Abstract
We conducted a retrospective study to investigate adverse drug reactions and associated medical costs among elderly individuals that could be avoided if pharmacotherapy was performed in accordance with the Beers Criteria: the Japanese Version (BCJV) and Guidelines for Medical Treatment and Its Safety in the Elderly 2015 (GL2015). Patients aged at least 65 years who were either hospitalized at Gifu Municipal Hospital between October 1 and November 30, 2014 (n = 1236) or had outpatient examinations at Gifu Municipal Hospital on October 1–2, 2014 (n = 980) were included in the study. The outcomes measured were usage rates of drugs listed in the BCJV and GL2015, incidence rates of adverse drug reactions, and additional costs incurred per patient due to adverse reactions. Among the inpatients, usage rates of drugs listed in the BCJV and GL2015 were 24.0 and 72.4%, respectively, and adverse reactions to these drugs occurred at rates of 3.0 and 8.2%, respectively. Among the outpatients, while the usage rates were 26.2% (BCJV) and 59.9% (GL2015), the incidence rates of adverse reactions were 4.7% (BCJV) and 3.9% (GL2015). The additional costs incurred due to adverse drug reactions ranged from 12713–163925 yen per patient. Our results demonstrate that appropriate use of drugs based on the BCJV and GL2015 can help prevent adverse reactions; this would reduce the overall medical costs.
INTRODUCTION
Elderly individuals are prone to adverse drug reactions because of their decreased physiological functions.1) Risk factors for adverse reactions in elderly individuals include concomitant use of multiple drugs, dementia, decreased visual acuity, renal failure, and liver impairment. Indices for determining the order of priority of prescription drugs are required to prevent adverse reactions.
The Beers criteria2) and the screening tool of older persons’ potentially inappropriate prescription (STOPP)/screening tool to alert doctors to right treatment (START) criteria3) are used as indices for identifying drugs that should be avoided in elderly patients. Studies using these indices for identifying drugs that need to be avoided or discontinued are being conducted in many countries.4–7) Based on these indices, 2.9–38.5% of prescriptions are potentially inappropriate for elderly individuals.4) Meanwhile, several countries have also been estimating the medical costs that could have been avoided by preventing adverse reactions to inappropriate drugs in elderly people.8–15) In the Netherlands, the avoidable drug-related hospitalization cost was reported to be approximately 11.6 billion yen per year, while in Germany, this cost amounted to 124.7 billion yen per year. Therefore, it is vital to identify adverse reactions associated with potentially inappropriate prescriptions and avoid the costs associated with their administration.
In Japan, the Beers Criteria: the Japanese Version (BCJV)16) established by the National Institute of Public Health, and the Guidelines for Medical Treatment and its Safety in the Elderly 2015 (GL2015),17) established by the Japan Geriatrics Society, were published in 2015,18) as indices for drugs that should be avoided in elderly patients as well as for those drugs that should be discontinued. Three investigations conducted in Japan reported that 43.6–56.1% of drug prescriptions are potentially inappropriate for elderly inpatients based on the BCJV.19–21) The GL2015 has been reported to be a useful support tool for making decisions regarding dose reduction and discontinuation processes in home-care patients.22) There has been no report on adverse drug reactions of potentially inappropriate prescriptions and related medical costs that could be avoided using the BCJV and GL2015 in both inpatient and outpatient settings. Therefore, it is very important to investigate avoidable adverse drug reactions and medical costs in clinical settings in Japan using these indices to identify widely used drugs that need to be avoided or discontinued.
In this study, we investigated avoidable adverse drug reactions and associated costs using BCJV- and GL2015-recommended pharmacotherapy practices as references.
PATIENTS AND METHODS
Subjects and the Studied DrugsThe subjects included patients aged at least 65 years who (a) were hospitalized at Gifu Municipal Hospital between October 1 and November 30, 2014, or (b) attended outpatient examinations at Gifu Municipal Hospital on October 1–2, 2014.
The studied drugs included those listed in the BCJV and GL2015 as potentially inappropriate prescriptions. The adverse reactions investigated were those described in each index as adverse reactions by potentially inappropriate prescriptions.
Study DetailsThe study was conducted retrospectively using electronic medical records. The investigated items included records on age, sex, treatment department, disease, length of hospitalization, medication history, drugs brought to the hospital, laboratory test results, and doctors/pharmacists/nurses. Diseases were classified according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision.
Study OutcomesThe evaluated outcomes included drug usage rates, incidence rates of adverse reactions associated with drug usage, and additional costs incurred per patient due to adverse reactions.
