JACC: CARDIOVASCULAR INTERVENTIONS VOL. 11, NO.

22, 2018

PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION

Strategies to Reduce Acute Kidney Injury

and Improve Clinical Outcomes Following
Percutaneous Coronary Intervention
A Subgroup Analysis of the PRESERVE Trial

Santiago Garcia, MD,a Deepak L. Bhatt, MD, MPH,b Martin Gallagher, MD, PHD,c Hani Jneid, MD,d
James Kaufman, MD,e Paul M. Palevsky, MD,f Hongsheng Wu, PHD,e Steven D. Weisbord, MD, MSC,f
for the PRESERVE Trial Group

ABSTRACT

OBJECTIVES The aim of this study was to compare intravenous (IV) sodium bicarbonate with IV sodium chloride and
oral acetylcysteine with placebo for the prevention of contrast-associated acute kidney injury (CAAKI) and intermediate-
term adverse outcomes.

BACKGROUND Data are conflicting on the optimal strategy to reduce CAAKI and related complications after percu-
taneous coronary intervention (PCI).

METHODS The PRESERVE (Prevention of Serious Adverse Events Following Angiography) trial used a 2
2 factorial
design to randomize 5,177 patients with stage III or IV chronic kidney disease undergoing angiography to IV 1.26% sodium
bicarbonate or IV 0.9% sodium chloride and 5 days of oral acetylcysteine or placebo. A subgroup analysis was conducted
of the efficacy of these interventions in patients who underwent PCI during the study angiographic examination. The
primary endpoint was a composite of death, need for dialysis, or persistent kidney impairment at 90 days; CAAKI was a
secondary endpoint.

RESULTS A total of 1,161 PRESERVE patients (mean age 69  8 years) underwent PCI. The median estimated glomerular
filtration rate was 50.7 ml/min/1.73 m2 (interquartile range: 41.7 to 60.1 ml/min/1.73 m2), and 952 patients (82%) had
diabetes mellitus. The primary endpoint occurred in 15 of 568 patients (2.6%) in the IV sodium bicarbonate group and 24
of 593 patients (4.0%) in the IV sodium chloride group (odds ratio: 0.64; 95% confidence interval: 0.33 to 1.24; p for
interaction ¼ 0.41) and in 23 of 598 patients (3.8%) in the acetylcysteine group and 16 of 563 patients (2.8%) in the
placebo group (odds ratio: 1.37; 95% confidence interval: 0.71 to 2.62; p for interaction ¼ 0.29). There were no sig-
nificant between-group differences in the rates of CAAKI.

CONCLUSIONS Among patients with CKD undergoing PCI, there was no benefit of IV sodium bicarbonate over IV
sodium chloride or of acetylcysteine over placebo for the prevention of CAAKI or intermediate-term adverse outcomes.
(J Am Coll Cardiol Intv 2018;11:2254–61) Published by Elsevier on behalf of the American College of Cardiology Foundation.

From the aMinneapolis VA Healthcare System, University of Minnesota, Minneapolis Heart Institute, Minneapolis, Minnesota;
b
VA Boston Healthcare System and Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston,
Massachusetts; cUniversity of Sydney, Sydney, Australia; dMichael E. DeBakey VA Medical Center and Baylor College of Medicine,
Houston, Texas; eVA Cooperative Studies Program Coordinating Center, VA Boston Healthcare System, Boston, Massachusetts;
and the fVA Pittsburgh Healthcare System and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. The con-
tents of this article do not represent the views of the U.S. Department of Veterans Affairs or U.S. government. This trial was funded by
the VA Cooperative Studies Program and the National Health and Medical Research Council of Australia. Dr. Garcia has received grant
support from Edwards Lifesciences; and consulting fees from Medtronic, Boston Scientific, Osprey Medical, and Surmodics. Dr. Bhatt
has received grant support from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi, The Medicines
Company, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Lilly, Chiesi, and Ironwood; has participated in an
unfunded research collaboration with FlowCo, PLx Pharma, Takeda, and Merck; has received fees for serving on data monitoring
committees and the operations committee, publications committee, and steering committee of the Population Health Research

ISSN 1936-8798/$36.00 https://doi.org/10.1016/j.jcin.2018.07.044

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 11, NO. 22, 2018 Garcia et al. 2255
NOVEMBER 26, 2018:2254–61 Renal Protection Before PCI

