Improving NSAIDs Prescription in Emergency Services Unit by a Point-of-Care–Based Renal Function Evaluation

The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–6, 2019 Ó 2019 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter

https://doi.org/10.1016/j.jemermed.2019.10.036

Clinical Laboratory in Emergency Medicine

IMPROVING NSAIDS PRESCRIPTION IN EMERGENCY SERVICES UNIT BY A POINT-OF-CARE–BASED RENAL FUNCTION EVALUATION Laurent Blairon, MD,* Musa Abbasi, MD,† Ingrid Beukinga, MD,* Christian Melot, MD, PHD,‡ and Mark Libertalis, MD* *Department of Laboratory Medicine, Iris Hospitals South, Brussels, Belgium, †Department of Emergency and Intensive Care Medicine, Iris Hospitals South, Brussels, Belgium, and ‡Department of Emergency Medicine, Erasme Academic Hospital, Brussels, Belgium Reprint Address: Laurent Blairon, MD, Department of Laboratory Medicine, Iris Hospitals South, Site Etterbeek-Ixelles, Laboratoire, Route 91, 63 rue Jean Paquot, Brussels B-1150, Belgium

, Abstract—Background: Patients evaluated in our emergency department (ED) often receive nonsteroidal antiinflammatory drugs (NSAIDs) without any determination of their renal function, despite the known nephrotoxicity of NSAIDs. Guidelines recommend NSAID avoidance in patients with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, and long-lasting therapy is not recommended in people with chronic kidney disease. Objective: We aimed to highlight the influence of a rapid measurement of the eGFR on NSAID prescriptions in patients at risk of impaired renal function using a point-ofcare (POC) device. Our goal was to prevent the potential nephrotoxicity of NSAIDs by allowing the physicians to modify their treatments after eGFR determination, while avoiding a standard blood test for patients that would extend the duration of stay in the ED. Methods: We included 192 patients evaluated in the ED for minor trauma or injury, with an indication of treatment with NSAIDs and no known contraindication to NSAIDs. Emergency physicians were asked to register their intention to actually prescribe NSAIDs based on their clinical gestalt with specific regard to kidney function. Immediately after, the creatinine level was measured in capillary blood and eGFR was calculated

using the POC device (StatSensor Creatinine; Nova Biomedical, Waltham, MA). Our physicians avoided NSAID prescriptions when eGFR was < 30 mL/min/1.73 m2, and prescribed a shorter NSAID regimen therapy in patient with eGFR < 45 mL/min/1.73 m2, with a reminder to assure hydration. The decision based on eGFR was compared with original clinician intention. Results: The clinicians intended to treat 164 patients with NSAIDs (group 1) and defer NSAIDs in 28 patients (group 2). In the first group, eGFR results supported no change in intended NSAID use in 144 patients, highlighted the need for a short regimen in 17 patients, and indicated contraindication to NSAIDs in 3 patients. In group 2, eGFR determination allowed prescription of NSAIDs in 21 patients, allowed utilization of NSAIDs with a short course in 5 patients, and supported the clinician decision to avoid NSAIDs in 2 patients. Conclusions: POC measurement of creatinine with eGFR estimation changed the prescription of NSAIDs in almost 25% of patients with previously unknown renal function. Ó 2019 Elsevier Inc. All rights reserved. , Keywords—estimated glomerular filtration rate; creatinine; nonsteroidal anti-inflammatory drugs; chronic kidney disease; emergency department; point-of-care testing

Nova Biomedical kindly provided material and reagents free of charge and did not play a role in the study design and collection, analysis, and interpretation of data. Musa Abbasi received a travel grant from Nova Biomedical for presenting the study outcome at EMS 2018.