Identification of Adverse Reactions and Evaluation of Their Likelihood and SeverityAdverse reactions were identified using the Global Trigger Tool23,24) as a reference. The Global Trigger Tool is a procedure for finding triggers and for identifying potential adverse events from a retrospective review of medical records by medical staff. It is considered to be the best method for detecting adverse events and is used worldwide. It can detect adverse events caused by all medical interventions. In this study, we focused on adverse drug reactions; we identified adverse reactions caused by drugs listed in the BCJV and GL2015 using this tool. Patients who were found to exhibit adverse reactions were classified based on a three-level likelihood scale: “possible,” “probable/likely,” and “certain.”25) “Certain” means that a doctor has concluded that the reaction was caused by the drug. “Probable/likely” means that the reaction was likely caused by the drug but that a doctor has not confirmed this. “Possible” means that the causal relationship between the drug and reaction could not be denied. Severity of adverse reactions was graded based on medical records and laboratory test results using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events version 2.0. Identification of adverse reactions and evaluation of their likelihood and severity were conducted by 2 pharmacists with at least 10 years of clinical experience and by a doctor as appropriate.
Calculation of Extra Costs Incurred Due to Adverse ReactionsTo estimate the total extra cost incurred due to adverse reactions in inpatients and outpatients throughout Japan, we used the following equation:
“Annual total extra costs incurred due to adverse reactions in inpatients or outpatients throughout Japan” (yen/year) = “the extra costs incurred per patient due to adverse reactions” (yen/person) (the values in this study) × “annual number of inpatients or outpatients aged at least 65 years throughout Japan” (person/year) (the values in the national data) × “rate of inpatients or outpatients listed according to either the BCJV or GL2015 compared to all inpatients or outpatients” (%) (the values in Results of this study)
During medical economic assessment, the so-called micro-costing method was used to estimate medical expenses.26,27) First, for inpatients or outpatients exhibiting adverse reactions, the extra costs incurred per patient due to these reactions were calculated. Using the micro-costing method, we calculated the “resource costs provided under the Social Security System,” which refers to the costs of drugs, diagnoses, tests, procedures, hospitalization, and rehabilitation that are subject to “benefit in kind” under the National Health Insurance. Drug costs were calculated using fiscal-year 2014 drug prices. Costs for diagnosis, tests, procedure services, hospitalization services, and rehabilitation services were calculated using the fiscal year 2014 National Health Insurance medical remuneration points system. Numbers for each service were calculated in the following three ways: (1) total for the first day of hospitalization, (2) total per month, and (3) total for each day the service was performed. When costs were totaled for the first day of hospitalization, the medical remuneration costs for each service were divided by the number of days of hospital stay to calculate the medical remuneration points for each day. When costs were totaled per month, the monthly cost was divided by the number of days in that month to calculate the medical remuneration points for each day. When costs were totaled for each day on which the service was performed, the costs calculated on that day were directly used to calculate the medical remuneration points. To calculate the cost of each service, the remuneration points for each day thus obtained were multiplied by the number of days for which treatment was provided (e.g., number of days for which a doctor prescribed any drug and/or for which a procedure was performed) for an adverse reaction. Second, we calculated the total extra costs incurred due to these reactions in inpatients or outpatients. Then, “the extra costs incurred per patient due to the adverse reactions” in all inpatients or all outpatients were calculated by dividing this value by the number of inpatients or outpatients in this study.
Third, we calculated the “annual number of inpatients or outpatients aged at least 65 years throughout Japan” using the results of the 2014 patient survey that estimated the annual number of patients aged at least 65 years who were hospitalized throughout Japan.28) For inpatients, the “number of inpatients aged at least 65 years per day (937300)” was multiplied by 365 d and divided by the “mean number of days in the hospital for patients aged at least 65 years (41.7 d).” Similarly, the number of outpatients treated each year was calculated by multiplying the “number of outpatients aged at least 65 years per day (3510200)” by 365 d.
Compliance with Ethical StandardsThis study was approved by the Institutional Review Boards of Gifu Municipal Hospital (approval no.: 328) and the Gifu Pharmaceutical University (approval no.: Hei 27 8). Furthermore, the opt-out consent approach, approved by both ethical committees, was used in this study. Based on the Ethical Guidelines for Medical and Health Research Involving Human Subjects (Ministry of Health, Labour and Welfare of Japan), obtaining written informed consent from patients was not compulsory because this was a pharmacoepidemiological study that did not require any interventions or interactions with patients because it used pre-existing materials and information. There were no financial grants or other sources of funding received in support of this project.
RESULTS
Subject Selection and Number of Analyzed PatientsAmong all the patients surveyed, 1236 were inpatients and 980 were outpatients. Among inpatients and outpatients, the usage rates for drugs listed in the BCJV were 24.0% (297/1236) and 26.2% (257/980), while those for drugs listed in the GL2015 were 72.4% (895/1236) and 59.9% (587/980), respectively (Fig. 1).
Patient AttributesTable 1 shows the attributes of patients who were prescribed drugs listed in the BCJV and GL2015.