A pproximately 7% of patients undergoing syndrome, and diabetes, which can exacer- ABBREVIATIONS

percutaneous coronary intervention (PCI) bate the deleterious effects of contrast media AND ACRONYMS

experience contrast-associated acute kidney (16,17). In fact, subsequent to the publication

injury (CAAKI), a complication strongly associated
with adverse clinical outcomes, including death and
increased hospital costs and lengths of stay (1–5). Cur-
rent guidelines recommend pre-procedural assess-
ment of risk for CAAKI prior to PCI and adequate
preparatory intravascular volume expansion in high-
risk patients (6). Two widely used strategies to pre-
vent CAAKI in clinical practice include the use of
intravenous (IV) sodium bicarbonate to induce urine
alkalization and scavenging of reactive oxygen spe-
cies through peri-procedural oral administration of
acetylcysteine (7–9). However, results of clinical trials
and meta-analyses of these interventions have
yielded inconsistent results, and their use remains
controversial (10–13).
SEE PAGE 2262
Our group recently completed the PRESERVE (Pre-
vention of Serious Adverse Events Following Angiog-
raphy) trial, which enrolled 4,993 patients with
chronic kidney disease who were undergoing coronary
or noncoronary angiography and used a 2
2 factorial
design to compare IV sodium bicarbonate with IV so-
dium chloride and oral acetylcysteine with placebo for
the prevention of 90-day death, need for dialysis,
persistent decline in kidney function, and CAAKI (13).
In the overall trial, we found no benefit of IV sodium
bicarbonate compared with IV sodium chloride or of
oral acetylcysteine compared with placebo for the
prevention of any of these outcomes (14).
Notwithstanding these results in the full study
population, patients undergoing PCI represent a sub-
set at higher risk for adverse kidney outcomes because
they receive higher volumes of contrast volume, a
known risk factor for CAAKI (15), and have a
high burden of comorbid conditions, including
decompensated heart failure, acute
CAAKI = contrast-associated
of the PRESERVE trial results, some have acute kidney injury
questioned the generalizability of the findings
CI = confidence interval
of the overall trial to very high-risk patients,
CKD = chronic kidney disease
such as those undergoing PCI (18). In light
eGFR = estimated glomerular
of such questions and the importance of filtration rate
establishing the standard of care for the
IV = intravenous
prevention of adverse kidney outcomes
PCI = percutaneous coronary
following PCI, we conducted a subgroup intervention
analysis of PRESERVE participants who un-
derwent PCI to compare the efficacy of IV sodium bi-
carbonate with that of IV sodium chloride and of oral
acetylcysteine compared with placebo in this high-risk
patient group.
METHODS
TRIAL DESIGN AND INTERVENTIONS. PRESERVE
was an international, double-blind, placebo- and
comparator-controlled, randomized clinical trial with
a 2
2 factorial design (NCT01467466). Patients were
enrolled at 53 medical centers in the United States (35
Veterans Affairs sites), Australia (13 sites), Malaysia
(3 sites), and New Zealand (2 sites). Study partici-
pants were randomized to receive IV 1.26% sodium
bicarbonate or IV 0.9% sodium chloride and oral
N-acetylcysteine or oral placebo using a centralized,
computer-generated permuted-block plan stratified
by site. The administration of IV fluids was based
on protocol-specified ranges: 1 to 3 ml/kg/h over 1 to
12 h for a total of 3 to 12 ml/kg prior to angiography,
1 to 1.5 ml/kg/h during angiography/PCI, and 1 to 3
ml/kg/h over 2 to 12 h for a total of 6 to 12 ml/kg
following angiography. A dose of 1,200 mg oral ace-
tylcysteine or matching placebo was administered
approximately 1 h before and 1 h after angiography
and continued twice daily for 4 days, for a total of
coronary 10 doses.

Institute; has received fees for serving as editor-in-chief of the Harvard Heart Letter from Belvoir Publications; has received fees
for serving as chief medical editor of Cardiology Today’s Intervention from Slack Publications; has received fees for serving on
steering committees for continuing medical education from WebMD; has received advisory board fees from Elsevier; has served
on advisory boards for Medscape Cardiology, Regado Biosciences, and Cardax; has received fees for serving as editor-in-chief of
the Journal of Invasive Cardiology from HMP Communications; has served as deputy editor for Clinical Cardiology; has received
fees for serving as guest editor and associate editor for the Journal of the American College of Cardiology; and has served as site
coinvestigator for St. Jude Medical, Biotronik, and Boston Scientific. Dr. Gallagher has served on a study steering committee for
Baxter Australia. Dr. Palevsky has received consulting fees and advisory committee fees from Durect; consulting fees from
HealthSpan Dx; fees for serving as a member of a data and safety monitoring board from Baxter; fees for serving as a member of an
endpoint adjudication committee from GE Healthcare; and consulting fees and advisory fees from Novartis. Dr. Weisbord has
received consulting fees and advisory fees from Durect. All other authors have reported that they have no relationships relevant to
the contents of this article to disclose.

