A Maastricht Contrast-Induiced-Nehropathy Guideline study (AMACING): prevention guidelines - appropriate and cost effective?

Contrast-induced nephropathy (CIN) is a side-effect of intravascular
administration of iodinated contrast material. It is defined as an absolute
(>44*mol/l) or relative (>25%) increase in serum creatinine from baseline
values within 48-72 hours of iodinated contrast material administration, and
usually resolves within two weeks. In some cases CIN has been associated with
persistent renal failure, increased risk of dialysis, and mortality. It is not
clear however, whether CIN is causally related to this increased risk or
whether risk of morbidity and mortality is inherent in those at risk of CIN.

CIN itself is asymptomatic and no treatment for CIN exists. Therefore, the
focus lies on its prevention. Prevention guidelines have been drawn up in most
countries and been implemented in most radiological departments. In the
Netherlands, currently two guidelines for the prevention of CIN co-exist,
issued by CBO (Centraal BegeleidingsOrgaan) and VMS (Veiligheids Management
Systeem).

The prevention guidelines aim to increase patient safety by identifying
patients that may be at risk of CIN (mostly patients with chronic renal
insufficiency), and subsequently administering prophylactic intravenous
hydration to the so identified patients, in order to prevent CIN (intravenous
normal saline 4-12 hours before and 4-12 hours after exposure to iodinated
contrast material).

Needless to say, the introduction of these guidelines has had a great impact on
patient- and health care burden. In the Netherlands alone it is estimated that
yearly 100 000 to 150 000 patients receive the prophylactic treatment,
incurring a total cost of over 50 million Euro. Considering the steady yearly
increase of contrast procedures and the ageing population, it is evident that,
in future, these numbers shall only further increase.

The prophylactic treatment prescribed by the guidelines is based on a consensus
of the opinion of experts in general agreement that the treatment is
beneficial. However, and perhaps surprisingly, the effectiveness of
prophylactic hydration has never been adequately evaluated. Randomised
double-blinded trials comparing prophylactic intravenous hydration with a
proper control group receiving no prophylactic treatment are not available, and
baseline CIN incidences in untreated populations are unknown. Thus, it is not
clear whether prophylactic hydration achieves its aim to prevent CIN.

Furthermore, studies evaluating the effect of various prophylactic treatments
invariably focus on CIN instead of clinically relevant measures as primary
outcome. CIN itself being asymptomatic, it is important to determine whether
prophylactic treatment has a preventive effect on clinically relevant endpoints
sometimes associated with CIN, such as dialysis and mortality. Consider for
example: even if it transpires that prophylactic treatment reduces CIN
incidence, it may be that intravenous hydration merely dilutes serum creatinine
to such an extent that it masks CIN, having no protective effect on renal
function. It has been shown that changes in volume status can influence serum
creatinine levels, but a potential dilution effect of intravenous hydration has
not been investigated to date.

On the other hand, it is important to realise that prophylactic intravenous
hydration is not without risk. Patients may suffer mild to serious
complications ranging from phlebitis to pulmonary oedema, the latter being
potentially fatal. Those patients selected according to the guidelines for the
risk of CIN - risk factors including poor renal function, age, diabetes and
cardiac disease - are especially sensitive to complications of intravenous
hydration. The risk of intravenous hydration in this population has not as yet
been charted, and is not taken into account by guidelines for the prevention of
CIN.

It stands to reason that a patient*s pre-existing hydration status may be a
determining factor for the net effect of intravenous hydration: from the same
treatment dehydrated patients may enjoy benefits, whereas overhydrated patients
may suffer complications. The importance of hydration status in determining the
effects of prophylactic hydration, however, has not been investigated to date.

The mechanism by which prophylactic hydration may protect renal function from
injury by iodinated contrast material is unclear, as the mechanism by which
iodinated contrast material may induce CIN is unclear. Indeed, in patients with
chronic renal insufficiency biological variation of serum creatinine in the
absence of contrast material has been shown to be indistinguishable from CIN.
The question has arisen in recent literature whether CIN is anything more than
an asymptomatic increase in serum creatinine, lacking any prognostic negative
impact, and not significantly different from that observed in controls not
receiving iodinated contrast material.
Recent studies comparing patients with chronic renal deficiency receiving
intravascular iodinated contrast material to those patients not receiving
iodinated contrast material found no association between increase in serum
creatinine (CIN) and contrast administration. Indeed, it has been suggested
that renal damage after intra-arterial procedures is caused, not by contrast
material, but by cholesterol embolism arising from the erosion of aortic
atheromatous plaques by the catheter used in such procedures.

