Potentially inappropriate medications prescribing to elderly patients with advanced chronic kidney by using 2019 American Geriatrics Society Beers Criteria

Abstract Background and aims A potentially inappropriate medication (PIM) is defined as a drug‐carrying risks outweighing the expected clinical benefits. Elderly patients with chronic kidney disease (CKD) are particularly at higher risk of drug‐related toxicities. In Lebanon, no studies have been conducted regarding the prescribing of PIMs in hospitalized CKD patients. This study aimed to check the prevalence of PIMs using the American Geriatrics Society (AGS) Beers criteria in elderly patients with advanced CKD stages including dialysis and to identify possible risk factors that may be associated with prescribing PIMs in this population. Methods A retrospective cross‐sectional study was conducted on patients with advanced CKD above the age of 65 years and admitted between January 2019 and June 2019 to two University Hospitals in Beirut, Lebanon. We used multiple logistic regression analysis to determine which factors were associated with prescription of PIMs according to AGS Beers criteria‐2019. Results The study sample included 199 patients with renal dysfunction, 75.9% were aged 70 years or more, 53.8% were females, and 61.8% were prescribed five drugs or more. Eighty‐two patients were receiving hemodialysis (41.2%). PIMs prevalence was 34.1% (68/199 patients) according to Beers criteria in elderly patients with advanced CKD stages. The most frequently prescribed PIMs were ranitidine (39.1%), enoxaparin (25%), tramadol (9.8%), and ciprofloxacin (5.4%). Polypharmacy (OR 2.1, CI 95% 1.58‐2.79), a higher number of comorbidities (OR 3.01, CI 95% 1.43‐6.30), and coronary artery diseases (OR 3.14 CI 95% 1.44‐6.85) were the factors associated with an increased risk of at least one PIM prescription. Conclusion Our study found that one out of three patients with advanced CKD had at least one PIM according to the latest Beers criteria. A large proportion of inappropriate prescribing is preventable by increasing awareness of prescribing physicians to the explicit lists of PIMs.


| INTRODUCTION
Chronic kidney disease (CKD) is a substantial public health problem with a global prevalence of 9.1%. 1 It is increasingly recognized as a crucial comorbid condition in elderly individuals aged >65 years. 2 Older adults with renal impairment are at high risk of drug-related problems due to their multiple comorbidities, polypharmacy, and the alterations in pharmacokinetics and pharmacodynamics of kidney excreted drugs due to reduced filtration rate, renal metabolism, or impaired tubular function. 3 The burden of polypharmacy, typically defined as using five or more medications per day, is high in this population. In CKD stages 2 to 5, patients have been prescribed a median of eight different medications and increases to 10 to 12 medications in dialysis patients. 4,5 Polypharmacy increases the risk of prescribing potentially inappropriate medications (PIMs), consequently increasing adverse effects. 6 PIMs are usually defined as "medications that should be avoided due to their risk which outweighs their benefit and when there are equally or more effective but lower risk alternatives are available." 7 Lately, various tools have been created to evaluate the appropriateness of medication use in the elderly. 8 The Beers Criteria are among the most widely used, it was first published almost 30 years ago, making them longtime used criteria by health care providers. This tool is primarily intended for practicing clinicians to manage and improve prescribing practices in older adults. 9 Optimal application of the Beers Criteria involves recognizing PIMs and offering safer alternatives where applicable. Clinicians can use this list when reviewing medications for a new patient or prescribing new medications regardless of whether they are hospitalized, institutionalized, or ambulatory. 9 There are two version of the American Geriatrics Society (AGS) Beers criteria focused on kidney function (2015 and 2019), 10,11 the most recent update was released in 2019 and contains an updated list of 23 medications that should be avoided or have their dosage reduced based on kidney function. 11 Two antibiotics have been added, ciprofloxacin and TMP-SMX. Dofetilide was also added and the creatinine clearance lower limit at which to avoid edoxaban has been reduced to less than 15 mL/min. 11 PIMs prescribing is considered one of the commonly experienced drug-related issues and its current rates in elderly CKD patients is alarming. A study of elderly hospitalized CKD patients found that 48% of patients were prescribed at least one PIM. [8][9][10][11][12] So far, the estimated prevalence of PIMs varied from 36% to 56% in patients with eGFR <30 mL/ min/1.73m 2 using Beers Criteria. 13,14 Moreover, in elderly dialysis patients, the reported prevalence of PIMs ranged from 43% to 57%. 15,16 Polypharmacy and the presence of comorbid conditions were the biggest factors associated with increased risk of prescribing PIM among elderly patients. 17 Several studies have shown that PIMs affect patients' morbidity, emergency department visits, hospitalization, mortality rates, and the adverse effects of PIMs add significantly to healthcare utilization and cost. [18][19][20] There is evidence that adverse drug reactions could be prevented by avoiding prescribing errors, 21 therefore, early detection of PIM may improve the quality of treatment.
In Lebanon, no studies have been conducted regarding PIMs prescription in hospitalized CKD patients. The study aimed to check the prevalence of PIMs using the AGS Beers criteria in elderly patients with advanced CKD stages including dialysis and to identify possible risk factors that may be associated with prescribing PIMs in this population.