Manuscript received April 13, 2018; revised manuscript received July 11, 2018, accepted July 17, 2018.
2256 Garcia et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 11, NO. 22, 2018

Renal Protection Before PCI NOVEMBER 26, 2018:2254–61

<15 ml/min/1.73 m 2. We also excluded patients with

T A B L E 1 Baseline and Procedural Characteristics of Patients Undergoing
Percutaneous Coronary Intervention and Coronary Angiography Without
recent exposure to acetylcysteine or contrast media,
Percutaneous Coronary Intervention those with allergies to acetylcysteine or contrast
media, pregnant patients, and those participating in
PCI No PCI
(n ¼ 1,161) (n ¼ 3,304) p Value another interventional trial for which dual enroll-
Demographic and clinical characteristics ment was not approved by the Veterans Affairs study
Age, years 69.3  8.4 69.8  8.2 0.07 sponsor. The present analysis is based on the sub-
Race <0.01 group of PRESERVE patients who underwent coro-
White 877 (75.5) 2,566 (77.7)
nary angiography with PCI.
Black 110 (9.5) 410 (12.4)
Other 174 (15.0) 328 (9.9)
TRIAL ENDPOINTS. The primary endpoint for the
Pre-angiography renal function
parent trial and the current subgroup analysis was a
Serum creatinine, mg/dl 1.5 (1.3–1.7) 1.5 (1.3–1.8) 0.03
2 composite of death, need for dialysis, or a persistent
eGFR, ml/min/1.73 m 50.7 (41.7–60.1) 50.2 (41.2–59.3) 0.17
Diabetes mellitus 952 (82.0) 2,692 (81.5) 0.69 increase of at least 50% in serum creatinine at 90 days
Procedural characteristics after angiography. CAAKI, defined as an increase in
Contrast type serum creatinine of at least 25% or 0.5 mg/dl at 4 days
Iodixanol 646 (55.6) 1,735 (52.5) 0.07 following angiography, was a secondary endpoint.
Contrast volume, ml 160 (115–220) 75 (50–105) <0.01
Puncture site 0.12
STATISTICAL ANALYSIS. To compare demographic,
Femoral 769 (66.2) 2,077 (62.9)
Radial 382 (32.9) 1,197 (36.3) clinical, and procedural variables between patients
Other 10 (0.86) 28 (0.85) who did and did not undergo PCI and between the
LV end-diastolic pressure, mm Hg 17.0  7.9 18.4  8.2 0.01
sodium bicarbonate and sodium chloride groups and
Volume, ml
Pre-angiography 350 (281–452) 342 (275–437.5) 0.04 acetylcysteine and placebo groups among patients
Intra-angiography 160 (110–220) 98 (63–141) <0.01 who underwent PCI, we used the Student’s t-test for
Post-angiography 588.5 (488-685) 565 (460-665) <0.01
normally distributed continuous data, the Wilcoxon
Duration, h
Pre-angiography 2.1 (1.3–3.5) 2.0 (1.3–3.2) 0.12 rank sum test for skewed continuous data, and the chi-
Intra-angiography 1.6 (1.2–2.1) 1.0 (0.7–1.3) <0.01 square test for categorical variables. To assess whether
Post-angiography 5.5 (4.0–6.1) 4.0 (3.2–5.2) <0.01 the effect of treatment groups on the primary endpoint
varied according to whether patients underwent PCI,
Values are mean  SD, n (%), or median (interquartile range).
eGFR ¼ estimated glomerular filtration rate; LV ¼ left ventricular; PCI ¼ percutaneous coronary intervention. we extended the multivariate logistic regression
model used in the main trial (14) to test for the inter-
action between PCI and treatment assignment. Within
SPONSOR. The trial was funded by the Veterans Af-
the subgroup of patients who underwent PCI, we also
fairs Cooperative Studies Program and the National
conducted exploratory analyses to detect heteroge-
Health and Medical Research Council of Australia.
neity in the treatment effect of sodium bicarbonate
INCLUSION AND EXCLUSION CRITERIA. The PRE- compared with sodium chloride and acetylcysteine
SERVE trial included patients undergoing coronary or compared with placebo among pre-specified sub-
noncoronary angiography who were able to provide groups of interest: according to eGFR stratum, the
informed consent and who had baseline estimated presence of diabetes, albuminuria stratum, contrast
glomerular filtration rates (eGFRs) of 15 to 44.9 volume, and country (United States vs. Australia, New
ml/min/1.73 m 2 body surface area or both an eGFR of Zealand, and Malaysia). All p values are 2-sided. SAS
45 to 59.9 ml/min/1.73 m 2 and diabetes. The eGFR version 9.4 (SAS Institute, Cary, North Carolina) was
used for screening patients was calculated using the used to conduct statistical analyses.
MDRD (Modification of Diet in Renal Disease) equa-
tion, on the basis of the most recent serum creatinine RESULTS
value obtained as part of routine clinical care within
30 days before angiography. We excluded patients In the parent trial, a total of 4,993 patients were
undergoing emergency angiography (e.g., those with included in the final modified intention-to-treat an-
ST-segment elevation myocardial infarction); those alytic cohort, of whom 4,466 (89%) underwent coro-
with unstable baseline levels of serum creatinine nary angiography. Of these 4,466 patients, 1,161 (26%)
($25% variation within 3 days prior to angiography); underwent PCI. Compared with the 3,305 patients
decompensated heart failure requiring IV inotropic who underwent coronary angiography without PCI,
support, ultrafiltration, or intra-aortic balloon pump; patients who underwent PCI received a higher me-
and patients on dialysis or with baseline eGFRs dian volume of contrast (160 ml vs. 75 ml; p < 0.001),
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 11, NO. 22, 2018 Garcia et al. 2257
NOVEMBER 26, 2018:2254–61 Renal Protection Before PCI