It is perhaps of importance to note that relatively recently, monomeric
non-ionic low-osmolar iodinated contrast materials - with less toxic properties
than *traditional* contrast materials - have been introduced and are now widely
used, perhaps altering the landscape of CIN.

In order to be able to take effective measures to the benefit of patient
safety, it is important to distinguish between the mechanisms underlying CIN
and the ensuing increased risk of morbidity and mortality: whether it be
biological variation of serum creatinine, renal damage, or cholesterol
embolism; whether any causality exists between these and iodinated contrast
material; and whether prophylactic intravenous hydration can prevent these from
occurring without incurring more risks than it removes. These, in short, are
the aims of the AMACING study.


Evaluation of the effect of blood sample collection on laboratory outcomes:
The AMACING study aims to minimise poatoent burden, and consequently blood is
not always collected in the same manner. It is known that certain laboratory
results differ in blood drawn intra-arterially, intravenously or from
capillaries, however it is not known whether this is so for (all) laboratory
results obtained for the AMCING study. In order to further enhance correct
interpretation of our results it is important to assess which, if any
differeneces exist and whether these differences are predictable.

The AMACING study aims to evaluate the (cost) effectiveness of guideline
prescribed intravenous prophylactic hydration in the prevention of: CIN,
decrease in renal function, renal damage, 30-day morbidity and 30-day
mortality; taking into account complications of intravenous hydration.

In addition, we shall attempt to answer the following questions:
I. Does biological and/or seasonal serum creatinine variation influence CIN
incidence recorded in clinical practice?
II. Does intravenous hydration protect renal function and prevent renal damage,
or does it merely dilute serum creatinine, masking the rise that would
otherwise be diagnosed as CIN?
III. Is intravenous hydration beneficial in all patients or only in those that
have a reduced circulating volume (are dehydrated) at the time of iodinated
contrast material administration?
IV. Does cholesterol embolization contribute to CIN?
V. Does a dose-response relationship exist between iodinated contrast material
administration and CIN, renal function, renal damage and 30-day morbidity and
mortality

Evaluation of the effect of blood sample collection on laboratory outcomes:
Do AMACING study laboratory outcomes differ when obtained from intraarterial
(from the access already available for catheterisation), intravenous (via
venapuncture) and capillary (fingerprick) blood samples?

Prospective non-inferiority randomized controlled trial comparing prophylactic
intravenous hydration with normal saline according to current guidelines, to a
control group not receiving intravenous hydration. Patients will be randomised
using stratifications for different subgroups.

Rather than an intervention, this study concerns the withholding of
prophylactic treatment.
Patients identified according to current CBO guidelines as being at risk of CIN
and having been referred for prophylactic treatment will be randomised to
either receive:
1. Standard care prophylactic treatment * i.e. intravenous hydration with
normal saline (0.9% NaCl) 4-12 hours before and 4-12 hours after administration
of iodinated contrast material.
2. No prophylactic intravenous hydration.

Patient Burden
Beyond the requirements of standard care, patient burden when participating in
AMACING will be as follows:
- Blood samples
2-3 blood samples of 17.5ml each will be collected on the day of the contrast
procedure for which no extra venepunctures are required since blood samples can
be taken from the pre-installed access device, installed for either iodinated
contrast material administration or for the prophylactic intravenous hydration
(2 samples will be collected from patients not receiving intravenous hydration
i.e. pre- and post- contrast procedure; 3 samples will be collected from
patients receiving intravenous hydration i.e. before the start of the
treatment, after pre-hydration and after post-hydration);
In order to evaluate whether differences in blood collection methods (a.o.
different access points) influence laboratory results, we will ask a subgroup
of patients * patients that will receive intra-arterial contrast via femoral
entry * for one extra 10 to 20 ml of blood withdrawal: a few drops from finger
prick and the rest by venepuncture. We will ask this BEFORE informed consent is
given for participation in the AMACING study.
In addition, a 17.5ml blood sample will be collected at the 3 follow-up
time-points of 2-5, 10-14 and 28-32 days after the contrast procedure.
- Urine samples
2-3 urine samples will be collected on the day of the contrast procedure (2
from patients not receiving intravenous hydration: pre- and post- contrast
procedure; 3 from patients receiving intravenous hydration: before the start of
the treatment, after pre-hydration and after post-hydration). The first sample
can be taken in from home.
In addition, urine samples will be collected at the 3 follow-up time-points of
2-5, 10-14 and 28-32 days after the contrast procedure (these can be taken in
from home).
- Physical measurements
We shall measure the patients* length once at baseline.
Blood pressure, pulse, bio impedance and weight will be measured at all
time-points
(i.e. before the contrast procedure /pre-hydration, after pre-hydration, after
contrast procedure /post-hydration, and at 2-5, 10-14, and 28-32 days after the
contrast procedure).
- Questionnaires
Patients will be asked to fill in a questionnaire before and after the
(treatment surrounding the) contrast procedure, and at each follow-up
time-point. The filling in of these questionnaires should not take more than
approximately 15 minutes each time.

