Association between potentially inappropriate prescribing, polypharmacy, and functional/cognitive impairment among Egyptian geriatric patients| JOURNAL OF GERONTOLOGY AND GERIATRICS

Abstract

Background and aims. Potentially inappropriate medications (PIM) use is common among seniors and could be related to various geriatric syndromes. The objective was to determine association between PIM use, polypharmacy, and functional/cognitive impairment among Egyptian geriatric patients.
Methods. A cross-sectional study included 251 older adults (aged ≥ 60 years), admitted at the geriatrics hospital of Ain Shams University, Egypt, between March and September 2022. Patients underwent taking of the medical history including age, sex, chronic diseases, geriatric syndromes, pre-hospitalization medications intake, and geriatric assessment; functional status by activities of daily living (ADL) and instrumental activities of daily living (IADL) and cognitive status by mini-mental state examination (MMSE). Multi-morbidity assessed by charlson comorbidity index (CCI). Polypharmacy identified as receiving ≥ 5 medications daily. PIM use defined by the American Geriatrics Society Beers criteria-2019 (AGS Beers criteria-2019). Logistic regression and Pearson correlation were applied.
Results. PIM use occurred in 126 (50.2%) patients. Polypharmacy, CCI, having diabetes mellitus, hypertension and a cardiac disease had significant association with PIM use. Polypharmacy (OR 5.514; 95% CI: 2.776- 10.952; P .000) and having a cardiac disease (OR 2.359; 95% CI: 1.239-4.490; P . 009) were independent predictors of PIM use. Number of PIM use had a significant negative correlation with MMSE scores. Use of diuretics, proton-pump inhibitors (PPIs) and digoxin were the most frequent PIM.
Conclusions. Polypharmacy and having a cardiac disease were predictors of PIM use. The total number of the used PIM negatively correlated with MMSE scores. Medications review and de-prescribing are essential for geriatric patients.

INTRODUCTION

Geriatric patients are more likely to have multi-morbidity with subsequent multiple medications usage and polypharmacy ¹. Aging is associated with an increased risk of adverse drug events (ADEs) due to reduced medication clearance and age-related metabolic changes ². Polypharmacy could be associated with prescribing cascades which occurs when an adverse effect is misinterpreted as a recent medical issue, with the subsequent prescription of another potentially inappropriate medications (PIM) ³.

ADEs could be a serious complication of PIM use ¹. It is significantly associated with the presence of common geriatric syndromes ⁴, such as frailty, cognitive impairment, and functional dependence ⁵. Accordingly, PIM use should be avoided because of the high risk of medication related harm in seniors ⁶.

In clinical practice, PIM could be identified through implicit and explicit methods ⁷. Implicit methods target defining PIM for a particular patient based on an expert opinion, which is a timely process ⁷. Explicit methods are criteria-based with a well-defined inventory of medications described as PIM that requires less time and has a higher benefit ⁸.

The American Geriatrics Society Beers criteria (AGS Beers criteria) are a widely used explicit list of PIM since 1991. It has been published by the AGS for practitioners to guide them towards safer prescribing for geriatric patients ⁶. For the AGS Beers criteria-2019 update, an interdisciplinary expert group reviewed the evidence published in 2015 to dictate if recent criteria should be added or if existing criteria should be deleted or modified ⁹.

This study aims to determine association between PIM use, polypharmacy, and functional/cognitive impairment and to describe pre-hospitalization prescribing patterns among Egyptian geriatric patients.

PATIENTS AND METHODS

A cross-sectional study included 251 older adults (aged ≥ 60 years), admitted at the geriatrics hospital of Ain Shams University, Egypt, between March and September 2022. Exclusion criteria involved patients/proxies who refused participation in the study and patients with missing medication history.

