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Strategies to Reduce Acute Kidney Injury and Improve Clinical Outcomes Following Percutaneous Coronary Intervention
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 intermediateterm adverse outcomes. BACKGROUND Data are conflicting on the optimal strategy to reduce CAAKI and related complications after percutaneous 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 significant 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 contents 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
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A
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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
of the PRESERVE trial results, some have
with adverse clinical outcomes, including death and
questioned the generalizability of the findings
increased hospital costs and lengths of stay (1–5). Cur-
of the overall trial to very high-risk patients,
rent guidelines recommend pre-procedural assess-
such as those undergoing PCI (18). In light
ment of risk for CAAKI prior to PCI and adequate
of such questions and the importance of
preparatory intravascular volume expansion in high-
establishing the standard of care for the
risk patients (6). Two widely used strategies to pre-
prevention
vent CAAKI in clinical practice include the use of
following PCI, we conducted a subgroup
intravenous (IV) sodium bicarbonate to induce urine
analysis of PRESERVE participants who un-
alkalization and scavenging of reactive oxygen spe-
derwent PCI to compare the efficacy of IV sodium bi-
cies through peri-procedural oral administration of
carbonate with that of IV sodium chloride and of oral
acetylcysteine (7–9). However, results of clinical trials
acetylcysteine compared with placebo in this high-risk
and meta-analyses of these interventions have
patient group.
of
adverse
kidney
outcomes
CAAKI = contrast-associated acute kidney injury
CI = confidence interval CKD = chronic kidney disease eGFR = estimated glomerular filtration rate
IV = intravenous PCI = percutaneous coronary intervention
yielded inconsistent results, and their use remains controversial (10–13).
METHODS
SEE PAGE 2262
TRIAL
DESIGN
AND
INTERVENTIONS. PRESERVE
Our group recently completed the PRESERVE (Pre-
was an international, double-blind, placebo- and
vention of Serious Adverse Events Following Angiog-
comparator-controlled, randomized clinical trial with
raphy) trial, which enrolled 4,993 patients with
a 2 2 factorial design (NCT01467466). Patients were
chronic kidney disease who were undergoing coronary
enrolled at 53 medical centers in the United States (35
or noncoronary angiography and used a 2 2 factorial
Veterans Affairs sites), Australia (13 sites), Malaysia
design to compare IV sodium bicarbonate with IV so-
(3 sites), and New Zealand (2 sites). Study partici-
dium chloride and oral acetylcysteine with placebo for
pants were randomized to receive IV 1.26% sodium
the prevention of 90-day death, need for dialysis,
bicarbonate or IV 0.9% sodium chloride and oral
persistent decline in kidney function, and CAAKI (13).
N-acetylcysteine or oral placebo using a centralized,
In the overall trial, we found no benefit of IV sodium
computer-generated permuted-block plan stratified
bicarbonate compared with IV sodium chloride or of
by site. The administration of IV fluids was based
oral acetylcysteine compared with placebo for the
on protocol-specified ranges: 1 to 3 ml/kg/h over 1 to
prevention of any of these outcomes (14).
12 h for a total of 3 to 12 ml/kg prior to angiography,
Notwithstanding these results in the full study
1 to 1.5 ml/kg/h during angiography/PCI, and 1 to 3
population, patients undergoing PCI represent a sub-
ml/kg/h over 2 to 12 h for a total of 6 to 12 ml/kg
set at higher risk for adverse kidney outcomes because
following angiography. A dose of 1,200 mg oral ace-
they receive higher volumes of contrast volume, a
tylcysteine or matching placebo was administered
known risk factor for CAAKI (15), and have a
approximately 1 h before and 1 h after angiography
high burden of comorbid conditions, including
and continued twice daily for 4 days, for a total of
decompensated
10 doses.
heart
failure,
acute
coronary
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.
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<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 (n ¼ 1,161)
No PCI (n ¼ 3,304)
p Value
69.3 8.4
69.8 8.2
0.07
Age, years
sponsor. The present analysis is based on the sub-
<0.01
group of PRESERVE patients who underwent coro-
Race White
877 (75.5)
2,566 (77.7)
Black
110 (9.5)
410 (12.4)
Other
174 (15.0)
328 (9.9)
1.5 (1.3–1.7)
1.5 (1.3–1.8)
0.03
50.7 (41.7–60.1)
50.2 (41.2–59.3)
0.17
952 (82.0)
2,692 (81.5)
0.69
nary angiography with PCI. TRIAL ENDPOINTS. The primary endpoint for the
Pre-angiography renal function Serum creatinine, mg/dl eGFR, ml/min/1.73 m
2
Diabetes mellitus
parent trial and the current subgroup analysis was a composite of death, need for dialysis, or a persistent increase of at least 50% in serum creatinine at 90 days after angiography. CAAKI, defined as an increase in
Procedural characteristics Contrast type Iodixanol Contrast volume, ml Puncture site Femoral Radial Other LV end-diastolic pressure, mm Hg Volume, ml Pre-angiography Intra-angiography Post-angiography Duration, h Pre-angiography Intra-angiography Post-angiography
another interventional trial for which dual enrollment was not approved by the Veterans Affairs study
Demographic and clinical characteristics
serum creatinine of at least 25% or 0.5 mg/dl at 4 days 646 (55.6) 160 (115–220)
1,735 (52.5) 75 (50–105)
0.07 <0.01 0.12
769 (66.2) 382 (32.9) 10 (0.86) 17.0 7.9
2,077 (62.9) 1,197 (36.3) 28 (0.85) 18.4 8.2
0.01
350 (281–452) 160 (110–220) 588.5 (488-685)
342 (275–437.5) 98 (63–141) 565 (460-665)
0.04 <0.01 <0.01
2.1 (1.3–3.5) 1.6 (1.2–2.1) 5.5 (4.0–6.1)
2.0 (1.3–3.2) 1.0 (0.7–1.3) 4.0 (3.2–5.2)
0.12 <0.01 <0.01
following angiography, was a secondary endpoint. STATISTICAL ANALYSIS. To compare demographic,
clinical, and procedural variables between patients who did and did not undergo PCI and between the
Values are mean SD, n (%), or median (interquartile range). eGFR ¼ estimated glomerular filtration rate; LV ¼ left ventricular; PCI ¼ percutaneous coronary intervention.
