Influence of Education Level of Older Patients on Polypharmacy, Potentially Inappropriate Medications Listed in Beer’s Criteria, and Unplanned Hospitalization: A Cross-Sectional Study in Lahore, Pakistan

Objective: To evaluate influence of education level of older patients on polypharmacy, potentially inappropriate medications (PIMs) listed in Beer’s Criteria, and unplanned hospitalization. Methods: A cross-sectional study was conducted among older people aged ≥65 years between 1 December 2017 and 28 February 2018. For data analysis, descriptive statistics and logistic regression analysis were employed. Results: Among 385 older patients, 88.8% were prescribed PIMs and 56.4% underwent PIMs associated unplanned hospitalization. Older people were less exposed to polypharmacy or excessive polypharmacy as their education levels increased (no formal education vs. primary vs. secondary vs. tertiary, 74% vs. 69.8% vs. 60.5% vs. 58.1%). Patients having higher education were also accompanied by significantly lower prescription of PIMs (no formal education vs. primary vs. secondary vs. tertiary, 96% vs. 87.3% vs. 84.5% vs. 79.1%) as well as unplanned hospitalization (no formal education vs. primary vs. secondary vs. tertiary, 64.7% vs. 76.2% vs. 40.3% vs. 46.5%). Results of regression analysis revealed that no formal education (OR = 1.202, 95% CI = 1.032–2.146, p-value = 0.003) and primary education level (OR = 1.175, 95% CI = 1.014–1.538, p-value = 0.039) were significantly associated with the use of polypharmacy among older people. On the other hand, no formal education was significantly associated with the prescription of PIMs (OR = 1.898, 95% CI = 1.151–2.786, p-value = 0.007). Furthermore, older people with no formal education (OR = 1.402, 95% CI = 1.123–1.994, p-value = 0.010) and primary education level (OR = 1.775, 95% CI = 1.281–3.018, p-value = <0.001) were significantly more likely to undergo unplanned hospitalization. Conclusions: Patients having low literacy level are more likely to receive PIMs, polypharmacy, and undergo unplanned hospitalization in comparison to highly educated patients. Hence, promotion of health literacy for patients is crucial to overcome these problems.


Introduction
Worldwide, the over-utilization of healthcare resources by the older population is a result of the increase in number of patients belongs to this age group [1,2]. The prime focus of pharmacotherapy given to elderly patients is to improve their quality of life (QoL). The older patients are at high risk of developing adverse drug events (ADEs) due to various factors (e.g., polypharmacy, by the older patients. Till date no clear estimates have been made about PIMs associated unplanned hospitalization of older adults. Thus, the present study aims to evaluate influence of education level of older patients on polypharmacy, PIMs listed in Beer's Criteria, and unplanned hospitalization.

Study Design
A quantitative, observational, cross-sectional and prospective study was conducted to scrutinize the influence of education level of older patients on polypharmacy, PIMs listed in Beer's Criteria, and unplanned hospitalization.

Study Settings
For this study, we divided Lahore into four zones i.e., north, south, east and west and obtained data from four different tertiary care hospitals of Lahore, Punjab, Pakistan (1: Bahria international hospital, 2: Doctors hospital, 3: Mayo hospital, and 4: Surgimed hospital). The healthcare settings were randomly selected and data were collected between 1 December 2017 and 28 February 2018. These selected settings were tertiary care public and private hospitals where inpatient healthcare services were also provided to the patients' aged ≥65 years. These were comparable in terms of staff, services and availability of formulary medicines, thus healthcare professionals followed the same prescribing practices. The random selection of patients from these tertiary care hospitals could have minimized the chances of selection bias.

Study Population and Sample Size
According to latest Pakistani census, the total population living in Pakistan is 201,995,540. Lahore is the capital city of Punjab province and the second largest city of Pakistan with an estimated population of 11,126,285 people [37]. By using Raosoft sample size calculator [38], minimum obligatory sample size was 385 with 95% confidence interval (CI) and 5% margin of error (Equation (1)). n = Nx/((N − 1) E2 + x) (1) where n = population size, x = CI, E = margin of error. Records of those patients were included in the study that were ≥65 years of age, chronically ill and hospitalized. While, the records of all those older patients were excluded who were hospitalized on planned basis for acute illness (burn, appendicitis), exacerbation of chronic diseases or infections (Alzheimer's disease, osteoporosis), end-stage life threatening diseases (cancer, HIV/AIDS), providing pre and post-surgery medical care, palliative care and short-term prognosis, had incomplete medical records.

