Point-of-care creatinine devices to assess kidney function before CT imaging with intravenous contrast

Evidence-based recommendations on point-of-care creatinine devices to assess kidney function before CT imaging with intravenous contrast. The tests are ABL800 FLEX, i-STAT Alinity and StatSensor, ABL90 FLEX PLUS, Dri chem NX500, epoc Blood Analysis System, and Piccolo Xpress.

# Recommendations
Point-of-care creatinine devices ABL800 FLEX, iSTAT Alinity and StatSensor, which calculate estimated glomerular filtration rate (eGFR), are recommended to assess kidney function to guide decisions on whether to use intravenous contrast during an outpatient CT scan in adults. They should only be used when current practice is that a recent eGFR result must be available before a person has a CT scan with intravenous contrast and if all the following apply:
a person presents for a CT scan without a recent eGFR result
the person has risk factors for acute kidney injury
clear governance structures for point-of-care testing are in place.
Take age, sex and ethnicity into account when assessing risk of acute kidney injury using a questionnaire-based tool (see section 4.13).
Point-of-care creatinine devices ABL90 FLEX PLUS, Drichem NX500, epoc Blood Analysis System, and Piccolo Xpress are not recommended to assess kidney function to guide decisions on whether to use intravenous contrast during an outpatient CT scan. This is because there are insufficient data to assess their diagnostic accuracy.
Further research is recommended to:
better understand the level of risk of contrast-induced acute kidney injury (see section 5.1)
identify the most appropriate tool for identifying risk factors (see section 5.2)
monitor the effect of implementation on patient experience and efficiency in radiology departments (see section 5.3).
Why the committee made these recommendations
It's important to check whether the kidneys are working properly by measuring eGFR before a contrast-enhanced CT scan. This is because the contrast agent can cause acute kidney injury in people with low eGFR.
Normally, referrers will provide a laboratory eGFR measurement before a CT scan appointment but in cases where a person presents without a recent eGFR result, point-of-care creatinine devices can measure creatinine levels and be used to calculate eGFR rapidly. This means that people who do not have a recent eGFR result will not need to have their CT scan cancelled so that their creatinine can be measured in the laboratory. Referrers providing a laboratory eGFR measurement before a CT scan appointment remains the optimal approach, and this approach should be encouraged to avoid higher numbers of patients needing point-of-care (POC) creatinine measurement before a contrast-enhanced CT scan.
Evidence suggests that the ABL800 FLEX, iSTAT Alinity and StatSensor all have acceptable accuracy in determining when eGFR is low (below 30 ml/min/1.73 m2). It was not possible to determine whether one is more accurate than another. Economic modelling shows that all 3 devices offer value for money to the NHS when compared with delaying scans for laboratory creatinine testing, although more people with an eGFR of less than 30 ml/min/1.73 m2 may be identified if they had laboratory testing. Using the devices can also avoid cancelling and rebooking CT scans, which is important for patients. The devices offer the most value for money when:
they are used only for people who have one or more risk factors for acute kidney injury and
cancelled CT scan appointments cannot be offered to other people.# The diagnostic tests

# Clinical need and practice

## The problem addressed
Point-of-care (POC) creatinine devices allow rapid measurement of creatinine levels and calculation of estimated glomerular filtration rate (eGFR). This can show whether the kidneys are working properly. The focus of this assessment is POC creatinine testing to assess kidney function before people have intravenous contrast for CT imaging. Intravenous iodine-based contrast agents used in CT scans can cause acute kidney injury (AKI), particularly in people who are at high risk and those with known kidney dysfunction. If a person has a low eGFR, intravenous hydration can be offered before the scan to reduce the risk of AKI. If a person does not have a recent eGFR measurement, their CT scan could be cancelled and rescheduled while a creatinine test is processed in the laboratory.
Using POC creatinine tests before outpatient contrast-enhanced CT scans in the radiology department could minimise the risk of kidney injury. It could also reduce the number of cancelled scans, which is important for patients.

## The condition
AKI covers injury to the kidneys from a number of causes; it often happens as a complication of another serious illness. If AKI is not treated promptly, levels of salts and chemicals in the body can increase, which affects the fluid balance in the body and how well other organs work.
Post-contrast AKI (PCAKI) is a sudden deterioration in kidney function within 48 to 72 hours of administering intravenous iodine-based contrast agent. Incidence in patients having non-emergency CT scans with intravenous contrast agent is reported to be less than 1% (Ozkok et al. 2017). Risk factors for PCAKI include chronic kidney disease, critical illness, contrast-enhanced imaging done as an emergency, older age, diabetes, use of nephrotoxic drugs and reduced kidney function (for example, if a person is dehydrated or has congestive heart failure). Short- and long-term mortality rates are significantly higher in patients with PCAKI than in patients without PCAKI. A history of PCAKI may be also be associated with development of chronic kidney disease and progression to end-stage renal disease.

