adjunctive Reperfusion Therapy–Thrombolysis in
Myocardial Infarction 28 (CLARITY-TIMI 28) trial (a trial
of patients with STEMI),47,48 there was a qualitative decline
in the efficacy of clopidogrel versus placebo as renal function worsened; the HRs (95% CIs) across renal function were
0.42 (0.26–0.69), 0.80 (0.51–1.25), and 1.42 (0.81–2.45) in
CREDO and 0.6 (0.40–0.90), 0.6 (0.40–0.70), and 1.0 (0.70–
1.6) in CLARITY-TIMI 28. In a substudy of the Clopidogrel

for High Atherothrombotic Risk and Ischemic Stabilization,
Management, and Avoidance (CHARISMA) trial, among
patients with and without diabetic nephropathy, the HRs (95%
CIs) for clopidogrel versus placebo were 0.9 (0.80–1.0) for
those without diabetic nephropathy and 1.1 (0.80–1.6) for
those with diabetic nephropathy.52,53
In terms of safety, more bleeding occurred with clopidogrel than placebo overall; however, there was no significant interaction based on renal function in CURE, CREDO,
or CLARITY-TIMI 28. Within the CHARISMA analysis,
the frequency of severe bleeding according to the Global
Utilization of Streptokinase and tPA for Occluded Arteries
(GUSTO) definition among patients with diabetic nephropathy was nonsignificantly higher with clopidogrel than with
placebo (2.6% versus 1.5%, P=0.075). In patients without diabetic nephropathy, there was no difference in GUSTO severe
bleeding between patients randomized to clopidogrel versus
placebo (1.5% versus 1.3%, P=0.28).53
Prasugrel and ticagrelor are P2Y12 inhibitors that exhibit
a more rapid onset, higher degrees of platelet inhibition, and less interpatient variability than clopidogrel. The
Trial to Assess Improvement in Therapeutic Outcomes by

Optimizing Platelet Inhibition With Prasugrel–Thrombolysis
in Myocardial Infarction (TRITON–TIMI 38) randomized
subjects who presented with moderate- to high-risk ACS with
scheduled PCI to either prasugrel or clopidogrel. Within this
study, the risk reduction associated with prasugrel versus
clopidogrel was 20% among those with CrCl ≥60 mL/min
and 14% among those with CrCl <60 mL/min.49 The Study of
Platelet Inhibition and Patient Outcomes (PLATO) randomized patients admitted to the hospital with an ACS to treatment
with ticagrelor or clopidogrel. The HRs (95% CIs) for ticagrelor versus clopidogrel for the primary composite outcome
were 0.90 (0.79–1.02) among subjects with CrCl ≥60 mL/min
and 0.77 (0.65–0.90) among those with CrCl <60 mL/min.50,51
The HRs (95% CIs) for ticagrelor versus clopidogrel for major

bleeding events were 1.08 (0.96–1.22) among patients with
CrCl >60 mL/min and 1.07 (0.88–1.30) among those with
CrCl <60 mL/min. Thus, the efficacy associated with prasugrel and ticagrelor compared with clopidogrel was apparent
among subjects with reduced and normal renal function.
In summary, randomized placebo-controlled trial data
on the use of clopidogrel in ACS patients with CKD have
been derived primarily from patients not undergoing an early
invasive strategy or primary PCI.43,47 The lack of a treatment-­
by–renal function interaction suggests clopidogrel should
be considered as a treatment option in this population. In
addition, although the observed rates of bleeding have been
higher with clopidogrel than with placebo in CKD patients,
the lack of a treatment interaction suggests no significant
increase in risk with the use of clopidogrel in ACS patients
with CKD. The efficacy associated with prasugrel compared
with clopidogrel and the efficacy and safety associated with
ticagrelor compared with clopidogrel were evident in patients
with and without CKD, and the data suggest these agents
should be considered in CKD patients who are not considered to be at high risk of bleeding. However, patients with
ESRD have been excluded from the landmark trials of these
newer agents.49,50
Glycoprotein IIb/IIIa Receptor Antagonists
The glycoprotein (GP) IIb/IIIa receptor antagonists have
been studied extensively in patients undergoing PCI and
in patients presenting with ACS. In the setting of STEMI,
recent guidelines give a Class IIa recommendation for the
use of the GP IIb/IIIa receptor antagonists at the time of
primary PCI in patients receiving unfractionated heparin
(UFH).26 Among patients presenting with unstable angina
(UA)/NSTEMI with medium- or high-risk features in whom

an initial invasive strategy is selected, current recommendations for the use of GP IIb/IIIa receptor antagonists include
the option for upstream initiation or initiation at the time
of PCI.42 Additionally, the guidelines favor a selective strategy of upstream use of GP IIb/IIIa receptor antagonists, and
the use of these agents as part of an upstream triple-antiplatelet therapy regimen may not be supported when there
is a concern for increased bleeding risk.42 Of the 3 agents
currently available in the United States, eptifibatide and
tirofiban are dependent on renal clearance for elimination,
and dose adjustment is required for the 2 agents in patients
with CrCl <50 mL/min and CrCl ≤60 mL/min (Table 1),


Washam et al   Pharmacotherapy in CKD Patients With ACS   9
Table 4.   Summary of Clopidogrel, Prasugrel, and Ticagrelor Studies in Patients With ACS and CKD
Study
CURE,
200143,44

CREDO,
200345,46

Study Design

Population

Subgroup analysis
of an RCT

12 253 patients who presented with ACS
without ST-segment elevation randomized
to clopidogrel or placebo in addition to

aspirin. Patients grouped based on tertiles
of eGFR*: upper tertile (>81.3 mL/min),
middle tertile (64–81.2 mL/min), lower
tertile (<64 mL/min). An eGFR <30 mL/min
was noted in 1.8% (n=224) of patients.

Cardiovascular death, MI,
or stroke through 1 y

Based on tertiles of renal function,† the RRs
(95% CIs) for clopidogrel vs placebo were 0.74
(0.60–0.93) for the upper third, 0.68 (0.56–
0.84) for the middle third, and 0.89 (0.76–1.05)
for the lower third (Pinteraction=0.11).

Major or life-threatening
bleeding

The RRs (95% CIs) for major or life-threatening
bleeding for clopidogrel vs placebo were 1.83
(1.23–2.73) for the upper third, 1.4 (0.97–2.02)
for the middle third, and 1.12 (0.83–1.51) for
the lower third.

2002 patients referred for a planned PCI
or coronary angiogram randomized to
clopidogrel initiated with a 300 mg load
followed by 75 mg daily vs clopidogrel 75
mg daily through 28 d. Patients grouped
according to CrCl: >90 (n=999), 60–89

(n=672), <60 mL/min (n=331)

Death, MI, or stroke
through 1 y

Based on estimated CrCl† (>90 [normal],
60–89 [mild CKD], <60 mL/min [moderate
CKD]), the HRs (95% CIs) for clopidogrel vs
placebo were 0.42 (0.26–0.69) for the normal
group, 0.80 (0.51–1.25) for mild CKD, and 1.41
(0.81–2.45) for moderate CKD.

Major bleeding through 1 y

The RRs (95% CIs) for clopidogrel vs placebo
were 1.17 (0.74–1.84) for the normal group,
1.59 (0.97–2.62) for mild CKD, and 1.12 (0.51–
2.48) for moderate CKD.

3252 patients who presented within 12 h
after the onset of an ST-segment elevation
MI who received fibrinolytic therapy
randomized to clopidogrel vs placebo.
Patients were stratified based on normal
(≥90) (n=841), mild (60– 89)(n=1,897) and
moderate (<60 mL/min/1.73 m2) (n=514)
reductions in GFR.*

Death, MI, or TIMI 0/1
flow through angiography

or day 8

The HRs (95% CIs) for clopidogrel vs placebo
were 0.6 (0.4–0.9) for the normal group, 0.6
(0.4–0.7) for mild CKD, and 1.0 (0.7–1.6) for
moderate CKD (P interaction=0.09).

TIMI major or minor bleeding
at 30 d

The adjusted ORs (95% CIs) for clopidogrel
vs placebo were 1.7 (0.5-5.3) for the normal
group, 1.3 (0.8–2.2) for the mild group, and
1.6 (0.7–3.7) for the group with moderate CKD
(Pinteraction=0.94).

Subgroup analysis
of an RCT

CLARITY-TIMI Subgroup analysis
28, 200547,48 of an RCT

End Points

Results

TRITON-TIMI
38, 200749

Subgroup analysis

of an RCT

13 608 patients with moderate- to high-risk
ACS with scheduled PCI randomized to
prasugrel vs clopidogrel. Patients grouped
according to CrCl†: >60 mL/min (11 890)
and <60 mL/min (n=1490)

Cardiovascular death, MI,
or stroke through 15 mo

The reduction in risk with prasugrel vs
clopidogrel was 20% among subjects with
CrCl† ≥60 mL/min and 14% among those with
CrCl <60 mL/min.

PLATO,
200950,51

Subgroup analysis
of an RCT

15 202 patients admitted to the hospital
with an ACS randomized to ticagrelor
vs clopidogrel. Patients were grouped
according to CrCl†: ≥60 mL/min
(n=11 965) and <60 mL/min (n=3237)

Cardiovascular death, MI,
or stroke through 12 mo

The HRs (95% CIs) for ticagrelor vs clopidogrel
were 0.90 (0.79–1.02) among subjects with
CrCl† ≥60 mL/min and 0.77 (0.65–0.90) among
those with CrCl <60 mL/min (Pinteraction=0.13).
The HR (95% CI) in those with CrCl <30 mL/min
(n=214) was 0.77 (0.49–1.30).

Major bleeding

In patients with CrCl <60 mL/min, the HR
(95% CI) for major bleeding events for
ticagrelor compared with clopidogrel was
1.07 (0.88–1.30).

ACS indicates acute coronary syndrome; CI, confidence interval; CKD, chronic kidney disease; CLARITY-TIMI 28, Clopidogrel as Adjunctive Reperfusion Therapy–
Thrombolysis in Myocardial Infarction 28; CrCl, creatinine clearance; CREDO, Clopidogrel for the Reduction of Events During Observation; CURE, Clopidogrel in Unstable
Angina to Prevent Recurrent Events; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary
intervention; PLATO, Study of Platelet Inhibition and Patient Outcomes; RCT, randomized controlled trial; RR, relative risk; TIMI, Thrombolysis in Myocardial Infarction;
and TRITON-TIMI 38, Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38.
*Calculated by modified Modification of Diet in Renal Disease equation.
†Calculated via Cockcroft-Gault equation.

respectively.54,55 In addition, eptifibatide is contraindicated in
patients requiring dialysis.54
Abciximab is cleared via the reticuloendothelial system,
and no current recommendations exist for dose adjustment for
patients with CKD. Data from randomized trials and observational studies on the clinical outcomes of ACS patients with
CKD receiving a GP IIb/IIIa receptor antagonist are summarized in Table 5.

