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Outcomes after angiography with sodium bicarbonate and acetylcysteine

Article in Journal of the Practice of Cardiovascular Sciences · January 2018

DOI: 10.4103/jpcs.jpcs_34_18

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Aayush Kumar Singal Bharath Raj Kidambi

All India Institute of Medical Sciences Al-Dhannah Hospital
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Curriculum in Cardiology
Journal Club
Outcomes after Angiography with Sodium Bicarbonate and
Acetylcysteine
Aayush Kumar Singal, Bharath Raj Kidambi
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
Citation
Weisbord SD, Gallagher M, Jneid H, Garcia S, Cass A,
Thwin S‑S, et al. Outcomes after angiography with sodium
bicarbonate and acetylcysteine. N Engl J Med. 2018 15;
378(7): 603‑14[1]
Background
• Patients with cardiac diseases often have underlying
kidney disease also
• Attempting diagnostic/therapeutic procedures requiring
radiocontrast dyes can potentially save the heart, but at
the cost of worsening renal functions
• Contrast‑associated‑acute kidney injury (CA‑AKI) is
defined as an increase in serum creatinine ≥0.3 mg/dL,
or ≥25% from baseline, within 48 h
• Attempts to find therapy, which can mitigate this dye‑related
damage, have been ongoing for the last 20 years
• Initial small single‑center studies suggested the benefits
of N‑acetyl cysteine (NAC)[2] and sodium bicarbonate.[3]
• Since then, >100 studies on NAC and >50 on sodium
bicarbonate have been published
• In the last 3 years itself, seven systematic reviews have
been done, but still the question as to the efficacy of these
agents remains unanswered
• Of these reviews, some[4‑6] favored the use of NAC and
some[7] suggested that there was a beneficial effect of
sodium bicarbonate. To oppose these, there were many
reviews which suggested that these agents were not useful
in protection against CA‑AKI[8‑10]
• To answer this clinical conundrum on a topic of such great
clinical significance, the PRESERVE trial was planned.
Study design
• Double blinded
• International, multicentric (4 countries, 53 sites:
the United States of America [35 Veterans Affairs
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sites], Australia [13 sites], Malaysia [3 sites], and
New Zealand [2 sites])
• Placebo and comparator drug controlled
• 2 × 2 factorial design
• Enrollment: February 2013 through March 2017
• Target sample size: 7680
• Funding – US Department of Veterans Affairs Office,
National Health and Medical Research Council of Australia.
Inclusion criteria
• Undergoing elective coronary or noncoronary angiography
• Estimated glomerular filtration rate (eGFR) of
15–44.9 ml/min/1.73 m2 or
• eGFR of 45–59.9 ml/min/1.73 m2 among those with
diabetes mellitus
• Able and willing to provide informed consent.
Exclusion criteria
• Emergency angiography (defined as need for angiogram
within 3 h of initial clinical presentation)
• Unstable baseline levels of blood creatinine (defined
as increase or decrease of ≥25% within 3 days before
angiography)
• Receiving dialysis, or chronic kidney disease 5
• Decompensated heart failure
• Receipt of iodinated contrast in the past 5 days
• Known allergy to acetylcysteine or iodinated contrast
• Pregnancy.
Study hypothesis
• Compared with isotonic intravenous (IV) NaCl, isotonic
IV NaHCO3 decreases serious adverse outcomes following
angiography
Address for correspondence: Dr. Aayush Kumar Singal,
Department of Cardiology, 7th Floor, CN Centre, All India Institute of Medical
Sciences, New Delhi ‑ 110 029, India.
E‑mail: doc.aayush@gmail.com
This is an open access journal, and articles are distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to
remix, tweak, and build upon the work non-commercially, as long as appropriate credit
is given and the new creations are licensed under the identical terms.
For reprints contact: reprints@medknow.com
How to cite this article: Singal AK, Kidambi BR. Outcomes after
angiography with sodium bicarbonate and acetylcysteine. J Pract Cardiovasc
Sci 2018;4:122-5.
[Downloaded free from http://www.j-pcs.org on Thursday, September 20, 2018, IP: 103.221.210.204]
Singal and Kidambi: The PRESERVE trial
• Compared with placebo, oral NAC decreases serious
adverse outcomes following angiography.
Study end points
• 1 end point
0
• Composite of death, need for dialysis, or persistent