sodium bicarbonate and sodium chloride groups and acetylcysteine and placebo groups among patients who underwent PCI, we used the Student’s t-test for normally distributed continuous data, the Wilcoxon rank sum test for skewed continuous data, and the chisquare test for categorical variables. To assess whether the effect of treatment groups on the primary endpoint varied according to whether patients underwent PCI, we extended the multivariate logistic regression model used in the main trial (14) to test for the inter-
SPONSOR. The trial was funded by the Veterans Af-
fairs Cooperative Studies Program and the National Health and Medical Research Council of Australia.
action between PCI and treatment assignment. Within the subgroup of patients who underwent PCI, we also conducted exploratory analyses to detect heterogeneity 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) equation, 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),
Garcia et al.
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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). BASELINE AND PROCEDURAL CHARACTERISTICS.
The mean age of the 1,161 patients who underwent PCI was 69 8 years, 952 (82%) had diabetes mellitus, and the median pre-angiography eGFR was 50 ml/min/ 1.73 m 2 (interquartile range: 41 to 60 ml/min/1.73 m2 ). Overall, 1,056 PCI procedures (90%) were performed at the same time as the diagnostic coronary angiographic study, while 105 (10%) were performed as staged procedures. The median contrast volume administered was 160 ml (interquartile range: 115 to 220 ml), and iso-osmolal iodixanol (Visipaque, GE Healthcare, Little Chalfont, United Kingdom) was used in 646 patients (55%). Access site was transfemoral in 67% and radial in the remaining 33% of PCI cases. The mean left ventricular end-diastolic pressure was 17 7 mm Hg. There were no significant differences in baseline clinical or procedural characteristics between the IV sodium bicarbonate and IV sodium chloride groups or between the acetylcysteine and placebo groups (Table 2). The median volume of trial IV fluid administered was 350 ml (interquartile range: 281 to 452 ml) prior to PCI, 160 ml (interquartile range: 110 to 220 ml) during PCI, and 590 ml (interquartile range: 490 to 687 ml) after PCI, with no differences in the total volume or duration of IV fluids across the comparator groups (Table 2). EFFECT
OF
STUDY
interaction ¼ 0.29) (Figure 2, Table 3). The interaction between sodium bicarbonate and acetylcysteine with respect to the primary endpoint was not significant in the parent trial (p ¼ 0.33). S e c o n d a r y e n d p o i n t . CAAKI occurred in 64 patients (11.3%) in the sodium bicarbonate group and 71 patients (12.0%) in the sodium chloride group (odds ratio: 0.93; 95% CI: 0.65 to 1.34; p for interaction ¼ 0.16) and in 69 patients (11.5%) in the acetylcysteine group compared with 71 patients (11.7%) in the placebo group (odds ratio: 0.98; 95% CI: 0.69 to 1.41; p for interaction ¼ 0.49) (Figure 2, Table 3). The interaction between sodium bicarbonate and acetylcysteine with respect to the secondary endpoint was not significant in the parent trial (p ¼ 0.46). S u b g r o u p s o f i n t e r e s t . There were no significant differences in the primary or secondary endpoints in any of the pre-specified subgroups for the comparison of sodium bicarbonate with sodium chloride or the comparison of acetylcysteine with placebo (Figure 3). In the eGFR stratum <45 ml/min/1.73 m2 , there was a statistically nonsignificant lower rate of the primary endpoint with sodium bicarbonate (odds ratio: 0.44; 95% CI: 0.20 to 0.95; p for interaction ¼ 0.07) without adjustment for multiple comparisons.
DISCUSSION
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
2257
2258
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Renal Protection Before PCI
T A B L E 2 Baseline and Procedural Characteristics of Patients Undergoing Percutaneous Coronary Intervention
IV Sodium Bicarbonate
IV Sodium Chloride
p Value
NAC
Placebo
p Value
69.1 8.4
69.5 8.4
0.92
69.5 8.4
69.1 8.3
0.80
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)
Demographic and clinical characteristics Age, years Race
Pre-angiography renal function Serum creatinine, mg/dl eGFR, ml/min/1.73 m2 Diabetes mellitus
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
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
464 (81.7)
488 (82.3)
0.79
486 (81.3)
466 (82.8)
0.51
324 (57) 155 (112.5–220)
322 (54.3) 160 (120–220)
0.35 0.52
330 (55.2) 170 (118–225)
316 (56.1) 150 (112–220)
0.75 0.06
381 (67.1) 184 (32.4) 3 (0.5) 17.1 8.2
388 (65.4) 198 (33.4) 7 (1.2) 17 7.7
0.44
368 (65.4) 191 (33.9) 4 (0.7) 16.7 7.3
0.68
0.41
401 (67.1) 191 (31.9) 6 (1) 17.4 8.5
0.04
354 (278–464) 152 (106–215) 588 (498–678)
348 (282–444) 167 (113–222) 590 (485–692)
0.35 0.05 0.64
350 (282–450) 160 (111–221) 588 (491–683)
348 (280–454) 160 (108–220) 590 (488–690)
0.97 0.89 0.92
2.1 (1.3–3.5) 1.5 (1.2–2) 5.2 (4–6.1)
2.1 (1.3–3.4) 1.6 (1.2–2.1) 5.6 (4–6)
0.51 0.19 0.76
2.1 (1.3–3.4) 1.6 (1.2–2.2) 5.3 (4–6.1)
2 (1.3–3.5) 1.5 (1.2–2) 5.6 (4–6)
0.38 0.32 0.94
Procedural characteristics Contrast type Iodixanol Contrast volume, ml Puncture site Femoral Radial Other LV end-diastolic pressure, mm Hg Volume, ml Pre-angiography Intra-angiography Post-angiography Duration, h Pre-angiography Intra-angiography Post-angiography
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
F I G U R E 2 Effect of Study Interventions on the Primary (Death, Dialysis, and Persistent
have been the subject of intense preclinical and
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 sodium bicarbonate with that of IV sodium chloride and