Table 1. Patient Attribute
| (A) Inpatients | | | | | | |
|---|
| Beers Criteria Japanese Version | Guidelines for Medical Treatment and Its Safety in the Elderly 2015 |
|---|
| Overall (n = 297) | Adverse reaction (n = 9) | No adverse reaction (n = 288) | Overall (n = 895) | Adverse reaction (n = 73) | No adverse reaction (n = 822) |
|---|
| Gender [n (%)] |
| Male | 179 (60.3%) | 6 (66.7%) | 173 (60.1%) | 530 (59.2%) | 37 (50.7%) | 493 (60.0%) |
| Female | 118 (39.7%) | 3 (33.3%) | 115 (39.9%) | 365 (40.8%) | 36 (49.3%) | 329 (40.0%) |
| Age [years, mean ± standard deviation] | 77.9 ± 6.8 | 81.1 ± 5.2 | 77.8 ± 6.8 | 77.7 ± 7.2 | 78.4 ± 8.2 | 77.7 ± 7.1 |
| Length of hospital stay [days, mean ± standard deviation] | 18.9 ± 23.2 | 23.1 ± 11.8 | 18.8 ± 23.5 | 17.9 ± 19.4 | 26.4 ± 17.0 | 17.2 ± 19.5 |
| Disease [n (%) ] |
| Certain infectious and parasitic diseases | 106 (35.7%) | 2 (22.2%) | 104 (36.1%) | 312 (34.9%) | 31 (42.5%) | 281 (34.2%) |
| Neoplasms | 138 (46.5%) | 3 (33.3%) | 135 (46.9%) | 441 (49.3%) | 37 (50.7%) | 404 (49.1%) |
| Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism | 81 (27.3%) | 1 (11.1%) | 80 (27.8%) | 226 (25.3%) | 28 (38.4%) | 198 (24.1%) |
| Endocrine, nutritional and metabolic diseases | 183 (61.6%) | 4 (44.4%) | 179 (62.2%) | 489 (54.6%) | 45 (61.6%) | 444 (54.0%) |
| Mental and behavioural disorders | 55 (18.5%) | 2 (22.2%) | 53 (18.4%) | 112 (12.5%) | 10 (13.7%) | 102 (12.4%) |
| Diseases of the nervous system | 100 (33.7%) | 4 (44.4%) | 96 (33.3%) | 304 (34.0%) | 31 (42.5%) | 273 (33.2%) |
| Diseases of the eye and adnexa | 85 (28.6%) | 3 (33.3%) | 82 (28.5%) | 213 (23.8%) | 22 (30.1%) | 191 (23.2%) |
| Diseases of the ear and mastoid process | 49 (16.5%) | 2 (22.2%) | 47 (16.3%) | 158 (17.7%) | 13 (17.8%) | 145 (17.6%) |
| Diseases of the circulatory system | 236 (79.5%) | 7 (11.5%) | 229 (79.5%) | 628 (70.2%) | 53 (72.6%) | 575 (70.0%) |
| Diseases of the respiratory system | 147 (49.5%) | 9 (100%) | 141 (49.0%) | 414 (46.3%) | 39 (53.4%) | 375 (45.6%) |
| Diseases of the digestive system | 225 (75.8%) | 7 (77.8%) | 218 (75.7%) | 676 (75.5%) | 58 (79.5%) | 618 (75.2%) |
| Diseases of the skin and subcutaneous tissue | 103 (34.7%) | 2 (22.2%) | 101 (35.7%) | 306 (34.2%) | 27 (37.0%) | 279 (33.9%) |
| Diseases of the musculoskeletal system and connective tissue | 136 (45.8%) | 5 (55.6%) | 131 (45.5%) | 461 (51.5%) | 46 (63.0%) | 415 (50.5%) |
| Diseases of the genitourinary system | 130 (43.8%) | 4 (44.4%) | 126 (43.8%) | 342 (38.2%) | 29 (39.7%) | 313 (38.1%) |
| Pregnancy, childbirth and the puerperium | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Certain conditions originating in the perinatal period | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Congenital malformations, deformations and chromosomal abnormalities | 2 (0.7%) | 0 (0%) | 2 (0.7%) | 3 (0.3%) | 1 (1.4%) | 2 (0%) |
| Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified | 111 (37.4%) | 5 (55.6%) | 106 (36.8%) | 330 (36.9%) | 33 (45.2%) | 297 (36.1%) |
| Injury, poisoning and certain other consequences of external causes | 27 (19.1%) | 1 (11.1%) | 26 (9.0%) | 84 (9.4%) | 5 (6.8%) | 79 (9.6%) |
| (B) Outpatients | | | | | | |
|---|
| Beers Criteria Japanese Version | Guidelines for Medical Treatment and Its Safety in the Elderly 2015 |
|---|
| Overall (n = 257) | Adverse reaction (n = 12) | No adverse reaction (n = 245) | Overall (n = 587) | Aderse reaction (n = 23) | No adverse reaction (n = 564) |
|---|
| Gender [n (%)] |
