Many studies have assessed the risk factors for adverse drug reactions (ADRs) in elderly patients. However, most of these studies have focused on risk factors for ADRs, not serious ADRs (s-ADRs). s-ADRs are commonly found in hospitalized patients. s-ADRs warrant imminent but thorough investigations, given their critical impact on patient health. Therefore, this retrospective study aimed to assess the associated risk factors for s-ADRs in elderly hospitalized patients.
In-patients aged >65 years having ADRs during hospitalization at a university hospital in Korea between 2010 and 2012 were included. Medical professionals spontaneously reported ADRs using an electronic submission system at the study hospital. Further, all descriptions of ADRs were characterized and categorized through the screening of electronic medical records. We compared the characteristics of patients having s-ADRs with those of patients not having s-ADRs.
There were 353 cases of ADRs, 67 of which were s-ADRs. Patients taking more than eight concomitant drugs showed the highest odds ratio (OR, 11.99; 95% confidence interval [CI], 3.42–42.03). The ratio of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) was also significantly related to s-ADRs (OR, 2.78; 95% CI, 1.33–5.81). The use of antibiotics (OR, 2.39; 95% CI, 1.13–5.02) and antineoplastics (OR, 4.17; 95% CI, 1.09–15.94) were significant risk factors.
Our findings highlight the importance of polypharmacy. Liver function tests (AST/ALT ratio) must be monitored carefully within high-risk groups for ADRs.
The elderly population is usually defined as individuals aged over 65 years [
The impact of ADRs increases the cost of patient care [
Serious ADRs are probably reported more systematically than ADRs because ADRs are only reported voluntarily by clinicians [
A retrospective observational study was conducted to compare the characteristics of patients having s-ADRs with patients having non-serious ADRs (non s-ADRs) during hospitalization (IRB no., DUIH 2012-25). The requirement for informed consent was waived by Dongguk University Ilsan Hospital instutional review board due to the retrospective nature of the study and the minimal risk involved in the study.
This study was conducted at Dongguk University Ilsan Hospital in a metropolitan area of South Korea, in a satellite city from the capital. Elderly patients were defined as those aged >65 years. There were 353 cases, of which 56.1% were comprised of women. The mean age was 73.74±6.56 years. The most frequent diagnoses were respiratory diseases (86 cases, 24.4%), infection (83 cases, 23.5%), cardiovascular diseases (65 cases, 18.4%), and neoplasms (46 cases, 13.0%), in descending order.
A total of 353 ADRs were gathered from e-subs between April 2010 and January 2012. We collected comprehensive data of ADRs not only from spontaneous reporting through the ADR reporting system by doctors and nurses but also from the deduction of descriptions about ADRs in medical records with the help of a medical informatics team. As the medical record system is completely electronic in the study hospital, we believe that all s-ADRs during the study period have been accounted for. Medical professionals reported ADRs using an ADR-reporting electronic interface. The reporters were asked to provide information on suggested culprit drugs, organ-specific adverse reactions (e.g., systemic fever, skin itching), severity, and duration. The history of medication was investigated using medical records of one day before the incident of ADRs. Laboratory tests were performed within 1–7 days prior to ADRs in the morning when the patients were in a fasting state. The e-sub was then transformed into a database for analyzing causal relationships by a medical informatics team comprising a drug allergist, pharmacists, and specialized nurses.
Reported and collected ADR data were reviewed by the ADR monitoring council in an RPVC within the hospital using the WHO-Uppsala Monitoring Center (WHO-UMC) criteria [
The present study compared the characteristics of elderly patients having s-ADRs with patients having non s-ADRs during admission. Frequencies were compared using the chi-square test. T-tests were used to compare alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratios. Logistic regression was performed to assess the significance and odds ratios (ORs) of the predictors related to s-ADR. Variables found to be statistically significant (P<0.05) in the univariate analysis were included in the multivariate analysis. All selected variables were assessed for correlation to avoid multicollinearity. Statistical analysis was performed using SPSS ver. 16.02 (SPSS Inc., Chicago, IL, USA).
There were 353 cases of ADRs, of which 67 were s-ADRs (18.9%). Out of 3,640 elderly patients admitted to the Department of Internal Medicine at the study hospital, 353 patients with ADRs were included in the study. A total of 26,810 adult patients were admitted to the study hospital during the study period. Furthermore, 1,650 ADR cases were reported (1,560/26,810, 5.8%). Thus, the proportion of ADRs in elderly patients (9.7% [353/3,640]) was higher than the ADR incidence in adult patients. A total of 56.1% of the cases were comprised of women, and the mean age was 73.74±6.56 years. The median number of concomitant drugs in all ADRs was eight, 12 in s-ADRs, and seven in non s-ADRs (
ADRs were reported by doctors (281 cases, 79.6%) and nurses (71 cases, 20.1%). A total of 80.6% of s-ADRs were reported by doctors. The causality assessment showed certain causality in 20 cases (5.7%), possible causality in 246 cases (69.7%), and probable causality in 87 cases (24.6%), of all ADR cases. There was an even distribution of causality assessment among s-ADRs and non s-ADRs.
The most frequent ADR clinical manifestation was skin lesions, including itching (115 matters, 40.2%) (
The drugs causing ADRs included antibiotics (147 cases, 41.6%), antituberculosis agents (61 cases, 17.3%), antihypertensive agents (50 cases, 17.3%), antihistamines (26 cases, 7.4%), anticonvulsants (19 cases, 5.4%), and non-steroidal anti-inflammatory drugs (19 cases, 5.4%). The three most common drugs involved in s-ADRs were antibiotics (77.6%), antineoplastic agents (16.4%), and antihypertensive agents (12.0%). In comparison, the drugs involved in non s-ADRs were antibiotics (33.2%), antituberculosis agents (21.0%), and antihypertensive agents (14.7%). Antibiotics and antineoplastic agents were more often involved in s-ADRs (P<0.001 and 0.003, respectively). Other culprit drugs were listed in Supplement 1.