F I G U R E 1 Enrollment and Randomization of Patients Who Underwent Percutaneous Coronary Intervention

PCI ¼ percutaneous coronary intervention.

with no other significant differences in clinical or compared with 24 patients (4.0%) in the sodium
procedural characteristics between these 2 groups chloride group (odds ratio: 0.64; 95% confidence in-
(Table 1). These 1,161 patients who underwent PCI terval [CI]: 0.33 to 1.24; p for interaction ¼ 0.41) and
were randomly assigned as part of the parent trial to in 23 patients (3.8%) in the acetylcysteine group
receive IV sodium bicarbonate (n ¼ 568) or IV sodium compared with 16 patients (2.8%) in the placebo
chloride (n ¼ 593) and acetylcysteine (n ¼ 598) or group (odds ratio: 1.37; 95% CI: 0.71 to 2.62; p for
placebo (n ¼ 563) (Figure 1). interaction ¼ 0.29) (Figure 2, Table 3). The interaction
between sodium bicarbonate and acetylcysteine with
BASELINE AND PROCEDURAL CHARACTERISTICS.
respect to the primary endpoint was not significant in
The mean age of the 1,161 patients who underwent
the parent trial (p ¼ 0.33).
PCI was 69  8 years, 952 (82%) had diabetes mellitus,
S e c o n d a r y e n d p o i n t . CAAKI occurred in 64 pa-
and the median pre-angiography eGFR was 50 ml/min/
tients (11.3%) in the sodium bicarbonate group and
1.73 m 2 (interquartile range: 41 to 60 ml/min/1.73 m2 ).
71 patients (12.0%) in the sodium chloride group
Overall, 1,056 PCI procedures (90%) were performed at
(odds ratio: 0.93; 95% CI: 0.65 to 1.34; p for
the same time as the diagnostic coronary angiographic
interaction ¼ 0.16) and in 69 patients (11.5%) in the
study, while 105 (10%) were performed as staged
acetylcysteine group compared with 71 patients
procedures. The median contrast volume adminis-
(11.7%) in the placebo group (odds ratio: 0.98; 95%
tered was 160 ml (interquartile range: 115 to 220 ml),
CI: 0.69 to 1.41; p for interaction ¼ 0.49) (Figure 2,
and iso-osmolal iodixanol (Visipaque, GE Healthcare,
Table 3). The interaction between sodium bicarbon-
Little Chalfont, United Kingdom) was used in 646
ate and acetylcysteine with respect to the secondary
patients (55%). Access site was transfemoral in
endpoint was not significant in the parent trial
67% and radial in the remaining 33% of PCI cases. The
(p ¼ 0.46).
mean left ventricular end-diastolic pressure was 17 
S u b g r o u p s o f i n t e r e s t . There were no significant
7 mm Hg. There were no significant differences in
differences in the primary or secondary endpoints in
baseline clinical or procedural characteristics between
any of the pre-specified subgroups for the comparison
the IV sodium bicarbonate and IV sodium chloride
of sodium bicarbonate with sodium chloride or the
groups or between the acetylcysteine and placebo
comparison of acetylcysteine with placebo (Figure 3).
groups (Table 2). The median volume of trial IV fluid
In the eGFR stratum <45 ml/min/1.73 m2 , there was a
administered was 350 ml (interquartile range: 281 to
statistically nonsignificant lower rate of the primary
452 ml) prior to PCI, 160 ml (interquartile range: 110 to
endpoint with sodium bicarbonate (odds ratio: 0.44;
220 ml) during PCI, and 590 ml (interquartile range:
95% CI: 0.20 to 0.95; p for interaction ¼ 0.07) without
490 to 687 ml) after PCI, with no differences in the
adjustment for multiple comparisons.
total volume or duration of IV fluids across the
comparator groups (Table 2). DISCUSSION
EFFECT OF STUDY INTERVENTIONS. P r i m a r y
e n d p o i n t . The primary composite endpoint occurred In this subgroup analysis of the PRESERVE trial
in 15 patients (2.6%) in the sodium bicarbonate group among high-risk patients with chronic kidney disease
2258 Garcia et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 11, NO. 22, 2018