| Male | 156 (60.7%) | 8 (66.7%) | 148 (60.4%) | 335 (57.1%) | 11 (47.8%) | 324 (57.4%) |
| Female | 101 (39.3%) | 4 (33.3%) | 97 (39.6%) | 252 (42.9%) | 12 (52.2%) | 240 (42.6%) |
| Age [years, mean ± standard deviation] | 76.1 ± 6.4 | 73.8 ± 7.0 | 76.1 ± 6.3 | 76.2 ± 6.4 | 77.4 ± 7.1 | 76.1 ± 6.3 |
| Disease [n (%) ] |
| Certain infectious and parasitic diseases | 126 (49.0%) | 6 (50.0%) | 120 (49.0%) | 271 (46.2%) | 13 (56.5%) | 258 (45.7%) |
| Neoplasms | 103 (40.1%) | 5 (41.7%) | 98 (40.0%) | 266 (45.3%) | 11 (47.8%) | 255 (45.2%) |
| Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism | 89 (34.6%) | 5 (41.7%) | 84 (34.3%) | 191 (32.5%) | 13 (56.5%) | 178 (31.6%) |
| Endocrine, nutritional and metabolic diseases | 173 (67.3%) | 9 (75.0%) | 164 (66.9%) | 394 (67.1%) | 18 (78.3%) | 376 (66.7%) |
| Mental and behavioural disorders | 89 (34.6%) | 5 (41.7%) | 84 (34.3%) | 162 (27.6%) | 5 (21.7%) | 157 (27.8%) |
| Diseases of the nervous system | 150 (58.4%) | 6 (50.0%) | 144 (58.8%) | 303 (51.6%) | 13 (56.5%) | 290 (51.4%) |
| Diseases of the eye and adnexa | 113 (44.0%) | 4 (33.3%) | 109 (44.5%) | 228 (38.8%) | 8 (34.8%) | 220 (39.0%) |
| Diseases of the ear and mastoid process | 72 (28.0%) | 3 (25.0%) | 69 (28.2%) | 154 (26.2%) | 6 (26.1%) | 148 (26.2%) |
| Diseases of the circulatory system | 204 (79.4%) | 11 (91.7%) | 193 (78.8%) | 436 (74.3%) | 20 (87.0%) | 416 (73.8%) |
| Diseases of the respiratory system | 147 (57.2%) | 6 (50.0%) | 141 (57.6%) | 323 (55.0%) | 14 (60.9%) | 309 (54.8%) |
| Diseases of the digestive system | 230 (89.5%) | 9 (75.0%) | 221 (90.2%) | 519 (88.4%) | 20 (87.0%) | 499 (88.5%) |
| Diseases of the skin and subcutaneous tissue | 150 (58.4%) | 5 (41.7%) | 145 (59.2%) | 293 (49.9%) | 13 (56.5%) | 282 (50.0%) |
| Diseases of the musculoskeletal system and connective tissue | 171 (66.5%) | 8 (66.7%) | 163 (66.5%) | 376 (64.1%) | 19 (82.6%) | 357 (63.3%) |
| Diseases of the genitourinary system | 108 (42.0%) | 6 (50.0%) | 102 (41.6%) | 243 (41.4%) | 10 (43.5%) | 233 (41.3%) |
| Pregnancy, childbirth and the puerperium | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Certain conditions originating in the perinatal period | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Congenital malformations, deformations and chromosomal abnormalities | 3 (1.2%) | 0 (0%) | 3 (1.2%) | 7 (1.2%) | 0 (0%) | 7 (1.2%) |
| Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified | 105 (40.9%) | 8 (66.7%) | 97 (39.6%) | 231 (39.4%) | 14 (60.9%) | 217 (38.5%) |
| Injury, poisoning and certain other consequences of external causes | 27 (10.5%) | 1 (8.3%) | 26 (10.6%) | 59 (10.1%) | 2 (8.7%) | 57 (10.1%) |
Among the inpatients who were prescribed drugs listed in the BCJV, 60.3% were men, with a mean age of 77.9 years and a mean hospital stay of 18.9 d. The most common reason for drug administration was cardiovascular disease. Meanwhile, 59.2% of the inpatients who were prescribed drugs listed in the GL2015 were men with a mean age of 77.7 years and a mean hospital stay of 17.9 d. The most common reason for prescription of these drugs in this group was gastrointestinal disease.
Among the outpatients who were prescribed drugs listed in the BCJV, 60.7% were men, with a mean age of 76.1 years. The most common reason for taking these drugs was gastrointestinal disease. Contrastingly, 57.1% of the outpatients who were prescribed drugs listed in the GL2015 were men, with a mean age of 76.2 years. The most common reason for prescription of these drugs in this group was also gastrointestinal disease.