When used at the time of PCI in ACS patients with CKD,
outcomes with the use of GP IIb/IIIa receptor antagonists
have been variable. A subgroup analysis of the Enhanced
Suppression of the Platelet IIb/IIIa Receptor With Integrilin
Therapy (ESPRIT) trial showed the treatment effect of
eptifibatide was maintained among those with CrCl <60
mL/min, and the presence of CKD was not associated with
an increased risk of bleeding with eptifibatide therapy.58


10  Circulation  March 24, 2015
Observational cohorts of ACS patients receiving GP IIb/IIIa
receptor antagonists at the time of PCI have provided additional insight into use in patients with CKD. Best et al57
assessed patients undergoing PCI in a large registry that
divided patients into 3 categories according to creatinine
clearance: >70, 50–69, or <50 mL/min. Among patients
receiving abciximab, the interaction between CrCl and major
bleeding was not statistically significant. Additionally, no
interaction was seen between CrCl and abciximab for the

frequency of death or MI (HR, 1.03; 95% CI, 0.97–1.08).
A second observational study categorized patients undergoing PCI into 5 strata by CrCl (≥90 mL/min, 60–89 mL/min,
30–59 mL/min, <30 mL/min, and requiring dialysis).59 After
controlling for CrCl stratum, GP IIb/IIIa receptor antagonist
use was associated with a lower risk of in-hospital mortality (OR, 0.34; 95% CI, 0.12–0.98) and an increased risk of
a major bleeding event (OR, 2.13; 95% CI, 1.39–3.27). A
final observational study reported the clinical outcomes of

Table 5.  Summary of GP IIb/IIIa Receptor Antagonist Studies in Patients With ACS and CKD
Study

PRISM-PLUS56

Best et al57

ESPRIT58

Study Design
Post hoc analysis
of an RCT

Observational cohort

Subgroup analysis
of an RCT

Population
1537 UA/NSTEMI patients randomized to
receive tirofiban or placebo. Renal function
classified by CrCl*: >75 mL/min (n=572),
60–75 mL/min (n=354), 30–60 mL/min
(n=571), <30 mL/min (n=40). Patients
with SCr ≥2.5 mg/dL were excluded from
the PRISM-PLUS trial.

4158 patients undergoing PCI (indication
for PCI was UA in 71% of patients in each
group and MI in the previous 7 d in 26% of
patients in the abciximab group and 15% of
patients in the no abciximab group). Renal
function classified based on CrCl*: >70

mL/min (n=647 who received abciximab
and n=1472 who did not), 50–69 mL/min
(n=367 who received abciximab and 820
who did not), and <50 mL/min (n=229 who
received abciximab and 585 who did not).

Patients randomized to eptifibatide or
placebo at the time of PCI. 2044 of 2064
patients had creatinine data available.
A total of 1755 patients had CrCl*
≥60 mL/min, and 289 patients had CrCl
<60 mL/min. Patients with SCr >4 mg/dL
were excluded. Indication for PCI was UA
in 44% of patients with CrCl ≥60 mL/min
and 54% in those with CrCl <60 mL/min.

End Points

Results

7-d death/MI/refractory
ischemia (primary
composite)

Decreasing renal function was strongly
associated with adverse outcomes,
however, there was no evidence of
treatment-by-CrCl interaction. The
incidence of the composite end point in the
tirofiban and placebo groups at 7 d was

35% vs 45% in patients with CrCl <30
mL/min, 17.9% vs 23.8% in patients with
CrCl 30–60 mL/min, 13.9% vs 15.5% in
patients with CrCl 60–75 mL/min, and 6.8%
vs 12.3% in patients with CrCl >75 mL/min.

TIMI major bleeding,
minor bleeding

No incremental risk for bleeding was
observed with tirofiban therapy among
the lowest CrCl categories. No TIMI
major bleeding events occurred in either
treatment group in the CrCl <30 mL/min
category; for the 30–60 mL/min category,
the number of major bleeding events was
4 (1.4%) in the placebo group vs 5 (1.8%)
in the tirofiban group.

Composite of death or MI

No interaction was seen between CrCl and
abciximab for the frequency of death or MI
(HR, 1.03; 95% CI, 0.97–1.08).

Major bleeding, minor
bleeding (follow-up 10 d)

CKD was associated with increased
bleeding complications. In patients who

received abciximab, the interaction between
CrCl and major bleeding (OR, 1.18; 95%
CI, 0.99–1.39) as well as CrCl and minor
bleeding (OR, 1.01; 95% CI, 0.83–1.23) did
not reach statistical significance.

Composite of death, MI,
TVR, or thrombotic bailout
assessed at 48 h

The adjusted ORs (95% CIs) for the effect
of eptifibatide on the primary outcome
remained for those with lower CrCl
(60 mL/min) 0.52 (0.33–0.81) compared
with those with higher CrCl (90 mL/min)
0.64 (0.46–0.89).

Major bleeding, minor
bleeding

Lower CrCl was not associated with an
increased risk of bleeding with eptifibatide
therapy (Pinteraction=0.791).
(Continued )


Washam et al   Pharmacotherapy in CKD Patients With ACS   11
Table 5.  Continued
Study
Freeman et al59

Frilling et al60

TARGET61

EARLY ACS62

Study Design
Observational,
cohort study

Single-center registry

Subgroup analysis
of an RCT

Subgroup analysis
of an RCT

Population

End Points

Results

889 patients with ACS, including 310
patients with renal insufficiency defined
as CrCl* <60 mL/min (222 patients had
CrCl of 30–59 mL/min, 63 had CrCl of
<30 mL/min, and 25 patients were

dialysis dependent). 312 of the 889
patients enrolled received a GP IIb/IIIa
antagonist.

In-hospital mortality

Although worsening CrCl stratum was a
predictor of in-hospital mortality, a lower
risk of in-hospital mortality was seen
with the use of GP IIb/IIIa antagonist after
controlling for CrCl (OR, 0.34; 95% CI,
0.12-0.98).

Major bleeding events

The use of GP IIb/IIIa antagonist was
associated with an increase in major
bleeding events (OR, 2.13; 95% CI,
1.39–3.27).

1040 patients including 44 with renal
insufficiency (defined as SCr ≥1.3 mg/dL)
undergoing PCI who received abciximab.
The indication for PCI was ACS in 718 of
996 patients without renal insufficiency
and 35 of 44 patients with renal
insufficiency.

MACCE: death, MI, stroke,
emergency aortocoronary

bypass operation or PCI

No statistically significant differences
were seen in MACCE rates between
groups. In-hospital mortality occurred in
4.5% of patients with renal insufficiency
vs 1.9% of patients without renal
insufficiency (P=0.223). Nonfatal
MACCE was reported in 4.5% and 6.7%,
respectively (P=0.569).

Major and minor bleeding
events

Major bleeding occurred in 4.5% of patients
with renal insufficiency vs 0.6% of those
without renal insufficiency (P=0.003). No
differences were seen in the rates of minor
bleeding events.

Composite of all-cause
mortality, MI, and TVR
at 30 d

Ischemic events occurred more frequently
in patients with lower CrCls. There was no
interaction between the GP IIb/IIIa receptor
antagonist used, CrCl, and ischemic or
bleeding outcomes. In patients with CrCl
<70 mL/min, the primary composite

occurred in 6% of the abciximab group and
8.7% of the tirofiban group (P=0.74).

Major bleeding, minor
bleeding

Bleeding events occurred more frequently
in patients with lower CrCls. Significant
treatment differences in major bleeding
were not detected. In patients with CrCl
<70 mL/min, increased rates of bleeding
were observed with abciximab vs tirofiban
(7.2% vs 3.4%; P=0.004).

Primary composite:
death, MI, recurrent
ischemia requiring urgent
revascularization, or
thrombotic bailout at 96 h

In patients with CrCl <50 mL/min: The
primary outcome occurred in 12.5% of
those receiving early eptifibatide compared
to 11.7% receiving a delayed provisional
eptifibatide strategy (OR (95% CI) 1.08
(0.80–1.45)). The rates of death or MI at
30 d were 15.6% in the early eptifibatide
group vs 15.1% in the delayed provisional
eptifibatide group (OR (95% CI) 1.03
(0.79–1.35)).

4623 patients undergoing PCI randomized
to abciximab or tirofiban were grouped
into CrCl* quartiles (>114, 90–114,
70–90, <70 mL/min). Patients with
SCr >2.5 mg/dL were excluded from
the TARGET trial. The indication for PCI
was ACS in 63% of patients.

8708 patients with UA/NSTEMI were
randomized to early eptifibatide or a
strategy of delayed provision eptifibatide.
A total of 1632 patients had a baseline
CrCl* <50 ­mL/min. Patients requiring
dialysis within the past month were
excluded.

Death or MI at 30 d

Rates of non-CABG
related TIMI major
bleeding and GUSTO
severe/moderate bleeding

The rates of TIMI major bleeding (2.4% vs
0.9%; OR, 2.91; 95% CI, 1.22–6.91) and
GUSTO severe/moderate bleeding (9.8%
vs 6.6%; OR, 1.52; 95% CI, 1.06-2.18)
were higher in the group receiving the early
eptifibatide strategy.

ACS indicates acute coronary syndrome; CABG, coronary artery bypass grafting; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine clearance;
EARLY ACS, Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome; ESPRIT, Enhanced Suppression of the Platelet IIb/IIIa Receptor
With Integrilin Therapy; GP, glycoprotein; GUSTO, Global Utilization of Streptokinase and tPA for Occluded Arteries; HR, hazard ratio; MACCE, major adverse cardiac or
cerebrovascular event; MI, myocardial infarction; NSTEMI, non–ST-segment–elevation myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention;
PRISM-PLUS, Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms; RCT, randomized controlled trial;
SCr, serum creatinine; TARGET, Do Tirofiban and ReoPro Give Similar Efficacy Outcome; TIMI, Thrombolysis in Myocardial Infarction; TVR, target-vessel revascularization;
and UA, unstable angina.
*Calculated via Cockcroft-Gault equation.


