PREDICTORS ASSOCIATED WITH ADVERSE DRUG REACTIONS AMONG GERIATRIC PATIENTS IN AN OUTPATIENT CLINIC

Objective: The process of aging involves an individual’s structural and functional depravity of their organ systems often results in compromised pharmacological principles of the prescribed drugs. Multimorbidity and polypharmacy along with change in pharmacokinetic and pharmacodynamic responses of drugs predispose the elderly to adverse drug reactions (ADRs). The present study was aimed to identify and report the characteristics and incidence of ADRs among geriatrics in an outpatient clinic. Methods: This was a 6-month prospective hospital-based observational study among patients of either sex aged 60 years and above visiting an outpatient clinic at the study site. The suspected ADRs were categorized according to the Will’s and Brown classification system. Causality of these ADRs was verified by applying the WHO-UMC criteria and the Naranjo’s scale. Severity and preventability of the ADRs were classified using the modified Hartwig and Siegel scale and modified Schumock and Thornton scale, respectively. Multivariate logistic regression was used to determine the risk factors for developing ADRs. Results: Among the 365 patients monitored, 57 (15%) patients experienced 60 ADRs. Therapeutic classes of drugs frequently associated with ADRs were the drugs used in hypertension (27 [45%]). Patients presenting with amlodipine (9 [15%]) induced pedal edema were observed with the highest frequency of ADRs. Polypharmacy (OR: 1.619, 95% confidence interval: 0.957−2.741, p=0.021) was observed as the influential risk factor for ADRs. Conclusion: Pharmacist’s services and involvement in geriatric patient’s centered care can be associated with their improved health, quality of life and economic outcomes, a reduction in medicine-related adverse events, and limiting the morbidity and mortality in this age band.


INTRODUCTION
The 21 st century has witnessed a significant and distinctive global demographic phase called "population aging" [1]. India is in its point of demographic transition and the aging population is growing faster [2]. Indian elderly represents 12.8% of the entire global elderly population [3]. Aging is an intricate process which is associated with several physiological changes of the organ systems exposing them to multiple chronic comorbidities such as hypertension, diabetes, dyslipidemia, and depression [4] which lead to the rigorous use of multiple drugs, in turn, call for extensive treatment regimens [5]. The use of multiple drugs in a patient is known as polypharmacy [6] and is soundly associated with multiple negative health consequences which include increased health-care costs due to the increase in harmful drug interactions [7], adverse drug reactions (ADRs) [8,9], functional impairment, etc., leading to unnecessary expenses in health care.
Globally, studies conducted have suggested ADR-related hospital admissions at a rate of 10% and 11% in geriatrics [10,11]. They account for almost two-thirds of all drug-related hospital admissions and emergency department visits [12,13]. ADRs result in increased health-care costs [14]. The previous studies have found that those presenting with an ADR have an extended hospital stay and succeeding outpatient health service use which is of higher rate than those without ADRs [15,16]. In a developing country like India, the coverage of insurance policies is limited and thus increasing out of pocket medical expenses resulting in economic burden. They have important consequences and one-third of such events are preventable or ameliorable. Hence, active pharmacovigilance (PV) surveillance activities, spontaneous reporting of ADRs, and conducting observational studies are important tools for identification, evaluation, and prevention of ADRs, minimalizing the financial burden on the victims.
PV is a hoard of activities in relation to the detection, assessment, understanding, and prevention of ADRs caused by medications. Drug safety and PV remain an active and rational discipline. PV studies need to be scrutinized in the older age group due to polypharmacy, which is a source of ADRs, prompting to hospital visits. In severe cases, this may lead to hospital readmissions resulting in additional treatment cost to cure the ADRs.
PV plays a pivotal role in confronting the risks posed by the increasing range and potency of medicines and to a greater extent in geriatrics, all of which carries an inexorable and sometimes an unpredictable source of harm. Hence, this study aims to assess the causative drugs, severity, and various factors responsible for causing an ADR and assess their preventability, causality, predictability, and severity in geriatric patients visiting an outpatient setting of a tertiary care hospital.

METHODS
This prospective observational study was carried out in elderly patients visiting a geriatric outpatient clinic of a tertiary care hospital in Bengaluru. Ethical clearance was obtained from the Institutional Ethics Committee. The study was conducted for a period of 6 months from October 2017 to April 2018. Patients of either sex, above 60 years visiting the clinic, were enrolled in the study. Those