Incidence and Severity Grading of Adverse ReactionsAmong inpatients, the incidence rates of adverse reactions to drugs listed in the BCJV and GL2015 were 3.0 and 8.2%, respectively. Table 2A summarizes the likelihood of adverse reactions and their severity grading. For patients who were prescribed drugs listed in the BCJV and GL2015, the adverse reactions were rated as possible (81.8 and 68.7%), likely (9.1 and 18.1%), or definite (9.1 and 13.3%, respectively). Similarly, in patients who were prescribed drugs listed in the BCJV and GL2015, adverse reaction severity was scored as grade 1 (9.1 and 39.8%), grade 2 (36.4 and 24.1%), grade 3 (18.2 and 15.7%), or grade 4 (36.4 and 20.5%, respectively).
Table 2. Likelihood and Severity Grading of Adverse Reactions
| (A) Inpatients | | |
|---|
| Beers Criteria Japanese Version (n = 11) | Guidelines for Medical Treatment and Its Safety in the Elderly 2015 (n = 83) |
|---|
| Likelihood scale |
| Possible | 9 (81.8%) | 57 (68.7%) |
| Probable/likely | 1 (9.1%) | 15 (18.1%) |
| Certain | 1 (9.1%) | 11 (13.3%) |
| Grade |
| 1 | 1 (9.1%) | 33 (39.8%) |
| 2 | 4 (36.4%) | 20 (24.1%) |
| 3 | 2 (18.2%) | 13 (15.7%) |
| 4 | 4 (36.4%) | 17 (20.5%) |
| (B) Outpatients | | |
|---|
| Beers Criteria Japanese Version (n = 12) | Guidelines for Medical Treatment and Its Safety in the Elderly 2015 (n = 34) |
|---|
| Likelihood scale |
| Possible | 3 (25.0%) | 6 (17.6%) |
| Probable/likely | 5 (41.7%) | 16 (47.1%) |
| Certain | 4 (33.3%) | 12 (35.3%) |
| Grade |
| 1 | 5 (41.7%) | 13 (38.2%) |
| 2 | 5 (41.7%) | 10 (29.4%) |
| 3 | 1 (8.3%) | 4 (11.8%) |
| 4 | 1 (8.3%) | 7 (20.6%) |
Among outpatients, the incidence rates of adverse reactions to drugs listed in the BCJV and GL2015 were 4.7 and 3.9%, respectively. Table 2B summarizes the likelihood of adverse reactions and their severity grading. For patients who were prescribed drugs listed in the BCJV and GL2015, adverse reactions were rated as possible (25.0 and 17.6%), probable/likely (41.7 and 47.1%), or certain (33.3 and 35.3%, respectively). Similarly, for patients who were prescribed drugs listed in the BCJV and GL2015, adverse reaction severity was scored as grade 1 (41.7 and 38.2%), grade 2 (41.7 and 29.4%), grade 3 (8.3 and 11.8%), or grade 4 (8.3 and 20.6%, respectively).
Incidence Rates of Adverse Reactions and Usage of Individual DrugsTable 3 shows the list of drugs to which adverse reactions were noted among inpatients and discharged patients, as well as the incidence rates of adverse reactions and usage of drugs listed in the BCJV and GL2015.
Table 3. Usage Rates for Individual Drugs and the Incidence of Adverse Reactions to Them
| (A) Inpatients | | | |
|---|
| Drug | Usage rate (A) | Adverse reaction incidence (B) | A × B |
|---|
| Beers Criteria Japanese Version |
| Nifedipine | 3.4% (42/1236) | 11.9% (5/42) | 0.40% (5/1236) |
| H2 blockers | 2.6% (32/1236) | 3.1% (1/32) | 0.08% (1/1236) |
| Zolpidem | 1.5% (19/1236) | 10.5% (2/19) | 0.16% (2/1236) |
| Sulpiride | 1.3% (16/1236) | 6.3% (1/16) | 0.08% (1/1236) |
| Amantadine | 0.7% (9/1236) | 22.2% (2/9) | 0.16% (2/1236) |
| Guidelines for Medical Treatment and Its Safety in the Elderly 2015 |
| NSAIDs | 30.7% (380/1236) | 1.3% (5/380) | 0.40% (5/1236) |
| H2 receptor antagonists | 14.5% (179/1236) | 4.5% (8/179) | 0.65% (8/1236) |
| Loop diuretics | 9.6% (119/1236) | 16.8% (20/119) | 1.62% (20/1236) |