14%
P= NS
12%
of adverse renal events in patients undergoing PCI,
10%
with inconsistent results (7–13). Important limitations
8%
of these previous studies include small sample sizes,
6% 4%
assessed the role of acetylcysteine for the prevention
inclusion of patients with normal or minimally
P= NS
impaired kidney function who were at low risk for
2%
developing CAAKI, and use of surrogate biochemical
0% Primary End-Point (death, dialysis, persistent decline in kidney funcon) Bicarbonate
Saline
CAAKI NAC
Placebo
markers, most commonly small changes in serum 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
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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 complications after administration of contrast media
N
(i.e., stage 3A chronic kidney disease with diabetes or
Sodium Bicarbonate (n ¼ 2,237)
Sodium Chloride (n ¼ 2,228)
15/568
24/593
0.64 (0.33–1.24)
78/1,669
87/1,635
0.87 (0.64–1.19)
PCI (1,161)†
stages 3B and 4 chronic kidney disease with or
No PCI (3,304)
without diabetes) and used a primary endpoint comprising death, dialysis, and a persistent decline in
NAC (n [ 2,237)
N
kidney function at 90 days. Moreover, the present
PCI (1,161)†
subgroup analysis of more than 1,150 patients, with
No PCI (3,304)
Placebo (n [ 2,228)
Odds Ratio (95% CI)
p Value*
0.29
16/563
1.37 (0.71–2.62)
79/1,639
86/1,665
0.93 (0.68–1.27)
CAAKI
largest trial of IV sodium bicarbonate and of ace-
Sodium Bicarbonate (n [ 2,237)
N
tylcysteine in patients undergoing PCI reported to
PCI (1,161)†
date.
No PCI (3,304)
A report on nearly 1 million patients undergoing PCI at 1,253 sites in the United States participating in
N
the National Cardiovascular Data Registry Cath-PCI
PCI (1,161)†
Registry demonstrated that the in-hospital mortality
No PCI (3,304)
after PCI was 9.7% for patients who developed CAAKI and 34% in patients who required dialysis, compared
Sodium Chloride (n [ 2,228)
Odds Ratio (95% CI)
p Value*
64/568
71/593
0.93 (0.65–1.34)
0.16
148/1,669
116/1,635
1.27 (0.99–1.24)
NAC (n [ 2,237)
Placebo (n [ 2,228)
Odds Ratio (95% CI)
69/598
66/563
0.98 (0.69–1.41)
139/1,639
125/1,665
1.14 (0.89–1.47)
p Value*
0.49
*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 not developed the primary endpoint.
with 0.5% for patients without CAAKI (1). Hence, 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-
0.41
Odds Ratio (95% CI)
23/598
more than 500 in each treatment arm, represents the
p Value*
compatibilities
with
cardiac
medications.
These
ican Heart Association, and Society for Cardiovas-
properties
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
could
simplify
renal
protection
by
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
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
nary angiography with PCI, intravascular volume
AMACING had limited power because of substantial
¼
media.
0.47)
(22).
This
prospective,
Notwithstanding
single-center,
this
finding,
2260
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Renal Protection Before PCI
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 Overall Cohort eGFR < 45 ml/min eGFR 45−60 Diabetes No Diabetes Urine ACR < 30 Urine ACR 30−300 Urine ACR >300 Contrast Volume > 125 ml Contrast Volume <= 125 ml USA VA Patients George Institute Patients
Contrast−Associated AKI Endpoint Overall Cohort eGFR < 45 ml/min eGFR 45−60 Diabetes No Diabetes Urine ACR < 30 Urine ACR 30−300 Urine ACR >300 Contrast Volume > 125 ml Contrast Volume <= 125 ml USA VA Patients George Institute Patients
n/N 39 / 1161 31 / 593 8 / 568 30 / 952 9 / 209 7 / 398 19 / 406 9 / 253 28 / 793 11 / 368 31 / 934 8 / 227 135 / 1161 71 / 593 64 / 568 121 / 952 14 / 209 32 / 398 56 / 406 37 / 253 98 / 793 37 / 368 104 / 934 31 / 227
P Value
Odds Ratio
0.07 0.2 0.37 0.84 0.15
0.93[0.65,1.34] 0.88[0.54,1.44] 1.00[0.59,1.68] 0.96[0.66,1.41] 0.74[0.25,2.22] 0.92[0.45,1.91] 0.90[0.51,1.60] 1.13[0.56,2.28] 0.80[0.52,1.22] 1.40[0.71,2.79] 0.94[0.63,1.42] 0.88[0.41,1.88]
0.73 0.66 0.88 0.17 0.87
Favors Bicarbonate
0
B
OR 95%CI 0.64[0.33,1.24] 0.44[0.20,0.95] 1.89[0.45,8.00] 0.80[0.38,1.66] 0.27[0.05,1.34] 0.17[0.02,1.39] 0.69[0.27,1.80] 0.75[0.20,2.87] 0.67[0.31,1.45] 0.58[0.17,2.01] 0.49[0.23,1.07] 1.62[0.38,6.95]
0.25
0.5
Favors Saline
1
2
4
8
Comparison of NAC with Placebo Primary Endpoint Overall Cohort eGFR < 45 ml/min eGFR 45−60 Diabetes No Diabetes Urine ACR < 30 Urine ACR 30−300 Urine ACR >300 Contrast Volume > 125 ml Contrast Volume <= 125 ml USA VA Patients George Institute Patients
Contrast−Associated AKI Endpoint Overall Cohort eGFR < 45 ml/min eGFR 45−60 Diabetes No Diabetes Urine ACR < 30 Urine ACR 30−300 Urine ACR >300 Contrast Volume > 125 ml Contrast Volume <= 125 ml USA VA Patients George Institute Patients
n/N 39 / 1161 31 / 593 8 / 568 30 / 952 9 / 209 7 / 398 19 / 406 9 / 253 28 / 793 11 / 368 31 / 934 8 / 227 135 / 1161 71 / 593 64 / 568 121 / 952 14 / 209 32 / 398 56 / 406 37 / 253 98 / 793 37 / 368 104 / 934 31 / 227
P Value
Odds Ratio
OR 95%CI 1.37[0.71,2.61] 1.54[0.73,3.23] 0.96[0.24,3.87] 1.10[0.53,2.27] 3.23[0.64,16.07] 1.62[0.35,7.37] 0.86[0.34,2.17] 1.97[0.48,8.04] 1.19[0.55,2.54] 1.91[0.55,6.65] 1.69[0.80,3.57] 0.63[0.15,2.70]
0.56 0.21 0.57 0.52 0.23
0.98[0.69,1.41] 0.85[0.51,1.39] 1.16[0.69,1.96] 0.93[0.64,1.40] 1.61[0.52,4.99] 0.75[0.36,1.56] 1.07[0.60,1.89] 0.90[0.45,1.80] 1.00[0.66,1.53] 0.90[0.45,1.77] 1.07[0.71,1.62] 0.74[0.34,1.59]
0.39 0.36 0.75 0.78 0.39
Favors NAC
0
0.25
0.5
Favors Placebo
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
of prophylactic IV isotonic fluid in this patient
(i.e., n ¼ 1,300). Moreover, it included many pa-
population.