increase in serum creatinine ≥50% at 90 days.
• 20 end points
• CA‑AKI (increase in serum creatinine ≥0.5 mg/dL
or ≥25% at 3–5 days)
• Individual components of 10 end point
• Hospitalization for heart failure, stroke, and acute
coronary syndrome by 90 days
• All‑cause hospitalization.
Methods
Patient recruitment
• Estimated sample size: 7680
• Trial was stopped after 5177 patients (67%) were
randomized because of results from preplanned interim
analysis, according to which, even with conservative
assumptions, there was <12% likelihood that the findings
would change and that there would be a statistically
significant finding favoring one of the interventions.
• A total of 4993 patients were included in the final analytic
cohort.
Study intervention
• IV fluids (1.26% NaHCO3, 0.9% NaCl)
• Preangio: 1–3 mL/kg/h over 1–12 h → total volume
3–12 mL/kg
• Intra‑angio: 1–1.5 mL/kg/h
• Postangio: 1–3 mL/kg/h over 2–12 h → total volume
6–12 mL/kg
• Local providers specified rate, duration, and volume
of these parameters.
• NAC/placebo capsules
• 1200 mg po bid × 5 days starting ~ 1 h prior to
angiography.
Study methodology
• An equal number of patients were randomized into the
four study arms: sodium bicarbonate, NAC, placebo, or
sodium chloride
• Protocol‑defined amounts of IV fluids were administered
• Blood samples were taken at baseline, between 3 and 5 days,
and between 90 and 104 days (maximum up to 180 days).
Statistical analysis
• Modified intention‑to‑treat analysis was used
• For baseline and procedural characteristics, t‑test,
Wilcoxon rank sum test, and Chi‑square test were used
• For interaction between NaCl and NaHCO3, multivariate
logistic regression model was utilized
• O’Brien–Fleming multiple testing procedure was used for
conducting the interim analysis, which was done after 50%
Journal of the Practice of Cardiovascular Sciences ¦ Volume 4 ¦ Issue 2 ¦ May-August 2018
of the estimated number of patients had been followed
through for 90 days
• P ≤ 0.05 was considered to indicate statistical significance
for the interaction term and for analysis of primary and
secondary outcomes
• Overall analysis was done using the SAS software,
version 9.4 (SAS Institute, North Carolina State
University, JMP).
Results
Patient characteristics and procedural comparisons
• The baseline demographics and procedural details were
similar across different study arms
• Mean age was 69.8 years, and 93.6% were men
• 80.9% were diabetics
• Baseline median serum creatinine was 1.5 mg/dL, and the
median eGFR was 50.2 mL/min/1.73 m2
• Nearly 90.5% of patients underwent coronary angiography,
while 9.5% underwent noncoronary angiography.
Percutaneous coronary intervention was done in 28.5%
of patients
• Median contrast volume used was 85 mL
• Iodixanol, a nonionic iso‑osmolar radiocontrast agent,
was used most frequently (>55% cases).
Primary outcomes
• Sodium bicarbonate and sodium chloride did not vary
with respect to the primary end point (4.4 vs. 4.7, odds
ratio [OR] 0.93 [95% confidence interval CI: −0.72–1.22]
P = 0.62)
• NAC was not better than placebo for the primary outcome
(4.6 vs. 4.5, OR 1.02 [95% CI − 0.78–1.33] P = 0.88)
Secondary outcomes
• None of the secondary end points were different in sodium
bicarbonate versus sodium chloride groups
• NAC was not better than placebo for any of the secondary
outcomes.
Discussion
• IV NaHCO3 is not more effective than IV NaCl for
prevention of serious outcomes or AKI following
angiography
• NAC is not effective in the prevention of serious outcomes
or AKI following angiography
• The current standard of care for prevention of CA‑AKI
and associated adverse outcomes should be IV isotonic
NaCl. There is no role of NAC for the same.
Critical analysis
Merits
• This study studied a highly relevant research question that
is of paramount clinical importance, yet whose answer had
remained ambiguous till before this study
• This was a double‑blinded, multicentric trial with robust
methodology and low risk of bias
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Singal and Kidambi: The PRESERVE trial
• This study has recruited the largest sample size till date
on this topic. Their trial population was more than twice
as large as the population in the largest previous trial of
acetylcysteine and much larger than the populations in all
the previous trials of IV sodium bicarbonate
• Hard primary end points, Major Adverse Kidney Events