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undergoing treatment with anticancer drugs, receiving hospice care, and those not willing to participate in the study were excluded from the study.
Appropriate consent was obtained from the patients before the data pertaining to patient demographics, diagnosis, prescribed medications, treatment durations and indications for each drug was recorded. Case notes and other relevant medical records along with patient interview were reviewed for the likelihood of occurrence of an ADR. Patients' who presented with suspected ADRs were followed up every 2 weeks for a minimum period of 8 weeks. The nature of the suspected ADR, suspected medications, and relevant clinical information was recorded. The suspected ADRs were categorized according to Wills and Brown classification system. Causality of ADRs was verified by applying the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale and Naranjo's criteria. ADR severity and preventability were classified using modified Hartwig and Siegel scale and modified Schumock and Thornton scale, respectively. Patients who presented with ADRs were also reviewed for their management and outcomes.
Collected data of the suspected drug were categorized and presented according to system organ classification. The suspected ADRs were reported to the treating physician. Patient details were analyzed using descriptive statistics. Risk factors for ADRs were determined at p<0.05 by investigating the effects of age, gender, number of diseases, and number of drugs prescribed. Multivariate logistic regression was used to evaluate the influence of these risk factors on the development of ADRs. All statistical calculations were performed using the Statistical Package for the Social Sciences Version 22.0 for Windows ® . p<0.05 was considered statistically significant.

RESULTS
Over the study period, 365 (male = 61% and female = 38.6%) patients who visited the geriatric clinic were assessed. Most of the patients visiting the clinic were between the age groups of 60 and 69 years (55.3%). Two hundred and two (55.34%) patients had at least 1-2 diseases. Two hundred and forty-eight(67.9%) patients had at least 1-5 drugs in their prescription and only 10 (2.7%) patients were observed to have more than 10 drugs in their prescription (Table 1).
The causality of the suspected ADRs was assessed using the WHO-UMC criteria where 78.4% of the reactions were classified as probable, Naranjo's scale, in which 90% of the suspected adverse reactions are probable (Table 3).

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Thirty-nine (65%) of the suspected reactions were mild in severity according to the modified Hartwig and Siegel's severity scale (Table 4).
Of the 60 ADRS noted, 10 (16.65%) were classified under the metabolic and nutritional disorders and 10 (16.65%) were categorized underbody as a whole general disorder according to the system organ class affected (Table 5).
Multivariate logistic regression was used to analyze the predictors of the suspected ADRs. Predictors which were determined were gender (female), number of diseases (>1), and polypharmacy (>5 drugs). Polypharmacy showed significance in the present study (p=0.021); p<0.05 was considered statistically significant (Table 6).

DISCUSSION
ADR poses a major threat to the health-related quality of life in frail elderly patients. With the advancement in age, the prevalence of drug use increases proportionally along with multiple comorbidities, thereby exposing geriatrics to an increased risk of drug-induced harm.  [17]. Multiple diseases make patients more vulnerable to ADRs due to the use of many drugs [19]. They have higher prevalence of chronic disease and comorbidities, often requiring more medication to multiple illnesses, thus increasing ADR risk. The average number of drugs per prescription in our study was 4.84 which are higher than the WHO optimal level of ≤3, indicating polypharmacy [20]. A higher rate of polypharmacy was seen in a study by Nandagopal et al., in Hyderabad, with an average of 7.02 [21]. Although the average in our study was lesser, it still requires that caution be taken to diminish the potentially higher risk of adverse health outcomes among the elderly.
In our study, hypertension (203 [55.6%]) and diabetes mellitus (168 [46%]) were the two most commonly occurring chronic conditions. While the findings in our study were analogous to a study conducted by Nagaraju et al.,in Bengaluru [22], they were not the same as when compared to a study by Mahesh et al. where diseases of the cardiovascular system (39.13%) and endocrine system (25%) were mostly reported [23].
The study revealed that the most common category of drugs that caused the ADRs was antihypertensives (n=27; 45%). The most prevalent drug which was involved in the response was amlodipine which manifested 9 (15%) of the reactions. The observations were undeviating with other studies where antihypertensives were often related with ADRs in the elderly. Our study showed that antihypertensives were the most commonly prescribed drug class followed by antidiabetics. In comparison to this, a study by Nandagopal et al. revealed that antidiabetics (21.9%), followed by antibiotics (17.78%), were frequently prescribed [21].   Female gender, chronic diseases, and number of drugs (≥5) were identified as the risk factors for developing ADRs which were consistent with literature [25][26][27][28]. The present study showed odds of 2.31 among those with multiple medications in developing ADRs. This was consistent with a study conducted by Nguyen et al. where subjects using ≥9 medications were 2.33 times more likely to develop a reaction indicating a positive relationship between the number of medications and ADRs [29]. High prescribing rates, although associated with severity of illness and severe morbidity, may also increase the occurrence of ADRs [30]. This necessitates a need to develop and implement strategies to minimize ADRs and increase safety among the elderly.

CONCLUSION
Older people are a heterogeneous population, with high levels of morbidity and polypharmacy. As the benefits of medications are always accompanied by harmful effects, it is not surprising that they are at increased risk of developing ADRs. The diagnosis of ADRs in these patients can be challenging. Patients in outpatient care and some post-acute settings have complex medication regimens, at times prescribed by multiple clinicians with far less monitoring compared with hospitalized patients. There exists scarce evidence regarding the ADRs in outpatient clinics.