In this multinational, randomized, controlled trial in patients with chronic kidney disease who were undergoing angiography, researchers found no benefit of intravenous sodium bicarbonate over intravenous sodium chloride or of oral acetylcysteine over oral placebo for the prevention of death, need for dialysis, or persistent kidney impairment at 90 days or for the prevention of contrast-associated acute kidney injury or other secondary end points.

1. PRESERVE Trial
N Engl J Med 2018; 378:603-614
DOI: 10.1056/NEJMoa1710933
Dr. Mohd Saif Khan,
BSc, MD, DNB, Fellowship (CCM), DM (CCM)

2. Introduction
• Contrast-induced Acute Kidney Injury(CIAKI), is defined as
an increase in serum creatinine levels of more than 25% or
44.2 µmol/L (0.5 mg/dL) within 3 days of intravascular
administration of contrast media in the absence of an
alternative cause.
• The reported incidence varies between 7% and 11%
depending upon the definition of CIN, study population, and
setting.
Main Risk Factors:

4. Preventive strategies
Prehydration
e.g. IV normal saline 1mL/kg/hr for 12-
24 hours prior to contrast
Intravenous volume expansion
60mg PO q12 hourly – 4 doses prior
to contrast
controversial
-> may decrease creatinine from
skeletal muscle as opposed to
effecting renal function directly
-> multiple meta-analyses and
flawed studies
? alkalinisation of renal tubular fluid -
> reduces levels of pH dependent
free radicals
154mEq HCO3 @ 3mL/kg over 1
hour prior to contrast -> 1mL/kg/hr
for 6 hours post contrast
N-acetyl cysteine IV NaHCO3

5. Recent literature
• Studies comparing NaCl, NaHCO3, NAC to
prevent Contrast induced AKI met with
inconsistent results.

6. Authors,
year
Sample size Results
Zapata-
Chica CA,
2015
Systematic analysis of 22
studies (n=5686)
Sodium bicarbonate versus
isotonic saline solution to
prevent contrast-induced
nephropathy
Sodium bicarbonate did not decrease the risk of
contrast-induced nephropathy (RD= 0.00; 95% CI= -
0.02 to 0.03; p= 0.83; I(2)= 0%). No significant
differences were found in the demand for renal
replacement therapy (RD= 0.00; 95% CI= -0.01 to 0-
01; I(2)= 0%; p= 0.99) or in mortality (RD= -0.00; 95%
CI= -0.001 to 0.001; I(2)= 0%; p= 0.51).
Zhang,
2015
Meta-analysis of 20 RCTs
(n=4280)
Hydration with sodium bicarbonate was associated
with a significant decrease in CIN among patients with
pre-existing renal insufficiency (OR 0.67, 95% CI 0.47
to 0.96; p=0.027). Sodium bicarbonate plus N-
acetylcysteine (OR 0.17, 95% CI 0.04 to 0.79;
p=0.024) was better than sodium bicarbonate alone
(OR 0.71, 95% CI 0.48 to 1.03; p=0.071).
Kang,
2015
Metaanalysis of 20 RCTs
n=3466 subjects (1756
assigned to NAC and 1710
assigned to the control) were
included in the pre-existing
renal dysfunction group.
Pooled analysis suggested a significant reduction in
CIN among this group (OR, 0.76; 95% CI, 0.61-0.93;
p = 0.008).
The benefit was not existed in patients with diabetes.
Colomb Med (Cali) 2015; 46: 90-103.
BMJ Open 2015; 5(3): e006989.
Ren Fail 2015; 37: 297-303.