12  Circulation  March 24, 2015
patients undergoing PCI who received abciximab.60 Of the
1040 patients included, 44 were classified as having renal
insufficiency. The authors reported no significant differences
in the rates of in-hospital mortality or nonfatal major adverse
cardiac events among patients with renal insufficiency compared with those without, although major bleeding occurred
more frequently among patients with renal insufficiency
(4.5% versus 0.6%; P=0.003). Although limited data are
available on the comparative safety and effectiveness of different GP IIb/IIIa receptor antagonists among patients with
CKD, a subgroup analysis of the Do Tirofiban and ReoPro
Give Similar Efficacy Outcome (TARGET) trial compared
the outcomes of patients with renal insufficiency undergoing
PCI who received either abciximab or tirofiban.61 The 4623
patients with a baseline SCr level available were divided into
CrCl quartiles (<70, 70–90, 90–114, and >114 mL/min).
Although the rates of both ischemic and bleeding events
were higher among patients with lower creatinine clearances, there was no interaction between the assigned GP
IIb/IIIa receptor antagonist, CrCl, and clinical outcome.
An analysis of the Platelet Receptor Inhibition in Ischemic

Syndrome Management in Patients Limited by Unstable Signs
and Symptoms (PRISM-PLUS) trial provided outcome data
on the upstream use of GP IIb/IIIa receptor antagonists among
patients presenting with ACS.56 This analysis showed tirofiban therapy to be effective in reducing ischemic events, with
no evidence of treatment-by-CrCl interaction. Additionally,
although decreasing renal function (P<0.001) and tirofiban
(P<0.001) were each associated with an increased risk for
bleeding events, tirofiban therapy was not associated with an
incremental increase in the risk for hemorrhage among those
with CKD. A subgroup analysis of the Early Glycoprotein IIb/
IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary
Syndrome (EARLY ACS) trial provided a comparative assessment of the early versus delayed provisional use of eptifibatide
among patients with CKD presenting with non–ST-segment
elevation ACS in whom coronary angiography was planned.62
This was the first large-scale randomized trial of eptifibatide that used the currently recommended dosing regimen
of 2 μg·kg−1·min−1 for patients with CrCl ≥50 mL/min and
1 μg·kg−1·min−1 for patients with CrCl <50 mL/min, with
patients requiring dialysis excluded from the trial. Among
patients with CrCl <50 mL/min, early eptifibatide compared
with a delayed provisional eptifibatide strategy was not associated with a reduction in the composite ischemic end point(s)
at 96 hours or at 30 days. Among patients with CrCl <50 mL/
min, rates of non–coronary artery bypass graft–related TIMI
major bleeding and GUSTO severe/moderate bleeding were
significantly higher with the early eptifibatide strategy.
In summary, data on the use of GP IIb/IIIa receptor antagonists in CKD patients with ACS indicate a reduction in ischemic events and a variable but overall increase in the risk of
bleeding events. In addition, in a recent trial comparing a strategy of early versus delayed provisional GP IIb/IIIa receptor
antagonist therapy in UA/NSTEMI patients, no reduction in
ischemic events and an increase in bleeding events were seen
with the early strategy in patients with CKD.62
Although the existing data do not support a preferred GP

IIb/IIIa receptor antagonist for use in patients with CKD, it is

important that clinicians follow dosing recommendations for
eptifibatide and tirofiban when either of these agents is used.

Anticoagulants
Unfractionated Heparin
UFH has been a mainstay in the treatment of ACS for several
decades.63 Current guidelines recommend UFH as an anticoagulant option across the spectrum of ACS presentations.26,42
Once administered, the primary route of UFH elimination is
via the reticuloendothelial system, with renal clearance being
a minor route for elimination.64 Few data are available from
early placebo-controlled trials on the treatment effect of UFH
therapy in CKD patients presenting with ACS. In addition,
given that UFH has often been the standard anticoagulant
with which newer agents have been compared, the outcome
data for UFH use in CKD patients will be discussed in the
sections below.
Low-Molecular-Weight Heparin
Enoxaparin
Enoxaparin is the most widely studied low-molecular-weight
heparin (LMWH) in the setting of ACS. Current guidelines
recommend enoxaparin as an anticoagulant option in UA/
NSTEMI patients being managed with either an early invasive (Class I recommendation) or initial conservative (Class I
recommendation) strategy.42 For patients presenting with
STEMI, current guidelines recommend enoxaparin as an
adjunctive anticoagulant option in conjunction with fibrinolytic therapy (Class I recommendation).26 Enoxaparin elimination is largely dependent on renal function, with ≈40% of
a dose being eliminated by glomerular filtration. The current
US Food and Drug Administration–approved dose for enoxaparin in ACS patients with CrCl <30 mL/min is 1 mg/kg subcutaneously every 24 hours. However, patients with CrCl <30
mL/min have been routinely excluded from randomized trials

of enoxaparin in ACS; therefore, limited data are available
from randomized controlled trials on the use of enoxaparin
in this population. Data from randomized trials and observational studies on the use of enoxaparin in ACS patients with
CKD are shown in Table 6.
A number of studies have shown increased anti-Xa activity in ACS patients with renal insufficiency receiving therapeutic doses of enoxaparin. In a substudy performed in 445
ACS patients enrolled in the TIMI 11A trial, the effect of renal
function and other patient characteristics on the pharmacokinetics and pharmacodynamics of enoxaparin was examined.70
In this analysis, CrCl was the most influential factor on pharmacokinetic and pharmacodynamic parameters of enoxaparin. Patients with CrCl <40 mL/min had higher peak and
trough anti-Xa activity than patients with CrCl ≥40 mL/min
and were more likely to have a major hemorrhagic event.70
Several clinical trials evaluating the use of enoxaparin in UA/
NSTEMI patients have provided data on the outcomes of
CKD patients receiving enoxaparin or UFH. A pooled analysis of CKD patients with severe renal impairment (defined
as CrCl ≤30 mL/min) enrolled in the Efficacy and Safety of
Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events
(ESSENCE) and TIMI 11B trials was performed to assess


Washam et al   Pharmacotherapy in CKD Patients With ACS   13
Table 6.  Summary of Enoxaparin Studies in Patients With ACS and CKD
Study
ESSENCETIMI 11B65

Collet et al66

ExTRACT-TIMI
25 Trial67

SYNERGY68

OASIS-569

Study Design
Pooled
subgroup
analysis of 2
RCTs

Observational
cohort (GRACE
registry)

Double blind
RCT

Open-label
RCT

Double-blind
RCT

Population

End Points

Results

7081 NSTE ACS patients enrolled in ESSENCE
(n=3171) and TIMI 11B (n=3910) randomized
to enoxaparin or UFH. CrCl ≤30 mL/min was

an exclusion in 1 trial (ESSENCE), whereas
SCr >2.0 mg/dL was an exclusion in the other
(TIMI 11B). Severe renal impairment (CrCl* ≤30
mL/min) was found in 74 UFH-treated patients
and 69 patients receiving enoxaparin (2%). The
enoxaparin dose was 1 mg/kg every 12 h.

All-cause death,
recurrent MI, and
urgent revas­
cularization at 43 d

In patients with CrCl <30 mL/min, the composite
primary outcome occurred in 32.4% of UFH
patients and 18.8% of enoxaparin patients (OR,
0.52; 95% CI, 0.23–1.19).

Major hemorrhage

Major hemorrhage occurred in 5.9% of UFH
patients and 7.5% of enoxaparin patients (OR,
1.53; 95% CI, 0.37–6.32).

11 881 patients presenting with UA/NSTEMI.
Patients were divided into 3 groups based on
CrCl*: >60 mL/min (n=7194), 31–60 mL/min
(n=3705), ≤30 mL/min (n=982). In the 3 renal
function groups, LMWH was used in 30%, 31%,
and 30%, respectively, whereas UFH was used
in 22%, 24%, and 28%, respectively.

Mortality (30 d)

Worsening renal function was an independent
predictor of 30-d mortality and in-hospital
major bleeding. Rates of 30-d mortality were
significantly lower with LMWH alone than with
UFH alone in patients with CrCl >60 mL/min and
in those with CrCl 31–60 mL/min. No significant
difference was seen in patients with CrCl <30
mL/min (15.4% vs 18.6%, respectively).

In-hospital major
bleeding

Rates of in-hospital major bleeding were significantly
lower with LMWH alone than with UFH alone in
patients with normal and moderate renal dysfunction.
No significant difference was seen in patients with
CrCl <30 mL/min (5.9% vs 9.3%, respectively).

20 479 patients with STEMI receiving
fibrinolytic therapy randomized to UFH or
enoxaparin. Patients with CrCl* <30 mL/min
received a maintenance enoxaparin dose of
1 mg/kg every 24 h. SCr >2.5 mg/dL for men
and >2.0 mg/dL for women was an exclusion.
Patients were divided into 4 groups based on
CrCl*: >90 (n=7462), >60 to 90 (n=7203),
30–60 (n=3671), and <30 mL/min (n=212).

All-cause death or
nonfatal recurrent MI
within 30 d

Adjusted OR (95% CI) for enoxaparin vs UFH
comparison: Primary end point: 0.69 (0.56– 0.84)
for CrCl >90 mL/min, 0.78 (0.66–0.92) for CrCl
>60 to 90 mL/min, 0.94 (0.78–1.12) for CrCl
30–60 mL/min, and 0.74 (0.38– 1.44) for CrCl
<30 mL/min

Major bleeding

Major bleeding: 1.49 (0.89–2.48) for CrCl >90
mL/min, 1.91 (1.30– 2.82) for CrCl >60 to 90
mL/min, 1.73 (1.11–2.70) for CrCl 30–60 mL/min,
and 3.60 (0.67–19.21) for CrCl <30 mL/min

10 027 NSTE ACS patients randomized to
enoxaparin or UFH. Maintenance dose of
enoxaparin was 1 mg/kg every 12 h. Early
angiography intended (median time, 22 h).
Patients with CrCl <30 mL/min were to be
excluded. Patients were grouped according to
CrCl*: ≥60 mL/min (n=6950), 30–59 mL/min
(n=2732), and <30 mL/min (n=156)

All-cause death or
nonfatal MI (30 d)

No significant treatment-by-CrCl interaction term
was found for all treatment outcomes. 30-d death
or MI in patients treated with UFH vs enoxaparin in
patients was 12.9% vs 12.7% for CrCl >60 mL/min,
17.7% vs 17.0% for CrCl 30–59 mL/min, and 23.3%
vs 25.7% for CrCl <30 mL/min

TIMI major bleeding

TIMI major bleeding in patients treated with UFH
vs enoxaparin in patients: CrCl >60 mL/min, 7.2%
vs 8.3%; CrCl 30–59 mL/min, 8.8% vs 11.2%;
CrCl <30 mL/min, 5.8% vs 10.0%

20 078 patients randomized to fondaparinux
or enoxaparin. SCr level >3 mg/dL was an
exclusion. Patients with CrCl* <30 mL/min
received an enoxaparin maintenance dose of
1 mg/kg every 12 h. Patients were grouped and
analyzed in quartiles based on eGFR.†

Primary efficacy end
point: Death, MI, or
refractory ischemia
at 9 d

HR (95% CI) for fondaparinux vs enoxaparin
comparison:
Efficacy end point at 30 d: 0.91 (0.74–1.12) for

eGFR ≥86 mL·min−1·1.73 m−2, 0.95 (0.76–1.18) for
eGFR 71 to <86 mL·min−1·1.73 m−2, 1.10 (0.90–
1.33) for eGFR 58 to <71 mL·min−1·1.73 m−2, and
0.81 (0.69–0.96) for eGFR <58 mL/min/1.73 m2

Major bleeding

Major bleeding at 30 d: 0.71 (0.53–0.96) for eGFR
≥86 mL·min−1·1.73 m−2, 0.87 (0.66–1.16) for
eGFR 71 to <86 mL·min−1·1.73 m−2, 0.74 (0.58–
0.95) for eGFR 58 to <71 mL·min−1·1.73 m−2, and
0.65 (0.52–0.80) for eGFR <58 mL·min−1·1.73 m−2

ACS indicates acute coronary syndrome; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; ESSENCE,
Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events; ExTRACT-TIMI 25, Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction
Treatment–Thrombolysis In Myocardial Infarction 25; GRACE, Global Registry of Acute Coronary Events; HR, hazard ratio; LMWH, low-molecular-weight heparin; MI, myocardial
infarction; NSTE, non–ST-segment elevation; NSTEMI, non–ST-segment–elevation myocardial infarction; OASIS-5, Organization for the Assessment of Strategies for Ischemic
Syndromes 5; OR, odds ratio; RCT, randomized controlled trial; SCr, serum creatinine; STEMI, ST-segment–elevation myocardial infarction; SYNERGY, Superior Yield of the New
Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors; TIMI, Thrombolysis in Myocardial Infarction; UA, unstable angina; and UFH, unfractionated heparin.
*Cockcroft-Gault Formula.
†eGFR assessed by Modification of Diet in Renal Disease formula.