## The care pathways
NICE's guideline on acute kidney injury: prevention, detection and management says that before using iodinated contrast agents for imaging, kidney function should be checked and the risk of AKI assessed. It recommends that eGFR should be measured within 3 months of using iodinated contrast agents.
The threshold for eGFR at which there is a risk of developing PCAKI varies across different guidelines, ranging between 30 ml/min/1.73 m2 (The Royal Australian and New Zealand College of Radiologists iodinated contrast guidelines , which have been endorsed by the Royal College of Radiologists) and 60 ml/min/1.73 m2 (Renal Association guideline on the prevention of CI-AKI in adult patients , in the Acute Kidney Injury guideline). Clinical experts suggested that people with an eGFR of less than 30 ml/min/1.73 m2 are at highest risk of developing PCAKI.
Guidelines recommend that adults having iodinated contrast agents at increased risk of PCAKI should:
be offered intravenous volume expansion
consider temporarily stopping angiotensin-converting enzyme inhibitors and angiotensin receptor blockers
have a nephrology team discuss their care if there are contraindications to intravenous fluids.
If PCAKI develops, NICE's guideline on acute kidney injury recommends:
renal replacement therapy (dialysis) in some situations
loop diuretics for treating fluid overload or oedema in people waiting to have dialysis, and in people who do not need dialysis.
Children were not included in the scope of this assessment because they often have alternative imaging, such as MRI scans, rather than CT scans. In addition, different eGFR equations are used for children and adults, so studies of POC creatinine devices in adult populations may not reflect the performance of these devices in children.

# The interventions
The POC creatinine devices included in table 1 are CE marked and measure creatinine using an enzymatic method. Devices are either handheld, table-top or portable and need very small samples of whole blood from either finger-prick or venous or arterial samples. Creatinine can be measured either as one component of a panel of parameters, or as a single measurement on a test card or cartridge specific for creatinine or kidney function.

## Table 1 POC creatinine devices
Manufacturer and devices
Device format
Parameters measured
Sample volume
Analysis time
eGFR equation used
Nova Biomedical
StatSensor
Handheld
Creatinine only
microlitres
seconds
MDRD, Cockcroft-Gault, CKD-EPI, Schwartz and Counahan-Barratt
Related models: StatSensor-i, StatSensor Xpress-i. All models allow offset adjustment of results. StatSensor and StatSensor-i also allow slope adjustment.
Abbott
iSTAT Alinity
Handheld
Multiple parameters
microlitres
minutes
MDRD and CKD-EPI
Related models: iSTAT 1, many studies simply state 'iSTAT'
Radiometer
ABL90 FLEX PLUS
Portable
parameters
microlitres
seconds
CKD-EPI, MDRD and Schwartz
ABL800 FLEX
Table-top
parameters
to 250 microlitres
minute
CKD-EPI and MDRD
Related models: ABL827, ABL837
Siemens Healthineers
Epoc Blood Analysis System
Handheld
parameters on 1 test card
microlitres
Less than 1 minute
CKD-EPI, MDRD and Schwartz
Abaxis
Piccolo Xpress
Table-top
Multiple parameters
microlitres
Less than 14 minutes
MDRD
Fujifilm
Drichem NX500
Table-top
Multiple parameters
microlitre
minutes
Expected
Abbreviations: CKD-EPI, chronic kidney disease epidemiology; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease.

# The comparators
There were 2 comparators used in the assessment:
laboratory-based serum creatinine measurement and eGFR
clinical judgement alone (no testing).# Evidence
The diagnostics advisory committee (section 7) considered evidence on point-of-care (POC) creatinine devices to assess kidney function before CT imaging with intravenous contrast from several sources. Full details of all the evidence are in the committee papers.

# Clinical effectiveness
The external assessment group (EAG) systematically reviewed:
studies comparing the results of POC creatinine tests with laboratory-based tests to assess kidney function in any non-emergency setting
studies reporting clinical or implementation outcomes of POC creatinine tests to assess kidney function before CT imaging in a non-emergency, outpatient setting.
There were 54 studies in the review. Of those, 12 studies reported diagnostic accuracy data for estimated glomerular filtration rate (eGFR), 7 studies reported diagnostic accuracy data for serum creatinine, 50 studies presented data on correlation or measurement bias between a POC creatinine device and a laboratory reference test, and 6 studies reported data on workflow or implementation.

## Correlation and measurement bias
Results from the StatSensor studies showed wide variation in the size and direction of measurement bias. StatSensor devices can be adjusted to correct for any bias seen, to align the POC creatinine device results with those from local laboratory methods. Only 2 StatSensor studies reported using an adjustment function for measurement bias. Although potentially important measurement bias was found in some studies of iSTAT and ABL devices, the concordance of results for these devices was generally better than for the StatSensor devices. A smaller number of studies were available on the epoc (1 study) and Piccolo Xpress (4 studies) devices.
There were 3 studies comparing different types of POC creatinine devices. Of these, 2 studies compared StatSensor, iSTAT and ABL800 FLEX. Both studies found that the ABL800 FLEX had the strongest agreement with laboratory serum creatinine, then iSTAT and then StatSensor. There was 1 study comparing an ABL827 device with an iSTAT device. It concluded that creatinine results from both devices correlated well with laboratory serum creatinine.
In some studies, measurement bias increased at higher creatinine levels (lower eGFR). This could affect care decisions for people at higher risk of kidney damage.