and Death, were studied, unlike the previous trials, which
relied on clinical surrogate outcomes
• Patients with preserved renal functions were excluded.
This overcame the potential dilution of the efficacy of
interventions, which was a serious flaw in the previous
studies. Compared from ACT study (acetylcysteine for
Contrast-Induced Nephropathy trial),[11] where inclusion
of many patients with preserved kidney function limited
the generalizability of the results.
Limitations
• Primary end point assessment was done at 90 days.
Thus, any intervening event such as coronary artery
bypass grafting could have masked the benefits of the
trial intervention. However, the fact that neither study
intervention showed benefit with respect to CA‑AKI
suggests that this chance event was not statistically
significant
• For assessment of CA‑AKI, serum creatinine was
measured at a single time point. Thus, patients with a rise
occurring beyond the specified time interval were missed.
Also, the study missed patients having a transient decrease
in renal functions
• Since the recruitment of patients was predominantly done
from Veteran Affairs hospitals, the study recruited males
disproportionately, thus raising question on generalized
applicability of the results to female population. However,
this male preponderance is in keeping with the natural
distribution of cardiac diseases and the ratio of males:
females undergoing diagnostic/therapeutic interventions
• This study only enrolled patients undergoing angiography,
thus raising a question on generalizability of the findings
for patients undergoing other procedures involving
iodinated contrast material. However, such a doubt lacks
a scientific plausibility
• The design protocol excluded 6642 potentially eligible
patients before randomization, reflecting a potential source
of bias
• A standard protocol for IV fluid administration was not
followed. All the patients did not receive identical fluid
volumes. However, similar fluid volume was used across
different groups
• Relatively small volumes of contrast were used (mean
85 ml), and percutaneous interventions were performed
in only ~28% of cases. This may account for the lesser
than expected number of patients developing CA‑AKI.
Critical appraisal
A tabulated form of appraisal is summarized in Table 1.
124 Journal of the Practice of Cardiovascular Sciences ¦ Volume 4 ¦ Issue 2 ¦ May-August 2018
Table 1: Critical appraisal of the PRESERVE trial
Outcomes of angiography with sodium bicarbonate and
acetylcysteine
Was the assignment of the patients to treatment valid? Yes
Was the randomization list concealed? Yes
Was the follow‑up of the patients sufficiently long and complete? Yes
Were the patients, clinicians, and the study personnel kept Yes
“blind” to treatment?
Were the groups treated equally, apart from experimental Yes
treatment?
Were the groups similar at the start of the trial apart from the Yes
experimental therapy?
Are our patients so different from those in the study that its No
results cannot apply?
Do these results apply to our patients? Yes
Conclusion
• These findings reaffirm the fact that expensive treatment
options may not necessarily be better than conventional
methods
• Small underpowered single‑center studies should be
regarded with skepticism until results from well‑designed,
randomized controlled clinical trials are available
• The PRESERVE trial results have effectively put an end
to any further studies of these particular interventions for
this purpose.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
1. Weisbord SD, Gallagher M, Jneid H, Garcia S, Cass A, Thwin SS,
et al. Outcomes after angiography with sodium bicarbonate and
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et al. Prevention of radiographic‑contrast‑agent‑induced reductions in
renal function by acetylcysteine. N Engl J Med 2000;343:180‑4.
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et al. Prevention of contrast‑induced nephropathy with sodium
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Ren Fail 2015;37:297‑303.
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9. Zapata‑Chica CA, Bello Marquez D, Serna‑Higuita LM, Nieto‑Ríos JF,
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Journal of the Practice of Cardiovascular Sciences ¦ Volume 4 ¦ Issue 2 ¦ May-August 2018 125

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