7. Authors,
year
Sample size Results
Zhu, 2016 The study included 11 480
participants and 1653 cases
of CIN.
The incidence of CIN was 12.8% in the NAC group
versus 16.0% in the control group (RR: 0.76, 95% CI:
0.66–0.88, P=0.0002). In the patients undergoing
coronary angiography, the incidence of CIN in
the NAC group versus the control group was 13.7%
versus 17.2% (RR: 0.74, 95% CI: 0.63–0.87, P=0.0002)
Subramani
am, 2016
54 RCTs on N-acetylcysteine
plus IV saline versus IV saline
with or without a placebo
Low-dose N-acetylcysteine plus IV saline compared
with IV saline (risk ratio [RR], 0.75 [95% CI, 0.63 to
0.89]; low SOE), N-acetylcysteine plus IV saline
compared with IV saline in patients receiving low-
osmolar contrast media (RR, 0.69 [CI, 0.58 to 0.84];
moderate SOE) had clinically important and
statistically significant benefits.
Zhao,
2016
16 RCTs (n=4432) Combining use of NAC and NaHCO3 was not
significantly superior to individual use method in the
prevention of CIN after cardiac catheterization and
PCI.
Aycock
2018
28 studies involving 107,335
participants
No association between IV contrast and acute kidney
injury.
J Am Heart Assoc 2016; 5(9): e003968.
Ann Intern Med 2016; 164:406-16.
Int J Cardiol 2016; 221: 251-9.
Ann Emerg Med. 2018 Jan;71(1):44-53

8. Methodology
• The trial was a double-blind, placebo and
comparator-drug–controlled, randomized trial
• From February 2013 through March 2017,
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).
• The trial was funded by the Veterans Affairs
Office of Research and Development and the
National Health and Medical Research Council of
Australia

9. Randomization and sample size
calculation
• Centralised, computer-generated permuted-block
randomisation with stratification according to trial site
• A modified intention-to-treat analysis was performed,
including all patients that underwent randomisation and
had received the assigned trial intervention.
• Sample size calculation at 90% power (10% probability of a
false negative, or type II error) estimated that 7680 patients
would be needed to detect a decrease in the rate of the
primary end point from 8.7% to 6.5% for each trial
intervention, assuming a 3% loss to follow-up and no
interaction between the trial interventions at a significance
level of 0.05 (chance of a false positive, or type 1 error of
5%)

10. Trial End Points
• The primary end point was
a composite of death, the
need for dialysis, or a
persistent increase of at
least 50% from baseline in
the serum creatinine level
at 90 to 104 days after
angiography and confirmed
at subsequent testing
within 14 days (defined as
persistent impairment in
kidney function).
• Secondary end points were
contrast-associated acute kidney
injury, which was defined as an
increase in serum creatinine of
either at least 25% or at least 0.5
mg per deciliter (44 μmol per liter)
from baseline at 3 to 5 days after
angiography; death within 90
days; dialysis of any kind within 90
days; confirmed persistent kidney
impairment at 90 to 104 days;
hospitalization with acute
coronary syndrome, heart failure,
or stroke within 90 days; and
hospitalization for any cause
within 90 days.

11. Population

12. Statistical Analysis
• Modified intention-to-treat analysis.
• Sample size and power: 680 patients would need
to be enrolled for the trial to have a power of
90% to detect a decrease in the rate of the
primary end point from 8.7% to 6.5% for each
trial intervention, assuming a 3% loss to follow-up
and no interaction between the trial
interventions.
• Statistical tests: t-test, Wilcoxon rank-sum test,
chi-square test.
• SAS software, version 9.4 (SAS Institute).

13. Intervention
• 1.26% sodium bicarbonate and/or oral acetylcysteine
– IV sodium bicarbonate administration was based on protocol-
specified ranges: 1 to 3 ml per kilogram of body weight per hour
during a period of 1 to 12 hours for a total volume of 3 to 12 ml
per kilogram before angiography, 1 to 1.5 ml per kilogram per
hour during angiography, and 1 to 3 ml per kilogram per hour
during a period of 2 to 12 hours for a total volume of 6 to 12 ml
per kilogram after angiography
– 1200 mg of oral acetylcysteine or matched placebo
approximately 1 hour before angiography and again 1 hour after
angiography. Patients were instructed to continue to take 1200
mg of acetylcysteine or matched placebo twice daily for the
following 4 days for a total of 10 doses

