On the basis of reports from a pharmacovigilance center at a single tertiary hospital in South Korea from 2011 through 2018, we estimated the characteristics and culprit agents of ADRs in patients 65 years of age or older. We found that the causes and clinical features of ADRs in the older adults differed considerably from those in younger patients, with observable differences in the manifestations of adverse reactions depending on the culprit drugs. We found tramadol and fentanyl to be the most frequently reported culprit drugs in the older adults, compared to the younger individuals: the high prevalence of older patients with neoplasms may account for the high number of ADRs related with analgesics, such as tramadol, fentanyl, and nefopam. Even though the frequencies of ADRs caused by NSAIDs and ICM were lower in the older adults than in their younger counterparts, the rates of serious ADRs to NSAIDs and ICM were significantly higher in the older adults than in the younger individuals. ICM was found to be related to higher risks of anaphylaxis and heart-related disorders in the older adults than in the younger individuals.
People aged 65 years and older are now the most rapidly growing population in the world and are particularly susceptible to ADRs because of multiple comorbidities, the use of multiple drugs, and age-related changes in pharmacokinetics and pharmacodynamics. Advancing age is associated with an increased prevalence of multiple morbidities, inevitably leading to the concurrent use of multiple medications. Polypharmacy can lead to increased risks of adverse drug-drug and drug-disease interactions, inappropriate medication use, under-use of effective treatment, poor medication adherence, and most importantly adverse drug events . Despite its dangers, there is evidence of rising rates of polypharmacy with potentially drug-drug interactions in older patients . While polypharmacy is likely inevitable, in many cases, it may be due to inappropriate prescription of medications and preventable problems . Therefore, physicians should regularly review and optimize medications to reduce unnecessary polypharmacy. They can prescribe safer alternatives when available and use lower doses for shorter durations, or can take measures to minimize adverse events with prescribing prophylactic medications and intensifying patient education . Also, they should prescribe new medications with clear therapeutic goals and consider the risk-to-benefit profiles when prescribing them to older patients. In addition, age-related physiological changes in pharmacokinetics and pharmacodynamics have significant clinical implications. With age, water content declines, while fat content rises, which influences the volume of distribution of drugs in older adults . Also, renal drug excretion and hepatic drug metabolism are reduced with aging: these changes can result in prolonged elimination half-life and drug accumulation [7, 18]. These factors make older patients more vulnerable to drug-drug interactions than younger individuals. Finally, older patients tend to be more sensitive to the effects of medications than younger individuals because of altered pharmacodynamics responses, which are generally predictable and can be minimized by titrating carefully from a low starting dose .
Korea offers universal access to health care, regardless of one’s ability to pay, through the National Health Insurance and Medical Aid program. All citizens can receive appropriate healthcare services, including examination, surgery, medication, etc. Research has shown that universal health coverage of medical services is associated with increased use of prescription drugs, which can result in an increased number of reported ADRs. We reviewed a large database of ADRs of certain or probable causality documented at a pharmacovigilance center. Similar with prior reports [19, 20], we noted 22.0% of all ADR cases occurred in adults older than 65 years. Notably, the prevalence of ADRs was higher in females than in males in both the older and younger patients. These results are in line with previous studies indicating that older age and female sex are associated with an increased risk for the development of ADRs [20, 21]. A higher prevalence of ADRs in females has been suggested as being related to differences in propensity for symptom reporting, drug prescription rates, medical care utilization, hormonal factors, and pharmacokinetic factors . We also documented a higher rate of severe ADRs of grades 3-5 based on CTCAE in the older adults than in the younger patients. Accordingly, we suspect that more complicated comorbidities and lower tolerance to adverse reactions in older adults can elicit more frequent occurrences of severe ADRs.