| Non-benzodiazepine sleeping pills | 8.1% (100/1236) | 4.0% (4/100) | 0.32% (4/1236) |
| Benzodiazepine sleeping pill/anti-anxiety agent | 7.9% (98/1236) | 11.2% (11/98) | 0.89% (11/1236) |
| Spironolactone | 7.0% (87/1236) | 6.9% (6/87) | 0.49% (6/1236) |
| Oral steroid agents | 6.6% (81/1236) | 1.2% (1/81) | 0.08% (1/1236) |
| Sliding-scale insulin therapy | 5.6% (69/1236) | 4.3% (3/69) | 0.24% (3/1236) |
| Non-dihydropyridine calcium blockers | 4.9% (61/1236) | 9.8% (6/61) | 0.49% (6/1236) |
| Sulfonylurea agents | 4.9% (60/1236) | 1.7% (1/60) | 0.08% (1/1236) |
| Beta-glucosidase inhibitors | 1.5% (19/1236) | 5.3% (1/19) | 0.08% (1/1236) |
| Opioids | 1.3% (16/1236) | 25.0% (4/16) | 0.32% (4/1236) |
| Anti-histamines | 0.9% (11/1236) | 9.1% (1/11) | 0.08% (1/1236) |
| Muscarinic receptor antagonists (overactive bladder medication) | 0.6% (8/1236) | 12.5% (1/8) | 0.08% (1/1236) |
| Beta 3 adrenergic drug receptor stimulants | 0.4% (5/1236) | 20.0% (1/5) | 0.08% (1/1236) |
| Parkinson’s disease medications | 0.2% (2/1236) | 50.0% (1/2) | 0.08% (1/1236) |
| (B) Outpatients | | | |
|---|
| Drug | Usage rate (A) | Adverse reaction incidence (B) | A × B |
|---|
| Beers Criteria Japanese Version |
| Aspirin | 6.0% (59/980) | 6.8% (4/59) | 0.41% (4/980) |
| Flunitrazepam | 2.9% (28/980) | 3.6% (1/28) | 0.10% (1/980) |
| Anticholinergic agents | 2.0% (20/980) | 5.0% (1/20) | 0.10% (1/980) |
| Long-acting benzodiazepines | 1.7% (17/980) | 5.9% (1/17) | 0.10% (1/980) |
| Doxazosin | 1.7% (17/980) | 5.9% (1/17) | 0.10% (1/980) |
| Nifedipine | 1.7% (17/980) | 5.9% (1/17) | 0.10% (1/980) |
| Pilsicainide | 1.3% (13/980) | 7.7% (1/13) | 0.20% (2/980) |
| Very long-acting benzodiazepines | 0.9% (9/980) | 22.2% (2/9) | 0.10% (1/980) |
| Guidelines for Medical Treatment and Its Safety in the Elderly 2015 |
| Non-dihydropyridine calcium blockers | 19.9% (195/980) | 1.0% (2/195) | 0.20% (2/980) |
| Antiplatelet drugs | 14.6% (143/980) | 4.9% (7/143) | 0.71% (7/980) |
| NSAIDs | 12.3% (121/980) | 1.7% (2/121) | 0.20% (2/980) |
| Benzodiazepine sleeping pill/anti-anxiety agent | 11.7% (115/980) | 8.7% (10/115) | 1.02% (10/980) |
| Non-benzodiazepine sleeping pills | 6.8% (67/980) | 4.5% (3/67) | 0.31% (3/980) |
| Spironolactone | 3.3% (32/980) | 3.1% (1/32) | 0.10% (1/980) |
| Biguanide | 3.2% (31/980) | 3.2% (1/31) | 0.10% (1/980) |
| Sulfonylurea agents | 2.8% (27/980) | 11.1% (3/27) | 0.31% (3/980) |
| Non-selective alfa 1 blockers | 2.0% (20/980) | 5.0% (1/20) | 0.10% (1/980) |
| Muscarinic receptor antagonists | 0.8% (8/980) | 25.0% (2/8) | 0.20% (2/980) |
| Parkinson’s disease medications | 0.7% (7/980) | 14.3% (1/7) | 0.10% (1/980) |
| Opioids | 0.7% (7/980) | 14.3% (1/7) | 0.10% (1/980) |
Table 4A summarizes the adverse reactions noted among inpatients. Among patients who were prescribed drugs listed in the BCJV, high incidence rates of constipation (11.4%) and delirium (8.8%) were noted, while among those who were prescribed drugs listed in the GL2015, high incidence rates of constipation (10.2%) and electrolyte imbalance (8.4%) were observed. Among patients who were prescribed drugs listed in the BCJV, delirium was the only grade 4 adverse reaction (80.0%) noted, while among those who were prescribed drugs listed in the GL2015, grade 4 hyperkalemia (16.7%), renal dysfunction (64.3%), and delirium (100%) were noted.