14  Circulation  March 24, 2015
the treatment effects of enoxaparin and UFH.65 Severe renal
impairment was identified in ≈2% of patients in this pooled
analysis. There was no statistically significant difference
between enoxaparin and UFH with regard to the rates of
occurrence of the primary composite end point (18.8% versus 32.4%, respectively; P=0.12) or major hemorrhage (7.5%
versus 5.8%, respectively; P=0.56) among patients with CrCl

≤30 mL/min. The association of CKD with outcomes among
patients enrolled in the Superior Yield of the New Strategy
of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa
Inhibitors (SYNERGY) trial who received either enoxaparin or UFH was also assessed.68 Patients were placed into
3 groups based on CrCl: <30 mL/min (n=156), 30–59 mL/
min (n=2732), and ≥60 mL/min (n=6950). No treatmentby-CrCl interaction was significant for the efficacy or safety
outcomes, although the rates of TIMI major and GUSTO
severe bleeding were numerically higher in patients with
CrCl <30 mL/min and those with CrCl 30 to 59 mL/min. An
analysis of GRACE evaluated the association of CKD with
outcomes among patients with non–ST-segment–elevation
ACS treated with either LMWH or UFH.66 Based on CrCl <30
mL/min (43 patients received UFH and 37 received LMWH),
30 to 59 mL/min (70 patients received UFH and 49 received
LMWH), and >60 mL/min (50 patients received UFH and
45 received LMWH), results of this analysis showed that
LMWH was associated with lower 30-day mortality (4.2%
versus 6.2%; P<0.0001) and a lower rate of in-hospital major
bleeds (2.1% versus 3.3%; P=0.0006), but the mortality and
in-­hospital major bleeding benefit was not statistically significant in the group with CrCl <30 mL/min.
The association of renal function with outcomes among
fibrinolytic agent–treated STEMI patients receiving enoxaparin or UFH was evaluated in an analysis of the Enoxaparin and
Thrombolysis Reperfusion for Acute Myocardial Infarction
Treatment–Thrombolysis In Myocardial Infarction 25
(ExTRACT-TIMI 25) trial.67 In this trial, patients with CrCl
<30 mL/min received a dose of enoxaparin of 1 mg/kg once
per day. On the basis of estimated CrCl <30 mL/min, 30 to
60 mL/min, >60 to 90 mL/min, and >90 mL/min, there was
a statistically significant benefit of enoxaparin on the primary
composite end point of death or nonfatal MI among patients

with CrCl >60 mL/min that was not seen in patients with
CrCl 30 to 60 mL/min or in those with CrCl <30 mL/min. In
addition, there was an increase in the risk of major and minor
bleeding events with enoxaparin treatment among patients
with renal dysfunction (defined as CrCl ≤60 mL/min).67
The randomized studies presented in this section have largely
excluded patients with severe renal impairment. In aggregate,
all demonstrate a stepwise increase in the incidence of death,
MI, and bleeding with increasing levels of kidney dysfunction. However, the differential treatment effect of UFH versus
LMWH on bleeding is more difficult to ascertain because of
a lack of power caused by the small number of patients with
severe renal impairment.65,68 Of the trials discussed in this
section, only the ExTRACT-TIMI 25 trial demonstrated an
association between treatment with enoxaparin and increased
bleeding risk with worsening renal function.67 A meta-­analysis
of LMWH studies, including smaller randomized trials and
observational studies in ACS and venous thromboembolism

that exclusively examined patients with renal dysfunction,
suggested that enoxaparin use was associated with a 2- to
3-fold increase in major bleeding events when CrCl was
<30 mL/min.71 In clinical practice, the use of enoxaparin in
ACS has been encumbered by challenges in correctly adjusting
the dose of enoxaparin for creatinine clearance. In an analysis
of the CRUSADE Quality Improvement Initiative, enoxaparin
was used in 40% of 33 094 patients with non–ST-segment–
elevation ACS.72 Only 50% of patients treated with enoxaparin received the recommended dose according to their renal
function, 18.7% received an excess dose, and 29.2% received
a lower dose. An excess dose was associated with increased
risk of major bleeding and in-hospital mortality. Major bleeding occurred in 14.2% and 7.3% of patients who received an

excess and a recommended dose, respectively (adjusted OR,
1.43; 95% CI, 1.18–1.75). In-hospital death occurred in 5.6%
and 2.4% of patients who received an excess and a recommended dose, respectively (OR, 1.35; 95% CI, 1.03–1.77).

Factor Xa Inhibitors
Fondaparinux
Fondaparinux is an indirect factor Xa inhibitor that has
recently been evaluated in the management of patients presenting with ACS. Current guidelines for fondaparinux in ACS
patients include a Class I recommendation for fondaparinux
use as an adjunctive anticoagulant for STEMI patients receiving fibrinolytic therapy and a Class I recommendation for UA/
NSTEMI patients being managed with either an invasive or
conservative strategy.26,73 In addition, the guidelines recommend fondaparinux as the preferred anticoagulant in UA/
NSTEMI patients being managed with a conservative strategy
who have an increased risk of bleeding.73 Fondaparinux is primarily excreted unchanged through renal elimination, and is
contraindicated in the United States for patients with severe
CKD (CrCl <30 mL/min).74
The Organization for the Assessment of Strategies for
Ischemic Syndromes (OASIS) 5 trial compared fondaparinux
to enoxaparin in 20 
078 patients with non–ST-segment–­
elevation ACS randomized to fondaparinux 2.5 mg subcutaneously once daily or enoxaparin 1 mg/kg subcutaneously twice
daily (dose adjusted to 1 mg/kg once daily in patients with
CrCl <30 mL/min).75 Although patients with SCr >3 mg/dL
were excluded, a specific analysis was designed to examine
efficacy and safety outcomes by quartiles of GFR (as estimated by the MDRD formula).69 This study showed a direct
relationship between degree of renal impairment and the
risk of death, MI, refractory ischemia, and bleeding. Among
patients with a GFR ≥58 mL·min−1·1.73 m−2, no significant
difference was seen between treatment groups in the primary
composite outcome of death, MI, or refractory ischemia at 9

days. However, at 30 days, the rate of the primary composite outcome was significantly lower among patients with a
GFR <58 mL·min−1·1.73 m−2 with fondaparinux (HR, 0.81;
95% CI, 0.69–0.96). Fondaparinux treatment was associated
with lower rates of major bleeding events at 9 days among
patients with a GFR <58 mL·min−1·1.73 m−2 (HR, 0.42; 95%
CI, 0.32–0.56). In addition, in the subgroup of patients with
CrCl <30 mL/min, the rates of major bleeding at 9 days were


Washam et al   Pharmacotherapy in CKD Patients With ACS   15
significantly lower in the group receiving fondaparinux (2.4%
versus 9.9%, P=0.001).75 Although the rates of major bleeding
were lower with fondaparinux across all quartiles of estimated
GFR, the difference was most marked among patients with a
GFR <58 mL·min−1·1.73 m−2.69

Direct Thrombin Inhibitors
Bivalirudin
Bivalirudin, a bivalent direct thrombin inhibitor, has been well
studied in patients undergoing PCI, including patients presenting with ACS. Current guidelines recommend bivalirudin as an
anticoagulant option in STEMI patients undergoing primary
PCI (Class I) and in UA/NSTEMI patients in whom an invasive strategy is selected (Class I).26,42 Elimination of bivalirudin
occurs through both proteolysis and renal clearance. In patients
with normal renal function (CrCl > 90mL/min) or mildly
impaired renal function (CrCl >60 mL/min), the pharmacokinetics of bivalirudin are linear, with an elimination half-life of
25 minutes. The elimination half-life is increased to 34 to 57
minutes in patients with moderate to severe renal impairment
(CrCl between 10 and 59 mL/min) and ≈3.5 hours in patients
with renal failure necessitating hemodialysis.76–78 For patients
with renal insufficiency, the product labeling recommends no

reduction in the bolus dose for any degree of renal impairment, although the infusion dose of bivalirudin may need to
be reduced and anticoagulant status monitored in patients with
renal impairment (Table 1).28 Data from randomized trials and
observational studies on the use of bivalirudin in ACS patients
with CKD are shown in Table 7.
A meta-analysis79 of 3 randomized trials comparing bivalirudin with UFH at the time of PCI (majority ACS) stratified by CrCl >90 mL/min (n=1578), CrCl 90 to 60 mL/
min (n=2163), CrCl 59 to 30 mL/min (n=1255), and CrCl
<30 mL/min (n=39) showed an increasing risk of ischemic and
bleeding events with increasing degrees of renal impairment.
The absolute benefit of bivalirudin on the ischemic and bleeding composite end point increased with decreasing CrCl strata
(2.2%, 5.8%, 7.7%, and 14.4%, respectively; Pinteraction=0.044).
Similarly, the association of CKD with adverse outcomes for
patients undergoing PCI (43% ACS) randomized to bivalirudin
and provisional GP IIb/IIIa inhibition or UFH and planned GP
IIb/IIIa inhibition was examined in the Second Randomized
Evaluation in PCI Linking Bivalirudin to Reduced Clinical
Events (REPLACE-2) trial.80 Patients were grouped according
to CrCl ≥60 mL/min (n=4824) and CrCl <60 mL/min (n=886).
Among patients with CrCl <60 mL/min, rates of 30-day ischemic events (death, MI, or urgent revascularization) were 9.7%
and 9.4% (P=0.870) in the bivalirudin and UFH and GP IIb/
IIIa receptor antagonist groups, respectively, but there were
significantly lower rates of TIMI major or minor hemorrhage
(3.2% versus 7.1%; P=0.009) with bivalirudin. There was no
observed interaction between treatment, bleeding or ischemic
events, and renal function. Although these bivalirudin studies
excluded dialysis-dependent patients, a retrospective analysis
comparing bivalirudin with UFH (GP IIb/IIIa receptor antagonists were excluded) in dialysis-dependent patients undergoing
PCI showed no significant difference in the rates of in-hospital
major bleeding (3.4% versus 3.1%, respectively; P=0.9)81 or