14. Control
• Intravenous 0.9% sodium chloride (154 mmol
per liter) prepared in matched 1-liter bags
(Baxter Healthcare)
• Matched placebo capsules for acetylcysteine
prepared by Moehs Catalana

15. Management common to both groups
• Baseline blood samples were collected from each
patient before the initiation of trial intravenous
fluids (baseline) and at 3 to 5 days and 90 to 104
days after angiography
• Specimens were shipped to a centralised trial
laboratory (Advanced Bio Medical Labs), where
serum creatinine was measured simultaneously
in all three samples for each patient by means of
an isotope dilution mass spectrometry (IDMS)
traceable assay

16. Results

18. Results
• Baseline Characteristics

21. Outcome
• Primary outcome:
• Composite outcome of death, dialysis or a >
50% creatinine increase at 90-104 days,
confirmed at subsequent testing within 14
days – no significant difference between
groups

22. • Secondary outcomes:
– Contrast-associated acute kidney injury – no significant difference
• In the sodium bicarbonate group compared with the sodium chloride group
(9.5% vs. 8.3%; odds ratio, 1.16; 95% CI, 0.96 to 1.41; P = 0.13)
• In the acetylcysteine group vs. placebo (9.1% vs. 8.7%; odds ratio, 1.06; 95%
CI, 0.87 to 1.28; P = 0.58)
– There was no significant interaction between sodium bicarbonate and
acetylcysteine with respect to contrast-associated acute kidney injury
(P = 0.46)]
• Sub-group analysis
– In patients who underwent non-coronary angiography, there was a
significant increase in rates of the primary outcome in patients who
had received sodium bicarbonate vs. sodium chloride, without
adjustment for multiple comparisons (Odds ratio 3.19; 95% C.I. 1.03-
9.94)

24. Conclusion
• In patients with impaired kidney function
undergoing angiography, there was no benefit
from peri-procedural IV isotonic sodium
bicarbonate or oral acetylcysteine with
respect to the risk of dialysis, death, or acute
kidney injury

25. Discussions
• In this multinational, randomized, controlled
trial in patients with chronic kidney disease
who were undergoing angiography, we found
no benefit of intravenous sodium bicarbonate
over intravenous sodium chloride or of oral
acetylcysteine over oral placebo for the
prevention of death, need for dialysis, or
persistent kidney impairment at 90 days or for
the prevention of contrast-associated acute
kidney injury or other secondary end points

26. Strengths
• The study was powered at 90% to detect a significant difference between the
groups
• Analysis was on an intention-to-treat basis
• The allocation concealment, randomisation and blinding by placebo control
processes were robust
• The groups were well-matched at baseline
• The primary outcome was a composite of three patient-centred outcomes, in
contrast to many of the previous studies in this area that have used creatinine as
an end-point
• A high-risk patient group for contrast-induced nephropathy was recruited,
meaning that the results were not diluted by the presence of healthy patients
• This was a multinational study, conducted in over 50 hospitals, so external validity
is high
• Testing for interaction between sodium bicarbonate and acetylcysteine was
performed and this was facilitated by the 2 x 2 factorial design
• The authors provided data on both the type and volume of contrast used
• The volume of IV fluid administered was protocolised to ensure that there were no
between-group differences

27. Weaknesses
• The study was stopped early after a pre-specified interim analysis,
so only 5177 out of a planned 7680 patients were recruited.
• The sample population was 94% male as it was conducted mainly in
Veteran’s Hospitals
• With the use of lower osmolarity, non-ionic contrast agents, the risk
of contrast-induced nephropathy is debatable. Even in this high-risk
population, acute kidney injury occurred in fewer than 10% of
patients. The authors may have been investigating a problem that
doesn’t exist.
• The volume and type of IV contrast may differ between angiography
and diagnostic imaging, so generalisability to other radiographic
procedures and investigations may be limited
• No creatinine measurements were obtained from between 3-5 days
and 90-104 days, so it is possible that there were transient
creatinine rises within this period that were undetected.

28. Appraisal of trial