Table 4. Incidence Rates and Severity of Adverse Reactions
| (A) Inpatients | | | | | |
|---|
| Adverse reaction | Incidence | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
|---|
| Beers Criteria Japanese Version |
| Constipation | 11.4% (5/44) | 0 (0%) | 4 (80.0%) | 1 (20.0%) | 0 (0%) |
| Delirium | 8.8% (5/57) | 0 (0%) | 0 (0%) | 1 (20.0%) | 4 (80.0%) |
| Fall | 2.1% (1/47) | 1 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Guidelines for Medical Treatment and its Safety in the Elderly 2015 |
| Constipation | 10.2% (14/137) | 0 (0%) | 11 (78.6%) | 3 (21.4%) | 0 (0%) |
| Electrolyte imbalance | 8.4% (10/119) | 6 (60.0%) | 3 (30.0%) | 1 (10.0%) | 0 (0%) |
| Hyperkalemia | 6.9% (6/87) | 3 (50.0%) | 1 (16.7%) | 1 (16.7%) | 1 (16.7%) |
| Ischuria | 5.6% (1/18) | 0 (0%) | 1 (100%) | 0 (0%) | 0 (0%) |
| Fall | 4.9% (11/226) | 11 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Hypoglycemia | 3.1% (4/128) | 2 (50.0%) | 1 (25.0%) | 1 (25.0%) | 0 (0%) |
| Renal dysfunction | 3.1% (14/452) | 0 (0%) | 0 (0%) | 5 (35.7%) | 9 (64.3%) |
| Delirium | 2.6% (7/266) | 0 (0%) | 0 (0%) | 0 (0%) | 7 (100%) |
| Decreased cognitive function | 2.5% (7/277) | 5 (71.4%) | 1 (14.3%) | 1 (14.3%) | 0 (0%) |
| Orthostatic hypotension | 2.3% (3/132) | 3 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Upper gastrointestinal bleeding | 1.1% (4/380) | 2 (50.0%) | 2 (50.0%) | 0 (0%) | 0 (0%) |
| Oversedation | 1.0% (1/101) | 0 (0%) | 0 (0%) | 1 (100%) | 0 (0%) |
| Peptic ulcer | 0.4% (1/274) | 1 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
| (B) Outpatients | | | | | |
|---|
| Adverse reaction | Incidence | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
|---|
| Beers Criteria Japanese Version |
| Long QT syndrome | 5.9% (1/17) | 0 (0%) | 1 (100%) | 0 (0%) | 0 (0%) |
| Platelet aggregation inhibition | 5.8% (4/69) | 3 (75.0%) | 1 (25.0%) | 0 (0%) | 0 (0%) |
| Orthostatic hypotension | 5.6% (1/18) | 1 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Constipation | 5.4% (2/37) | 0 (0%) | 2 (100%) | 0 (0%) | 0 (0%) |
| Fall | 4.6% (3/65) | 0 (0%) | 1 (33.3%) | 1 (33.3%) | 1 (33.3%) |
| Decreased cognitive function | 0.8% (1/124) | 1 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Guidelines for Medical Treatment and its Safety in the Elderly 2015 |
| Hypoglycemia | 7.5% (4/53) | 2 (50.0%) | 1 (25.0%) | 0 (0%) | 1 (25.0%) |
| Dipsia | 5.9% (1/17) | 1 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Constipation | 5.4% (5/93) | 0 (0%) | 5 (100%) | 0 (0%) | 0 (0%) |
| Fall | 5.3% (12/227) | 2 (16.7%) | 2 (16.7%) | 4 (33.3%) | 4 (33.3%) |
| Bleeding risk | 4.9% (7/143) | 5 (71.4%) | 2 (28.6%) | 0 (0%) | 0 (0%) |
| Hyperkalemia | 3.1% (1/32) | 1 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Orthostatic hypotension | 1.2% (1/81) | 1 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Renal dysfunction | 1.2% (2/173) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (100%) |
| Decreased cognitive function | 0.6% (1/169) | 1 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
Table 4B summarizes the adverse reactions observed among outpatients. Among patients who were prescribed drugs listed in the BCJV, high incidence rates of long QT syndrome (5.9%) and platelet aggregation inhibition (5.8%) were noted, while among those who were prescribed drugs listed in the GL2015, high incidence rates of hypoglycemia (7.5%) and polydipsia (5.9%) were observed. Among patients who were prescribed drugs listed in the BCJV, falling was the only grade 4 adverse reaction (33.3%); however, grade 4 hypoglycemia (25.0%), falling (33.3%), and renal dysfunction (100%) were observed in patients who were prescribed drugs listed in the GL2015.
Calculation of Extra Costs Incurred Due to Adverse ReactionsThe extra cost incurred due to adverse reactions per inpatient who was prescribed drugs listed in the BCJV and GL2015 were 1109 and 13371 yen that added up to annual national costs of 2.18 and 79.42 billion yen per year, respectively. Similarly, the extra costs incurred due to adverse reactions per outpatient who was prescribed drugs listed in the BCJV and GL2015 were 798 and 497 yen that added up to annual national costs of 267.87 and 381.42 billion yen per year, respectively.