Blood and urine samples will be stored at the MUMC Biobank for a maximum of 10
years.

Patients will be asked to make extra visits to the outpatient clinic for this
trial. The visit and a 5ml blood sample at 2-5 days after the contrast
procedure is standard care for our patient group (i.e. patients considered to
be at risk of CIN according to the guidelines), as is the follow up visit at
10-14 days for those patients whose renal function deviates from baseline at
2-5 days, and the follow up visit at 28-32 days for those patients whose renal
function deviates from baseline at 10-14 days.


Patient risk
Any risk incurred by participating in the aMACING study will be due to not
receiving prophylactic intravenous hydration, since the collection of extra
blood and urine samples incurs no extra risk. The true risk incurred from
foregoing prophylactic treatment is unknown; however, recent literature
suggests that it is likely to be minimal.

As stated above, the estimation of risk of CIN according to current guidelines
is largely based on renal function and an eGFR threshold of <60 ml/min/1.73 m2
in combination with other risk factors is currently applied for prophylactic
hydration according to Dutch guidelines. The incidence of chronic kidney
disease stage 3 (eGFR 30-60 ml/min/1,73m2) in the Netherlands is 5.3%, of which
at most an estimated third will have an eGFR <45 ml/min/1,73m2.

The European Society of Urogenital Radiology updated their CIN prevention
guidelines in 2011 to indicate that intravenous prophylactic hydration is
unnecessary in patients with an eGFR *45 ml/min/1.73m2 before intravenous
contrast administration. Risk analyses revealed that intravenous contrast
administration does not impose a nephrotoxic risk above an eGFR of
30ml/min/1.73m2. Indeed, zero incidence of dialysis and mortality is
consistently reported after intravenous contrast administration, even in
patients with severe renal insufficiency (eGFR<30) and in absence of
prophylactic treatment. Since intravenous contrast administration procedures
make up more than an estimated 70% of all contrast procedures this implies that
prophylactic intravenous hydration is superfluous in the majority of patients
currently receiving it. This patient population is also the larger proportion
of patients to be included in our randomized controlled trial - an estimated
75% - who are therefore not thought to incur any risk from participation and
not receiving prophylactic intravenous hydration.

The other 25% of patients we shall include may incur some risk of CIN: some
have an eGFR between 30-44 ml/min/1.73m2, and some will be administered
iodinated contrast material intra-arterially. The risk of CIN for the first
group does not appear to be much elevated. A pooled overview of studies
involving iodinated contrast material administration without prophylactic
intravenous hydration yielded a CIN incidence of 3.9% (30/760): 25 of the 30
patients diagnosed with CIN had an eGFR of *45 ml/min/1.73 m2, and the baseline
eGFR range of the other five CIN cases was not published.

As for the second group, although cases of long term adverse effects such as
dialysis and mortality have rarely been reported following CIN after
intravenous contrast administration, they have been reported after
intra-arterial contrast administration. It has been thought, therefore, that
intra-arterial administration led to more nefarious effects of iodinated
contrast material than intravenous administration. This too, however, has been
repeatedly put to question. A recent study found no difference in the risk of
CIN after intra-arterial or intravenous contrast administration when an
adjustment was made for patient related risk factors. Several studies found no
increased risk of CIN after intra-arterial contrast administration as compared
to intravenous administration, and one report even goes against all previous
literature portraying a higher risk of morbidity and mortality after
intravenous contrast administration than after intra-arterial administration.
In short, it is not clear whether an increased risk of dialysis and mortality
arises from contrast administration and CIN or whether it is inherent in the
patient population studied (i.e. a population requiring intra-arterial contrast
procedures or requiring prophylactic hydration according to CIN prevention
guidelines may conceivably have such an increased inherent risk). Indeed,
chronic kidney disease, the main criterion in the guidelines for increased risk
of CIN, in itself increases the risk of all-cause mortality, cardiovascular
disease and progression to kidney failure.