Patients underwent taking of the medical history including age, sex, co-morbidities, pre-hospitalization medications intake and geriatric syndromes including dementia, polypharmacy, falls, fractures, pressure ulcers, and urinary/fecal incontinence besides geriatric assessment including mini-mental state examination (MMSE) for cognitive assessment ¹⁰ and activities of daily living (ADL) ¹¹ and instrumental activities of daily living (IADL) ¹² for determination of functional status.

The total number of medications intake before hospitalization was determined for each patient. Polypharmacy was identified as receiving ≥ 5 medications per day ¹³. Multimorbidity was determined by charlson comorbidity index (CCI) ¹⁴. PIM use was identified in accordance with the AGS Beers criteria-2019 ⁹. Patients were classified into 2 groups either with or without PIM use.

STATISTICAL ANALYSIS

Values were presented as numbers and proportions for qualitative variables or mean and standard deviation for quantitative variables. Quantitative variables were checked for normality by Shapiro-Wilk test. Unadjusted odds ratio (OR) was calculated to detect variables with potential association with PIM use. Outcomes with significant un-adjusted OR were then entered into logistic regression analysis to detect significant predictors for PIM use. Pearson correlation was performed to test correlation between number of PIM and geriatric assessment domains.

All tests were bilateral and a P-value of 5% was the limit of statistical significance. Analysis was performed by statistical package software IBM- SPSS version 24.

RESULTS

A total of 251 geriatric patients were included with a mean age of 73.31 ± 8.368 years. PIM use occurred in 126 (50.2%) patients. Participant’s characteristics were compared between those with and without PIM use. Univariable analysis was done to detect potential association between various variables and PIM use. The following variables were found to have a significant association with PIM use: polypharmacy, CCI, having a cardiac disease, hypertension, and diabetes mellitus. Having polypharmacy would increase the odds of PIM use by 6.750 times. By 95%, having polypharmacy would increase the odds of PIM use from 3.669 to 12.420 as described in Table I.

The significant variables were entered into multivariate regression analysis. Significant predictors for PIM use were polypharmacy (OR 5.514; 95% CI: 2.776-10.952; P .000), and presence of a cardiac disease (OR 2.359; 95% CI: 1.239-4.490; P. 009). The model was able to explain 28.8% of the variability of PIM use as indicated by Nagelkerke R Square value. It was able to correctly predict PIM use by 72.8%. The results showed that with polypharmacy, the odds of PIM use would increase by 5.51 times and with the presence of a cardiac disease, the odds of PIM use would increase by 2.35 times. The 95% CI means that by 95% we are confident that taking ≥ 5 medications daily would increase the odds of PIM use from 2.776 to 10.952 times. While, having a cardiac disease would increase the PIM use odds from 1.239 to 4.490 times as described in Table II.

Based on AGS Beers criteria PIM were subdivided into 6 groups: PIM, drugs to be avoided, PIM use due to drug-syndrome interaction, PIM; drugs to be used with caution, potentially clinically important drug-drug interactions, medications need adjustment according to renal function, and use of drugs with strong anticholinergics effects. Diuretics, proton-pump inhibitors (PPIs) and digoxin were the most frequently used PIM among 62 (24.7), 38 (15.1), and 15 (6.0) participants, respectively. The frequency, distribution and ranking of PIM among participants are described in Table III and Figure 1.

Number of PIM showed a negative correlation with MMSE, ADL and IADL scores, but only significant correlation was found between the number of PIM and MMSE scores (r -.252, P .019) as described in Table IV.

The ranking and frequencies of pre-hospitalization medications use among geriatric patients is described in Table SI.

DISCUSSION

There is a paucity of data regarding PIM use among geriatric patients in developing countries that make not only defining these medications essential but also avoiding them to mitigate ADEs ¹⁵. The study utilized the AGS Beers criteria-2019 to define PIM ⁹. PIM use was common in older patients, it occurred in 126 (50.2) patients. The association between PIM use and every other variable was assessed by logistic regression analysis. Factors associated with PIM use were polypharmacy, CCI, and chronic diseases including diabetes mellitus, hypertension and cardiac disease. After multivariate analysis, polypharmacy and the presence of a cardiac disease were independent predictors of PIM use. These data coincide with a recent study that included 496 older adults in Kuwait applying the same explicit criteria that revealed PIM use among 58.4% of patients and polypharmacy as the most likely predictor of PIM use ¹⁶. This high prevalence of PIM use could be related to the complexity of the management of geriatric patients and ill-defined approaches in a given nation ¹⁶.