in the rates of the primary composite ischemic end point of
in-hospital death, Q-wave MI, and urgent target-vessel revascularization (1.8% versus 0.8%, respectively; P=0.7).
Analyses from 2 randomized trials provide data on the association of CKD with outcomes among patients with ACS receiving bivalirudin. In a substudy of the Acute Catheterization and
Urgent Intervention Triage Strategy (ACUITY) trial, Mehran
and colleagues82 showed that patients with CKD (defined as
CrCl <60 mL/min) had worse 30-day and 1-year clinical outcomes than those with normal renal function. Patients with
CrCl <30 mL/min were excluded from this trial. There were
no significant differences between bivalirudin monotherapy
and heparin plus a GP IIb/IIIa receptor antagonist in rates
of 30-day composite ischemia (11.1% versus 9.4%; P=0.27)
and net clinical adverse outcomes (16.1% versus 16.9%;
P=0.65). There was significantly less major bleeding (6.2%
versus 9.8%; P=0.008) at 30 days but no significant difference in 1-year composite ischemia (22.0% versus 18.9%;
P=0.10) or mortality (7.1% versus 7.3%; P=0.96). A substudy
of the Harmonizing Outcomes With Revascularization and
Stents in Acute Myocardial Infarction (HORIZONS-AMI)
trial provided an assessment of the association of CKD with
outcomes with bivalirudin use among patients undergoing primary PCI. Approximately 15% of patients enrolled had CrCl
of 30 to 60 mL/min, whereas 1.4% had CrCl of ≤30 mL/min.
This analysis showed patients with CKD had higher rates of
clinical events at 30 days, including death and major bleeding.83 Multivariable analysis identified baseline creatinine as
an independent predictor of death at 3 years (HR, 1.51; 95%
CI, 1.21–1.87; P<0.001). Patients with CKD (defined as CrCl
<60 mL/min) randomized to bivalirudin monotherapy versus
heparin plus GP IIb/IIIa receptor antagonist had no significant
difference in major bleeding (12.3% versus 15.3%; HR, 0.79;
95% CI, 0.50–1.25) or death (8.4% versus 7.9%; HR, 1.09;
95% CI, 0.61–1.95) at 30 days.
Taken collectively, the randomized controlled trial data on
anticoagulation therapy in CKD patients presenting with ACS

are limited by the underrepresentation of patients with stage
4 and 5 CKD, which makes definitive conclusions about the
treatment effect of anticoagulant agents challenging. Although
a number of trials excluded patients with CrCl <30 mL/min,
the ExTRACT-TIMI-25, OASIS-5, and HORIZONS-AMI
trials did not.75,84,85 The association of treatment with enoxaparin and increased bleeding risk with worsening renal function observed in the ExTRACT-TIMI-25 trial, as well as
the increased rates of major bleeding in patients with CrCl
<30 mL/min with enoxaparin therapy observed in the OASIS-5
trial, suggests that caution is warranted when enoxaparin is
used in this population.67,75

Anti-Ischemic Therapies
β-Blockers
β-Blockers are recommended for all patients with ACS unless
contraindicated.86,87 Metoprolol, atenolol, and propranolol have
been studied in the setting of AMI, and carvedilol has been studied in the setting of AMI with left ventricular dysfunction.88–92
Atenolol is renally eliminated and requires dose adjustment in
those with renal impairment. Dose adjustment is recommended


16  Circulation  March 24, 2015
Table 7.  Summary of Bivalirudin Studies in Patients With ACS and CKD
Study

Study Design

Chew et al

79

REPLACE-280

Delhaye et al81

ACUITY82

HORIZONS-AMI83

Meta-analysis
of 3 trials: the
Bivalirudin
Angioplasty Study,
CACHET trial and
REPLACE-1

Subgroup analysis
of an RCT

Retrospective
analysis of
single-center
registry

Subgroup analysis
of an RCT

Subgroup analysis
of an RCT

Population

End Points

Results

The trials included patients undergoing
PCI receiving bivalirudin or UFH during
PCI. Patients were stratified by CrCl* into
groups: CrCl >90 mL/min (n=1578), CrCl
60–90 mL/min (n=2163), CrCl 30–59
mL/min (n=1255), and CrCl <30 mL/min
(n=39). Patients with SCr >3 mg/dL were
excluded from the trials. The indication for
PCI was UA in ≈65% of patients in
this analysis.

Primary efficacy end
point: composite of
death, MI, or urgent
revascularization

Adverse ischemic and bleeding events increased
with worsening renal function. The ORs (95% CIs)
for reduction of the composite ischemic end point
with bivalirudin in the 4 CrCl strata were 0.79
(0.52–1.18), 0.73 (0.53–0.99), 0.77 (0.55-1.07),
and 0.81 (0.12–5.23), respectively.

Bleeding (definition
varied by trial)

The ORs (95% CIs) for reduction in bleeding
events were 0.45 (0.21–0.96), 0.40 (0.09–1.86),
and 0.46 (0.30-0.70) for patients in the CrCl >90
mL/min, CrCl 60–90 mL/min, and CrCl 30–59
mL/min groups, respectively. The absence of
bleeding events in the CrCl <30 mL/min bivalirudin
group precluded an estimate of relative benefit.

Patients undergoing PCI randomized
to bivalirudin and provisional GP IIb/IIIa
inhibitor vs UFH and planned GP IIb/IIIa
inhibitor. Exclusion criteria included
SCr >4 mg/dL. In this analysis, patients
were grouped based on CrCl*: CrCl ≥60
mL/min (n=4824) and CrCl <60 mL/min
(n=886). The indication for PCI was ACS
in ≈43% of patients enrolled in this trial.

Primary efficacy end
point: 30-d composite
of death, MI, or urgent
revascularization

A significant increase in adverse events was noted
in the group with renal insufficiency. In patients
with CrCl <60 mL/min, the rates of the composite
ischemic outcome in the bivalirudin and UFH plus
GP IIb/IIIa inhibitor groups were 7.4% and 6.7%
(P=0.276), respectively.

Major bleeding

The rates of protocol-defined major bleeding
were 5.1% in the bivalirudin group vs 7.1% in
the UFH plus GP IIb/IIIa inhibitor group (P=0.205),
respectively. In patients with CKD, the rate of TIMI
major bleeding events was significantly less in the
bivalirudin group (3.2% vs 7.1%; P=0.009).

Chronic dialysis-dependent patients
undergoing PCI receiving adjusted-dose
bivalirudin (n=267) or UFH (n=129).
Patients receiving GP IIb/IIIa inhibitor were
excluded. ACS was the indication for PCI
in 77% of patients receiving bivalirudin
and 84% of those receiving UFH.

Primary ischemic end
The rates of the composite ischemic end point in
point was the composite the bivalirudin and UFH groups were 1.8% and
of in-hospital death,
0.8% (P=0.7), respectively.
Q-wave MI, or urgent TVR
In-hospital major bleed

The rate of in-hospital major bleeding was
3.4% vs 3.1% (P=0.9) in the bivalirudin and UFH
groups, respectively.

The ACUITY trial enrolled moderate- to
high-risk ACS patients undergoing an
early invasive management strategy.
Patients were randomized to 1 of 3
groups: a heparin (UFH or enoxaparin)
plus a GP IIb/IIIa inhibitor, bivalirudin plus
a GP IIb/IIIa inhibitor, or bivalirudin with
provisional GP IIb/IIIa inhibitor use. Patients
were grouped based on calculated CrCl*:
CrCl ≥60 mL/min (n=10 470) and CrCl
<60 mL/min (n=2469). Although CrCl
<30 mL/min was an exclusion criterion,
189 patients were enrolled.

Composite ischemic
end point of death,
MI, or unplanned
revascularization

Patients with CKD had worse 30-d and 1-y
outcomes. At 30 d, in patients with CKD (CrCl
<60 mL/min), the rates of the composite
ischemic outcome in the bivalirudin alone vs
heparin plus GP IIb/IIIa inhibitor groups were
11.1% vs 9.4%, respectively (RR, 1.18; 95%
CI, 0.88-1.57). No significant difference was
seen in the net clinical outcome at 30 d between
treatment groups in those with CKD.

Non-CABG-related

major bleeding

Rates of 30-d major bleeding (non–CABG related)
were 6.2% vs 9.8% (RR, 0.64; 95% CI, 0.45–
0.89) favoring bivalirudin alone.

Patients undergoing primary PCI for
STEMI randomized to bivalirudin or UFH
plus a GP IIb/IIIa inhibitor. Patients were
grouped based on CrCl*: CrCl ≥60 mL/
min (n=2783) and CrCl <60 mL/min
(n=554). There were 48 patients with
CrCl <30 mL/min

NACE (30 d): Major
bleeding (non–CABG
related), or a composite
of MACE including death,
MI, stroke, or TVR for
ischemia

Patients with CKD (CrCl <60 mL/min) had higher
rates of NACE and major bleeding (non–CABG related)
at 30 d, 1 y, and 3 y. In patients with CKD, 30-d
event rates and HRs (95% CIs) for patients receiving
bivalirudin vs UFH plus a GP IIb/IIIa inhibitor were as
follows: MACE, 12.7% vs 10.6% (1.22; 0.75–1.99);
NACE 21.1% vs 21.6% (0.98; 0.68–1.41).

Non–CABG-related

major bleeding (30 d)

Rate of major bleeding (non-CABG) for bivalirudin
vs UFH plus a GP IIb/IIIa inhibitor was 12.3% vs
15.3% (HR, 0.79; 95% CI, 0.50–1.25).

Net clinical outcome
(ischemic composite or
major bleeding)

ACS indicates acute coronary syndrome; ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy; CABG, coronary artery bypass grafting; CACHET,
Comparison of Abciximab Complications With Hirulog for Ischemic Events Trial; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine clearance; GP,
glycoprotein; HORIZONS-AMI, Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction; HR, hazard ratio; MACE, major adverse cardiac
events; MI, myocardial infarction; NACE, net adverse clinical events; OR, odds ratio; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; REPLACE,
Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events; RR, relative risk; SCr, serum creatinine; TIMI, Thrombolysis in Myocardial Infarction; TVR,
target-vessel revascularization; UA, unstable angina; and UFH, unfractionated heparin.
*CrCl calculated by the Cockcroft-Gault formula.