Renal Protection Before PCI NOVEMBER 26, 2018:2254–61

T A B L E 2 Baseline and Procedural Characteristics of Patients Undergoing Percutaneous Coronary Intervention

IV Sodium IV Sodium
Bicarbonate Chloride p Value NAC Placebo p Value

Demographic and clinical characteristics

Age, years 69.1  8.4 69.5  8.4 0.92 69.5  8.4 69.1  8.3 0.80
Race
White 425 (74.8) 452 (76.2) 0.48 457 (76.4) 420 (74.6) 0.73
Black 51 (9) 59 (9.9) 56 (9.4) 54 (9.6)
Other 92 (16.2) 82 (13.8) 85 (14.2) 89 (15.8)
Pre-angiography renal function
Serum creatinine, mg/dl 1.5 (1.3–1.8) 1.5 (1.3–1.7) 0.38 1.5 (1.3–1.7) 1.5 (1.3–1.7) 0.64
eGFR, ml/min/1.73 m2 50.3 (40.9–60.3) 51.3 (42.7–59.9) 0.40 50.9 (42.5–60.1) 50.5 (41.1–60.1) 0.50
Diabetes mellitus 464 (81.7) 488 (82.3) 0.79 486 (81.3) 466 (82.8) 0.51
Procedural characteristics
Contrast type
Iodixanol 324 (57) 322 (54.3) 0.35 330 (55.2) 316 (56.1) 0.75
Contrast volume, ml 155 (112.5–220) 160 (120–220) 0.52 170 (118–225) 150 (112–220) 0.06
Puncture site
Femoral 381 (67.1) 388 (65.4) 0.44 401 (67.1) 368 (65.4) 0.68
Radial 184 (32.4) 198 (33.4) 191 (31.9) 191 (33.9)
Other 3 (0.5) 7 (1.2) 6 (1) 4 (0.7)
LV end-diastolic pressure, mm Hg 17.1  8.2 17  7.7 0.41 17.4  8.5 16.7  7.3 0.04
Volume, ml
Pre-angiography 354 (278–464) 348 (282–444) 0.35 350 (282–450) 348 (280–454) 0.97
Intra-angiography 152 (106–215) 167 (113–222) 0.05 160 (111–221) 160 (108–220) 0.89
Post-angiography 588 (498–678) 590 (485–692) 0.64 588 (491–683) 590 (488–690) 0.92
Duration, h
Pre-angiography 2.1 (1.3–3.5) 2.1 (1.3–3.4) 0.51 2.1 (1.3–3.4) 2 (1.3–3.5) 0.38
Intra-angiography 1.5 (1.2–2) 1.6 (1.2–2.1) 0.19 1.6 (1.2–2.2) 1.5 (1.2–2) 0.32
Post-angiography 5.2 (4–6.1) 5.6 (4–6) 0.76 5.3 (4–6.1) 5.6 (4–6) 0.94

Values are mean  SD, n (%), or median (interquartile range).

IV ¼ intravenous; NAC ¼ N-acetylcysteine; other abbreviations as in Table 1

who underwent PCI, we found that neither IV sodium The deleterious effects of iodinated contrast on
bicarbonate (compared with IV sodium chloride) nor kidney function are thought to be mediated by
oral acetylcysteine (compared with placebo) was su- impaired renal hemodynamic status and direct toxic
perior in reducing serious adverse 90-day events or effects on tubular epithelial cells (19). There is evi-
CAAKI. These findings have important implications dence that reactive oxygen species play a role in the
for current clinical practice. pathophysiology of CAAKI; hence urinary alkalization
and the use of scavengers of reactive oxygen species
have been the subject of intense preclinical and
F I G U R E 2 Effect of Study Interventions on the Primary (Death, Dialysis, and Persistent
Decline in Renal Function) and Secondary (Contrast-Associated Acute Kidney Injury) clinical research (20,21). Multiple previous trials and
Endpoints Among Patients Undergoing Percutaneous Coronary Intervention meta-analyses have compared the efficacy of IV so-
dium bicarbonate with that of IV sodium chloride and
14%
P= NS assessed the role of acetylcysteine for the prevention
12%
of adverse renal events in patients undergoing PCI,
10%
with inconsistent results (7–13). Important limitations
8%