INTRODUCTION Chronic kidney disease (CKD) is a major health problem with an increasing incidence and prevalence, particularly

RECEIVED: 15 June 2019; FINAL SUBMISSION RECEIVED: 9 October 2019; ACCEPTED: 27 October 2019 1

2

L. Blairon et al.

in elderly patients (1–4). Hypertension and diabetes are the leading causes of CKD (1). Elderly patients often require emergency care and are often prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management (5–7). These drugs are known to be nephrotoxic, among other toxicities. In individuals with underlying kidney impairment, they can have both acute and chronic effects on kidney function (8,9). Previous studies have reported that NSAIDs are associated with a decrease in kidney function (10–12). Managing patients with trauma and other painful emergent clinical conditions is routine in an emergency department (ED) and NSAIDs are often prescribed in such circumstances. At our institution, emergency physicians usually prescribe them for 7–10 days. Many patients evaluated in the ED do not have a recent kidney function test in their medical records, and the time required for obtaining the results of a standard blood test can be long. Based on monthly analysis of median turnaround time, obtaining creatinine/ estimated glomerular filtration rate (eGFR) values from our central laboratory can take up to 60 min, including the administrative processing steps and the transport of the samples. Therefore, patients in the ED often received NSAIDs without any determination of their renal function. We designed a study testing the influence of an eGFRmeasuring point-of-care (POC) device on prescription of NSAIDs for patients at risk of kidney disease and present-

a

eGFR ¼ 141  minðScr=k; 1Þ  maxðScr=k; 1Þ

1:209

ing to the ED, in order to avoid nephrotoxicity. To the best of our knowledge, this issue not been addressed in the literature. MATERIALS AND METHODS This prospective, nonrandomized study was conducted over a 1-year period between March 8, 2017 and March 12, 2018 at a single 550-bed hospital site. Inclusion criteria for patients were emergency admission for minor traumas or injuries, age over 70 years or over 50 years for patients with diabetes or hypertension, presenting during working hours and only on weekdays. The study protocol was established in a collaboration between emergency physicians and nephrologists and was approved by the Ethics Committee of our institution. Only patients who signed an informed consent were included in the study. Were excluded patients with no plan to prescribe pain control with NSAIDs, or with a known contraindication to NSAIDs (e.g., allergy, history

of gastric ulcer or bleeding, or history of chronic kidney disease). Physicians were requested to complete a form regarding their intention to actually prescribe the indicated NSAID to the patient based on their clinical gestalt with specific regard to kidney function before performing the creatinine POC measurement and the eGFR calculation. Once the test was done, the physician immediately had the result to adjust the treatment as required by the protocol. International guidelines recommend NSAID avoidance in patients with eGFR < 30 mL/ min/1.73 m2 and prolonged therapy is not recommended in people with eGFR < 60 mL/min/1.73 m2 (13). Therefore, in our protocol based solely on creatinine measurement, our physicians agreed to avoid NSAID prescription when eGFR was < 30 mL/min/1.73 m2, and to prescribe a shorter NSAID regimen therapy in patient with eGFR < 45 mL/min/1.73 m2 associated with a reminder to assure hydration, thereby raising awareness about potential nephrotoxicity. The study form included a reminder of the instructions to follow regarding the eGFR results. The calculation of eGFR was performed using the CKDEPI (Chronic Kidney Disease Epidemiology Collaboration) formula using a StatSensor Creatinine portable device (Nova Biomedical, Waltham, MA) validated in our laboratory previously. The CKD-EPI formula is:

 0:993Age  1:018½if female  1:159 ½if black;

where Scr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, a is –0.329 for females and –0.411 for males, min is the minimum of Scr/k or 1, and max is the maximum of Scr/k or 1 (14). The creatinine level is measured in 30 s by using a drop of finger-drawn whole blood on a test strip. Statistical analysis was performed using MedCalc, version 10.4.0.0 (MedCalc software, Ostend, Belgium). The normality of the continuous variables was checked using the c2 test. Age, creatinine, and eGFR variables were not normal and were expressed as median with 95% confidence interval (CI). StatSensor computes eGFR up to 90 mL/min/ 1.73 m2. Values above this limit were manually calculated. The linear regression with the coefficient of correlation r was calculated when indicated. A weighted k-statistics with 95% CI was used to assess concordance of NSAID prescription between POC measurement and attending physician’s clinical intention to treat.