Studies on ADRs in older adults over the past few decades have shown divergent results on causative agents and clinical features. Accounting for the heterogeneity between studies may be variations in how researchers have defined and assessed ADRs . Moreover, demographics, prevalent diseases, economic states, genetic differences, and prescription patterns in different countries can influence the characteristics of ADRs. In the present study, the most common culprit drugs for ADRs in the older adults were analgesics, contrast media, antibiotics, and NSAIDs, results that are similar with those at other pharmacovigilance centers in Korea [19, 22, 23]. Cutaneous and gastrointestinal disorders were the most frequent manifestations in our study, with significantly different occurrence rates between the older and younger patients, which is consistent with the results of previous studies in Korea [20, 22, 23]. Meanwhile, results on causative drugs and clinical manifestations differ among various clinical settings and countries. A previous study in Spain showed that the most common ADRs leading to hospitalization were acute renal failure induced by renin-angiotensin system inhibitors, gastrointestinal bleeding related to anti-thrombotics and/or NSAIDs, and intracranial bleeding caused by vitamin K antagonists . Another study in Canada reported that the two most common drug categories implicated in hospitalizations for ADRs in older adults were cardiovascular agents and analgesics/anti-inflammatory drugs . Hospitalization after emergency department visits for adverse drug events in older Americans resulted most commonly from warfarin, insulins, oral antiplatelet agents, and oral hypoglycemic agents .
Serious ADRs leading to morbidity, mortality, and high healthcare costs are a major concern. In the present study, the two most common drug categories implicated in serious ADRs in the older adults were NSAIDs and antibiotics, similar to two retrospective studies of a spontaneous reporting database at a pharmacovigilance center [19, 26]. Accordingly, physicians should consider the risk-to-benefit profiles of these drugs when prescribing them . The older adults in this study also experienced nearly twice as many anaphylactic reactions caused by ICM, compared with the younger group. Similarly, a recent study also found that older patients over 60 years were more likely to experience anaphylaxis due to nonionic low osmolality contrast media . With the recent increase in the use of computed tomography, ICM use has also steadily increased. Although ICM is administered once in conjunction with CT scans, whereas most prescribed medications are generally used for several days, our results showed that ICM was a common culprit drug for ADRs. Thus, physicians should be aware of the potential risks posed by ICM to older adults and be prepared to administer appropriate emergency management of the adverse events associated with the use thereof.
Several studies have been performed in regards to the epidemiology, causative drugs, and risk factors associated with ADRs in older adults. However, to our knowledge, few have investigated the characteristics of ADRs in older adults in comparison to those in younger individuals, which is the strength of the current study. Furthermore, previous studies using databases of ADRs have only analyzed numbers of adverse events, the use of which may not be reliable, because the prescription of several drugs at a time can result in an increased number of reported ADRs. We, however, used ADR reports per 1,000 patients to assess high- and low-risk medications in older adults to obtain reliable numbers of ADR cases and patients taking at least one medication during the study period. In addition, we only included ADR cases of certain or probable causality based on the WHO-UMC criteria, supporting the relevance and validity of the relationships between the culprit drugs and adverse events.
Despite the strengths above, there are several limitations to the present study. First, this study relied on spontaneously reported ADRs, which may pose some underestimation of ADRs, since adverse events are underreported by clinicians and nurses. Also, as a retrospectively designed study, we were not able to reduce possible bias caused by missing data. Second, there could be potential bias in causality assessment evaluated by physicians or pharmacists. Though these processes are not perfect, we also used diagnostic tools, such as skin testing, blood tests measuring specific immunoglobulin E, and drug provocation tests. Third, our findings on the most commonly reported causative agents and clinical symptoms may be divergent from other populations with different prescribing patterns, disease epidemiology, and ethnicities. Fourth, we did not collect data on adverse events associated with non-prescription drugs, such as complementary or alternative medications, although these drugs are commonly used in older adults. Alternative medications may lead to serious adverse events, including palpitations, chest pain, or hepatotoxicity, as well as potential interactions with prescriptions drugs [6, 29]. Further studies are needed to increase awareness of the potential risks of non-prescription drugs among physicians.