6%
of these previous studies include small sample sizes,
4%
P= NS inclusion of patients with normal or minimally
2% impaired kidney function who were at low risk for
0% developing CAAKI, and use of surrogate biochemical
Primary End-Point (death, dialysis, persistent decline in kidney CAAKI
funcon) markers, most commonly small changes in serum
Bicarbonate Saline NAC Placebo creatinine, as primary endpoints. For example, in
ACT (Acetylcysteine for Contrast-Induced Nephropa-
NAC ¼ N-acetylcysteine. thy Trial), more than 50% of patients had baseline
eGFR values >60 ml/min/1.73 m 2, the primary
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 11, NO. 22, 2018 Garcia et al. 2259
NOVEMBER 26, 2018:2254–61 Renal Protection Before PCI

endpoint was a 25% increase in serum creatinine at 48

T A B L E 3 Effect of Study Interventions on the Primary Endpoint and Contrast-Associated
to 96 h, and a minority of patients (n ¼ 665 [29%]) Acute Kidney Injury
underwent PCI (9). In contrast, the PRESERVE trial
Primary Endpoint
enrolled patients who were at higher risk for renal
Sodium Bicarbonate Sodium Chloride Odds Ratio
complications after administration of contrast media N (n ¼ 2,237) (n ¼ 2,228) (95% CI) p Value*
(i.e., stage 3A chronic kidney disease with diabetes or
PCI (1,161)† 15/568 24/593 0.64 (0.33–1.24) 0.41
stages 3B and 4 chronic kidney disease with or No PCI (3,304) 78/1,669 87/1,635 0.87 (0.64–1.19)
without diabetes) and used a primary endpoint NAC Placebo Odds Ratio
comprising death, dialysis, and a persistent decline in N (n [ 2,237) (n [ 2,228) (95% CI) p Value*

kidney function at 90 days. Moreover, the present PCI (1,161)† 23/598 16/563 1.37 (0.71–2.62) 0.29

subgroup analysis of more than 1,150 patients, with No PCI (3,304) 79/1,639 86/1,665 0.93 (0.68–1.27)

more than 500 in each treatment arm, represents the CAAKI

largest trial of IV sodium bicarbonate and of ace- Sodium Bicarbonate Sodium Chloride Odds Ratio
N (n [ 2,237) (n [ 2,228) (95% CI) p Value*
tylcysteine in patients undergoing PCI reported to
PCI (1,161)† 64/568 71/593 0.93 (0.65–1.34) 0.16
date.
No PCI (3,304) 148/1,669 116/1,635 1.27 (0.99–1.24)
A report on nearly 1 million patients undergoing
PCI at 1,253 sites in the United States participating in NAC Placebo Odds Ratio
N (n [ 2,237) (n [ 2,228) (95% CI) p Value*
the National Cardiovascular Data Registry Cath-PCI
PCI (1,161)† 69/598 66/563 0.98 (0.69–1.41) 0.49
Registry demonstrated that the in-hospital mortality
No PCI (3,304) 139/1,639 125/1,665 1.14 (0.89–1.47)
after PCI was 9.7% for patients who developed CAAKI
and 34% in patients who required dialysis, compared *p value for interaction of PCI with treatment assignment. †49 patients (4%) did not complete primary endpoint
ascertainment (5 withdrew from the study and 44 were lost to follow-up). These patients were assumed to have
with 0.5% for patients without CAAKI (1). Hence, not developed the primary endpoint.
strategies to prevent CAAKI, and reduce its attendant CAAKI ¼ contrast-associated acute kidney injury; CI ¼ confidence interval; other abbreviations as in Tables 1
and 2.
complications, are of great clinical importance. The
risk for CAAKI is particularly high in patients who
undergo PCI. This is evident in the present study, in
which patients who underwent PCI received more expansion with isotonic sodium chloride should be
than double the median volume of contrast (160 ml considered the standard of care for the prevention
vs. 75 ml) and had a 30% higher incidence of CAAKI of adverse renal outcomes. In addition to its lack of
relative to participants in the PRESERVE trial who superiority compared with IV sodium chloride, the
underwent coronary angiography without PCI. Un- use of IV 1.26% sodium bicarbonate in clinical
fortunately, even in this high-risk subset of patients, practice is problematic because it requires formula-
IV sodium bicarbonate was not superior to IV saline, tion by local pharmacies, which introduces the po-
and acetylcysteine was not effective for the preven- tential for a delay in availability and compounding
tion of CAAKI or patient-centered clinical events. errors and is incompatible with other cardiac med-
These results are consistent with the overall trial and ications such as norepinephrine and dobutamine,
provide additional evidence to discontinue these which may require a separate IV infusion. In
widely used interventions in the cardiac catheteriza- contrast, IV sodium chloride is readily available in
tion laboratory. hospital settings and does not have such in-
Current American College of Cardiology, Amer- compatibilities with cardiac medications. These
ican Heart Association, and Society for Cardiovas- properties could simplify renal protection by
cular Angiography and Interventions PCI guidelines ensuring timely administration of IV fluids prior to
recommend that patients undergoing cardiac cath- contrast exposure. Of note, the recently published
eterization with contrast media receive adequate AMACING (Maastricht Contrast-Induced Nephropa-
preparatory intravascular volume expansion with thy Guideline) trial challenged the role of prophy-
isotonic crystalloids (6). On the basis of the lack of lactic IV fluid prior to administration of iodinated
clinical benefit of IV sodium bicarbonate compared contrast media. This prospective, single-center,
with IV sodium chloride seen in the PRESERVE noninferiority randomized clinical trial of 660 pa-
study, we believe this recommendation should be tients with chronic kidney disease found that no IV
updated in favor of IV sodium chloride. Further- fluid was noninferior to prophylactic IV isotonic
more, the present study demonstrates that even in saline for the prevention of CAAKI (2.6% vs. 2.7%,
the highest risk patients who are undergoing coro- p ¼ 0.47) (22). Notwithstanding this finding,
nary angiography with PCI, intravascular volume AMACING had limited power because of substantial
2260 Garcia et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 11, NO. 22, 2018

