Abstract
Background
Patients with chronic kidney disease (CKD) are at high risk for adverse drug events related to medication dosing errors and prescriptions for relatively contraindicated medications, such as non-steroidal anti-inflammatory drugs (NSAIDs).
Objectives
To examine the scope of and variation in prescribing relatively contraindicated medications and medications above the recommended dose levels among patients with stage III/IV CKD in primary care practice.
Methods
This is a cross-sectional descriptive study that used structured electronic health record data. The study participants were patients aged 18 years and older from three primary care clinics in a practice-based research network. Number/proportion of adult patients with stage III/IV CKD; proportion of these patients with at least one NSAID or other relatively contraindicated medication prescribed over 2 years.
Results
Of the 7586 eligible adult patients, 4.9% had stage III/IV CKD; 46.6% of these 373 patients with stage III/IV CKD were prescribed at least one relatively contraindicated drug (acarbose, chlorpropamide, glyburide, nitrofurantoin or any NSAID) during the 2-year study period; and 34.0% of patients with stage III/IV CKD were prescribed NSAIDs.
Conclusions
Primary care patients with stage III/IV CKD were frequently prescribed or had documented use of relatively contraindicated drugs and thus were at risk of adverse drug events. Given the significant number of individuals with CKD in the USA, research that examines rates of adverse events related to these prescriptions and that tests primary care-based interventions to decrease inappropriate prescribing of relatively contraindicated medications to these patients is needed.
Keywords: Chronic kidney disease, drug prescription, electronic health record data, non-steroidal anti-inflammatory agents, primary health care
Introduction
Numerous medications are relatively contraindicated (to be used with caution) or require dose adjustment in patients with chronic kidney disease (CKD) due to alterations in pharmacokinetic and pharmacodynamic parameters caused by impaired renal function (1,2). Although guidelines and recommendations that include lists of relatively contraindicated medications and those requiring renal dose adjustment (2–4) are widely available, rates of non-compliance with dosing guidelines and use of relatively contraindicated medications are common in patients with CKD and may lead to toxic effects or ineffective pharmacotherapy (1,5–7). In their review, Long et al. found inappropriate medication dosing among patients in inpatient and long-term care facilities with CKD ranging from 17% to 69% of prescriptions (7). A retrospective population-based study of older persons living in Ontario, Canada, found that 66.3% of 1464 antibiotic prescriptions filled from 2003 to 2010 were contraindicated in CKD or dosed in excess of recommendations (8). The incidence of adverse drug events is higher among patients with CKD compared with those without CKD (9,10), and inappropriate medication use in patients with renal insufficiency has been associated with increased mortality (11). Furthermore, older adults are at a greater risk for adverse drug events due to age-related kidney function change. However, few studies have examined the rate of inappropriate dosing in this population (12,13). Although the majority of medications are prescribed in outpatient settings, the overall rate of inappropriate medication use and dosing among patients with CKD in the ambulatory setting is largely unknown (6–8).
Inappropriate non-steroidal anti-inflammatory drug (NSAID) use is of particular concern in CKD. NSAIDs are associated with acute kidney injury and may contribute to further disease progression in patients with CKD (14–16). NSAID use is rising in the USA: an estimated 12.8% of adults in 2010 reported using NSAIDs at least three times weekly for the past 3 months (17). It has been estimated that ~870000 people in the USA with moderate to severe CKD use NSAIDs (18). The reasons for inappropriate medication use in CKD may include patients’ lack of awareness of their CKD diagnosis (19), inadequate documentation of CKD in the medical record (6) and patients’ or providers’ lack of awareness of medications to avoid (6,20).
This study used electronic health record (EHR) data to pragmatically examine the scope of and variation in prescribing relatively contraindicated medications and medications above the recommended dose levels among patients with stage III/IV CKD in primary care practices.