## Diagnostic accuracy based on eGFR thresholds
There were 12 studies reporting diagnostic accuracy data on eGFR thresholds. Studies were of different devices, with some studies assessing more than one device:
iSTAT studies
StatSensor studies
studies included a Radiometer POC device (ABL800 or ABL827)
studies assessed 3 POC devices (ABL, iSTAT and StatSensor) and
study looked at 2 devices (ABL and iSTAT).There were no studies of ABL90 FLEX PLUS, Drichem NX500, epoc Blood Analysis System and Piccolo Xpress. The eGFR equations used in the studies varied, with only 3 studies using chronic kidney disease epidemiology (CKD-EPI). There were 3 StatSensor and 2 iSTAT studies that used an adjustment function to correct for any measurement bias between the POC creatinine test results and laboratory test results from the study sample. Adjusted and unadjusted results were reported in all 3 StatSensor studies, but only adjusted results were presented in the 2 iSTAT studies. Most studies used an enzymatic method as the laboratory reference, but the Jaffe method was used in 2 studies and the reference method was not reported in 1 study.
There were 6 studies at low risk across all risk of bias areas, including 2 studies of ABL800, 3 studies of iSTAT and 3 studies of StatSensor. The other 6 studies had at least one domain at unclear or high risk of bias. Risks of bias related to:
how the adjustment function to correct for measurement bias was applied
patient selection
the use of a different modification of the diet in renal disease (MDRD) eGFR equation between the POC creatinine test and laboratory reference test
the use of a Jaffe method for the laboratory reference test (compared with an enzymatic method for the POC creatinine test).
There were low concerns about the applicability of results across all domains for only 2 studies, including 1 study of ABL800, iSTAT and StatSensor (Snaith et al. 2018), and 1 study of iSTAT (Snaith et al. 2019). The most common concern was the use of eGFR threshold; 3 studies used an eGFR cut-off of 60 ml/min/1.73 m2 or above. Several studies included disease-specific populations, therefore their applicability to a broader population of outpatients referred for CT scan without a recent eGFR may be limited.
The EAG quantitatively analysed the study results. The probabilities of being in each eGFR category were calculated from the number of people in each category reported by all included studies (regardless of the device assessed). The pooled probabilities of being in each of the 4 categories are in table 2. Most studies only included a few people in category 1 (eGFR less than 30 ml/min/1.73 m2) and more people in higher eGFR categories.

## Table 2 Estimated probabilities of being in each eGFR category
Category
eGFR
(ml/min/1.73 m
All data
Median
% CrI
to 29
to 0.017
to 44
to 0.064
to 59
to 0.159
-r higher
to 0.803
Abbreviations: eGFR, estimated glomerular filtration rate; CrI, credible interval.
The pooled probabilities of having a classification by a POC creatinine device in each eGFR category (k) and in each laboratory-defined eGFR category (j) are given in table 3. The iSTAT and ABL devices have higher median probabilities of correct classification in each of the 3 lowest categories (p, p, p) compared with the StatSensor. StatSensor was particularly poor at correctly classifying category 3 (eGFR 45 to 59 ml/min/1.73 m2). However, there is considerable uncertainty in these probabilities for all devices.

## Table 3 Estimated probabilities of being classified in each eGFR category by POC creatinine device
p
StatSensor
iSTAT
ABL (Radiometer)
Median
% CrI
Median
% CrI
Median
% CrI
p
to 0.85
to 0.94
to 0.95
p
to 0.30
to 0.18
to 0.14
p
to 0.12
to 0.18
to 0.14
p
to 0.11
to 0.16
to 0.15
p
to 0.19
to 0.21
to 0.11
p
to 0.71
to 0.87
to 0.90
p
to 0.36
to 0.21
to 0.29
p
to 0.24
to 0.06
to 0.15
p
to 0.03
to 0.05
to 0.08
p
to 0.20
to 0.17
to 0.16
p
to 0.34
to 0.88
to 0.85
p
to 0.69
to 0.13
to 0.26
p
to 0.01
to 0.01
to 0.01
p
to 0.01
to 0.02
to 0.01
p
to 0.08
to 0.10
to 0.01
p
to 0.95
to 0.93
to 0.99
eGFR categories (ml/min/1.73 m2): 1=0 to 29; 2=30 to 44, 3=5 to 59; 4=60 or higher.
Abbreviation: CrI, credible interval.
Additional analyses were done to assess the effect of removing studies with limited applicability to clinical practice in the NHS. The pooled probabilities from these analyses were used in scenario analyses in the economic model:
StatSensor devices allow a user-specified adjustment if systematic measurement bias is identified. An additional analysis including the adjusted data reported by Korpi-Steiner et al. (2009) and Shephard et al. (2010) was done. The Inoue et al. (2017) study was not included in this analysis because the reported adjustment could not be replicated in NHS practice.
Only 2 studies used the CKD-EPI equation to calculate eGFR, all others used the MDRD equation. Of these studies, one included StatSensor, iSTAT and ABL800 FLEX devices (Snaith et al. 2018) and the other only included an iSTAT device (Snaith et al. 2019). An additional analysis using only the data in these 2 studies was done.

## Clinical, workflow or implementation outcomes
There were 6 studies reporting a relevant outcome after using a POC creatinine device. The results showed variation in practice in both the proportions of patients who do not have a recent eGFR result and in the management decisions when a POC creatinine device shows an abnormal eGFR. For example, the proportion of people offered scans with or without contrast, or offered a reduced dose of contrast. Also, many of the studies were done several years ago so the value of their results is limited because eGFR thresholds for defining an abnormal result have decreased over time. No data were available on clinical outcomes such as need for renal replacement therapy or hospital admissions.

# Cost effectiveness
The EAG identified existing studies on the cost effectiveness of POC creatinine tests in an outpatient non-emergency secondary care setting, to assess kidney function before contrast-enhanced CT imaging. Because only a single cost-consequence analysis was found, provided as an academic-in-confidence manuscript, the EAG also constructed a de novo economic model to assess the cost effectiveness of POC creatinine tests.