Multimorbidity is significantly related to polypharmacy ¹. Multimorbidity, as assessed by CCI, was significantly associated with PIM use in our study and previous studies ¹⁶. In this study, polypharmacy was defined as use of ≥ 5 medications per day, it occurred in 85 (33.9) patients. Polypharmacy pooled prevalence was 49% (95% CI: 42-56; P < 0.01) in a previous meta-analysis including 27 studies in India ¹⁷. The variability of the prevalence of polypharmacy could be related to different settings and cut-offs for defining polypharmacy among various studies.

The current study also highlighted the significant relationship between cognition and PIM use as patients with lower scores on the MMSE used more PIM (r -.252, P value .019) in line with other studies reporting that geriatric patients with lower scores on the MMSE took more medications and utilized more PIM ¹⁸. However, the results did not show a significant association between functional impairment as assessed by ADL/IADL and PIM use compared to other studies reporting a significant association between functional dependence and PIM use ¹⁹. This discrepancy in data further supports the thought of context-specific risk factors as they could be affected by the criteria to detect PIM, as well as the setting of the study.

Based on applying the AGS Beers criteria-2019 on participants’ prescriptions before hospital admission ⁹, PPIs were the most commonly prescribed PIM; drugs to be avoided. The most commonly prescribed PIM that should be used with caution were diuretics. The most frequently reported potential drug-drug interaction was an inhibitor of the renin-angiotensin system (RAS) with potassium-sparing diuretics. The most frequently involved drug-syndrome interactions were dementia/cognitive impairment with antipsychotics and falls/fractures with antidepressants. The most commonly prescribed PIM in the category of “renal dose adjustment” was spironolactone. Strong anticholinergics included clomipramine, olanzapine, benztropine, dimenhyrinate and paroxitine. These findings correlate to a great extent with another similar study ¹⁶. Here is a further discussion of the reported PIM use among participants in the study.

First, PIM; drugs to be avoided

It occurred in 80 (31.9) patients. PPIs were the most frequently reported PIM in this category of PIM. The excessive use of PPIs is related to reduced bone mineral density, fracture, vitamin B-12 deficiency, pneumonia and colon cancer ²⁰. The study highlights the widespread use of PPIs among geriatric patients with non-evidence-based need ²¹.

Glimepiride and glibenclamide were used in 14 (5.6) and 3 (1.2) patients, respectively. These medications are associated with a higher risk of hypoglycemia among seniors. Methyldopa was reported in 6 (2.4) patients. It has poor effects on the central nervous system (CNS) and should be avoided as the first-line medication for hypertension in seniors ⁹.

Diclofenac use had occurred in 6 (2.4) patients, it is a non steroidal anti-inflammatory drug (NSAID) with multiple ADEs in geriatric patients such as hypertension, cardiovascular disease (CVD), gastrointestinal disease, and renal disease ²². Pain management via physical therapy and acetaminophen are preferable choices ²². A previous study showed that more than 30% of geriatric patients in general practice were taking a NSAID on a regular basis ²³. A previous study also compared the effects of various painkillers on blood pressure in hypertensive patients. Compared with patients on acetaminophen, NSAID users had a higher proneness to blood pressure elevation ²⁴.

Regular human insulin (sliding scale) use had reported in 3 (1.2) patients. Its use is inappropriate when it is not used concomitantly with long-acting insulin due to the higher risk of hypoglycemia and poor control of hyperglycemia ⁹. Antipsychotic use had been reported in 3 (1.2) patients. It is related to increased risk of cognitive decline, cerebrovascular accidents, and mortality in patients with dementia ⁹.