Rapid eGFR Measurement and NSAID Prescription

RESULTS We obtained written informed consent from 212 patients who presented for minor traumatic injuries. Etiologies, based on the final diagnosis written in the chart, were fracture (n = 72), contusion (n = 62), osteoarthritis (n = 18), low back pain (n = 16), tendinopathy (n = 15), sprain (n = 11), wound (n = 8), dislocation (n = 2), and others (n = 8). The flow chart is shown in Figure 1. Twenty patients were excluded from the study either for no plan of treatment with NSAIDs or for known contraindication to NSAIDs. In the remaining 192 patients, the median age was 77 years (95% CI 73–80 years; range 51–99 years); 76% were 65 years or older. The male to female ratio was 1:2. Median creatinine level was 0.90 mg/dL (95% CI 0.90–0.98 mg/dL; range 0.40–2.07 mg/dL). Median eGFR was 69 mL/min/1.73 m2 (95% CI 65– 73 mL/min/1.73 m2; range 27 to 138 mL/min/ 1.73 m2). The clinicians had the intention to treat 164 patients with NSAIDs prior to POC creatinine measurement. Linear regression gave eGFR = 104–0.41 age (r2 = 0.311; p < 0.001), indicating that 31% of the renal function (eGFR) is explained by age (13). Patients aged 65 years or younger had no alteration of renal function. Five patients older than 65 years had eGFR < 30 mL/min/1.73 m2, indicating that

3

NSAIDs are contraindicated, and 22 patients had eGFR between 30 and 45 mL/min/1.73 m2, requiring adjustment of the regimen prescription for NSAIDs. Clinicians intended to refrain from prescribing NSAIDs because of kidney dysfunction in 28 patients (14.6%) based on their clinical gestalt. The reasons provided for this decision were reported as follow: advanced age or comorbidities (n = 9), polypharmacy or risk of drug interaction (n = 8), suspected CKD at the anamnesis (n = 6), and history of long-term NSAID use (n = 1). Reason was not specified in 4 cases. Of these 28 patients, only 2 had an eGFR < 30 mL/min/ 1.73 m2, confirming the clinical decision to refrain from prescribing NSAID therapy. Five patients met criteria for NSAID utilization with a shorter time course due to eGFR between 30 and 45 mL/min/ 1.73 m2, and 21 patients had no nephrologic contraindications for usual NSAID prescription, with an eGFR > 45 mL/min/1.73 m2. The intention to treat was positive in 164 cases (85.4%), with normal eGFR in 144 patients. The treatment regimen with NSAIDs had to be adjusted in 17 patients and was contraindicated in 3 (Figure 1). The weighted k = 0.110 (95% CI –0.027 to 0.248) indicates no agreement between the POC measurement and the intention of the physician for an indication of treatment with NSAID. Patients meeting inclusion criteria with informed consent N=212

Patients included N=192

No indication of NSAIDs N=14

Intention to treat = YES N=164

eGFR>45 N=144

eGFR 30-45 N=17

Contraindications to NSAIDs N=6

Intention to treat = NO N=28

eGFR<30 N=3

eGFR>45 N=21

eGFR 30-45 N=5

eGFR<30 N=2

Impact of StatSensor Creatinine on clinical decision N=46

Figure 1. Flow chart (eGFR: estimated glomerular filtration rate; NSAID’s: non-steroidal anti-inflammatory drugs).