Methods
Study design, setting and population
This cross-sectional, descriptive study was conducted at three geographically diverse primary care clinics in the WWAMI region Practice and Research Network (WPRN), a practice-based research network in the five-state Washington, Wyoming, Alaska, Montana and Idaho (WWAMI) region. The three clinics—one hospital-affiliated, one university-based, and one community health center-based—are Family Medicine teaching practices within differing organizational systems. The clinics participating in this study self-identified as interested in this topic and were able to conduct a simple extraction of data from the EHR. Outpatient visits at the clinics ranged from ~17000 to 26000 per year. The WPRN Coordinating Center, based in the University of Washington’s Institute of Translational Health Sciences and Department of Family Medicine, coordinated the study.
Data sources
Study data came from each site’s EHR for the period from 1 January 2009 to 31 December 2011.
Inclusion and exclusion criteria
Patients included in the study were aged 18 years or older at the start of the study observation period (1 July 2009–30 June 2011); had at least one clinical encounter during the study observation period, the 6 months prior to and the 6 months after the study period; and had stage III/IV CKD. Stage III/IV CKD was defined as a glomerular filtration rate (GFR) listed in the EHR between 15 and 59 ml/minute on two occasions at least 90 days or more apart during the 2-year study period (with all values between the two occasions also within 15–59 ml/minute) (4). Patients with ICD-9 codes for haemodialysis or peritoneal dialysis or related complications (996.1, 996.56, 996.62, 996.68, 996.73, E870.2, E871.2, E872.2, E874.2, E879.1, V56) were excluded from the study sample.
Data extraction and analysis
The aim of the study was to conduct a highly pragmatic, simple data-pull approach across different EHRs to estimate the magnitude of and variation in the prescription of relatively contraindicated medications for patients with stage III/IV CKD. Data were collected in two stages. In Stage I, an individual patient-level dataset from one of the sites was used to inform the development of study data parameters [i.e. to ensure the analytic variables (in particular, the medication-related variables) could be created from the data available in an EHR]. In Stage II, information technology (IT) personnel at the other two sites queried their EHRs to return aggregate data in accordance with these parameters. The WPRN Coordinating Center met with IT staff at each site to review the data parameters and verify that the query was performed as requested. The Coordinating Center compiled data from all three sites.
Study variables
The sites provided aggregate data on the primary outcome measures: the total number of patients with stage III/IV CKD and the proportion of these patients with at least one NSAID or other relatively contraindicated medication (Table 1) with a prescribing date during the study period. Over-the-counter NSAIDs documented as a prescription in the EHR during the study period were included. A secondary outcome is the proportion of patients with stage III/IV CKD who were prescribed at least one medication requiring dose adjustment during the study period. A published list in the family medicine literature identified the medications that were relatively contraindicated or required dose adjustment in CKD (2). The sites also provided the aggregate number of patients with stage III/IV CKD in different sex, age, race and insurance status categories. For the one site with patient-level data, we calculated the proportion of patients with any relatively contraindicated medication by patient characteristics (age, gender, race/ethnicity, insurance status).
Table 1.
List of high-risk medications for patients with stage III/IV chronic kidney disease
| Tier 1: relatively contraindicated: NSAIDs | Tier 2: relatively contraindicated: other | Tier 3: needs dose adjustment |
|---|---|---|
| Diclofenac | Acarbose | Benazepril |
| Diflunisal | Chlorpropamide | Captopril |
| Etodolac | Glyburide | Lisinopril |
| Fenoprofen calcium | Nitrofurantoin | Ramipril |
| Flurbiprofen | Acebutolol | |
| Floctafenine | Atenolol | |
| Ibuprofen | Bisoprolol | |
| Indomethacin | Amiloride | |
| Ketoprofen | Metformin | |
| Ketorolac tromethamine | Fluconazole | |
| Meclofenamate sodium | Imipenem/Cilastatin | |
| Mefenamic acid | Cefixime | |
| Meloxicam | Cefprozil | |
| Nabumetone | Ceftibuten | |
| Naproxen | Ciprofloxacin | |
| Oxaprozin | Ofloxacin | |
| Piroxicam | Allopurinol | |
| Celecoxib | Famotidine | |
| Sulindac | Metoclopram | |
| Tiaprofenic acid | Ranitidine | |
| Tolmetin |
NSAID, non-steroidal anti-inflammatory drug.