Data Collection
A data collection form was designed that consisted of five major parts: (1) demographic characteristics, (2) socio-economic characteristics, (3) health-related characteristics, (4) clinical indications, and (5) past medication history. SPSS version 21.0 was used for calculation of reliability coefficients. Internal consistency was measured by Cronbach's alpha, while reproducibility was evaluated by using intra-class correlation for each item in the scales, with acceptable values ≥0.6. The Cronbach's alpha value was 0.74 demonstrating the excellent reliability. A pilot study was undertaken between October and November, 2017 for pre-testing the study instrument.

Demographic Characteristics
The following characteristics were evaluated in the demographic data of selected patients; gender (male/female), age (65-74, 75-84 and ≥84) and civil status (single, married, widowed, and divorced).

Socioeconomic Characteristics
The socioeconomic characteristics were; education level (no formal education, primary, secondary, tertiary), employment status (employed, unemployed, retired), annual income (low class, middle class, upper class), residence (rural, urban). The patients who were unemployed but received revenue from their lands, business, or pensions were considered as employed.

Health-Related Characteristics
Prescriptions were used to collect medical data while patients' attendants were consulted for demographic, socio-economic and health-related information. Health-related characteristics included the following parameters: Self-reported health (good, moderate, poor), health service utilization (number of clinic visits of ≤3/year and ≥4/year), health risks (smoking, alcohol consumption, obesity) and comorbidities (present, absent) which included chronic diseases like diabetes mellitus, coronary vascular disease, respiratory, gastrointestinal, joint diseases, hypertension, central nervous system disorders, etc. Body mass index (BMI) was used to determine obesity and patients were considered as either normal (BMI < 25 kg/m 2 ), over weight (25 ≤ BMI < 30 kg/m 2 ) or obese (BMI ≥ 30 kg/m 2 ) [39].

Drug Utilization Evaluation
After collecting data from all the patients, a list of PIMs was made for categorizing the drugs as low, medium and highly prescribed medications. The Anatomical Therapeutic Chemical Classification system (ATC) was used for the estimation of drug utilization patterns [40]. The prescribed active substances were classified as: Low (prescribed to <10% of selected patients), medium (prescribed to ≥10% of the selected patients but <40%) and high (prescribed to >40% of selected patients).

Potentially Inappropriate Medications Evaluation
For examining PIMs, medicines prescribed to the selected patients were evaluated according to the 2015 Beer's Criteria [41]. Detection of PIMs was based on past medication history of patients. All the drugs mentioned in the past medication history were checked for appropriateness with respect to indications and interactions. Disease dependent PIMs were defined on the basis of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes [42]. The expert opinions of physicians and clinical pharmacists were also taken in account before reaching the final decision.

Unplanned Hospitalization Evaluation
All those selected cases were referred to as "unplanned hospitalization" in which patients visited the emergency department and their clinical sign and symptoms did not improve within 24 h, and there had been the need of further investigation or treatment which compelled the healthcare professionals to admit them in the inpatient ward directly from the emergency room. Therefore, the patient's profile of all the selected participants were scrutinized to check the clinical presentation and diagnostic tests results at the time of their visit to the emergency room as well as unplanned admission in the inpatient ward. On the basis of diagnostic findings and the sound clinical judgment of physicians and clinical pharmacist, if the possibility of unplanned hospitalization due to underlying diseases was ruled out then the patients were asked to show their all prescriptions and pertinent lab test results as well as diagnostic findings one month prior to their hospitalization. According to the guidelines of American Academy of Family Physicians (AAFP), it is rare for any drug that the interval between initiation of therapy and onset of adverse drug reaction is less than 1 week or more than 1 month [43]. Thus, the utilization of PIMs one month prior to unplanned hospitalization was evaluated. All the information pertaining to drug utilization before unplanned hospitalization was then confirmed by conducting face-to-face interviews of the patient's attendants. Based on past medical history, any such drug was said to be PIM if it was contraindicated to the patient according to Beer's Criteria [41]. In this way the utilization of any PIM by the patients within 1 month prior to their unplanned hospitalization was checked. , WA, USA) were used for data analysis. Descriptive statistics such as frequencies and percentages were used to present the data. Furthermore, logistic regression analysis was performed to evaluate the influence of educational level on polypharmacy, PIMs and unplanned hospitalization. Results were expressed as Odds Ratio (OR) accompanied by 95% Confidence Intervals (95% CI) and a p-value < 0.05 was used for statistical significance of differences.

Ethics Approval and Consent to Participate
Ethical Approval including verbal informed consent process was obtained from Pharmacy Research Ethics Committee of Akhtar Saeed College of Pharmaceutical Sciences, Lahore (Reference: 08-2017/PREC, 22 September 2017). Before conducting the study, permission was granted from the hospital administrators. The purpose and protocols of this study were thoroughly explained to every participant and their verbal consents were obtained. Written consent was not possible for most of the respondents because either they acquired no formal education or they had problems in reading and/or signing the consent document.