4

L. Blairon et al.

DISCUSSION The vast majority of patients at risk for renal disease and treated in our ED for minor trauma, injuries, osteoarthritis, and low back pain are prescribed NSAIDs. However, kidney function is information usually unavailable to the physician in this particular setting. Our study aimed to evaluate how rapid determination of kidney function would influence the physician’s decision to prescribe or refrain from prescribing NSAIDs. By comparing the intention to prescribe NSAIDs with the actual measured renal function, we found that clinical gestalt can be misleading. Indeed, rapid creatinine measurement and eGFR determination by the use of a POC device in the ED provided information that recommended against the clinical decision in 46 patients (46 of 192 [24%]), either by allowing local usual NSAID prescription (n = 21), by shortening the NSAID regimen with awareness about potential nephrotoxicity (n = 22), or by impeding NSAID treatment in 3 patients. The use of a POC device to obtain rapid determination of the kidney function provides an opportunity to standardize patient care without affecting the throughput of the ED, by offering the benefit of avoiding the typical waiting time for the standard renal function determination, which is inappropriate in this setting. Limitations In some published studies, it has been reported that StatSensor Creatinine under- or overestimated creatinine/ eGFR compared to the routine analyzer method used that may be related to method standardization (15–18). In other studies, the analytical performance of this device has previously been shown to be comparable to laboratory methods (19–21). The POC instrument is easy to use and does not require any special training, but is more expensive than a creatinine dosage in routine chemistry. Inclusions criteria therefore focused on patients at risk of CKD, and only during working hours and on weekdays to ensure proper adherence by clinicians. Finally, this single-center study is limited to a single side effect of NSAIDs—nephrotoxicity—but it has shown how difficult it can be to evaluate clinically.

CONCLUSIONS Our results show that almost 25% of patients would benefit from a change in NSAID prescription if an objective determination of their kidney function was made available. In the ED setting, where these medications are commonly considered, this information must be given

specific attention, especially in elderly, hypertensive, or diabetic patients. This suggests a potential interest for generalized POC eGFR determination in EDs in order to allow more accurate NSAID regimens in an appropriately targeted population. Multicentric trials should help better define that population. Specific attention must be given to cost-effectiveness, taking into account both the higher price of POC testing and the burden of kidney injury attributable to NSAIDs. Acknowledgments—We would like to thank Dr. Mehdi Aarab, Dr. Sophie Collignon, Dr. Fadi Daud, Dr. Louise Delhaye, Dr. Marc Hildebrand, Dr. Dejan Izgarevic, Dr. Thierry Kamba, Dr. Pierre Lutula, Dr. Bogdan Nedelea, Dr. Christel Van Lier, and all the nurses from the Ixelles emergency department who participated in the study. We would also like to pay tribute to Dr. Didier Chochrad, head of the Emergency Department who brutally disappeared before publication of this article.

REFERENCES 1. Mills KT, Xu Y, Zhang W, et al. A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010. Kidney Int 2015;88:950–7. 2. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013; 20(382):260–72. 3. Nixon AC, Bampouras TM, Pendleton N, et al. Frailty and chronic kidney disease: current evidence and continuing uncertainties. Clin Kidney J 2018;11:236–45. 4. Arora P, Jalal K, Gupta A, et al. Progression of kidney disease in elderly stage 3 and 4 chronic kidney disease patients. Int Urol Nephrol 2017;49:1033–40. 5. Gnjidic D, Blyth FM, Le Couteur DG, et al. Nonsteroidal antiinflammatory drugs (NSAIDs) in older people: prescribing patterns according to pain prevalence and adherence to clinical guidelines. Pain 2014;155:1814–20. 6. Davis JS, Lee HY, Kim J, et al. Use of non-steroidal anti-inflammatory drugs in US adults: changes over time and by demographic. Open Heart 2017;4:e000550. 7. Caramona MM, Santos AT, Santiago LM, et al. The role of the pharmacist in a primary health care unit: the use of NSAIDs in elderly patients. Int J Clin Pharm 2013;35(suppl 2):895–6. 8. Griffin MR, Yared A, Ray WA. Nonsteroidal anti-inflammatory drugs and acute renal failure in elderly persons. Am J Epidemiol 2000;151:488–96. 9. Dixit M, Doan T, Kirschner R, et al. significant acute kidney injury due to non-steroidal antiinflammatory drugs inpatient setting. Pharmaceuticals 2010;3:1279–85. 10. Curhan GC, Knight EL, Rosner B, et al. Lifetime nonnarcotic analgesic use and decline in renal function in women. Arch Intern Med 2004;164:1519–24. 11. Rexrode KM, Buring JE, Glynn RJ, et al. Analgesic use and renal function in men. JAMA 2001;286:315–21. 12. Wei L, MacDonald TM, Jennings C, et al. Estimated GFR reporting is associated with decreased nonsteroidal anti-inflammatory drug prescribing and increased renal function. Kidney Int 2013;84: 174–8. 13. KDIGO CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 2013;3:19–62. 14. Levey AS, Stevens LA, Schmid CH, et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation

Rapid eGFR Measurement and NSAID Prescription to estimate glomerular filtration rate. Ann Intern Med 2009;150: 604–12. 15. Houben IPL, van Berlo CJLY, Bekers O, et al. Assessing the risk of contrast-induced nephropathy using a finger stick analysis in recalls from breast screening: the CINFIBS Explorative Study. Contrast Media Mol Imaging 2017;2017:5670384. 16. Korpi-Steiner NL, Williamson EE, Karon BS. Comparison of three whole blood creatinine methods for estimation of glomerular filtration rate before radiographic contrast administration. Am J Clin Pathol 2009;132:920–6. 17. Shephard M, Peake M, Corso O, et al. Assessment of the Nova StatSensor whole blood point-of-care creatinine analyzer for the measurement of kidney function in screening for chronic kidney disease. Clin Chem Lab Med 2010;48:1113–9.

5 18. Straseski JA, Lyon ME, Clarke W, et al. Investigating interferences of a whole-blood point-of-care creatinine analyzer: comparison to plasma enzymatic and definitive creatinine methods in an acutecare setting. Clin Chem 2011;57:1566–73. 19. Schnabl KL, Bagherpoor S, Diker P, et al. Evaluation of the analytical performance of the Nova StatSensor creatinine meter and reagent strip technology for whole blood testing. Clin Biochem 2010;43:1026–9. 20. Kosack CS, de Kieviet W, Bayrak K, et al. Evaluation of the Nova StatSensorÒ XpressÔ creatinine point-of-care handheld analyzer. PLoS One 2015;10:e0122433. 21. Srihong C, Pangsapa K, Chuaboonmee K, et al. Evaluation of the analytical performance of the nova StatSensor creatinine meter for blood testing. J Med Assoc Thai 2012;95:1225–31.

6

L. Blairon et al.

ARTICLE SUMMARY 1. Why is this topic important? Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is widespread; these drugs are often prescribed in the emergency setting. Nephrotoxicity of NSAIDs is well known, however, studies have shown that NSAIDs are often prescribed to patients with chronic kidney disease. With the ongoing opioid crisis, use of nonopioid medications, such as NSAIDs, will be emphasized. 2. What does this study attempt to show? Our goal was to prevent the potential nephrotoxicity of NSAIDs by allowing the emergency physician to modify their treatment prescriptions after estimated glomerular filtration rate (eGFR) determination, while avoiding a blood test in patients that would extend the duration of their stay in the emergency department. 3. What are the key findings? Our study found that information concerning renal function using a point-of-care device can change prescription of NSAIDs in almost 25% of patients. In this specific population of elderly, hypertensive, or diabetic patients, special care is required. 4. How is patient care impacted? Pain management is influenced by eGFR determination in patients presenting to the emergency setting for trauma, both in prescribing NSAIDs to patients who were clinically assessed as ‘‘at risk’’ of NSAID acute kidney injury, and in withholding NSAIDs in those assessed as ‘‘not at risk.’’