Renal Protection Before PCI NOVEMBER 26, 2018:2254–61

F I G U R E 3 Forest Plot of Treatment Effects in Pre-Specified Subgroup Analysis

A Comparison of Sodium Bicarbonate with Sodium Chloride

Primary Endpoint n/N P Value Odds Ratio OR 95%CI
Overall Cohort 39 / 1161 0.64[0.33,1.24]
eGFR < 45 ml/min 31 / 593 0.44[0.20,0.95]
eGFR 45−60 8 / 568 0.07 1.89[0.45,8.00]
Diabetes 30 / 952 0.80[0.38,1.66]
No Diabetes 9 / 209 0.2 0.27[0.05,1.34]
Urine ACR < 30 7 / 398 0.17[0.02,1.39]
Urine ACR 30−300 19 / 406 0.69[0.27,1.80]
Urine ACR >300 9 / 253 0.37 0.75[0.20,2.87]
Contrast Volume > 125 ml 28 / 793 0.67[0.31,1.45]
Contrast Volume <= 125 ml 11 / 368 0.84 0.58[0.17,2.01]
USA VA Patients 31 / 934 0.49[0.23,1.07]
George Institute Patients 8 / 227 0.15 1.62[0.38,6.95]
Contrast−Associated AKI Endpoint
Overall Cohort 135 / 1161 0.93[0.65,1.34]
eGFR < 45 ml/min 71 / 593 0.88[0.54,1.44]
eGFR 45−60 64 / 568 0.73 1.00[0.59,1.68]
Diabetes 121 / 952 0.96[0.66,1.41]
No Diabetes 14 / 209 0.66 0.74[0.25,2.22]
Urine ACR < 30 32 / 398 0.92[0.45,1.91]
Urine ACR 30−300 56 / 406 0.90[0.51,1.60]
Urine ACR >300 37 / 253 0.88 1.13[0.56,2.28]
Contrast Volume > 125 ml 98 / 793 0.80[0.52,1.22]
Contrast Volume <= 125 ml 37 / 368 0.17 1.40[0.71,2.79]
USA VA Patients 104 / 934 0.94[0.63,1.42]
George Institute Patients 31 / 227 0.87 0.88[0.41,1.88]