tients who underwent procedures with IV rather
STUDY
than intra-arterial contrast and who had more pre-
excluded some very high-risk patients (i.e., those
served kidney function (i.e., eGFR 45 to 60 ml/min/
with ST-segment elevation myocardial infarction
1.73 m 2) and were hence at much lower risk for
and/or cardiogenic shock). Hence, our findings may
kidney injury. Finally, just 14% of patients under-
not be generalizable to these patients. Second, the
went interventional procedures. Consequently, the
power of the present analysis was limited because of
results of the AMACING trial are poorly generaliz-
the smaller number of patients compared with the
able to high-risk patients undergoing coronary in-
overall PRESERVE trial; however, our results are fully
terventions and do not substantiate the withholding
consistent with those of the overall trial, supporting
LIMITATIONS. First,
the
PRESERVE
trial
Garcia et al.
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Renal Protection Before PCI
the study conclusions. Finally, the study cohort was predominantly
male;
caution
is
required
when
extrapolating results to female patients.
PERSPECTIVES WHAT IS KNOWN? Periprocedural administration of acetylcysteine and IV sodium bicarbonate is commonly used to prevent
CONCLUSIONS
CAAKI in clinical practice.
Among patients with chronic kidney disease undergoing PCI, there was no benefit of IV sodium bicarbonate compared with IV sodium chloride or of oral acetylcysteine for the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of CAAKI. These results are consistent with the overall trial and support a discontinuation in the use of these interventions in the catheterization laboratory.
Garcia, 920 East 28th Street, Suite 300, Minneapolis Institute,
Minneapolis,
1,150 patients with chronic kidney disease undergoing PCI, we found that neither IV sodium bicarbonate (compared with IV sodium chloride) nor oral acetylcysteine (compared with placebo) was superior in reducing serious adverse 90-day events or CAAKI. WHAT IS NEXT? Our results support a discontinuation in the use of these interventions in the catheterization laboratory.
ADDRESS FOR CORRESPONDENCE: Dr. Santiago
Heart
WHAT IS NEW? In the present subgroup analysis of more than
Minnesota
55407.
Intravascular volume expansion with isotonic sodium chloride should be considered the standard of care for the prevention of adverse renal outcomes.
E-mail: [email protected].
REFERENCES 1. Tsai TT, Patel UD, Chang TI, et al. Contemporary incidence, predictors, and outcomes of acute kidney injury in patients undergoing percutaneous coronary interventions: insights from the NCDR Cath-PCI registry. J Am Coll Cardiol Intv 2014;7:1–9. 2. Parikh PB, Jeremias A, Naidu SS, et al. Impact of severity of renal dysfunction on determinants of in-hospital mortality among patients undergoing percutaneous coronary intervention. Catheter Cardiovasc Interv 2012;80:352–7. 3. Gruberg L, Mintz GS, Mehran R, et al. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol 2000;36:1542–8. 4. Gruberg L, Mehran R, Dangas G, et al. Acute renal failure requiring dialysis after percutaneous coronary interventions. Catheter Cardiovasc Interv 2001;52:409–16. 5. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365–70. 6. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44–122. 7. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent–induced reductions in renal function by acetylcysteine. N Engl J Med
sodium bicarbonate: a randomized controlled trial. JAMA 2004;291:2328–34. 9. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT). Circulation 2011;124:1250–9. 10. Zhang B, Liang L, Chen W, Liang C, Zhang S. The efficacy of sodium bicarbonate in preventing contrast-induced nephropathy in patients with pre-existing renal insufficiency: a meta-analysis. BMJ Open 2015;5:e006989.
17. Weisbord SD, Mor MK, Resnick AL, et al. Prevention, incidence, and outcomes of contrastinduced acute kidney injury. Arch Intern Med 2008;168:1325–32. 18. Solomon R. Acute kidney injury: antioxidants do not PRESERVE kidney function after contrast exposure. Nat Rev Nephrol 2018;14:148–9.
11. Subramaniam RM, Suarez-Cuervo C, Wilson RF, et al. Effectiveness of prevention strategies for contrast-induced nephropathy: a systematic review and meta-analysis. Ann Intern Med 2016;164:406–16.
19. Itoh Y, Yano T, Sendo T, Oishi R. Clinical and experimental evidence for prevention of acute renal failure induced by radiographic contrast media. J Pharmacol Sci 2005;97:473–88.