Metoclopramide was reported in 1 (0.4) patient. It is related to the risk of extrapyramidal manifestations such as dystonia, secondary parkinsonism, and tardive dyskinesia ²⁵. Chlorzoxazone use occurred in 1 (0.4) patient. It is a skeletal muscle relaxant with anticholinergic consequences ⁹. The study highlighted the potentially inappropriate use of anticholinergics among older adults. Anticholinergics could be associated with a higher risk of delirium and in-hospital mortality in frail seniors ²⁶.

PIM use due to drug-syndrome interactions

It occurred in 9 (3.6) patients. Medications may interact with geriatric syndromes by having a role in deteriorating these conditions ²⁷. Dementia and falls/fractures were the observed geriatric syndromes with PIM use. Demented patients were on anticholinergics and antipsychotics among 3 and 4 cases, respectively. Falls with a coexisting use of antidepressants and opioids were reported among 4 and 1 patient, respectively. These data alarm physicians towards screening for geriatric syndromes and the eminent need to de-prescribe PIM in frail elders.

PIM; drugs to be used with caution

Despite the acceptable use of these medications, careful observation is mandatory because of the high risk of ADEs. The study showed that 76 (30.3) patients utilized these medications. Diuretics were the most frequent medications among 62 (24.7) patients. Diuretics cause electrolyte imbalance and pre-renal azotemia. Also, certain antidepressants such as selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI) and mirtazapine had been reported in 8 (3.2), 2 (0.8), and 3 (1.2) patients, respectively. These medications could induce hyponatremia in seniors ⁹.

Rivaroxaban use had been reported in 3 (1.2) patients. It is a new oral anticoagulant (NOAC) with a higher risk of hemorrhage compared to other NOAC ⁹.

Tramadol use had been reported in 3 (1.2) patients. It should be used cautiously for pain control due to the high risk of syndrome of inappropriate antidiuretic hormone secretion (SIADH). Similarly, oxcarbazepine may be related to SIADH ⁹.

Aspirin for primary prevention of CVD reported in 1 (0.4) patient. Aspirin is preferable for secondary prevention in geriatric patients with settled CVD ⁹.

Potentially clinically important drug-drug interactions

It occurred in 17 (6.8) patients. Inhibitors of the RAS with potassium-sparing diuretics represented the most frequent interaction with high risk of hyperkalemia. Also, concomitant use of corticosteroids with NSAID had reported in 4 (1.6) patients with subsequent high risk of bleeding ⁹.

A combination of ≥ 3 CNS-active medications appeared in 3 (1.2) patients. Simultaneous use of CNS-acting medications is frequent among elders and commonly associated with several ADEs such as respiratory tract infections, serotonin syndrome, falls and fractures ²⁸.

Use of warfarin with a NSAID occurred in 2 (0.8) patients. The risk of hemorrhage is higher with the simultaneous use of warfarin and a NSAID as compared with utilizing warfarin alone ²⁹.

An anticholinergic use with another anticholinergic reported in 1 (0.4) case. This combination is deleterious as taking several medications with anticholinergic consequences for different diseases is common in older adults and could be under-evaluated ³⁰. The total burden could be summated in the anticholinergic burden (ACB) to estimate the risk of getting ADEs such as constipation, and cognitive decline ³⁰. Recently, multiple scales have been used to help practitioners in estimating ACB ³¹. But little evidence of ascendancy of one scale over the other has been found ³².

Medications need adjustment according to renal function

PIM use with the need for renal dose adjustments occurred in 3 (1.2) patients. Medication dose adjustment according to creatinine clearance (Cr.Cl.) is an integral part of the proper management of geriatric patients, as aging induces reduced glomerular filtration rate (GFR) that necessitates dose reduction and meticulous follow-up of renal function ³³. Spironolactone and apixaban were the reported medications in this category. Cr.Cl. according to the Cockcroft-Gault equation is a preferable estimate of renal function as GFR could overestimate kidney function in geriatric patients ³³. Accordingly; Cr.Cl. should be recognized during prescribing for geriatric patients ³⁴.