Washam et al   Pharmacotherapy in CKD Patients With ACS   17
with CrCl <35 mL/min (50 mg once daily for 15–35 mL/min
and 25 mg once daily for CrCl <15 mL/min).93 Metoprolol, propranolol, and carvedilol are all extensively hepatically metabolized, with <5% of an oral dose excreted in the urine unchanged,
so they do not require dose adjustments in renal impairment.
Observational studies assessing CKD patients have analyzed
all β-blockers together. Data on the use of β-blockers for ACS
patients with CKD are summarized in Table 8.
Limited data are available from randomized trials on
the use of β-blockers in ACS in patients with CKD. A post
hoc analysis of pooled data from patients enrolled in the
Carvedilol Postinfarct Survival Control in Left Ventricular

Dysfunction (CAPRICORN) and Carvedilol Prospective
Randomized, Cumulative Survival (COPERNICUS) trials
assessed carvedilol therapy in MI patients with left ventricular dysfunction (CAPRICORN) and in chronic systolic heart
failure patients with CKD (COPERNICUS).94 In the group of
patients with CKD (defined as eGFR ≤60 mL·min−1·1.73 m−2),
treatment with carvedilol was associated with a reduction in
all-cause mortality (HR, 0.76; 95% CI, 0.63–0.93) and cardiovascular mortality (HR, 0.77; 95% CI, 0.62–0.94). However,
a sensitivity analysis among the subgroup of patients with an
eGFR <45 mL·min−1·1.73 m−2 (n=1116) failed to show a significant benefit for carvedilol therapy with regard to the primary or
secondary outcomes. Several observational cohort studies have
evaluated whether β-blockers were beneficial among patients
with various degrees of renal impairment. These observational
studies have found that the benefit of discharge β-blocker use
was preserved across all degrees of renal dysfunction.2,32,38,95
One of the largest observational studies evaluated Medicare
beneficiaries with AMI included in the ESRD program as part
of the Cooperative Cardiovascular Project (CCP).19 This study
identified a cohort of 145 765 patients with AMI, among whom
1025 had stage 5D CKD. They found that although β-blocker
use did not reduce mortality to as great an extent among those
receiving dialysis as among those without ESRD, the benefit
was still significant. β-Blocker use was associated with a 40%
relative reduction in mortality among those undergoing dialysis and a 56% relative reduction among those without ESRD
(P<0.001 for both groups).19
Collectively, the data from randomized and observational
studies support the routine use of β-blocker therapy in CKD
patients presenting with ACS when no contraindications are
present.
Angiotensin Blockade
For patients with ACS, angiotensin-converting enzyme (ACE)

inhibitors are recommended by current guidelines to be initiated
and continued indefinitely in all patients with a left ventricular
ejection fraction <40% and for those with hypertension, diabetes mellitus, and CKD unless contraindicated.73,87 For patients
who are considered intolerant to ACE inhibitors, angiotensin
receptor blockers (ARBs) can be considered as an alternative.73,87 These Class I recommendations are based on data from
several large randomized trials and meta-analyses documenting
significant reductions in mortality among patients with ACS, in
which the greatest benefit was demonstrated when angiotensin
blockade was administered within the first 24 hours after an
MI.96–100 Additionally, receipt of an ACE inhibitor or ARB after

ACS for patients with left ventricular systolic dysfunction at
the time of hospital discharge has become an important reportable quality performance measure via which many hospitals
are compared.101 Unfortunately, among patients with renal
dysfunction, these evidenced-based pharmacotherapies in the
hospital and at discharge are often significantly underused, particularly for those with ESRD.3,19,21,102–107
The most common concerns with ACE inhibitors or ARBs
include perceived worsening renal function and hyperkalemia.108 There is no absolute level of SCr that precludes the use
of these agents; however, if the SCr exceeds 2.5 mg/dL, caution is warranted.109,110 In a review of 12 randomized controlled
trials of ACE inhibitor use in patients with renal dysfunction
(SCr >1.4 mg/dL), acute increases in SCr of up to 30% that
stabilized within the first 2 months of therapy initiation were
associated with a 55% to 75% risk reduction in renal disease
progression compared with those with normal renal function.111 Practically, the use of ACE inhibitors or ARBs can be
considered in patients with CKD as long as the SCr does not
increase beyond this point and the serum potassium remains
<5.5 mEq/L.112 For patients with ESRD, the administration of
these medications can be problematic. The use of ACE inhibitors or ARBs in patients undergoing chronic dialysis has been
associated with an increased risk of hyperkalemia, although
study results have been variable.113–115

Most of the large randomized controlled trials evaluating the effectiveness of ACE inhibitors or ARBs in postMI patients with left ventricular dysfunction have excluded
patients with ESRD, with SCr cut offs ranging from 2 to
3.4 mg/dL. Nonetheless, the ability of these agents to prevent
ventricular dilation and to significantly improve mortality for
patients with compromised cardiac function should not be
underestimated. Although randomized trials of ACE inhibitor therapy in ACS have systematically excluded patients with
ESRD, the Fosinopril in Dialysis (FOSIDIAL) study was
undertaken in chronic ESRD patients to assess the impact of
fosinopril therapy on cardiovascular events.116 No significant
benefit was seen with fosinopril in the intention-to-treat analysis for the composite of cardiovascular events (RR, 0.93; 95%
CI, 0.68–1.26), although a per protocol analysis suggested a
trend toward benefit for fosinopril (RR, 0.79; 95% CI, 0.59–
1.1). Subgroup analyses from randomized trials and observational studies have suggested that among patients with ACS
with reduced left ventricular ejection fraction, the use of ACE
inhibitors or ARBs may be more beneficial when renal insufficiency coexists.103,117–122 Data on the use of ACE inhibitors or
ARBs in ACS patients with CKD are summarized in Table 9.
In summary, the data on the use of ACE inhibitors in patients
with post-MI left ventricular dysfunction and CKD consistently show improved outcomes with ACE inhibitor therapy.
Caution is warranted at the time of initiation, and monitoring
of serum creatinine and potassium is required.
Aldosterone Receptor Antagonists
According to the American College of Cardiology/American
Heart Association guidelines, the use of aldosterone antagonists
such as spironolactone and eplerenone have a Class IA recommendation for post-MI patients who are receiving therapeutic
doses of an ACE inhibitor and a β-blocker, have a left ventricular


18  Circulation  March 24, 2015
Table 8.  Summary of β-Blocker Studies in Patients With ACS and CKD
Study

Wali et al

94

Study Design

Population

Post hoc analysis of
pooled data from 2
RCTs (CAPRICORN and
COPERNICUS)

4217 patients with either post-MI left
ventricular dysfunction (CAPRICORN)
or severe chronic HF (COPERNICUS)
randomized to carvedilol or placebo; 46%
of patients were from the CAPRICORN trial.
Patients categorized based on eGFR*: eGFR
>60 mL/min/1.73 m2 (n=1,651), eGFR ≤60
(n=2,566). Among those with eGFR ≤60,
1,116 had an eGFR <45 mL/min/1.73 m2

End Points
All-cause mortality
(primary)
Cardiovascular
mortality, HF mortality

Results

No statistically significant interactions were
observed between the randomized treatment
and the study type for each clinical outcome.
Adjusted HRs (95% CI) for carvedilol treatment
were as follows: All-cause mortality: eGFR >60:
0.59 (0.43–0.81); eGFR ≤60: 0.78 (0.64-0.95).
In the subgroup with eGFR <45, HR was 0.94
(95% CI, 0.72–1.23). Cardiovascular mortality:
eGFR >60: 0.59 (0.42-0.82); eGFR ≤60: 0.77
(0.62–0.94).
HF mortality: eGFR >60: 0.58 (0.34-0.99);
eGFR ≤60: 0.68 (0.52–0.88); in the subgroup
with eGFR <45: 0.86 (0.61–1.21).

Yan et al38

Observational,
prospective
cohort study

3510 patients hospitalized for ACS with
normal renal function (CrCl† ≥90 mL/min;
n=1152), mild renal dysfunction (CrCl 60–89
mL/min; n=1253), moderate renal dysfunction
(CrCl 30–59 mL/min; n=944), and severe
renal dysfunction (CrCl <30 mL/min; n=161)

One-year survival

β-Blockers were associated with improved 1-y

survival to a similar extent among those with
normal and impaired renal function. Discharge
β-blocker use–adjusted OR, 0.76 (95% CI,
0.56–1.02), P=0.07; P=0.37 for heterogeneity
across CrCl <60 vs ≥60 mL/min.

Wright et al2

Observational, retro­
spective cohort study

3106 patients with AMI with no renal disease
(n=1320), mild chronic renal insufficiency
(CrCl >50 but ≤75 mL/min; n=860), moderate
renal dysfunction (CrCl >35 but ≤50 mL/min;
n=491), severe renal insufficiency (CrCl†
<35 mL/min; n=391), or ESRD (n=44)

Short- and long-term
survival stratified
by CrCl

β-Blockers were associated with improved
postdischarge survival across the spectrum
of renal failure (adjusted HR, 0.7; 95% CI,
0.6–0.9); P<0.001).

Bae et al95

Observational,

retrospective analysis
of KAMIR cohort

13 901 consecutive patients with AMI
divided into strata based on eGFR* ≥90
(n=3491; reference), ≥60 to <90 (n=5791,
group 2), ≥30 to <60 (n=2609, group 3),
≥15 to <30 (n=439, group 4), and <15
(n=306, group 5) mL·min−1·1.73 m−2

Short and long-term
MACE

Use of β-blockers, ACE inhibitors, and statins
(analyzed together) was associated with decreased
risk of short- and long-term MACE. HRs (95% CIs)
improved across the spectrum of renal impairment
when discharge medication use was added to
model that included age, Killip class >1, diabetes
mellitus and hypertension, hs-CRP, and PCI. Group
2: 0.93 (0.79–1.09) vs 0.97 (0.82–1.14); group
3: 1.58 (1.32-1.90) vs 1.73 (1.44–2.07); group 4:
2.12 (1.63–2.75) vs 2.26 (1.74–2.93); and group 5:
2.50 (1.89–3.29) vs 2.69 (2.04–3.56). Additionally,
1-mo and 1-y MACE were improved in a stepwise
fashion with 3 medications vs 2 medications vs 1
medication vs no medications.

Keough-Ryan
et al32

Observational cohort

5549 consecutive patients with ACS.
Renal function classified as >80 (n=1430),
60–80 (n=2018), 30–59 (n=1795), and
<30 (n=306) mL·min−1·1.73 m−2 *

Death, secondary
outcomes length
of stay, surgical
interventions

Discharge β-blockers were associated with
significant reduction in mortality (HR, 0.91; 95%
CI, 0.855-0.97), with no interaction with degree
of renal impairment (P>0.10).

Berger et al19

Observational,
retrospective analysis
of CCP and USRDS

AMI patients: 145 740 patients without
ESRD and 1025 patients with ESRD
receiving dialysis

Mortality (30 d)

β-Blocker therapy was associated with a 40%
relative reduction in mortality in those receiving
dialysis (P<0.001) and a 56% relative reduction
among those without ESRD (P<0.001).

McCullough
et al21

Observational,
prospective
cohort study

1724 patients with STEMI. Renal function
was classified by quartile corrected
creatinine clearance‡ >81.5 mL/min
(n=524), 63.1 to ≤81.5 (n=421), 46.2 to
≤63.1 (n=421), ≤46.2 not undergoing
dialysis (n=310), and chronic dialysis (n=47).

In-hospital mortality

Adjusted RR reduction for the combination of
in-hospital aspirin and β-blocker was 80%,
74.9%, 69%, 64.3%, and 77.9% across the
quartiles of corrected CrCl, respectively.