Favors Favors
Bicarbonate Saline
0 0.25 0.5 1 2 4 8

B Comparison of NAC with Placebo

Primary Endpoint n/N P Value Odds Ratio OR 95%CI
Overall Cohort 39 / 1161 1.37[0.71,2.61]
eGFR < 45 ml/min 31 / 593 1.54[0.73,3.23]
eGFR 45−60 8 / 568 0.56 0.96[0.24,3.87]
Diabetes 30 / 952 1.10[0.53,2.27]
No Diabetes 9 / 209 0.21 3.23[0.64,16.07]
Urine ACR < 30 7 / 398 1.62[0.35,7.37]
Urine ACR 30−300 19 / 406 0.86[0.34,2.17]
Urine ACR >300 9 / 253 0.57 1.97[0.48,8.04]
Contrast Volume > 125 ml 28 / 793 1.19[0.55,2.54]
Contrast Volume <= 125 ml 11 / 368 0.52 1.91[0.55,6.65]
USA VA Patients 31 / 934 1.69[0.80,3.57]
George Institute Patients 8 / 227 0.23 0.63[0.15,2.70]
Contrast−Associated AKI Endpoint
Overall Cohort 135 / 1161 0.98[0.69,1.41]
eGFR < 45 ml/min 71 / 593 0.85[0.51,1.39]
eGFR 45−60 64 / 568 0.39 1.16[0.69,1.96]
Diabetes 121 / 952 0.93[0.64,1.40]
No Diabetes 14 / 209 0.36 1.61[0.52,4.99]
Urine ACR < 30 32 / 398 0.75[0.36,1.56]
Urine ACR 30−300 56 / 406 1.07[0.60,1.89]
Urine ACR >300 37 / 253 0.75 0.90[0.45,1.80]
Contrast Volume > 125 ml 98 / 793 1.00[0.66,1.53]
Contrast Volume <= 125 ml 37 / 368 0.78 0.90[0.45,1.77]
USA VA Patients 104 / 934 1.07[0.71,1.62]
George Institute Patients 31 / 227 0.39 0.74[0.34,1.59]

Favors Favors
NAC Placebo
0 0.25 0.5 1 2 4 8 16

Results are presented as odds ratios (squares) with 95% confidence intervals (horizontal lines) and p values for the interaction between each
subgroup variable with respect to the primary endpoint and contrast-associated acute kidney injury (AKI) for the comparisons between
sodium bicarbonate and sodium chloride (A) and between acetylcysteine and placebo (B). ACR ¼ albumin-to-creatinine ratio; CI ¼ confidence
interval; eGFR ¼ estimated glomerular filtration rate; NAC ¼ N-acetylcysteine; OR ¼ odds ratio; VA ¼ Veterans Affairs.

underenrollment relative to the target sample size
(i.e., n ¼ 1,300). Moreover, it included many pa-
tients who underwent procedures with IV rather
than intra-arterial contrast and who had more pre-
served kidney function (i.e., eGFR 45 to 60 ml/min/
1.73 m 2) and were hence at much lower risk for
kidney injury. Finally, just 14% of patients under-
went interventional procedures. Consequently, the
results of the AMACING trial are poorly generaliz-
able to high-risk patients undergoing coronary in-
terventions and do not substantiate the withholding
of prophylactic IV isotonic fluid in this patient
population.
STUDY LIMITATIONS. First, the PRESERVE trial
excluded some very high-risk patients (i.e., those
with ST-segment elevation myocardial infarction
and/or cardiogenic shock). Hence, our findings may
not be generalizable to these patients. Second, the
power of the present analysis was limited because of
the smaller number of patients compared with the
overall PRESERVE trial; however, our results are fully
consistent with those of the overall trial, supporting
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 11, NO. 22, 2018 Garcia et al. 2261
NOVEMBER 26, 2018:2254–61 Renal Protection Before PCI

the study conclusions. Finally, the study cohort was PERSPECTIVES

predominantly male; caution is required when
extrapolating results to female patients.
WHAT IS KNOWN? Periprocedural administration of acetyl-

CONCLUSIONS cysteine and IV sodium bicarbonate is commonly used to prevent

CAAKI in clinical practice.
Among patients with chronic kidney disease under-
WHAT IS NEW? In the present subgroup analysis of more than
going PCI, there was no benefit of IV sodium bicar-
1,150 patients with chronic kidney disease undergoing PCI, we
bonate compared with IV sodium chloride or of oral
found that neither IV sodium bicarbonate (compared with IV
acetylcysteine for the prevention of death, need for
sodium chloride) nor oral acetylcysteine (compared with pla-
dialysis, or persistent decline in kidney function at 90
cebo) was superior in reducing serious adverse 90-day events or
days or for the prevention of CAAKI. These results are
CAAKI.
consistent with the overall trial and support a
discontinuation in the use of these interventions in
WHAT IS NEXT? Our results support a discontinuation in the
the catheterization laboratory.
use of these interventions in the catheterization laboratory.
Intravascular volume expansion with isotonic sodium chloride
ADDRESS FOR CORRESPONDENCE: Dr. Santiago
should be considered the standard of care for the prevention of
Garcia, 920 East 28th Street, Suite 300, Minneapolis
adverse renal outcomes.
Heart Institute, Minneapolis, Minnesota 55407.
E-mail: garci205@umn.edu.

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KEY WORDS acute kidney injury,
percutaneous coronary intervention,
prevention