## Model structure
The model assessed a cohort of outpatients presenting for a non-emergency contrast-enhanced CT scan without a recent eGFR measurement. Costs were presented from the perspective of the NHS and personal social services and were reported in UK pounds at 2018 prices. Outcomes after the first year were discounted at a rate of 3.5% per year. Most costs happened in the first year and were therefore not discounted.
The model used a decision tree cohort approach to estimate the costs and health outcomes of the different testing and treatment strategies. The model captured:
true eGFR status (less than 30 ml/min/1.73 m2 or 30 ml/min/1.73 m2 and above)
how eGFR status is classified by different testing strategies, using the eGFR cut-off value of 30 ml/min/1.73 m2 and probabilities conditional on true eGFR status
any actions to reduce post-contrast acute kidney injury (PCAKI) risk in patients with eGFR below the cut-off value (correct or incorrect eGFR)
the subsequent risk of PCAKI (depends on eGFR status and any actions to reduce PCAKI risk)
the risk of renal replacement therapy (depends on whether a patient had a PCAKI).
The model assessed 6 strategies to identify and manage treatment for patients with an eGFR less than 30 ml/min/1.73 m2:
laboratory testing only
risk factor screening with POC creatinine testing
risk factor screening with laboratory testing
risk factor screening with POC creatinine testing and laboratory testing
POC creatinine testing only
POC creatinine testing with laboratory testing.For strategies with sequential tests, only people who have a test result of eGFR less than 30 ml/min/1.73 m2 would go on to receive the next test in the sequence.
For each strategy that includes POC creatinine testing, the model considered separate strategies for each of the POC devices, to give 14 alternative testing strategies. The 3 devices considered in the model were iSTAT Alinity, ABL800 FLEX and StatSensor because only these had sufficient data available to calculate classification probabilities.

## Model inputs
Population characteristics, including the probability of a patient being in 1 of 4 eGFR categories, are presented in table 4. The proportion of people attending a CT scan appointment without a recent eGFR measurement was used to estimate the throughput of POC creatinine devices.

## Table 4 Population parameters used in the model
Parameter
Input
Source
Probability of eGFR
Below 30 ml/min/1.73 m2: 0.006
to 45 ml/min/1.73 m2: 0.063
to 60 ml/min/1.73 m2: 0.154
ml/min/1.73 m2 or higher:0.777
Gamma distribution fitted to Mid Yorkshire NHS trust data
Age and proportion of men
years, 51.7%
Snaith et al. (2019)
% missing eGFR
Cope et al. (2017)
Patients per site
per month
Mid Yorkshire NHS trust data
Abbreviation: eGFR, estimated glomerular filtration rate.
The diagnostic accuracy data used for each of the tests included in the model are in table 5. The cut-off used to define a positive result is eGFR less than 30 ml/min/1.73 m2. The sensitivity of the tests is equivalent to the probability that a person with eGFR less than 30 ml/min/1.73 m2 is correctly categorised as having eGFR less than 30 ml/min/1.73 m2. The specificity of the POC creatinine devices was calculated by combining information on the distribution of population eGFR with the probability of having a classification of eGFR less than 30 ml/min/1.73 m2 for a given true eGFR category (a weighted average).

## Table 5 Diagnostic accuracy data
Test
Input
Source
Lab test
Sensitivity: 100%
Specificity: 100%
Assumption
iSTAT Alinity
Sensitivity: 84.1%
Specificity: 98.9%
Evidence synthesis of point-of-care diagnostic accuracy  main analysis
ABL80 FLEX
Sensitivity: 86.1%
Specificity: 99.2%
StatSensor
Sensitivity: 73.9%
Specificity: 99.1%
Risk factor questionnaire
Sensitivity: 100%
Specificity: 65.2%
Too et al. (2015)
In the base-case analysis, an odds ratio of 0.97 (95% confidence interval  0.52 to 1.9) for the effect of preventative intravenous hydration was used for patients with an eGFR below 30 ml/min/1.73 m2 (Ahmed et al. 2018). It was assumed there would be no effect of intravenous hydration on risk for patients with an eGFR above 30 ml/min/1.73 m2 (AMACING trial). A scenario analysis was done using the lower bound of the odds ratio (0.52), implying a greater protective effect of intravenous hydration compared with the base-case analysis.
A fixed effects meta-analysis of 3 studies (Hinson et al. 2017; Davenport et al. 2013; McDonald et al. 2014) suggested no effect of contrast on PCAKI risk (odds ratio  0.98; 95% CI 0.88 to 1.08). It was therefore assumed in the base case that there was no effect of contrast on the risk of PCAKI. A scenario analysis exploring a greater risk of PCAKI in people with an eGFR of less than 30 ml/min/1.73 m2 was done.
The probability of having AKI after contrast for people with an eGFR of less than 30 ml/min/1.73 m2 or 30 ml/min/1.73 m2 and above depending on whether they had intravenous hydration or not is shown in table 6.