12. Kang X, Hu DY, Li CB, Ai ZS, Peng A. N-acetylcysteine for the prevention of
20. Zhang H, Spapen H, Nguyen DN, Rogiers P, Bakker J, Vincent JL. Effects of N-acetyl-L-
contrast-induced nephropathy in patients with pre-existing renal insufficiency or diabetes: a systematic review and metaanalysis. Ren Fail 2015;37:297–303.
cysteine on regional blood flow during endotoxic shock. Eur Surg Res 1995;27:292–300.
13. Weisbord SD, Gallagher M, Kaufman J, et al. Prevention of contrast-induced AKI: a review of published trials and the design of the Prevention of Serious Adverse Events Following Angiography (PRESERVE) trial. Clin J Am Soc Nephrol 2013;8: 1618–31. 14. Weisbord SD, Gallagher M, Jneid H, et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med 2018; 378:603–14.
8. Merten GJ, Burgess WP, Gray LV, et al. Pre-
15. Gurm HS, Dixon SR, Smith DE, et al. Renal function-based contrast dosing to define safe limits of radiographic contrast media in patients undergoing percutaneous coronary interventions.
vention of contrast-induced nephropathy with
J Am Coll Cardiol 2011;58:907–14.
2000;343:180–4.
16. Recio-Mayoral A, Chaparro M, Prado B, et al. The reno-protective effect of hydration with sodium bicarbonate plus N-acetylcysteine in patients undergoing emergency percutaneous coronary intervention: the RENO study. J Am Coll Cardiol 2007;49:1283–8.
21. DiMari J, Megyesi J, Udvarhelyi N, Price P, Davis R, Safirstein R. N-acetyl cysteine ameliorates ischemic renal failure. Am J Physiol 1997;272: F292–8. 22. Nijssen EC, Rennenberg RJ, Nelemans PJ, et al. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet 2017; 389:1312–22.
KEY WORDS acute kidney injury, percutaneous coronary intervention, prevention
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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 intermediateterm adverse outcomes. BACKGROUND Data are conflicting on the optimal strategy to reduce CAAKI and related complications after percutaneous 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 significant 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 contents 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
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A
2255
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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
of the PRESERVE trial results, some have
with adverse clinical outcomes, including death and
questioned the generalizability of the findings
increased hospital costs and lengths of stay (1–5). Cur-
of the overall trial to very high-risk patients,
rent guidelines recommend pre-procedural assess-
such as those undergoing PCI (18). In light
ment of risk for CAAKI prior to PCI and adequate
of such questions and the importance of
preparatory intravascular volume expansion in high-
establishing the standard of care for the
risk patients (6). Two widely used strategies to pre-
prevention
vent CAAKI in clinical practice include the use of
following PCI, we conducted a subgroup
intravenous (IV) sodium bicarbonate to induce urine
analysis of PRESERVE participants who un-
alkalization and scavenging of reactive oxygen spe-
derwent PCI to compare the efficacy of IV sodium bi-
cies through peri-procedural oral administration of
carbonate with that of IV sodium chloride and of oral
acetylcysteine (7–9). However, results of clinical trials
acetylcysteine compared with placebo in this high-risk
and meta-analyses of these interventions have
patient group.
of
adverse
kidney
outcomes
CAAKI = contrast-associated acute kidney injury
CI = confidence interval CKD = chronic kidney disease eGFR = estimated glomerular filtration rate
IV = intravenous PCI = percutaneous coronary intervention
yielded inconsistent results, and their use remains controversial (10–13).
METHODS
SEE PAGE 2262
TRIAL
DESIGN
AND
INTERVENTIONS. PRESERVE
Our group recently completed the PRESERVE (Pre-
was an international, double-blind, placebo- and
vention of Serious Adverse Events Following Angiog-
comparator-controlled, randomized clinical trial with
raphy) trial, which enrolled 4,993 patients with
a 2 2 factorial design (NCT01467466). Patients were
chronic kidney disease who were undergoing coronary
enrolled at 53 medical centers in the United States (35
or noncoronary angiography and used a 2 2 factorial
Veterans Affairs sites), Australia (13 sites), Malaysia
design to compare IV sodium bicarbonate with IV so-
(3 sites), and New Zealand (2 sites). Study partici-
dium chloride and oral acetylcysteine with placebo for
pants were randomized to receive IV 1.26% sodium
the prevention of 90-day death, need for dialysis,
bicarbonate or IV 0.9% sodium chloride and oral
persistent decline in kidney function, and CAAKI (13).
N-acetylcysteine or oral placebo using a centralized,
In the overall trial, we found no benefit of IV sodium
computer-generated permuted-block plan stratified
bicarbonate compared with IV sodium chloride or of
by site. The administration of IV fluids was based
oral acetylcysteine compared with placebo for the
on protocol-specified ranges: 1 to 3 ml/kg/h over 1 to
prevention of any of these outcomes (14).
12 h for a total of 3 to 12 ml/kg prior to angiography,
Notwithstanding these results in the full study
1 to 1.5 ml/kg/h during angiography/PCI, and 1 to 3
population, patients undergoing PCI represent a sub-
ml/kg/h over 2 to 12 h for a total of 6 to 12 ml/kg
set at higher risk for adverse kidney outcomes because
following angiography. A dose of 1,200 mg oral ace-
they receive higher volumes of contrast volume, a
tylcysteine or matching placebo was administered
known risk factor for CAAKI (15), and have a
approximately 1 h before and 1 h after angiography
high burden of comorbid conditions, including
and continued twice daily for 4 days, for a total of
decompensated
10 doses.
heart
failure,
acute
coronary
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.