Characteristics of the Participants
A total of 419 older hospitalized patients in government and private hospitals of Lahore were approached and 385 consented patients (response rate = 91.8%) were included according to inclusion and exclusion criteria.

Educational Level Associated with Polypharmacy, PIMs and Unplanned Hospitalization
Logistic regression analysis evaluated the association of polypharmacy, PIMs and unplanned hospitalization with the educational level of study participants. Results revealed that older patients with no formal education and primary education level were 1.202 times (OR = 1.202, 95% CI = 1.032-2.146, p-value = 0.003) and 1.175 times (OR = 1.175, 95% CI = 1.014-1.538, p-value = 0.039) as likely to be prescribed polypharmacy as compared to those had tertiary level of education (Table 4). While, examining the association between education level and PIMs, individuals with no formal education were 1.898 times (OR = 1.898, 95% CI = 1.151-2.786, p-value = 0.007), respectively, as likely to be prescribed PIMs as compared to those had highest level of education (Table 4). Furthermore, this analysis examined the association between education level and unplanned hospitalization. Results revealed that older patients with no formal education and primary education level were 1.402 times (OR = 1.402, 95% CI = 1.123-1.994, p-value = 0.010) and 1.775 times OR = 1.775, 95% CI = 1.281-3.018, p-value = <0.001), respectively, as likely to undergo unplanned hospitalization as compared to those had tertiary level of education (Table 4).

Discussion
The current study set out to determine the influence of patient's education on the utilization of polypharmacy, PIMs and unplanned hospitalization. The rational for doing so is to inform the healthcare policy makers about the current situation who may take adequate steps for formulating appropriate strategies to prevent this population from untoward effects of improper use of medicines. The findings of present study revealed that prior to unplanned hospitalization most of the patients were prescribed with PIMs including aspirin, omeprazole, insulin, esomeprazole, amlodipine and diphenhydramine, and had been suffering from disorders of CVS, respiratory system, endocrine system and metabolic system.
These results are in line with the previously published study in Nepal where the utilization of PIMs by older patients was quite high and most of them were prescribed with amlodipine (23.16%) and diphenhydramine (4.6%) [44]. Insulin is a frequently used therapeutic agent in the management of diabetes mellitus. But it is also associated with untoward health outcomes like hypoglycemia and seizures. Due to this reason, a national survey in the USA described the use of insulin among 206 older patients per 100,000 outpatient prescription visits as one of the major reasons for unplanned hospitalization [45]. Another study conducted in Karachi, Pakistan had revealed that at least 1 PIM was prescribed to more than half (64%) of the older population [46]. It is suggested that many of the PIMs like antihistaminic agents (e.g., diphenhydramine), proton pump inhibitors (e.g., omeprazole and esomeprazole) and analgesics (e.g., aspirin and non-steroidal anti-inflammatory drugs (NSAIDS)) are more frequently used by older people than any other age group [47][48][49]. This might be attributable to the reason that old age people mostly suffer from insomnia, heart burn, acid reflex, headache, muscle pain, and joint pain due to multiple co-morbidities and the physicians in developing countries like Pakistan are usually inefficient in diagnosing the underlying cause [50,51]. Furthermore, no clinical guidelines have been approved in Pakistan for the diagnosis and management of ailments especially among older patients. Although many international guidelines like Beers criteria [41] and STOP/START criteria [27] are available for assisting in the selection of appropriate medications for this high risk population but unfortunately these guidelines are poorly implemented in public and private healthcare settings of this region [52]. It is the result of urbanization that patient load in public hospitals of Pakistan is increasing day by day. Thus, patients have to wait in long queues for the consultation with physicians. Due to limited hospital timings many patients fail to get consultation from the physicians. In such scenario, physicians give less than 2.5 min per patient and this time duration is inadequate for medical examination and proper counseling of patients [53][54][55]. These are the reasons that account for non-implementation of international guidelines and higher number of PIMs prescribing among older patients.
Logistic regression analysis was used to estimate association of polypharmacy, PIMs, and unplanned hospitalization with participant's education level. Findings suggested that older patients having no formal and primary level of education were significantly associated with polypharmacy. Similar results were obtained in a national survey conducted on Malaysian older population where patients having primary education were more likely to be prescribed with polypharmacy [56]. A register based survey conducted in Sweden had revealed that older people having low literacy level were significantly associated with the concurrent use of more than five medicines [57]. It is due to the fact that a vast majority of patients having no formal or primary level of education are unaware of their basic health need and expect physicians to prescribe more number of medications [58]. It was also found that older patients with no formal education had significant correlation with the prescribing of PIMs. This finding is parallel with the results of a study conducted in Brazil where similar association between the patient's education level and the prescribing practices of PIMs was found [59]. Studies revealed that low literacy level is a significant patient related barrier in establishing good relationship between the patients and physicians [60][61][62]. Due to this reason, patients feel hesitation in discussing their health related problems with the physicians. It may have a negative effect on physician's ability in making the accurate clinical judgment about patient's health. Thus, such patients may be prescribed with PIMs [63]. Furthermore, like the previously published studies [64][65][66], older people with no formal and primary level of education were found to be significantly associated with unplanned hospitalization. It is primarily because of the fact that such patients were not able to understand and follow the instructions of their healthcare providers properly. Patients having low level of education are less likely to have self-care maintenance and management skills which may have a negative impact on their QoL, thus these patients are at high risk of undergoing unplanned hospitalization as compared to highly educated older patients.
Thus, the rational use of medicines among older patients requires their limited access towards PIMs. A multidisciplinary collaborative approach is needed for defining protocols pertaining to disease management and improving QoL of older patients. As the negligence towards PIMs associated health crises and unplanned hospitalization can economically burden the society and the healthcare system, so it becomes mandatory for policy makers to formulate national action plan and healthcare professionals must implement international treatment guidelines in their routine practice. Also, healthcare professionals must provide proper counseling to all patients especially those having low literacy level. Such patients must be encouraged to communicate openly about their health issues with the physicians and the pharmacists. The health ministry in collaboration with multidisciplinary healthcare providers, national and international organizations should organize educational seminars and campaigns in order to spread awareness regarding health literacy among the local masses especially older patients who have low level of education.