## Table 6 Probability of AKI after contrast
eGFR (ml/min/1.73 m
                  and hydration
Probability of AKI
Source
eGFR below 30 and IV hydration
Park et al. (2016)
eGFR below 30 and no IV hydration
Park et al. (2010), Ahmed et al. (2018)
eGFR 30 and above with IV hydration
Park et al. (2016)
eGFR 30 and above with no IV hydration
Assumption
Abbreviations: AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; IV, intravenous.
After having a CT scan, the probability that people who did not develop AKI after contrast needed renal replacement therapy was 0.014 and for people who did develop AKI after contrast was 0.111.
The model did not consider the effect of a delay in the planned CT scan on patient outcomes because of any change in their underlying condition during the waiting period.
It was assumed that 94.5% of people were alive 6 months after they had the CT scan, based on data reported in Park et al. (2016). The health-related quality-of-life data used in the base case are shown in table 7. No disutility from PCAKI or intravenous hydration was included in the model.

## Table 7 Health-related quality of life
Parameter
Value (QALYs)
Source
HRQoL adjusted life expectancy
Calculated from ONS mortality data and Ara and Brazier, 2010 general population utility equation
QALY loss from RRT
Wyld et al. (2012), and assuming 3 months of RRT
QALY loss from anxiety caused by delays
Assumption
Abbreviations: HRQoL, health-related quality of life; QALY, quality-adjusted life year; ONS, Office for National Statistics; RRT, renal replacement therapy.
Costs were calculated for each POC creatinine test, laboratory test, CT scan, intravenous hydration and for associated adverse events. The costs used in the model are shown in table 8. It was estimated that 92.6 patients per month would have a POC creatinine test. Risk factor screening before a POC creatinine test resulted in an estimated 32.6 patients per month having a POC test.

## Table 8 Costs used in the model
Parameter
Value
Source
Laboratory test
NHS reference costs 2017/18
Risk factor screening
Lederman et al. (2010), NHS reference costs 2017/18
iSTAT Alinity without risk factor screening
Calculated from company data
ABL800 FLEX without risk factor screening
Calculated from company data
StatSensor without risk factor screening
Calculated from company data
iSTAT Alinity with risk factor screening
Calculated from company data
ABL800 FLEX with risk factor screening
Calculated from company data
StatSensor with risk factor screening
Calculated from company data
Contrast-enhanced CT scan
NHS reference costs 2017/18
CT scan cancellation
NHS reference costs 2017/18, assumed to be the cost of an unenhanced CT scan
Intravenous hydration
NHS reference costs 2017/18
Adverse events from intravenous hydration
Nijssen et al. (2017), NHS reference costs 2017/18
Renal medicine follow up if test positive (from last test in sequence)
NHS reference costs 2017/18
Renal replacement therapy
NHS reference costs 2017/18; assuming 3 sessions per week over 3 months

## Base-case assumptions
The following assumptions were applied in the base-case analysis:
The laboratory test would have perfect diagnostic accuracy (100% sensitivity and specificity).
Risk factor screening in the model would be done with a generic risk factor questionnaire.
All patients having a laboratory test would have their CT scan cancelled and rebooked.
A positive test result at the last step of the testing sequence resulted in the scan being cancelled and rebooked with intravenous hydration and contrast-enhanced CT scan.
Adverse events from intravenous hydration were associated with costs but no health-related quality-of-life loss.
Mortality in the model was the same for all patients regardless of PCAKI status.
Mortality was independent of eGFR levels and PCAKI.
Renal replacement therapy consisted of haemodialysis.

## Base-case results
Deterministic and probabilistic results were presented as net monetary benefit and net health benefit using a maximum acceptable incremental cost-effectiveness ratio (ICER) of 20,000 per quality-adjusted life year (QALY) gained. Incremental net benefit was calculated for each strategy compared with laboratory testing. A fully incremental analysis was also done, but because the incremental cost and QALY differences between the strategies were so small, the ICERs are of limited use. This is because they are very sensitive to extremely small differences in the QALYs. If pairwise ICERs had been calculated, all strategies that include POC creatinine devices would cost less and be less effective than the strategy of laboratory testing for all. Full results of the base case are shown in tables 9 and 10. In general:
Strategies that combine risk factor screening with POC creatinine testing and laboratory testing result in higher net benefit than other types of strategies, because they have a high positive predictive value. This avoids unnecessarily offering people who have false positive results intravenous hydration, which is associated with costs including cancelling and rebooking CT scans, giving intravenous hydration, treating intravenous hydration adverse events and patient follow up.
Strategies that combine risk factor screening with POC creatinine testing, without confirmatory laboratory testing, are the next highest ranking. These have lower overall specificity and give more false positive results, which are associated with increased costs from unnecessary management for patients whose results were misclassified as eGFR less than 30 ml/min/1.73 m2 (cancelling and rebooking CT scans, giving intravenous hydration, treating intravenous hydration adverse events and patient follow up).
Strategies with POC creatinine testing that do not use risk factor screening have lower average net benefit than POC creatinine test strategies that do, because of the higher costs of testing when all patients have POC creatinine testing.
The strategies using POC creatinine in isolation are the lowest ranking strategies involving POC creatinine testing, because they misclassify more patients' results as false positives and all patients incur the cost of POC testing.
Laboratory testing alone and risk factor screening then laboratory testing are the lowest ranking strategies. Although they have the highest QALY gains because they give no false positives or false negatives, they are associated with the highest costs, because of cancellation, rebooking and managing treatment for people who test positive.