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<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 (n ¼ 1,161)
No PCI (n ¼ 3,304)
p Value
69.3 8.4
69.8 8.2
0.07
Age, years
sponsor. The present analysis is based on the sub-
<0.01
group of PRESERVE patients who underwent coro-
Race White
877 (75.5)
2,566 (77.7)
Black
110 (9.5)
410 (12.4)
Other
174 (15.0)
328 (9.9)
1.5 (1.3–1.7)
1.5 (1.3–1.8)
0.03
50.7 (41.7–60.1)
50.2 (41.2–59.3)
0.17
952 (82.0)
2,692 (81.5)
0.69
nary angiography with PCI. TRIAL ENDPOINTS. The primary endpoint for the
Pre-angiography renal function Serum creatinine, mg/dl eGFR, ml/min/1.73 m
2
Diabetes mellitus
parent trial and the current subgroup analysis was a composite of death, need for dialysis, or a persistent increase of at least 50% in serum creatinine at 90 days after angiography. CAAKI, defined as an increase in
Procedural characteristics Contrast type Iodixanol Contrast volume, ml Puncture site Femoral Radial Other LV end-diastolic pressure, mm Hg Volume, ml Pre-angiography Intra-angiography Post-angiography Duration, h Pre-angiography Intra-angiography Post-angiography
another interventional trial for which dual enrollment was not approved by the Veterans Affairs study
Demographic and clinical characteristics
serum creatinine of at least 25% or 0.5 mg/dl at 4 days 646 (55.6) 160 (115–220)
1,735 (52.5) 75 (50–105)
0.07 <0.01 0.12
769 (66.2) 382 (32.9) 10 (0.86) 17.0 7.9
2,077 (62.9) 1,197 (36.3) 28 (0.85) 18.4 8.2
0.01
350 (281–452) 160 (110–220) 588.5 (488-685)
342 (275–437.5) 98 (63–141) 565 (460-665)
0.04 <0.01 <0.01
2.1 (1.3–3.5) 1.6 (1.2–2.1) 5.5 (4.0–6.1)
2.0 (1.3–3.2) 1.0 (0.7–1.3) 4.0 (3.2–5.2)
0.12 <0.01 <0.01
following angiography, was a secondary endpoint. STATISTICAL ANALYSIS. To compare demographic,
clinical, and procedural variables between patients who did and did not undergo PCI and between the
Values are mean SD, n (%), or median (interquartile range). eGFR ¼ estimated glomerular filtration rate; LV ¼ left ventricular; PCI ¼ percutaneous coronary intervention.
sodium bicarbonate and sodium chloride groups and acetylcysteine and placebo groups among patients who underwent PCI, we used the Student’s t-test for normally distributed continuous data, the Wilcoxon rank sum test for skewed continuous data, and the chisquare test for categorical variables. To assess whether the effect of treatment groups on the primary endpoint varied according to whether patients underwent PCI, we extended the multivariate logistic regression model used in the main trial (14) to test for the inter-
SPONSOR. The trial was funded by the Veterans Af-
fairs Cooperative Studies Program and the National Health and Medical Research Council of Australia.
action between PCI and treatment assignment. Within the subgroup of patients who underwent PCI, we also conducted exploratory analyses to detect heterogeneity 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) equation, 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),
Garcia et al.
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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). BASELINE AND PROCEDURAL CHARACTERISTICS.
The mean age of the 1,161 patients who underwent PCI was 69 8 years, 952 (82%) had diabetes mellitus, and the median pre-angiography eGFR was 50 ml/min/ 1.73 m 2 (interquartile range: 41 to 60 ml/min/1.73 m2 ). Overall, 1,056 PCI procedures (90%) were performed at the same time as the diagnostic coronary angiographic study, while 105 (10%) were performed as staged procedures. The median contrast volume administered was 160 ml (interquartile range: 115 to 220 ml), and iso-osmolal iodixanol (Visipaque, GE Healthcare, Little Chalfont, United Kingdom) was used in 646 patients (55%). Access site was transfemoral in 67% and radial in the remaining 33% of PCI cases. The mean left ventricular end-diastolic pressure was 17 7 mm Hg. There were no significant differences in baseline clinical or procedural characteristics between the IV sodium bicarbonate and IV sodium chloride groups or between the acetylcysteine and placebo groups (Table 2). The median volume of trial IV fluid administered was 350 ml (interquartile range: 281 to 452 ml) prior to PCI, 160 ml (interquartile range: 110 to 220 ml) during PCI, and 590 ml (interquartile range: 490 to 687 ml) after PCI, with no differences in the total volume or duration of IV fluids across the comparator groups (Table 2). EFFECT
OF
STUDY
interaction ¼ 0.29) (Figure 2, Table 3). The interaction between sodium bicarbonate and acetylcysteine with respect to the primary endpoint was not significant in the parent trial (p ¼ 0.33). S e c o n d a r y e n d p o i n t . CAAKI occurred in 64 patients (11.3%) in the sodium bicarbonate group and 71 patients (12.0%) in the sodium chloride group (odds ratio: 0.93; 95% CI: 0.65 to 1.34; p for interaction ¼ 0.16) and in 69 patients (11.5%) in the acetylcysteine group compared with 71 patients (11.7%) in the placebo group (odds ratio: 0.98; 95% CI: 0.69 to 1.41; p for interaction ¼ 0.49) (Figure 2, Table 3). The interaction between sodium bicarbonate and acetylcysteine with respect to the secondary endpoint was not significant in the parent trial (p ¼ 0.46). S u b g r o u p s o f i n t e r e s t . There were no significant differences in the primary or secondary endpoints in any of the pre-specified subgroups for the comparison of sodium bicarbonate with sodium chloride or the comparison of acetylcysteine with placebo (Figure 3). In the eGFR stratum <45 ml/min/1.73 m2 , there was a statistically nonsignificant lower rate of the primary endpoint with sodium bicarbonate (odds ratio: 0.44; 95% CI: 0.20 to 0.95; p for interaction ¼ 0.07) without adjustment for multiple comparisons.