| Study design, setting, and participants
This retrospective cross-sectional study was conducted between January 2019 and June 2019 at two university hospitals in Beirut, Lebanon. The study inclusion criteria were as follows: all elderly patients aged ≥65 years admitted to the hospital for ≥ one night, received at least one medication, and diagnosed with advanced CKD stages G4 (GFR 15-29 mL/min) or G5 (GFR <15 mL/min). 22 Those who had an incomplete medical record were excluded. The study protocol was reviewed and approved by the Institutional Review Board of each hospital. The anonymity and confidentiality of patients and their data were protected at all times.

| Data collection and variables
Databases of the two hospitals were computerized; medical records of all patients admitted during the study period to any hospital ward were screened. Initially, databases were searched using the International Statistical Classification of Diseases and Related Health Problems (ICD-10) 23 coding system for code of N18 (CKD). Beers list of medications that should be avoided or its dose should be reduced with advanced stages of kidney dysfunction in older adults (Table S1).
Independent study variables were gender, age range, number of drugs prescribed, CCI, CKD stage, the reason for admission, dialysis, ward (Cardiology Unit, Internal Medicine, Intensive Care Unit) and length of hospitalization. The dependent variable was the number of patients with at least one PIM detected in their medication list in the hospital.    Figure 1).

| Statistical analysis
In dialysis patients, 33 out of 82 had at least one PIM making the prevalence of PIMs 40.2% vs 30% in nondialysis patients.
Univariate analysis identified statistically significant differences in PIM prescription among subjects with respect to the number of drugs prescribed (P = .00), the number of comorbidities (P = .03), and specific diseases as diabetes mellitus (P = .02) and coronary heart diseases (P = .04). At least one PIM was found to be more common in females, internal medicine service, CKD G5 stage and hospitalized for 8 days or more but there were no significant differences.

| DISCUSSION
As far as we know, this is the first study to estimate the prevalence of PIMs in Lebanese hospitalized older adults with renal impairment.
Our study indicates that the overall prevalence of PIMs in patients with chronic and end-stage kidney disease was 34.1%. In patients with advanced CKD stages receiving conservative treatment, the prevalence of PIMs was 30% vs 40.2% in hemodialysis patients.
These findings were consistent with previously published data using Beers criteria. [12][13][14][15][16] In a study conducted by Kondo et al, 16 PIMs were identified in more than 50% of the dialysis patients. Hannah et al, 25 found that 32.3% of hospitalized patients with renal impairment had PIMs. Whereas, the lowest frequency of PIMs (13%) in elderly patients with CKD stages 3 to 5 has been revealed by Jones and Bhandari. 14 Our results were within the prevalence range (13%-50%) reported by previous studies and the conceivable explanation behind the discrepancies in the estimated prevalence of PIMs may be the different prescribing practices of each country and research methodologies.
Overall, the histamine-2 receptor blocker ranitidine was the most common medication identified as PIM in our study. These findings are consistent with Kondo et al, 16 and Alhawassi et al. 26 The main reason for this inappropriateness was using ranitidine without dose adjustment-reduction that is, 5 mg IV every 6 hours or as 6.25 mg/ hour continuous infusion, in patients with advanced CKD stages.
Renal function impairment is associated with increased plasma ranitidine levels and altered disposition of the drug, which may result in central nervous system-adverse drug reactions such as lethargy, confusion, somnolence, disorientation, and possibly hallucinations. 27 In Lebanon, ranitidine is commonly over-prescribed for stress ulcer prophylaxis in hospitalized patients. 28  Furthermore, conversely to our findings, benzodiazepines, firstgeneration antihistamines, and αblockers were reported as the most common PIM classes in other studies using different criteria. 15,16 The majority of published data indicated that aging, late-stage kidney disease, the high number of medications, and the presence of multiple comorbidities were major factors significantly associated with PIMs. 25,34,35 In our study, only polypharmacy, multimorbidity, and coronary artery disease were associated with PIMs. There is clear evidence that the use of multiple medications to treat multiple comorbidities increase the risk of receiving inappropriate drugs.
In accordance with findings of San-José et al, 36

| CONCLUSION
Our study found that one out of three patients with advanced CKD had at least one PIM according to 2019 AGS Beers criteria. This high frequency of inappropriate prescribing is preventable by increasing awareness of prescribing physicians to the explicit lists of PIMs that are typically avoided or require dosing reduction based on renal function. Moreover, clinical pharmacist medication review can draw attention to PIMs through medication therapy management to achieve optimal prescribing practices in older adults.

CONFLICT OF INTEREST
The author declares no conflict of interest.

Methodology: Bahia Chahine
Writing -Original Draft preparation: Bahia Chahine Writing -Review and Editing: Bahia Chahine All authors have read and approved the final version of the manuscript.
Bahia Chahine had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

TRANSPARENCY STATEMENT
Bahia Chahine affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available on reasonable request.