For the site with patient-level data, we also hand-calculated each patient’s daily dose of the medications requiring dose adjustment by multiplying the dosage by the number of daily administrations. We identified the maximum recommended daily dose of these medications using three sources (2,21,22) and reconciled differences in dose adjustment recommendations (e.g. differences in GFR thresholds, dose reduction recommended) by using the highest maximum daily dosage recommended for a particular CKD stage III or stage IV GFR range category (details available on request). We then compared the maximum daily dose recommended with the actual daily dose for each prescription and calculated the proportion of patients on a higher than recommended dose at any time during the study period.
Analysis
We present descriptive frequencies of the characteristics of patients with stage III/IV CKD at each participating clinical site, and test for statistically significant differences in patient characteristics across the sites using the chi-square statistic. We used the chi-square statistic to test for differences across the sites in proportion of patients with stage III/IV CKD who were prescribed NSAIDs and/or other relatively contraindicated medications. Finally, for the one site with patient-level data, we tested for differences by patient characteristics in the proportion of patients who were prescribed any relatively contraindicated medication.
Results
Across the three sites, 7586 patients aged 18 years or older had a clinical encounter before, during and after the study observation period. Of these, 373 (4.9%) patients overall had stage III/IV CKD. Roughly, two-thirds of the patients with stage III/IV CKD were 65 years or older, with Site 2 having the youngest patients with CKD (Table 2). The majority of patients with CKD were Caucasian, with Site 2 having the largest proportion of non-Caucasian patients with CKD. The majority of patients with CKD at all sites were publicly insured, with 12.1% insured by Medicaid and 69.7% by Medicare. There were no significant differences in patient sex or types of insurance coverage between the three clinical sites.
Table 2.
Demographic characteristics of patients identified with stage III/IV chronic kidney disease during the study period (1 July 2009–30 June 2011), overall and by clinical site
| Total (%), n = 373 | Clinical Site 1 (%), n = 172 | Clinical Site 2 (%), n = 103 | Clinical Site 3 (%), n = 98 | |
|---|---|---|---|---|
| Age*** | ||||
| 18–49 | 8.8 | 4.1 | 23.3 | 2.0 |
| 50–64 | 24.9 | 22.7 | 30.1 | 23.5 |
| 65–74 | 26.3 | 22.1 | 26.2 | 33.7 |
| 75+ | 39.9 | 51.2 | 20.4 | 40.8 |
| Sex | ||||
| Male | 37.5 | 43.6 | 30.1 | 34.7 |
| Female | 62.5 | 56.4 | 69.9 | 65.3 |
| Race/ethnicitya,*** | ||||
| Caucasian | 79.1 | 79.1 | 68.9 | 89.8 |
| Black or African American | 6.4 | 2.9 | 16.5 | 2.0 |
| Asian/Pacific Islander | 6.7 | 10.5 | 6.8 | 0 |
| Hispanic/Latino | 2.7 | 4.1 | 2.9 | 0 |
| Other or unknown | 5.1 | 3.5 | 4.9 | 8.2 |
| Insurance | ||||
| Medicaid | 12.1 | 8.7 | 24.3 | 5.1 |
| Medicare | 69.7 | 72.1 | 64.1 | 71.4 |
| Private | 16.4 | 18.0 | 8.7 | 24.4 |
| Self/uninsured | 1.3 | 0 | 2.9 | 2.0 |
| Other or unknown | 0.5 | 1.2 | 0 | 0 |
aBecause of empty cells, we tested Caucasian versus non-Caucasian, P ≤ 0.001.
***P ≤ 0.001.
Overall, 46.6% of patients had a prescription in the EHR for any relatively contraindicated drug (acarbose, chlorpropamide, glyburide, nitrofurantoin or any NSAID) during the observation period (Table 3). About a third of the patients (34.0%) had a prescription for NSAIDs; this ranged from 21.5% to 53.1% in the individual clinics (overall chi-square P < 0.001). The use of NSAIDs was highest at Site 3; the use of other relatively contraindicated drugs was highest at Site 2. Ibuprofen, naproxen and diclofenac were the most commonly used NSAIDs. At the one site with patient-level data, there were no statistically significant differences by patient age, gender, race/ethnicity or insurance type in the proportion of patients who were prescribed any relatively contraindicated drugs (Table 4).