DISCUSSION
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
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Renal Protection Before PCI
T A B L E 2 Baseline and Procedural Characteristics of Patients Undergoing Percutaneous Coronary Intervention
IV Sodium Bicarbonate
IV Sodium Chloride
p Value
NAC
Placebo
p Value
69.1 8.4
69.5 8.4
0.92
69.5 8.4
69.1 8.3
0.80
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)
Demographic and clinical characteristics Age, years Race
Pre-angiography renal function Serum creatinine, mg/dl eGFR, ml/min/1.73 m2 Diabetes mellitus
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
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
464 (81.7)
488 (82.3)
0.79
486 (81.3)
466 (82.8)
0.51
324 (57) 155 (112.5–220)
322 (54.3) 160 (120–220)
0.35 0.52
330 (55.2) 170 (118–225)
316 (56.1) 150 (112–220)
0.75 0.06
381 (67.1) 184 (32.4) 3 (0.5) 17.1 8.2
388 (65.4) 198 (33.4) 7 (1.2) 17 7.7
0.44
368 (65.4) 191 (33.9) 4 (0.7) 16.7 7.3
0.68
0.41
401 (67.1) 191 (31.9) 6 (1) 17.4 8.5
0.04
354 (278–464) 152 (106–215) 588 (498–678)
348 (282–444) 167 (113–222) 590 (485–692)
0.35 0.05 0.64
350 (282–450) 160 (111–221) 588 (491–683)
348 (280–454) 160 (108–220) 590 (488–690)
0.97 0.89 0.92
2.1 (1.3–3.5) 1.5 (1.2–2) 5.2 (4–6.1)
2.1 (1.3–3.4) 1.6 (1.2–2.1) 5.6 (4–6)
0.51 0.19 0.76
2.1 (1.3–3.4) 1.6 (1.2–2.2) 5.3 (4–6.1)
2 (1.3–3.5) 1.5 (1.2–2) 5.6 (4–6)
0.38 0.32 0.94
Procedural characteristics Contrast type Iodixanol Contrast volume, ml Puncture site Femoral Radial Other LV end-diastolic pressure, mm Hg Volume, ml Pre-angiography Intra-angiography Post-angiography Duration, h Pre-angiography Intra-angiography Post-angiography
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
F I G U R E 2 Effect of Study Interventions on the Primary (Death, Dialysis, and Persistent
have been the subject of intense preclinical and
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 sodium bicarbonate with that of IV sodium chloride and
14%
P= NS
12%
of adverse renal events in patients undergoing PCI,
10%
with inconsistent results (7–13). Important limitations
8%
of these previous studies include small sample sizes,
6% 4%
assessed the role of acetylcysteine for the prevention
inclusion of patients with normal or minimally
P= NS
impaired kidney function who were at low risk for
2%
developing CAAKI, and use of surrogate biochemical
0% Primary End-Point (death, dialysis, persistent decline in kidney funcon) Bicarbonate
Saline
CAAKI NAC
Placebo
markers, most commonly small changes in serum 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
Garcia et al.
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2259
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 complications after administration of contrast media
N
(i.e., stage 3A chronic kidney disease with diabetes or
Sodium Bicarbonate (n ¼ 2,237)
Sodium Chloride (n ¼ 2,228)
15/568
24/593
0.64 (0.33–1.24)
78/1,669
87/1,635
0.87 (0.64–1.19)
PCI (1,161)†
stages 3B and 4 chronic kidney disease with or
No PCI (3,304)
without diabetes) and used a primary endpoint comprising death, dialysis, and a persistent decline in
NAC (n [ 2,237)
N
kidney function at 90 days. Moreover, the present
PCI (1,161)†
subgroup analysis of more than 1,150 patients, with
No PCI (3,304)
Placebo (n [ 2,228)
Odds Ratio (95% CI)
p Value*
0.29
16/563
1.37 (0.71–2.62)
79/1,639
86/1,665
0.93 (0.68–1.27)
CAAKI
largest trial of IV sodium bicarbonate and of ace-
Sodium Bicarbonate (n [ 2,237)
N
tylcysteine in patients undergoing PCI reported to
PCI (1,161)†
date.
No PCI (3,304)
A report on nearly 1 million patients undergoing PCI at 1,253 sites in the United States participating in
N
the National Cardiovascular Data Registry Cath-PCI
PCI (1,161)†
Registry demonstrated that the in-hospital mortality
No PCI (3,304)
after PCI was 9.7% for patients who developed CAAKI and 34% in patients who required dialysis, compared
Sodium Chloride (n [ 2,228)
Odds Ratio (95% CI)
p Value*
64/568
71/593
0.93 (0.65–1.34)
0.16
148/1,669
116/1,635
1.27 (0.99–1.24)
NAC (n [ 2,237)
Placebo (n [ 2,228)
Odds Ratio (95% CI)
69/598
66/563
0.98 (0.69–1.41)
139/1,639
125/1,665
1.14 (0.89–1.47)
p Value*
0.49
*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 not developed the primary endpoint.
with 0.5% for patients without CAAKI (1). Hence, 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-
0.41
Odds Ratio (95% CI)
23/598
more than 500 in each treatment arm, represents the
p Value*
compatibilities
with
cardiac
medications.
These
ican Heart Association, and Society for Cardiovas-
properties
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
could
simplify
renal
protection
by
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
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
nary angiography with PCI, intravascular volume
AMACING had limited power because of substantial
¼
media.
0.47)
(22).