Implication for Policy and Practice
The findings of present study have implications for clinical practice. As there is no literature available that gives an insight about the utilization of healthcare resources and the influence of patient's education level on polypharmacy, PIMs and unplanned hospitalization in low-middle income countries (LMICs) like Pakistan, so this study plays a substantial role in this context. This study raises the question on the adequacy of clinical practice in Pakistan. The utilization pattern of PIMs reflects unavailability of national guidelines and the disobedience of international guidelines in the management of health related issues among older patients. Such circumstances have threatened the QoL of older patients especially those having low level of education. The promotion of health literacy is mandatory to address these issues.

Strengths and Limitations
To our best knowledge this is a first study in Pakistan that gives an insight about the influence of education level of older people on utilization of PIMs, polypharmacy and unplanned hospitalization. The previously published studies conducted in this region had also considered older people as a high-risk population for irrational use of medicines but the spectrum of their findings was confined to the assessment of utilization pattern of PIMs either during or after hospitalization. This study highlights the need of developing standard treatment protocols and implementing systematic drug monitoring system.
The present study has some limitations. First, this is a cross-sectional study with small sample size, lack of matched control design and data were collected for short duration of time, so the association may not be valid in other populations and countries. Second, the defined daily doses (DDD) of PIMs could not be calculated, so the assumed average maintenance dose per day for a drug used for its main indication was not evaluated. Third, as the appropriateness was checked only for drug indications and interactions, while appropriateness with respect to directions of taking medicines, duplication and duration of therapy was not taken into account, so the investigators were unable to evaluate that either the hospitalization was the result of inappropriate use of PIMs or just having a report of using a PIM prior to admission. In addition, in Pakistan, there are no criteria for assessing PIMs among older patients. Beer's criteria are not country specific and were specifically designed for older patients of the USA. Medications may be available in Pakistan that are potentially inappropriate but are not included in the list. Therefore, the investigators were unable to evaluate PIMs other than those listed in Beer's criteria.

Conclusions
The present study concluded that PIMs were commonly utilized among older patients. The consumption of aspirin, omeprazole, insulin and diphenhydramine was associated with the unplanned hospitalization of these patients. This might be attributable to the unavailability of national standard treatment protocols and disobedience of international guidelines for older patients in Pakistan. The older patients having low level of education were significantly associated with the prescribing practices of PIMs, polypharmacy and unplanned hospitalization as compared to those who had higher level of education. It might be the result of communication gap between prescribers and patients and poor self-care skills. Hence, health literacy must be promoted among older patients especially those having low level of education and provider education regarding PIMS is also needed.
Author Contributions: M.R.S. conceptualized and designed the study. M.S. and S.I. analyzed and interpreted the data. M.R.S. and S.I. drafted the manuscript. M.S. and M.R.S. critically revised the manuscript. All authors read and approved final version of the manuscript.

Funding:
No funding was involved in the preparation of this manuscript or in the decision to submit it for publication.