## Table 9 Base-case probabilistic cost-effectiveness results  net benefit per patient presenting without a recent eGFR

## Table 10 Base-case cost-effectiveness deterministic results  full incremental analysis per patient presenting without a recent eGFR
The strategy with the highest incremental net benefit was strategy 6 (risk factor screening plus iSTAT Alinity plus laboratory testing). In the probabilistic sensitivity analysis, this strategy had the highest probability of being the most cost effective (79.3% for maximum acceptable ICERs of 20,000 and 30,000 per QALY gained). It was also the least costly of all strategies compared, but gave fewer QALYs than most other strategies. The corresponding strategy with StatSensor, strategy 8, only had a marginally smaller average incremental net benefit (87.11 compared with 87.42 for strategy 6). In the probabilistic sensitivity analysis, the probability of this strategy being the most cost effective at maximum acceptable ICERs of 20,000 and 30,000 per QALY gained was 20.7%. Although ABL800 FLEX has the best diagnostic accuracy, strategies including testing with ABL800 FLEX have consistently lower net benefit than corresponding strategies with iSTAT Alinity and StatSensor because of the higher costs of testing with this device.
The fully incremental ICER analysis showed that most strategies were dominated or extendedly dominated by strategy 6. Strategy 5 (risk factor screening plus laboratory testing) had an ICER of 3.61 billion per QALY gained compared with strategy 6.

## Analysis of alternative scenarios
Several scenario analyses were explored; results from most of the analyses were robust to changes in the assumptions. Some analyses caused strategy 8 (risk factor screening plus StatSensor plus laboratory testing) to become more cost effective than strategy 6 (risk factor screening plus iSTAT Alinity plus laboratory testing). This was generally because of changes to the assumptions about the diagnostic accuracy and the costs of the POC creatinine tests. The scenario analysis in which there were no delays to CT scanning from laboratory testing with or without intravenous hydration resulted in strategy 5 (risk factor screening plus laboratory testing) and strategy 1 (laboratory testing) being more cost effective than strategies involving POC creatinine devices.
The base-case analysis was also replicated, adding 2 new strategies:
a 'no testing' strategy when all patients had a contrast-enhanced CT scan without testing for risk of PCAKI
a 'no testing' strategy combined with a greater reduction in risk of PCAKI from intravenous hydration.Both these strategies were associated with higher net benefit than other strategies included in the base-case analysis. That is, the no testing strategies were both less effective and cheaper than all other strategies.
An additional scenario analysis was done to consider the effect on the results if there was a higher risk of PCAKI than in the base case; the risk from contrast agent was increased and the protective effect of intravenous hydration was increased to give an absolute risk difference with and without hydration of 10.3%. The results of this analysis were consistent with the base case.# Committee discussion

# Current practice

## The safety of contrast agents has improved over time, but they may still increase the risk of acute kidney injury in some people
Historically contrast agents were much more toxic than those used in current practice, with side effects including kidney damage. Clinical experts noted that the risk of developing acute kidney injury (AKI) from contrast agents currently used in the NHS is thought to be very low, especially in people with an estimated glomerular filtration rate (eGFR) of 30 ml/min/1.73 m2 and above. However, they noted that there is some concern about the risk of post-contrast AKI (PCAKI) for people with an eGFR of less than 30 ml/min/1.73 m2, especially if they have other risk factors for kidney disease. Although end-stage renal disease after PCAKI is extremely rare, transient rises in creatinine (decreases in eGFR) can have clinical effects and increase mortality, especially if there are repeated rises. Patient experts noted that when a contrast-enhanced CT scan does lead to substantial kidney damage, the effect on a person's quality of life can be considerable. The committee concluded that the risk of PCAKI is very low for most people, but there may be a higher risk if eGFR is less than 30 ml/min/1.73 m2.

## NHS clinical practice varies on whether an eGFR result is needed for everyone having a contrast-enhanced CT scan
NICE's guideline on acute kidney injury recommends that the risk of AKI should be assessed before offering iodinated contrast agents to adults for emergency or nonemergency imaging, and that increased risk is associated with an eGFR less than 40 ml/min/1.73 m2. However, the Royal Australian and New Zealand College of Radiologists iodinated contrast guidelines, which have been endorsed by the Royal College of Radiologists, recommend that an eGFR is only needed before offering iodinated contrast agents if there are risk factors for AKI. The committee noted that these 2 approaches have resulted in variation in clinical practice in the NHS. Some trusts need a recent eGFR result from all patients before doing a contrast-enhanced CT scan. Other trusts will do a contrast-enhanced CT scan without a recent eGFR result if there is a low risk of AKI. The definition of 'recent' may vary between 3 and 12 months in practice.

# Clinical effectiveness

## The diagnostic accuracy of the point-of-care creatinine devices is acceptable, but there is uncertainty, particularly for StatSensor
The evidence showed that the 3 devices with diagnostic accuracy data (ABL800 FLEX, iSTAT Alinity and StatSensor) perform reasonably well in classifying eGFR into the correct categories. The committee noted that measuring creatinine using the point-of-care (POC) creatinine devices is not as accurate as laboratory measurement. Therefore, there would be some false positive results (incorrectly categorised as eGFR below 30 ml/min/1.73 m2; people would have intravenous hydration unnecessarily) and false negative results (incorrectly categorised as an eGFR of 30 ml/min/1.73 m2 and above; people would miss out on intravenous hydration). However, the number of these would be small. A clinical expert explained that the tests are more accurate at high levels of creatinine (low eGFR values), which is when clinical decision making is the most critical. StatSensor appeared to be less accurate than the other 2 devices, but the committee noted that the 95% credible intervals for sensitivity for the different devices overlapped. This means that the sensitivity of StatSensor could be as good as the other devices. The committee acknowledged that the laboratory reference standard used to calculate diagnostic accuracy for the POC creatinine devices was assumed to be 100% accurate, which is probably not the case. It also noted that the studies would have been done under controlled conditions and that the devices may not perform as well in clinical practice. The committee concluded that there was some uncertainty about whether ABL800 FLEX, iSTAT Alinity and StatSensor can correctly categorise eGFR, but in general, the accuracy of the devices was acceptable.