Table 3.
Proportion of patients with stage III/IV chronic kidney disease who were prescribed non-steroidal anti-inflammatory drugs and other relatively contraindicated medications during the study period (1 July 2009–30 June 2011), overall and by clinical site
| Total (%), n = 373 | Clinical Site 1 (%), n = 172 | Clinical Site 2 (%), n = 103 | Clinical Site 3 (%), n = 98 | |
|---|---|---|---|---|
| NSAIDs*** | 34.0 | 21.5 | 36.9 | 53.1 |
| Other relatively contraindicated medicationa,*** | 17.7 | 14.0 | 30.1 | 11.2 |
| Any relatively contraindicated medications (NSAIDs + others)*** | 46.6 | 33.1 | 57.3 | 59.2 |
NSAID, non-steroidal anti-inflammatory drug.
aOther relatively contraindicated medications: acarbose, chlorpropamide, glyburide and nitrofurantoin.
***P ≤ 0.001.
Table 4.
Proportion of patients with stage III/IV chronic kidney disease at Clinical Site 1 who were prescribed any relatively contraindicated medications during the study period (1 July 2009–30 June 2011), by patient characteristics. Any relatively contraindicated medications: non-steroidal anti-inflammatorydrug, acarbose, chlorpropamide, glyburide and nitrofurantoin
| Gender | |
| Female (n = 97) | 34.0% |
| Male (n = 75) | 32.0% |
| Age | |
| 18–49 (n = 7) | 42.9% |
| 50–64 (n = 39) | 35.9% |
| 65–74 (n = 38) | 29.0% |
| 75+ (n = 88) | 33.0% |
| Race/ethnicity | |
| Caucasian (n = 136) | 32.4% |
| Non-Caucasian (n = 36) | 36.1% |
| Insurance status | |
| Medicaid, self-insured, uninsured (n = 15) | 33.3% |
| Privately insured, Medicare, other insurance (n = 157) | 33.1% |
There are no statistically significant differences in rates of prescription of any relatively contraindicated medications by patient characteristic.
Over three-quarters (76.1%) of eligible CKD III/IV patients were taking medications requiring renal dose adjustment (data not shown). At the one site with individual patient-level data, we found that 29.0% of patients taking medications requiring dose adjustment were prescribed amounts above the recommended doses; 97% of these patients were on metformin. Prescribed metformin doses ranged from 1250 to 2000 mg daily (56.7% of the higher doses were at 2000 mg daily), while the maximum recommended dosing based on clinical references at that time was 1225 and 637.5 mg daily for CKD III and IV patients, respectively (2,21,22).
Discussion
This study demonstrates that in three primary care practices with ~5% of active adult patients having laboratory test values consistent with CKD III/IV, there is a high frequency of relatively contraindicated drugs prescribed or documented in the EHR for these patients. In the one practice with patient-level data, this finding did not vary by patient characteristics. NSAIDs appear to pose a particular problem, with one clinic reporting over half of their stage III/IV CKD patients having documented evidence of NSAID use. This finding likely represents the tip of the iceberg, as NSAID use is underreported in the EHR. Most patients are taking NSAIDs that are available over the counter (18), and many may not report it to their physician. In contrast to an analysis of decade-old National Health and Nutrition Examination Survey (NHANES, 1999–2004) data showing that 5.0% of stage III/IV CKD patients report current use (nearly every day for 30 days or longer) of any over the counter or prescribed NSAID (18), our study showed a far higher frequency (34%) of documented NSAID use in patients with CKD. Some of this mismatch may be explained by our study’s inclusion of NSAID use at any frequency and duration in the observation year rather than current regular use, and the fact that our study includes only individuals using the health care system, whereas the NHANES-based study includes users and non-users of the health care system. Individuals using the health care system may have additional health conditions that increase their likelihood of using medications like NSAIDs. However, our study also probably underestimated the use of NSAIDs because we captured only EHR-documented prescriptions. Given the increasing regular use of NSAIDs in the US population overall (17), our study highlights a potentially larger problem than previously reported (15) and may reflect variation in regional prescribing practices. There are many medications for which dose adjustment is recommended if a patient has CKD. However, given the lack of direct evidence and the variability in dose adjustment guidance for ambulatory medications (23,24), the clinical meaningfulness of such adjustments remains unclear. Therefore, the 29% of patients with stage III/IV CKD who were prescribed drugs above the recommended dose at the one study clinic for which we had these detailed data may or may not represent a clinically significant finding. In our study, the drug most frequently prescribed above the maximum daily dose at the time of this study was metformin (30 of 31 individuals taking a medication over the recommended daily dose). Prescription of metformin among patients with stage III/IV CKD has been documented in the literature (25–27); this study contributes population-based data from a primary care practice on the proportion of patients with CKD who were prescribed higher than recommended doses.