This
prospective,
Notwithstanding
single-center,
this
finding,
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Garcia et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 11, NO. 22, 2018 NOVEMBER 26, 2018:2254–61
Renal Protection Before PCI
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 Overall Cohort eGFR < 45 ml/min eGFR 45−60 Diabetes No Diabetes Urine ACR < 30 Urine ACR 30−300 Urine ACR >300 Contrast Volume > 125 ml Contrast Volume <= 125 ml USA VA Patients George Institute Patients
Contrast−Associated AKI Endpoint Overall Cohort eGFR < 45 ml/min eGFR 45−60 Diabetes No Diabetes Urine ACR < 30 Urine ACR 30−300 Urine ACR >300 Contrast Volume > 125 ml Contrast Volume <= 125 ml USA VA Patients George Institute Patients
n/N 39 / 1161 31 / 593 8 / 568 30 / 952 9 / 209 7 / 398 19 / 406 9 / 253 28 / 793 11 / 368 31 / 934 8 / 227 135 / 1161 71 / 593 64 / 568 121 / 952 14 / 209 32 / 398 56 / 406 37 / 253 98 / 793 37 / 368 104 / 934 31 / 227
P Value
Odds Ratio
0.07 0.2 0.37 0.84 0.15
0.93[0.65,1.34] 0.88[0.54,1.44] 1.00[0.59,1.68] 0.96[0.66,1.41] 0.74[0.25,2.22] 0.92[0.45,1.91] 0.90[0.51,1.60] 1.13[0.56,2.28] 0.80[0.52,1.22] 1.40[0.71,2.79] 0.94[0.63,1.42] 0.88[0.41,1.88]
0.73 0.66 0.88 0.17 0.87
Favors Bicarbonate
0
B
OR 95%CI 0.64[0.33,1.24] 0.44[0.20,0.95] 1.89[0.45,8.00] 0.80[0.38,1.66] 0.27[0.05,1.34] 0.17[0.02,1.39] 0.69[0.27,1.80] 0.75[0.20,2.87] 0.67[0.31,1.45] 0.58[0.17,2.01] 0.49[0.23,1.07] 1.62[0.38,6.95]
0.25
0.5
Favors Saline
1
2
4
8
Comparison of NAC with Placebo Primary Endpoint Overall Cohort eGFR < 45 ml/min eGFR 45−60 Diabetes No Diabetes Urine ACR < 30 Urine ACR 30−300 Urine ACR >300 Contrast Volume > 125 ml Contrast Volume <= 125 ml USA VA Patients George Institute Patients
Contrast−Associated AKI Endpoint Overall Cohort eGFR < 45 ml/min eGFR 45−60 Diabetes No Diabetes Urine ACR < 30 Urine ACR 30−300 Urine ACR >300 Contrast Volume > 125 ml Contrast Volume <= 125 ml USA VA Patients George Institute Patients
n/N 39 / 1161 31 / 593 8 / 568 30 / 952 9 / 209 7 / 398 19 / 406 9 / 253 28 / 793 11 / 368 31 / 934 8 / 227 135 / 1161 71 / 593 64 / 568 121 / 952 14 / 209 32 / 398 56 / 406 37 / 253 98 / 793 37 / 368 104 / 934 31 / 227
P Value
Odds Ratio
OR 95%CI 1.37[0.71,2.61] 1.54[0.73,3.23] 0.96[0.24,3.87] 1.10[0.53,2.27] 3.23[0.64,16.07] 1.62[0.35,7.37] 0.86[0.34,2.17] 1.97[0.48,8.04] 1.19[0.55,2.54] 1.91[0.55,6.65] 1.69[0.80,3.57] 0.63[0.15,2.70]
0.56 0.21 0.57 0.52 0.23
0.98[0.69,1.41] 0.85[0.51,1.39] 1.16[0.69,1.96] 0.93[0.64,1.40] 1.61[0.52,4.99] 0.75[0.36,1.56] 1.07[0.60,1.89] 0.90[0.45,1.80] 1.00[0.66,1.53] 0.90[0.45,1.77] 1.07[0.71,1.62] 0.74[0.34,1.59]
0.39 0.36 0.75 0.78 0.39
Favors NAC
0
0.25
0.5
Favors Placebo
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
of prophylactic IV isotonic fluid in this patient
(i.e., n ¼ 1,300). Moreover, it included many pa-
population.
tients who underwent procedures with IV rather
STUDY
than intra-arterial contrast and who had more pre-
excluded some very high-risk patients (i.e., those
served kidney function (i.e., eGFR 45 to 60 ml/min/
with ST-segment elevation myocardial infarction
1.73 m 2) and were hence at much lower risk for
and/or cardiogenic shock). Hence, our findings may
kidney injury. Finally, just 14% of patients under-
not be generalizable to these patients. Second, the
went interventional procedures. Consequently, the
power of the present analysis was limited because of
results of the AMACING trial are poorly generaliz-
the smaller number of patients compared with the
able to high-risk patients undergoing coronary in-
overall PRESERVE trial; however, our results are fully
terventions and do not substantiate the withholding
consistent with those of the overall trial, supporting
LIMITATIONS. First,
the
PRESERVE
trial
Garcia et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 11, NO. 22, 2018 NOVEMBER 26, 2018:2254–61
Renal Protection Before PCI
the study conclusions. Finally, the study cohort was predominantly
male;
caution
is
required
when
extrapolating results to female patients.
PERSPECTIVES WHAT IS KNOWN? Periprocedural administration of acetylcysteine and IV sodium bicarbonate is commonly used to prevent
CONCLUSIONS
CAAKI in clinical practice.
Among patients with chronic kidney disease undergoing PCI, there was no benefit of IV sodium bicarbonate compared with IV sodium chloride or of oral acetylcysteine for the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of CAAKI. These results are consistent with the overall trial and support a discontinuation in the use of these interventions in the catheterization laboratory.
Garcia, 920 East 28th Street, Suite 300, Minneapolis Institute,
Minneapolis,
1,150 patients with chronic kidney disease undergoing PCI, we found that neither IV sodium bicarbonate (compared with IV sodium chloride) nor oral acetylcysteine (compared with placebo) was superior in reducing serious adverse 90-day events or CAAKI. WHAT IS NEXT? Our results support a discontinuation in the use of these interventions in the catheterization laboratory.
ADDRESS FOR CORRESPONDENCE: Dr. Santiago
Heart
WHAT IS NEW? In the present subgroup analysis of more than
Minnesota
55407.
Intravascular volume expansion with isotonic sodium chloride should be considered the standard of care for the prevention of adverse renal outcomes.
E-mail: [email protected].
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KEY WORDS acute kidney injury, percutaneous coronary intervention, prevention
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