## Further research in people with an eGFR of less than 30 ml/min/1.73 m2 would be helpful
The diagnostic accuracy studies included very few people with an eGFR less than 30 ml/min/1.73 m2. The committee noted that although this could affect the confidence placed on sensitivity calculations, it does reflect clinical practice because most people present for an outpatient CT scan with an eGFR of 30 ml/min/1.73 m2 and above. The committee concluded that further research in a population with eGFR less than 30 ml/min/1.73 m2 would be beneficial (see section 5.1).

## There is no evidence on rates of cancelled CT scans, PCAKI and patient experience
The value of the POC creatinine devices is that they prevent the cancellation and rebooking of CT scans, reduce PCAKI and improve the experience for patients attending for a CT scan by allowing same day assessment and decisions. The committee noted that there was no evidence on these outcomes and encouraged further research incorporating them (see section 5.3).

# Cost effectiveness

## The structure, inputs and assumptions used in the model are appropriate
The model only included people who present for an outpatient CT scan without a recent (within 3 months) eGFR result; it did not assess strategies for increasing the number of people who present for their CT scan with a recent eGFR result. The committee considered that the structure, inputs and assumptions used in the model were appropriate. It noted that the external assessment group (EAG) was unable to include the effect of delaying a planned CT scan on clinical outcomes relating to the underlying condition during a wait for a rescheduled scan. This was because there are many different reasons for having a CT scan and the effect of them all could not be quantified. The committee also noted that costs for training and laboratory governance of the POC creatinine devices were not included. A clinical expert explained that laboratory governance costs can vary considerably between trusts, depending on how much POC testing is already done across the trust and whether IT connectivity is already in place. The EAG estimated that annual implementation and governance costs would have to be over 80,000 to change conclusions from the economic model. Clinical experts agreed that these costs would be much lower than this and therefore concluded that the model analyses were acceptable for decision making.

## The strategy of 'no testing' is not an appropriate comparator for the model
The testing strategy in which people presenting for a CT scan without a recent eGFR had no further testing and had a contrast-enhanced scan without intravenous hydration resulted in the highest net benefit. The committee considered however, that no testing for anybody, regardless of whether risk factors were present, and giving contrast agent to all without intravenous hydration was not an appropriate comparator in the model. This was because it is not in line with national and international guidelines, which recommend assessing the risk of AKI because, although rare, when PCAKI does occur the consequences for an individual are substantial (see section4.1).

## The different testing strategies result in similar QALYs
The differences in quality-adjusted life years (QALYs) between the different testing strategies assessed were extremely small. The strategy in which all people presenting for a CT scan without a recent eGFR would have a laboratory test was associated with more QALYs than the strategies involving a POC creatinine device. The EAG explained that this was because the number of false negative test results (that is, when true eGFR is less than 30 ml/min/1.73 m2 but the test suggests an eGFR of 30 ml/min/1.73 m2 and above) is higher for strategies including POC creatinine devices than for the laboratory test (which is assumed to have 100% sensitivity). However, the QALY gain from appropriately managing treatment for people who have an eGFR of less than 30 ml/min/1.73 m2 is very small. The committee concluded that overall the clinical effectiveness is very similar across the different strategies. But it noted that the effect on quality of life for the small number of people who do develop kidney damage after a contrast-enhanced scan can be considerable (see section 4.1).

## The ABL800 FLEX has a higher cost per test than the iSTAT Alinity and StatSensor
In the model, the POC creatinine devices were assumed to be used only for measuring creatinine and calculating eGFR, but the committee noted that some of the devices have multiple uses. For example, the ABL800 FLEX can measure 18 analytes, but test costs were not apportioned to other uses. Therefore, the cost per test for ABL800 FLEX was higher than for the iSTAT Alinity and StatSensor. This led to strategies including ABL800 FLEX having lower net benefit than strategies involving iSTAT Alinity or StatSensor. The committee noted that, depending on the setting of the radiology department, an ABL800 FLEX could also be used by different departments, which would reduce the cost per test because the throughput would be higher.

## The opportunity cost of cancelling CT scans is a key factor influencing model results
In the model, if a scan was cancelled and rebooked because of a positive POC creatinine test result or the need for a laboratory test, then a cost of 87.92 (equal to the cost of an unenhanced scan) was included. The committee noted that this assumes that the cancelled CT scan appointment cannot be filled. Clinical experts explained that in radiology departments that do both acute (emergency and inpatients) and elective (outpatient) CT scans these cancelled appointments would be filled by other patients waiting for CT scans. However, if the radiology department only does elective CT scans, for example a mobile clinic, then the cancelled appointment is unlikely to be filled and the cost assigned to a cancelled scan is appropriate. The committee also considered that using an unenhanced CT reference cost as a proxy for the rebooked CT scan could overestimate the opportunity cost because the cost of cancellation would already be accounted for in the fully absorbed reference cost. The committee noted that a scenario analysis of the model was run in which no CT scans were cancelled because of a laboratory test. The results of this analysis showed that the strategies of laboratory testing for all or risk factor screening followed by laboratory testing were the most cost effective. However, in the scenario in which 25% of CT scans were cancelled because of a laboratory test, laboratory testing for all returned to being the least cost-effective strategy. The committee acknowledged that cancelled CT scans are not only an opportunity cost for the NHS, but would not be good for patients, who would have to return to the hospital for a rebooked CT scan. The committee concluded that there was uncertainty in the opportunity cost associated with cancelling CT scans and therefore in the optimal strategy.