Medications with strong anticholinergic effects

Anticholinergics antagonize the action of acetylcholine, a key neurotransmitter with prominent effects on the nervous system ³⁰. Geriatric patients are more vulnerable to anticholinergics ³⁵. Strong anticholinergics use had been occurred in 4 (1.6) patients; the culprit medications were clomipramine; tricyclic antidepressant (TCA), paroxetine; SSRI, dimenhydrinate; a first-generation H1 receptor antagonist, benztropine; an antiparkinson and olanzapine; a second-generation antipsychotic ³⁶.

It is worth reporting that; clomipramine has stronger anticholinergic adverse effects than paroxetine. But, paroxetine has a higher affinity for muscarinic acetylcholine receptors than other SSRI ³⁷. Accordingly, classical TCAs should be prohibited as SSRI are safer alternatives in older adults. De-prescribing should be an integral part of the comprehensive medication management of seniors ³⁸.

On the other side of our analysis, the study showed pre-hospitalization prescribing patterns among geriatric patients. Beta-blockers were the most frequently prescribed, followed by acetylsalicylic acid, Insulin Isophane (NPH), PPIs, loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, atorvastatin, amlodipine, metformin, nitroglycerin, and hydrochlorothiazide/metolazone. These results showed that the top ten prescribed drugs were to treat CVD and metabolic disorders in line with previous studies ^39,40.

Cardiovascular-acting drugs were the most commonly used drugs. It could be explained by the predominance of hypertension among 160 (63.7) patients and supported by describing heart disease as the leading cause of death in older adults worldwide ^41,42. The ranking for all the used medications among participants seemed logical and followed the prevalent chronic conditions in the study. The differences between various studies are related to socioeconomic factors and changes in the prescribing patterns of different times and settings.

Strengths and limitations

It is the first study conducted in Egypt to assess PIM use and describe prescribing patterns among older adults. The study provided a thorough description of both PIM and prescribing patterns among geriatric patients before hospitalization. It highlighted the association between PIM use and common geriatric syndromes. The study supports the international attempts to combat ADEs through promoting pharmacovigilance ⁴³. Limitations include its limited generalizability because of the involvement of geriatric patients at a single institute in Egypt with the inclusion of relatively small sample size, especially for particular variables such as MMSE and ADL/IADL. Also, the study was conducted on patients admitted to the hospital and did not include patients from outpatient clinics. Patients admitted to the hospital usually have more comorbidities with more polypharmacy compared to outpatients. That is why including outpatients may minimize the percentage of PIM use. Finally, the study lacked frailty assessment and the duration of PIM use.

CONCLUSIONS

PIM use is common among geriatric patients. Polypharmacy and having a cardiac disease are predictors of PIM use. The study provides an overview of the culprit PIM and common prescribing patterns among geriatric patients. Careful medication review and de-prescribing are essential to mitigate ADEs and prescribing cascades among geriatric patients.

Acknowledgements

Authors thank all participants in the study.

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

Both authors have considerably contributed to the study through data analysis, interpretation and manuscript writing. Khalid Elsayed Elsorady has also contributed to the study’s design/conceptualization, participant’s selection, data gathering/processing and manuscript drafting. Both authors read and approved the final manuscript.

Ethical consideration

The study’s protocol got an approval code: FMASU R 52/2022 on 23/3/2022 from the Research Ethics Review Committee at the faculty of Medicine, Ain Shams University. The study protocol was also revised and approved by the ethical committee in the geriatrics hospital of Ain Shams University where the study was conducted.

Figures and tables

Figure 1.Ranking and frequencies of potentially inappropriate medications used before hospitalization among participants.

SUPPLEMENTARY MATERIALS

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