We were surprised that the clinic with the largest Medicaid population did not have the highest NSAID rate, as Medicaid often provides coverage for prescription NSAIDs and applies some restrictions on opioid prescriptions (28,29). Factors such as incomplete patient reporting of medications and incomplete medication documentation might have contributed to this finding, and/or providers in that clinic might have been prescribing opioid medications within the limits of the Medicaid restrictions.
This study aimed to estimate the scope of the problem in prescribing relatively contraindicated medications and medications above the recommended dose levels for patients with stage III/IV CKD in primary care. We have corroborated the high rate of relatively contraindicated medications and inappropriate medication dosing found in other studies, including a systematic review that reported rates from 13% to 80% internationally (30), indicating the need for interventions to improve safe medication prescribing in patients with CKD in primary care settings. Tesfave’s systematic review demonstrates that there is remarkably scant information on NSAID prescribing among patients with CKD in US outpatient settings (30). The fact that this study took place in teaching practices highlights the need to expand curricula to include more emphasis on safe prescribing.
Limitations to this study include its conduct in only three primary care sites with small numbers, potentially limiting generalizability. Second, it is likely that the EHR underreports the use of over-the-counter NSAIDs. In addition, the EHR does not differentiate those NSAID medications prescribed by providers in the clinic versus those over-the-counter NSAIDs that providers entered into the EHR. Nonetheless, NSAIDs were documented in the EHR because either the medication was prescribed or the patient reported taking it; primary care physicians are responsible for verifying medication lists and advising appropriate changes during office visits. Also, this study did not measure whether patients were taking NSAIDs intermittently or chronically. Some recommendations suggest that harms of NSAID use are correlated with dose and duration of NSAID therapy (4,31). Because both relatively contraindicated medication use and the definition of CKD were measured at any time in the 2-year study period, it is possible that the use of relatively contraindicated medications could have taken place before the CKD diagnosis. We conducted additional analyses using the patient-level data available from one study site to identify that 84.2% of individuals with CKD had a prescription for a relatively contraindicated medication documented on or after the finding of an elevated GFR. This finding supports our conclusion that there is a high frequency of relatively contraindicated drugs prescribed or documented in the EHR for patients with CKD. Finally, this research used a list of medications that were relatively contraindicated at the time of the study. Since that time, the Federal Drug Administration has revised its recommendations regarding the use of metformin-containing drugs among patients with mild-to-moderate renal impairment, liberalizing their use if the patient’s GFR is over 45 ml/minute (32).
Our study supports the need for future research in several areas, such as identifying the rate of adverse events among patients who were prescribed relatively contraindicated medications and establishing evidence-based practices to promote safe prescribing in patients with CKD. Additional research in this area of safe prescribing, particularly research implementing safe prescribing guidance into EHR systems, is particularly timely given the substantial number of individuals with CKD (33).
Acknowledgement
The authors thank Ching-Ping Lin, PhD for her assistance with defining the data extract.
Declaration
Funding: This project was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000423. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Ethical approval: This study received approval from the University of Washington Human Subjects Division.
Conflicts of interest: The authors have no conflicts of interest or financial disclosures to report.
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