## Risk factor screening is an appropriate first step for people presenting for a CT scan without a recent eGFR result
Strategies in which risk factor screening was done first followed by a POC creatinine test for people who were identified as having at least one risk factor were more cost effective than strategies in which POC creatinine testing was done for all people presenting for a CT scan without an eGFR. The committee noted that including risk factor screening as a first step reduced the number of POC creatinine tests that would be done, which reduced the overall cost of testing. In the model, risk factor screening was assumed to be done with a generic risk factor questionnaire that had 100% sensitivity and 65.2% specificity. The committee agreed that risk factor screening should identify people at higher risk of AKI. But it noted that defined questionnaires had not been assessed, although risk factors are clearly stated in national and international guidelines. The committee concluded that risk factor screening is likely to be an appropriate first step for people presenting for a CT scan without an eGFR, but that further research should be done to develop a suitable risk tool or validate an existing risk tool for use in the NHS (see section 5.2).

## Test strategies that include laboratory confirmation of a positive result from a POC device would not be good for patients
The strategies with the highest net benefit in the model were those that combined risk factor screening, a POC creatinine test for all people identified as having at least one risk factor, and a final confirmatory laboratory test for people who have a positive test result from a POC device. A confirmatory laboratory test would result in the CT scan being cancelled and rebooked. In practice this often means that the referral for CT would be cancelled, resulting in another referral having to be made for the patient. A patient expert explained that cancelling a CT scan would not be good for patients and their carers because it would take time to go for a blood test, wait for another referral and return to the hospital for the rebooked CT scan. This may also be associated with travel expenses, time off work, and anxiety about the scan and the underlying clinical condition, most of which were not captured in the model. The committee noted that people with a true eGFR of 30 ml/min/1.73 m2 and above who are identified as having an eGFR of less than 30 ml/min/1.73 m2 using a POC creatinine device (false positive) would have intravenous hydration unnecessarily, which is associated with additional cost, but not with a QALY loss. It therefore concluded that although a strategy with a confirmatory laboratory test is slightly cheaper, it should not be considered further because of the negative experience for patients and their carers of cancelling the CT scan, going for a blood test and returning for the rescheduled CT scan.

## POC creatinine devices could have a greater benefit for some people
Men, people over the age of 60, and those of African-Caribbean, African or South Asian family origin are at higher risk of kidney disease than others. The committee noted that people of these family origins are not often included in research studies, but the availability of POC creatinine devices could have a greater benefit for them than for the rest of the population. This is because in some trusts if a person is at low risk of PCAKI, eGFR would not be measured before a contrast-enhanced CT scan (see section 4.2). Men, people over the age of 60, and those of African-Caribbean, African or South Asian family origin thought to be at low risk of PCAKI based on clinical factors may still have a higher risk than other people.

## POC creatinine devices are likely to be a cost-effective use of NHS resources and improve patient experience in some situations
The committee concluded that using POC creatinine devices to guide the use of contrast in outpatient CT scans is likely to be cost effective and improve patient experience if current protocols need all outpatients to have a recent eGFR result before a contrast-enhanced CT scan can be done (see section 4.2). The committee agreed that the most appropriate testing strategy was to use a risk factor screening questionnaire and then a POC creatinine device to test people with one or more risk factors (see section 4.11), without laboratory confirmation of positive test results (eGFR less than 30 ml/min/1.73 m2; see section 4.12). It acknowledged that:
POC creatinine test results should not be used to make decisions about care other than the decision to give contrast agent because of their lower accuracy than laboratory creatinine measurement.
POC creatinine testing should be set up and run as a collaboration between the radiology department and the pathology laboratory.
POC creatinine testing should only be done when clear laboratory governance structures for point-of-care testing are in place.

## Optimal care is for the referrer to provide a recent eGFR measurement and for all patients to receive diagnostic imaging
The committee noted that a risk of PCAKI should not prevent diagnostic images being taken to inform treatment decisions. All patients in whom contrast-enhanced CT imaging is indicated should get a form of imaging that enables access to treatment they might need. The committee acknowledged that POC creatinine devices are less accurate than laboratory creatinine testing. Therefore, patients who arrive at a CT scan appointment with a recent eGFR result are most likely to have appropriate management of their condition. The committee noted that these patients were not included in the economic model, but that a scenario in which all referrers provide an eGFR measurement before a CT scan appointment is likely to be the optimal approach, and that this approach should be encouraged to avoid higher numbers of patients needing POC creatinine measurement before a contrast-enhanced CT scan.# Recommendations for further research
The committee recommended further research on the incidence and effect of post-contrast acute kidney injury (PCAKI) in people with eGFR less than 30 ml/min/1.73 m2.
The committee recommended that a suitable risk factor screening tool for identifying risk of PCAKI for use across the NHS in people presenting for an outpatient CT scan with contrast agent is developed or an existing tool is validated.
The committee recommended studies to collect data on the rates of cancelled CT scans, whether cancelled appointments are filled and the effect on patients' experience before and after the introduction of point-of-care (POC) creatinine devices to radiology departments.