The elderly population is usually defined as individuals aged over 65 years [1], which is rapidly growing in modernized society due to advances in medical treatment. Extended longevity is inevitably accompanied by a medical phenomenon called polypharmacy. Polypharmacy is a well-known risk factor for adverse drug reactions (ADRs) [2-6]. Elderly patients are susceptible to ADRs, according to the definition established by the World Health Organization (WHO) [7]. Elderly patients are at high risk for ADRs due to decreased renal function, altered drug metabolism in the body, and multiple comorbidities. However, recent studies have shown that an increasing number of drugs taken or comorbidities are the major factors for ADRs, rather than advanced age itself [8,9]. Thus, it is possible to prevent ADRs if clinicians have sufficient knowledge of such risk factors and pay close attention to them.

The impact of ADRs increases the cost of patient care [10]. ADRs require further investigation or treatment in many cases. In serious cases, they can induce a longer hospital stay, which may even be fatal. Serious ADRs (s-ADRs) are defined as follows [11] : an ADR which “results in death,” “requires hospitalization,” “prolongs existing hospitalization,” “results in persistent or significant disability/incapacity,” or “is life-threatening.” However, only a few studies have assessed the related risk factors for s-ADRs. Studies on ADRs as the cause of hospitalizations or emergencies might be acknowledged as studies on s-ADRs. However, given its seriousness, s-ADRs should not be a single subset of ADRs. Most studies have focused on the predictors and risk factors for ADRs rather than s-ADRs. Moreover, the investigators of a few previous studies that compared patients with ADRs and patients without ADRs relied on Caucasian subjects. ADRs are likely to differ according to the health care system and patient ethnicity. Evidently, s-ADRs also have a more demanding impact than ADRs regarding health outcomes and the cost of patient hospital care. If the risk factors for s-ADRs can be thoroughly outlined, more effective strategies can be sought to prevent s-ADRs.

Serious ADRs are probably reported more systematically than ADRs because ADRs are only reported voluntarily by clinicians [12]. As suggested by a previous study, spontaneous reporting can be limited in terms of its low reporting rate. In 2006, the Korea Food and Drug Administration established nationwide regional pharmacovigilance centers (RPVCs) to encourage ADR reporting [13]. Currently, there are 27 RPVCs in Korea, mostly located within university hospitals [14]. The establishment of RPVCs in Korea has dramatically increased the reporting of ADRs. Although there is still room for development in terms of quality and quantity, Korean RPVCs have made efforts to facilitate valuable reports. One such effort is to set up computerized access to an ADR reporting system to increase the reporting rate by making it faster and more convenient to report ADRs. We investigated the risk factors for s-ADRs through electronic submission (e-sub) in elderly inpatients.

Identifying the risk factors for s-ADRs is the first step in their prevention. Our study revealed two important risk factors for s-ADRs in the elderly. One is a well-known risk factor for ADRs, polypharmacy. The other is liver function, which is a less-known factor. To the best of our knowledge, this is a new marker for s-ADRs.

Polypharmacy is a well-established risk factor for ADRs [16]. Polypharmacy is defined as the use of six or more medications per day [17]. Most studies have reported five drugs as the mean number of drugs in an ADR group [18]. Another recent study concluded that the absolute number of concurrently used drugs was the strongest predictor of ADRs [4]; for five to seven concomitant drugs, the OR increased 1.9-fold. For more than eight drugs, the OR increased as high as 4.07 in this study. Eight concomitant drugs corresponded to a significant risk factor for s-ADRs in our study. Our study findings highlight the importance of polypharmacy in terms of s-ADRs. This is practically useful because the use of multiple medications is modifiable. Evidently, polypharmacy is a major risk factor for ADRs, as well as s-ADRs. As s-ADR is a type of ADR, it is reasonable to prove that an increasing number of drugs is an important risk factor for s-ADRs. Polypharmacy is a notable phenomenon in elderly patients who are also vulnerable to s-ADRs. Therefore, the importance of minimizing the number of concurrent drugs for these patients cannot be overemphasized. We found that the number of drugs was a matter of paramount importance to s-ADRs in elderly patients.

Our study identified liver function as a new risk factor for s-ADR. The liver plays a major role in the metabolism of many drugs; thus, liver function reflects the degree of damage caused by drugs. AST is known to be a marker for hepatic dysfunction due to drugs or alcohol [19]. Aging has been known to diminish the hepatic clearance of drugs due to a decline in hepatic blood flow and volume, although there is interindividual variability in the geriatric population [20]. Our findings demonstrated that AST could be a useful surrogate marker and prognostic factor for the prediction of s-ADRs. We confirmed that the AST/ALT ratio was maintained within the normal range of liver function in our study participants (data not shown). Some questions may arise regarding the necessity of blood tests. However, in-patients usually undergo routine laboratory tests to screen for organ function and potential complications of treatments. The significant laboratory findings we checked were performed within the range of clinical practice through chart review. Thus, careful attention to liver function (AST) is worthwhile for predicting s-ADRs. Further studies are required to confirm this phenomenon.