ACE indicates angiotensin-converting enzyme; ACS, acute coronary syndrome; AMI, acute myocardial infarction; CAPRICORN, Carvedilol Postinfarct Survival Control
in Left Ventricular Dysfunction; CCP, Cooperative Cardiovascular Project; CI, confidence interval; CKD, chronic kidney disease; COPERNICUS, Carvedilol Prospective
Randomized, Cumulative Survival; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HF, heart failure; HR, hazard
ratio; hs-CRP, high-sensitivity C-reactive protein; KAMIR, Korean Acute Myocardial Infarction Registry; MACE, major adverse cardiovascular events; MI, myocardial

infarction; OR, odds ratio; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; RR, relative risk; STEMI, ST-segment–elevation myocardial
infarction; and USRDS, United States Renal Data System.
*Glomerular filtration rate calculated by the modified Modification of Diet in Renal Disease equation.
†CrCl calculated via Cockcroft-Gault equation.
‡Corrected CrCl calculated as (140−age)/serum creatinine, multiplied by 0.85 if female.


Washam et al   Pharmacotherapy in CKD Patients With ACS   19
Table 9.  Summary of ACE Inhibitor Studies in Patients With ACS and CKD
Study

Study Design

Population

End Points

Results

Frances et al,
2000118

Observational,
retrospective cohort
of the CCP database

20 902 Medicare beneficiaries admitted
for MI with LVEF <40%; 19 320 with SCr
≤3 mg/dL and 1582 with SCr >3 mg/dL

All-cause
mortality (1 y)

In the multivariate analysis, the HR (95% CI) for
ACE inhibitor therapy at hospital on discharge
on mortality at 1 y was 0.84 (­0.77–0.92) in
those with SCr ≤3 mg/dL and 0.63 (0.48–0.84)
in those with SCr >3 mg/dL.

Shlipak et al,
2001122

Observational,
retrospective
analysis of the CCP
database

20 902 Medicare beneficiaries admitted
for MI with LVEF <40%. SCr ≥2 mg/dL
was seen in 4133 patients.

All-cause
mortality (1 y)

In the multivariate analysis, ACE inhibitor
exposure was associated with a 23% increase
in 1-y survival for patients with SCr ≥2 mg/dL
(HR, 0.77; 95% CI, 0.66–0.90).

Berger et al,

200319

Observational,
retrospective cohort
using ESRD and CCP
database

145 740 patients without ESRD and 1025
patients with ESRD admitted for MI using
peritoneal dialysis or hemodialysis before
admission

All-cause
mortality (30 d)

Compared with ESRD patients not receiving
an ACE inhibitor, those with ESRD receiving
an ACE inhibitor exhibited a 48% lower 30-d
mortality (P<0.001).

CATS119

Post hoc analysis
of an RCT

298 patients with a first anterior wall MI

Change in GFR*
from baseline over
a 12-mo period

Patients receiving captopril had an annual
decline of only 0.5 mL/min in GFR vs 5.5 mL/min
in the placebo group (P<0.05). Patients with
compromised renal function at baseline (<81
mL/min) had the greatest improvement in GFR.

SAVE121

Post hoc analysis
of an RCT

2183 patients with LVEF ≤40% post-MI
with SCr <2.5 mg/dL. Patients were
grouped by eGFR*: eGFR >60 (n=1464)
and eGFR <60 mL·min−1·1.73 m−2
(n=719).

All-cause and
cardiovascular
mortality and morbidity
stratified
by GFR* (4 y)

The relative risk reduction for all-cause
vcardiovascular mortality/morbidity, the
relative risk reduction was higher for those
treated with captopril with CKD than for those
without CKD (31% vs 20%, respectively;
P=0.29 for interaction).

Krause et al,
2004120

Observational,
retrospective cohort
of the CCP

1342 Medicare beneficiaries post-MI with
mild (GFR 60–89), moderate (GFR 30–59),
and severe (GFR 15–29 mL·min−1·1.73
m−2) renal dysfunction†

300–400-d all-cause
mortality

In the adjusted analysis, patients receiving
aspirin, β-blocker, and ACE inhibitor exhibited
the following reductions in mortality based on
renal function: mild, HR 0.54 (95% CI, 0.261.12); moderate, HR 0.50 (95% CI, 0.28–0.88);
and severe, HR 0.35 (95% CI, 0.09–1.42).

Reddan et al,
2005103

Post hoc analysis of
the SYMPHONY trials

13 707 patients with CKD post-MI grouped
based on CrCl: ≥90 (n=6840), 60–89

(n=5909), and 30–59 mL/min (n=955)

Association between
The interaction between use of ACE inhibitors
CrCl and 90-d all-cause and CrCl was significantly associated with
mortality‡
improved outcomes, with the greatest
benefit in seen in patients with CrCl of 30–59
mL·min−1·1.73 m−2 (P=0.0005 for interaction).

ACE indicates angiotensin-converting enzyme; ACS, acute coronary syndrome; CATS, Captopril and Thrombolysis Study; CKD, chronic kidney disease; CCP, Cooperative
Cardiovascular Project; CI, confidence interval; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GFR, glomerular
filtration rate; HR, hazard ratio; LVEF, left ventricular ejection fraction; MI, myocardial infarction; RCT, randomized controlled trial; SAVE, Survival And Ventricular Enlargement
study; SCr, serum creatinine; and SYMPHONY, Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-Acute Coronary Syndromes.
*GFR calculated by the modified Modification of Diet in Renal Disease equation.
†GFR calculated via Cockcroft-Gault equation.
‡CrCl calculated by modified Modification of Diet in Renal Disease equation.

ejection fraction <40%, and have either diabetes mellitus or heart
failure.87 These recommendations are primarily derived from
the Eplerenone Post-Acute Myocardial Infarction Heart Failure
Efficacy and Survival (EPHESUS) trial, which demonstrated a
15% all-cause mortality risk reduction (P=0.008) and a 13%
reduction in cardiovascular-related mortality or cardiovascular
hospitalizations (P=0.002) among post-MI patients with a left
ventricular ejection fraction ≤40% who received eplerenone 25
to 50 mg/d in addition to background heart failure therapy with
an ACE inhibitor or ARB and β-blocker.123 However, important
exclusion criteria for the EPHESUS trial were SCr >2.5 mg/dL
or a serum potassium >5.0 mEq/L. Serious hyperkalemia (≥6.0

mEq/L) occurred in 5.5% of patients receiving eplerenone compared with 3.9% in the placebo group (P=0.002). For patients
with CrCl <50 mL/min, the incidence of serious hyperkalemia
increased to 10.1% among those receiving eplerenone compared with 5.9% in the placebo group (P=0.006). Since the

publication of the Randomized Aldactone Evaluation Study
(RALES), concerns have been raised regarding the increased
risk of life-threatening hyperkalemia attributable to aldosterone antagonists, particularly when combined with angiotensin
blockade.124 Therefore, the American College of Cardiology/
American Heart Association guidelines recommend against
using aldosterone blockade if significant renal dysfunction (SCr
>2.5 mg/dL in men and >2.0 mg/dL in women) or hyperkalemia (serum potassium >5.0 mEq/L) coexists.87
A post hoc analysis of the EPHESUS trial evaluated serial
changes in eGFR related to eplerenone use in patients after
ACS. In this analysis, Rossignol et al125 found that 5792 patients
assigned to eplerenone 25 to 50 mg/d had a significant decline
in their eGFR, with a mean adjusted difference of −1.4±0.3
mL·min−1·1.73 m−2 compared with placebo (P<0.0001). This
effect occurred within the first month and persisted throughout
the 24-month follow-up. Patients receiving eplerenone had


20  Circulation  March 24, 2015
Table 10.  Summary of Statin Studies in Patients With ACS and CKD
Study

Study Design

Population

Lim et al

Observational,
retrospective analysis
of KAMIR cohort

12 865 AMI patients; 3256 patients with
AMI and renal insufficiency (eGFR<60
mL/min)* were included; 2218 were taking
statins and 1038 were not

Death and
complications during
hospital course

Adjusted for covariates, HR (95% CI) 2.2
(1.696–2.881), P<0.001 in renal dysfunction
group with no statin therapy vs other groups.
For eGFR <30 but ≥15 mL/min and no statin
therapy: HR, 2.0; 95% CI, 1.2–3.5; P=0.008.
For eGFR <15 mL/min: HR, 2.3; 95% CI, 1.1–
4.8; P=0.036 compared with statin therapy.

CARE135

Post hoc analysis
of an RCT

1711 participants with CrCl† ≤75 mL/min
with AMI 3–20 mo before randomization
randomized to pravastatin or placebo

Death of coronary
disease or symptomatic
nonfatal MI confirmed
by CK

Adjusted for covariates, HR (95% CI) with
pravastatin 0.72 (0.55–0.95); P=0.02
compared with placebo.

Keough-Ryan
et al32

Observational cohort

5549 consecutive patients with ACS.
Renal function classified as >80 (n=1430),
60–80 (n=2018), 30–59 (n=1795), or <30
(n=306) mL·min−1·1.73 m−2‡

Death, secondary
outcomes length
of stay, surgical
interventions

Discharge lipid-lowering therapy was
associated with significant reduction in
mortality (HR, 0.835; 95% CI, 0.783–0.890)
with no significant interaction with degree of
renal impairment (P>0.10).

Szummer
et al133

Observational analysis
of the SWEDEHEART
registry

42 814 survivors of MI without statin therapy
on admission classified into 5 renal function
stages according to eGFR‡: ≥90 (n=9935),
60–89 (n=20 135), 30–59 (n=11 103),
15–29 (n=1273), and <15 mL·min−1·1.73
m−2 or undergoing dialysis (n=368)

Mortality at 1y

Statin therapy was associated with a
37% reduction in risk of death (adjusted
HR, 0.63; 95% CI, 0.58–0.69; P<0.001).
After adjustment, there was a significant
interaction between statin therapy and
renal function stage (P<0.001). Benefit was
significant in all groups except those with
eGFR <15 mL·min−1·1.73 m−2 or undergoing
dialysis Adjusted HRs (95% CI) across the
groups were as follows: 0.53 (0.41–0.67),
0.60 (0.52–0.68), 0.67 (0.60–0.76), 0.72
(0.56–0.94), and 1.13 (0.76–1.67) in
≥90, 60–89, 30–59, 15–29, and <15

mL·min−1·1.73 m−2/dialysis, respectively.

Shibui et al134

Observational cohort

501 patients presenting with ACS who
underwent successful PCI; 324 patients
(64.7%) had CKD based on eGFR <60
mL·min−1·1.73 m−2. Statin therapy was
used in 34.3% of patients with CKD.

Composite end point
of cardiac death or
readmissions for ACS
over a mean follow-up
of 5.2 y

The composite end point occurred in 16.2%
of CKD patients treated with statins compared
with 26.3% of CKD patients not treated with
statin therapy (HR, 0.58; 95% CI, 0.34–0.98;
P=0.039).