Causality between an increase in serum creatinine after contrast administration
(CIN) and adverse events has not been shown to exist. A recent meta-analysis by
McDonald et al including a 157 140 contrast procedures showed no difference in
incidences of CIN, dialysis, or death between patient groups receiving contrast
material versus patients not receiving contrast material (7.2% CIN after
contrast-enhanced scans versus 11.1% CIN after unenhanced scans in medium- to
high-risk populations, suggesting that contrast material may not be causally
related to CIN). More and more the opinion rises that, where it occurs, it is
the risk inherent to specific populations that leads to higher
morbidity/mortality incidence after CIN or specific administration routes, and
that CIN is merely a marker for such populations instead of there being a
causal relationship between CIN and morbidity/mortality, or even a causal
relationship between all diagnosed CIN and intravascular contrast material
administration.

On the other hand there is no evidence that prophylactic intravenous hydration
has a protective effect on renal function. Almost all studies evaluating
prophylactic intravenous hydration to date are uncontrolled trials or
retrospective cohort analyses, often involving experimental additions to the
standard administration of saline prescribed in the guidelines, and thus no
conclusions on its effectiveness can be drawn.

In a recent Dutch study on CIN, 35 of 454 patients at risk of CIN according to
current guidelines did not receive prophylactic intravenous hydration (for
reasons unexplained); yet the incidence of CIN in this subgroup was not
significantly higher than that found in the population having received
prophylactic treatment (1/35 or 2.9%, versus 10/419 or 2.4%). Furthermore, in
studies including patients receiving contrast material without prophylactic
intravenous hydration (up to 94% of the patients did not undergo prophylactic
intravenous hydration in some of these studies), and having severely diminished
renal function (up to 49.3% of patients), low CIN incidences were seen (range:
1.3% - 5.2%; pooled incidence 3.6%), and zero long term adverse effects were
reported.

Another issue is that prophylactic intravenous hydration is not without risk.
Complications may occur, especially in those patients with cardiac and/or
kidney disease, such as pulmonary oedema and/or cardiac failure which could
lead to respiratory insufficiency. There is a considerable overlap between
patients considered to be at risk of developing CIN and patients with at risk
of complications from prophylactic intravenous hydration, and therefore this is
a real concern in clinical practice. A study performed in a Dutch hospital
using Dutch CIN prevention guidelines reported an incidence of serious
complications of intravenous hydration of 1.4% in hydrated patients. The
incidence of clinically relevant events after CIN is <1% when monomeric
non-ionic low-osmolar iodinated contrast material is used, thus putting the
appropriateness of the prophylactic treatment to question, and highlighting the
importance of its evaluation against a proper control group not receiving
intravenous hydration.

The AMACING study will be pivotal in deciding the future role of prophylactic
intravenous hydration in routine clinical practice. Considering the potential
benefits of the results of this study to a large population - who are perhaps
burdened with unnecessary and sometimes harmful treatments - and the potential
benefits to our health care system in terms of efficiency and costs, we believe
the risk for all patients included in this RCT is acceptable. The incidence of
CIN is low, CIN itself has no direct relevant clinical implications, and
prophylactic intravenous hydration may have negative effects largely
disregarded until now. Based on current evidence, therefore, we see no ethical
barriers to performing the RCT in our study population. Importantly, we will
not include patients that have an eGFR of < 30 ml/min/1.73m2 even though in all
probability even these patients will not be at greater risk without intravenous
hydration, and we will include only those procedures involving non-ionic low
osmolality monomer contrast material.


Patient risk: extra precautions taken
Despite the evidence, uncertainties and questions laid out above, we wish to
take seriously the warning that the occurrence of CIN may imply for the
potential occurrence of clinically relevant effects. Therefore, any patient
diagnosed with CIN will be closely monitored.

If renal function has not normalised at 10-14 days after the contrast
procedure, as would normally be expected, or if a patient*s eGFR drops below 30
ml/min/1.73m2 or if a patient*s eGFR decreases by *10ml/min/1.73m2, we shall
inform the referring physician.

A data safety monitoring board (DSMB) will further ensure patient safety, and
the trial will be monitored according to ICH-GCP guidelines by the Clinical
Trial Centre Maastricht (CTCM).