In the univariate analysis, there were no differences in gender between ADR and s-ADR cases. The mean age was higher in s-ADRs than in non s-ADRs (P<0.001) (
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 [
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 [
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 [
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 [
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 [
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.
No potential conflict of interest relevant to this article was reported.
We appreciate the research nurse Sun Young Jung in the regional pharmacovigilance center of the study hospital for her assistance.
Supplementary materials can be found via
List of “other” culprit drugs of non-serious adverse drug reaction vs. serious adverse drug reaction group
Demographic and medical characteristics of the study sample of 353 elderly inpatients
Characteristic | ADRs but not serious (n=286) | Serious ADRs (n=67) | P-value |
---|---|---|---|
Gender | 0.072 |
||
Female | 167 (58.4) | 31 (46.3) | |
Male | 119 (41.6) | 36 (53.7) | |
Age (y) | 73.26±6.321 | 75.79±7.187 | 0.004 |
No. of concomitant drugs | <0.001 |
||
≥8 | 135 (47.2) | 55 (82.1) | |
≤7 | 151 (52.8) | 12 (17.9) | |
AST (IU/L) | 21.0 (6–205) | 22.2 (9–165) | 0.232 |
ALT (IU/L) | 15.5 (4–144) | 14.0 (2–174) | 0.793 |
Creatinine (mg/dL) | 0.9 (0–20) | 0.84 (0–6) | 0.626 |
Clinical manifestations | |||
Skin lesion, itching | 115 (40.2) | 24 (35.8) | 0.058 |
Gastrointestinal symptoms |
105 (36.7) | 13 (19.4) | <0.001 |
Dizziness | 31 (10.8) | 3 (4.5) | 0.041 |
Impaired renal function | 22 (7.7) | 7 (10.4) | 0.887 |
Dyspnea | 17 (5.9) | 6 (9.0) | 0.725 |
Abnormal haematological finding |
14 (4.9) | 39 (58.2) | <0.001 |
Anaphylaxis | 9 (3.1) | 10 (15.0) | 0.004 |
Increase in AST, ALT level | 7 (2.4) | 5 (7.5) | 0.159 |
Etc. |
77 (26.9) | 12 (17.9) | |
Culprit drugs | |||
Antibiotics | 95 (33.2) | 52 (77.6) | <0.001 |
Anti-tuberculosis drugs | 60 (21.0) | 1 (1.5) | <0.001 |
Antihypertensive agents | 42 (14.7) | 8 (12.0) | 0.522 |
Antihistamine | 26 (9.1) | 0 | 0.010 |
Antineoplastics | 15 (5.2) | 11 (16.4) | 0.003 |
Antacid | 17 (6.0) | 5 (7.5) | 0.782 |
Parenteral nutrition | 20 (7.0) | 1 (1.5) | 0.095 |
Anticonvulsants | 17 (6.0) | 2 (3.0) | 0.553 |
Nonsteroidal anti-inflammatory drugs | 16 (5.6) | 3 (4.5) | >0.999 |
Others | 136 (47.6) | 24 (35.8) | |
Major diagnoses | |||
Respiratory diseases | 73 (25.5) | 13 (19.4) | 0.201 |
Infection | 63 (22.0) | 20 (29.9) | 0.321 |
Cardiovascular diseases | 52 (18.2) | 13 (19.4) | 0.978 |
Neoplasms | 31 (10.8) | 15 (22.4) | 0.026 |
Cerebrovascular diseases | 33 (11.5) | 5 (7.5) | 0.264 |
Musculoskeletal diseases | 34 (11.9) | 2 (3.0) | 0.023 |
Gastrointestinal/hepatic diseases | 22 (7.7) | 1 (1.5) | 0.061 |
Endocrinologic diseases | 16 (5.6) | 6 (9.0) | 0.414 |
Chronic renal failure | 18 (6.3) | 2 (3.0) | 0.392 |
Neuropsychiatric diseases | 5 (1.7) | 2 (3.0) | 0.632 |
hematologic disease | 3 (1.0) | 4 (6.0) | 0.033 |
Etc. |
31 (10.8) | 13 (19.4) | 0.102 |
Values are presented as numbers (%), mean±standard deviation, or median (min–max).
ADR, adverse drug reaction; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
By chi-square test.
By independent t-test.
By Mann-Whitney test.
Nausea, vomiting, diarrhea, constipation.
Eosinophilia, neutropenia.
Edema, arrhythmia, fever, confusion, chest discomfort.
By Fisher’s exact test.
Dermatitis, electrolyte imbalance, eye diseases, urologic diseases.
Factors associated with serious adverse drug reactions in multivariate logistic regression model
Variable | Odds ratio (95% confidence interval) | P-value |
---|---|---|
Gender | 0.458 | |
Male | 1.32 (0.63–2.76) | |
Female | - | |
Age | 1.01 (0.95–1.06) | 0.839 |
No. of pharmaceutical | <0.001 | |
≥8 | 11.99 (3.42–42.03) | |
≤7 | - | |
AST/ALT ratio | 0.007 | |
≥1.3 |
2.78 (1.33–5.81) | |
<1.3 | - | |
Taking antibiotics | 2.39 (1.13–5.03) | 0.022 |
Taking antineoplastics | 4.17 (1.09–15.94) | 0.037 |
Reference group is non-serious adverse drug reactions.
AST, aspartate aminotransferase; ALT, alanine aminotransferase.
1.3 was the median value of AST/ALT ratio in this data.