132

End Points

Results

ACS indicates acute coronary syndrome; AMI, acute myocardial infarction; CARE, Cholesterol and Recurrent Events trial; CI, confidence interval; CK, creatine kinase;
CKD, chronic kidney disease; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; HR, hazard ratio; KAMIR, Korean Acute Myocardial Infarction Registry;
MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; and SWEDEHEART, Swedish Web System for Enhancement and
Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies.
*Glomerular filtration rate calculated via Cockcroft-Gault equation.
†CrCl calculated by modified Modification of Diet in Renal Disease equation.
‡Glomerular filtration rate calculated by the modified Modification of Diet in Renal Disease equation.

a 1.15-fold increased odds of experiencing a >20% decline
in eGFR within the first month compared with placebo
(P=0.017).125 However, an eGFR ≤60 mL·min−1·1.73 m−2 was
not associated with early worsening renal function, and there
was no interaction between worsening renal function and the
favorable effects of eplerenone on cardiovascular death or
hospitalization (P=0.77 for interaction) and hospitalization
for heart failure (P=0.82 for interaction).125
Statins
A large body of literature supports of the use of statins after
an ACS to reduce the risk of death or vascular events. Current
guidelines recommend statins regardless of baseline low-density lipoprotein level in all ACS patients in the absence of contraindications.26,27 With regard to CKD patients, those receiving
chronic dialysis in particular, the use of statins has been more
controversial. No randomized controlled trials have assessed
the safety and efficacy of statins in patients with ACS and

CKD. Furthermore, patients with SCr >2 mg/dL were excluded
from the original ACS randomized trials of early initiation of
statins.126,127 However, in primary prevention, randomized trials of statin therapy in patients with CKD have yielded mixed
results.128–131 Early studies found no benefit of statin therapy
among patients with CKD (mostly dialysis dependent),129–131
which led to speculation that in ESRD, there may be a more

advanced atherosclerotic state that leads to more sudden deaths
caused by arrhythmias than among patients without ESRD.
However, more recently, the largest of these studies, the Study
of Heart and Renal Protection (SHARP), included patients
with CKD both on dialysis and not on dialysis and showed
a benefit of simvastatin plus ezetimibe therapy on the risk of
the primary composite end point of first major atherosclerotic
event (RR, 0.83; 95% CI, 0.74–0.94; P=0.0021), although no
statistically significant difference was observed for the risk of
vascular death (RR, 0.93; 95% CI, 0.80–1.07).128 Although


Washam et al   Pharmacotherapy in CKD Patients With ACS   21
Table 11.  Summary of Evidence for Pharmacotherapy for ACS Patients With CKD*
Medication Class

Summary

Aspirin

Available data suggest aspirin should be used in patients with CKD presenting with ACS

Fibrinolytic

Available data suggest fibrinolytic therapy should be considered as a treatment strategy in STEMI patients with CKD
presenting within 12 h of symptom onset when primary PCI is not available. Observed rates of ICH were higher in CKD
patients receiving fibrinolytics than in non-CKD patients

Oral P2Y12 receptor antagonist

Available data suggest these agents should be considered in CKD patients presenting with ACS. Data from RCTs of newer
agents (prasugrel and ticagrelor) suggest these agents should be considered in CKD patients not requiring dialysis.

Glycoprotein IIb/IIIa receptor antagonist

Available data suggest glycoprotein IIb/IIIa receptor antagonist therapy, within the context of labeled dosing modifications
and exclusions for each agent, can be considered as a treatment strategy in CKD patients presenting with ACS. The data
also suggest an increased rate of bleeding in patients with CKD.

Anticoagulant

Available data suggest anticoagulant therapy should be considered in CKD patients presenting with ACS. The data support
consideration for fondaparinux and bivalirudin as strategies with lower rates of bleeding in patients with stage 3 and 4
CKD (relatively few patients with stage 4 CKD were included in the randomized trials evaluating these agents). Relevant
labeled dosing modifications and contraindications should be considered for each agent.

β-Blocker

Available data suggest β-blocker therapy should be considered in CKD patients presenting with ACS who do not have a
contraindication to β-blocker therapy.

ACE inhibitor/ARB

Available data suggest ACE inhibitor or ARB therapy should be considered in CKD patients presenting with ACS and LV
dysfunction. Potassium and SCr should be monitored closely.

Aldosterone blocker

Limited available data suggest aldosterone blocker therapy should be considered for CKD patients with post-MI LV
dysfunction (with either diabetes mellitus or heart failure signs or symptoms) and baseline SCr ≤2.5 mg/dL and serum

potassium <5.0 mmol/L. Serum potassium should be monitored closely.

Statin

Available data suggest statin therapy should be considered in CKD patients presenting with ACS.

ACE indicates angiotensin-converting enzyme; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; ICH, intracranial
hemorrhage; LV, left ventricular; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; SCr, serum creatinine; and STEMI,
ST-segment–elevation myocardial infarction.
*A detailed discussion and all references can be found in the text of each respective drug section.

statin trials in ACS have largely excluded patients with CKD,
observational studies have evaluated the safety and efficacy of
statins in these patients.32,132–134 The data on the use of statins
in ACS patients with CKD are summarized in Table 10. The
Korea Acute Myocardial Infarction Registry (KAMIR) study
was observational and evaluated 12 865 patients with MI,
3256 of whom had renal dysfunction (defined as eGFR <60
mL·min−1·1.73 m−2).132 The study found that patients with renal
dysfunction not taking statins were at significantly increased
risk of in-hospital and 1-month major adverse cardiovascular
events and cardiac death at 1 year. These results were also
consistent among those with severe renal insufficiency (eGFR
<30 but ≥15 mL·min−1·1.73 m−2 and eGFR <15 mL·min−1·1.73
m−2).132 Although the Cholesterol and Recurrent Events
(CARE) study excluded participants with >2+ proteinuria or
SCr >1.5 times the upper limit of normal, subgroup analysis of
those with mild renal insufficiency (CrCl ≤75 mL/min) found
that pravastatin reduced the risk of death of coronary disease
or symptomatic nonfatal MI by 28% (adjusted HR, 0.72; 95%

CI, 0.55–0.95; P=0.02) among patients with AMI between 3
and 20 months before randomization (Table 10).135 The analysis also found that adverse events were infrequent among those
with chronic renal insufficiency, with no significant differences
in frequency compared with placebo.135
Taken together, these data show a consistent benefit with
regard to a reduction in cardiovascular events with statin therapy in CKD patients who present with ACS and support the
routine use of statins in this population. However, the data are
somewhat limited by the lack of information on statin dose,
as well as medication side effects. These are important considerations, because patients with CKD may be at higher risk

for muscle-related side effects associated with statin therapy,136
although randomized trials evaluating moderate-intensity statin
therapy in patients with advanced CKD (including ESRD)
without ACS have not supported this observation.128,129,131

Summary/Future Directions
In patients presenting with ACS, declining renal function has
been associated with increased risk for adverse clinical outcomes,
including death, MI, and bleeding events. In spite of the high risk
of adverse events in this population, CKD patients have largely
been excluded from or underrepresented in randomized controlled
trials in patients presenting with ACS. This presents a challenging situation for clinicians to make evidence-based medication
choices, as well as for understanding the risk and benefits of different therapy combinations. Taken collectively, the available data
suggest that patients with CKD benefit from the evidence-based
medications routinely used in all patients presenting with ACS
(Table 11); however, important considerations are necessary to
provide the greatest benefit while limiting the chance for harm.
These would include careful assessment of renal function, use of a
validated equation for dose adjustment of medications, avoidance
of medications that are contraindicated in patients with stage 4 and

5 CKD, and avoidance or limiting of the use of emerging medications that have not been formally studied in patients with CKD.
Currently, the US Food and Drug Administration provides
guidance and recommendations for the pharmaceutical industry on the design and conduct of pharmacokinetic studies in
patients with impaired renal function.137 However, moving forward, inclusion and better representation of patients with CKD
in randomized clinical trials will be necessary to accurately
assess the risks and benefits of medications in this population.


22  Circulation  March 24, 2015

Disclosures
Writing Group Disclosures
Writing Group
Member

Employment

Research Grant

Other Research
Support

Speakers’
Bureau/
Honoraria

Expert
Witness

None

None

None

None

None

Amylin*; Bristol MyersSquibb*; Duke†;
Eli Lilly & Co*;
GlaxoSmithKline†;
Johnson & Johnson*;
Merck & Co†; NIH†;
Regado Biosciences*

None

None

None

None

Ownership Consultant/Advisory
Interest
Board

Jeffrey B.
Washam

Duke Heart Center

L. Kristin
Newby

Duke University
Medical Center

Amber L.
Beitelshees

University of Maryland

None

None

None

None

None

None

None

Mauricio G.
Cohen

University of Miami
Miller School of
Medicine

None

None

None

None

None

Daiichi-Sankyo†;
AstraZeneca†;
The Medicines
Company*

None

Timothy D.
Henry

Cedars-Sinai Heart
Institute

None

None

None

None

None

Daiichi Sankyo*;
Eli Lilly*; The
Medicines
Company*

None

Charles A.
Herzog

Hennepin Healthcare
System, Inc

Navin K. Kapur Tufts Medical Center
Jessica L.
Mega

Brigham & Women’s
Hospital

Venu Menon

Cleveland Clinic

Robert L.
Page II

University of Colorado
School of Pharmacy

AHRQ DEcIDE Network†; Affymax*; Amgen†; CardioRenal
NIH/NIDDK†; NHLBI† Gilead†; Johnson &
Society of
Johnson†
America & NKF
of Arizona*;
Greenfield
Health
System*;
Keryx*

None

None

Other
None

Amgen†;
American
AstraZeneca*; Heart Journal*;
Cubist*; Daiichi Society of Chest

Sankyo*;
Pain Centers*;
Genentech*;
JAHA*
GlaxoSmithKline*;
Novartis*

Boston
Abbott*; Affymax*;
Scientific*;
Amgen†;
Cambridge
CorMedix*;
Heart*;
FibroGen*;
Johnson & Fresenius*; Keryx*;
Johnson*; GlaxoSmithKline*;
Merck*
AbbVie*

None

None

None

None

None

None

None

None

Daiichi Sankyo†;
AstraZeneca†

None

None

None

None

Bayer*; Janssen*;
Portola*

None

AstraZeneca†

None

None

None

None

None

None

None

None

None

None

None

None

None

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the
Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person
receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the
entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
*Modest.
†Significant.


Washam et al   Pharmacotherapy in CKD Patients With ACS   23
Reviewer Disclosures

Reviewer

Other Research
Support

Speakers’ Bureau/
Honoraria

Expert Witness

Ownership
Interest

Consultant/
Advisory Board

Other

NHLBI (PI of the
ISCHEMIA CKD
trial)†

None

None

None

None

None

None

Mayo Clinic

None

None

None

None

None

None

None

Brigham and Women’s
Hospital

NIH†

Medtronic†

None

Fresenius†

None

Keryx*;
Medtronic*

None

Baylor University Medical
Center, Baylor Heart and
Vascular Institute, Baylor
Jack and Jane Hamilton
Heart and Vascular Hospital,
Dallas, TX, The Heart
Hospital, Plano, TX

None

None

None

None

None

None

None

Employment

Research Grant

Sripal Bangalore

New York University

Gregory Barsness
David Charytan
Peter McCullough

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure
Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during
any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more
of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
*Modest.
†Significant.

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