Clinical manifestations were different in s-ADRs compared with non s-ADRs. Anaphylaxis and abnormal hematological findings were significantly more frequent in s-ADRs than in non s-ADRs. On the contrary, dizziness and gastrointestinal disturbances were significantly more frequent in non s-ADRs, as assessed in previous studies [21,22]. Drugs involved in s-ADRs were antibiotics and antineoplastic agents, while those involved in non s-ADRs were antituberculosis drugs and antihistamines. Antineoplastics and antibiotics are known to be high-risk drugs for s-ADRs, according to previous studies [2,7,8]. These medications are potent but also have high innate toxicities [21]. A recent study in Spain also reported that antineoplastic drugs were most commonly associated with ADR-related hospitalization [23]. This is consistent with Australian data, which used a hospital morbidity data system for the elderly. Antibiotics are the most common drug related to ADR in Korea [13], whereas cardiovascular drugs are the most common in Western countries. We demonstrated that antibiotics are also the causative drugs of s-ADRs. As there are insufficient studies on s-ADRs, it is unclear at this point whether drugs involved in s-ADRs result from differences in disease prevalence or the severity of ADR from country to country.

The geriatric population has and will continue to grow rapidly, doubling to 1.4 billion or 14% of the world’s population by 2040. Elderly individuals are at high risk for ADRs [24,25]. According to a meta-analysis, elderly individuals have four times the risk of hospitalization due to ADR-related problems compared with younger individuals [26]. The primary reasons are multiple drug regimens for various comorbidities and age-associated physiological changes, affecting the pharmacokinetics and pharmacodynamics of many drugs [27,28]. However, the reported prevalence of ADR has not increased over the past decade despite a tremendous increase in the use of medications. In Korea, the number of concomitant drugs is particularly high in elderly patients [6]. For instance, the average number of drugs taken by elderly in-patients in Korea is 18.0±13.7, and 5.8±5.6 in elderly out-patients [29]. Studies from the United States and England report an average of nine drugs for in-patients and three for out-patients in the elderly. However, because of the comparatively lower incidence of ADRs in Korea than in Western countries, awareness and reporting rates might also be low. One can also assume that voluntary reporting leads to considerable under-reporting. Several factors limit spontaneous reporting [12]. Correct identification of ADRs is not feasible for all clinicians, nurses, pharmacists, or patients [30]. Moreover, individual factors such as carelessness for reporting or indifference to ADRs influence the reporting rate. Therefore, an easily accessible reporting system is necessary to enhance the reporting of ADRs. Fortunately, an e-sub system has become possible through advances in the Internet. This system was programmed as an integrated part of the electronic medical records in the hospital, aimed at enabling a convenient and imminent response to ADRs. Collected reports and data can be easily converted into a database for ADRs, with speed and accuracy for routine assessment and validation by experts. This system is also used to alert physicians and nurses of each patient’s previous ADR in the study hospital. A need for accurate prediction tools for ADRs remains, even with the recent emergence of risk prediction models and programs for ADRs [30]. We believe that noticeable progress could be made by upgrading this e-sub system into a program that calculates each patient’s risk score for ADRs or into an alarm system that prevents inappropriate prescriptions for the elderly. It would be ideal if each hospital’s e-sub system for ADRs could be standardized and integrated into a national pharmacovigilance center.

Our study has the following strengths: the study population was comprised of in-patients; thus, they could not self-medicate or take health supplements without medical supervision. Possible ADRs were investigated using an electronic medical record system. It enhanced the reporting rate of all ADRs, particularly that of s-ADRs. As s-ADRs require medical assessments and emergent interventions, they should be avoided as quickly as possible. Among ADRs, s-ADRs take priority for investigation for the sake of patient health. Therefore, especially in elderly patients, focusing on s-ADRs and identifying their risk factors and prognostic factors is an urgent need. Our results showed that AST and the absolute number of drugs were significantly higher in s-ADRs than in non s-ADRs. Physicians should pay attention to patients’ liver function and the concurrent use of drugs to lower s-ADRs in elderly patients.

This study has certain limitations. First, multi-comorbidity is known to be an important risk factor for ADR in elderly patients [8,31]. However, the influence of comorbidities was not considered in this study. Future studies should include information on comorbidities. Second, this study was based on data from in-patients in a single hospital; thus, it may be limited in terms of generalization. Third, this was a retrospective study; therefore, it could be exposed to bias due to its design. Furthermore, data on the previous occurrence of ADRs or inappropriate prescriptions were unavailable. Fourth, various laboratory data on renal function were not considered in the current study. Although we checked that elevated serum creatinine did not affect our results, it would be needed for future studies on ADRs in the elderly to include more tests such as blood urea nitrogen, serum electrolyte level, and glomerular filtration rate tests. Lastly, multiple logistic regression was used to prove the significant number of pharmaceuticals taken in this study. However, the area under the receiver operating characteristic (ROC) curve is also an established method to investigate cutoff values. Thus, it would be helpful to generate ROCs to evaluate the cutoff values of the number of pharmaceuticals in further studies.

A prospective study on the risk factors for s-ADRs based on community-dwelling elderly patients is necessary. We suggest more evolved reporting systems, such as a software with electronic prescribing databases that enable efficient detection of ADRs in the elderly both on in-hospital and community bases.