DISCUSSION
It is very important to investigate avoidable adverse drug reactions and medical costs in clinical settings in Japan using the BCJV and GL2015 indices for identifying widely used drugs that need to be avoided or discontinued. There has been no report on adverse drug reactions of potentially inappropriate prescriptions and related avoidable medical costs in both inpatient and outpatient settings using the BCJV and GL2015 indices as references. Therefore, we conducted this retrospective study to investigate adverse reactions associated with potentially inappropriate prescriptions of drugs listed in the BCJV and GL2015. We also estimated the medical costs associated with these adverse reactions.
A fact-finding survey conducted at an acute care hospital in Japan reported that adverse reactions to drugs occurred at a rate of 9.2% among inpatients.29) The incidence rate of adverse reactions in elderly inpatients in this study was lower than that reported in patients of all ages by previous studies in Japan; this may be because doctors prescribe drugs listed in the BCJV and GL2015 more carefully to elderly patients than to patients of other ages. Actually, the usage rate of potentially inappropriate drugs according to the BCJV (24.0%) in our study was lower than that in previous reports (43.6–56.1%).19–21) According to a survey conducted in the United States, adverse reactions occurred in 10% or more of elderly outpatients and in 15–20% of residents in elder-care facilities every year.30) The present survey focused exclusively on adverse reactions in patients who received drugs listed in the BCJV and GL2015, and we found that the incidence rates ranged from 3.0–8.2% in inpatients and outpatients. The incidence rate of adverse reactions in elderly inpatients was lower in this study than that reported by previous studies that were conducted overseas, despite the differences between the countries; this may be because doctors prescribe drugs listed in the BCJV and GL2015 more carefully to elderly patients than to patients of other ages. This study is the first one to report these incidence rates and is, therefore, the only available reference for such data.
The usage rates for drugs listed in the BCJV (24.0% in inpatients and 26.2% in outpatients) in our study were lower than the rates for those listed in the GL2015 (72.4 and 59.9%, respectively); this would be because a narrower range of drugs is listed in the BCJV than in the GL2015.22) Slight differences were observed in incidence rates of adverse reactions, likelihood of adverse reactions, and severity grading between drugs listed in the BCJV and GL2015. The BCJV and GL2015 had similar potentials for avoiding adverse drug reactions in elderly patients.
Among patients who were prescribed drugs listed in the BCJV and GL2015, delirium and fall were the most common adverse reactions among inpatients and outpatients, respectively. We found that 80 and 100% of inpatients who developed delirium after being prescribed drugs listed in the BCJV and GL2015, respectively, had grade 4 delirium. Similarly, among outpatients who were prescribed drugs listed in these 2 indices, 33.3% of the fall cases were rated grade 4. These data indicate the severity of both the adverse reactions. Delirium is a type of temporary disturbance of consciousness that frequently occurs in elderly people and can cause accidents such as falls and removal of tubing/lines. Therefore, care must be taken to prevent this reaction from becoming severe when drugs listed in the 2 indices are administered to inpatients. As outpatients perform a wider range of activities than inpatients, they are at a higher risk for falls. Falls not only cause physical disorders from injuries and fractures, but they also greatly lower the patient’s QOL. Therefore, it is important to prevent falls by using the 2 indices as references for proposing optimal prescriptions for outpatients. Constipation and falls were commonly noted among inpatients and outpatients. Constipation was noted in 26 patients, of which 84.6 and 15.4% had grade 2 and grade 3 constipation, respectively. This suggests that constipation needs to be treated in many patients before it reaches grade 3, at which stage stool extraction is required. Falls were noted in 27 patients, of which 37% experienced grade 3 and grade 4 falls; these patients were incapable of independent daily activities. Wide variation was noted in the severity of falls, indicating that it depends on the circumstances under which the falls occur.
Based on the product of the usage rate and incidence of adverse reactions, benzodiazepines (BZs) and non-benzodiazepines (non-BZs) were found to be the most common drugs that caused a high incidence of adverse reactions in both inpatients and outpatients. BZs are used as sleeping pills and anti-anxiety agents, while non-BZs are used only as sleeping pills. As usage rates and incidence of adverse reactions related with these drugs are high, extra care needs to be taken while administering them. Meanwhile, the 2010 Report of the International Narcotics Control Board commented on the high consumption of BZs in Japan and reported that the reason for this was inappropriate prescriptions.31) However, we confirmed that the use of the 2 indices for BZs and non-BZs was versatile and useful for prescribing these drugs to elderly patients. Therefore, referring to these indices for pharmacotherapy is likely to reduce the prevalence of such inappropriate prescriptions. An epidemiological study conducted in Japan found that complaints of insomnia were more common in individuals aged 60 years or older (29.5%) than in individuals aged 59 years or younger (18.5%).32) These findings indicate that these 2 indices should be carefully used while deciding appropriate prescriptions of sleeping aids for elderly patients.
The extra annual cost per patient for tests and treatment of adverse reactions was found to be 36596–163925 yen for inpatients and 12713–17076 yen for outpatients. A previous study reported these costs to be 943.40–7192.36 euro for inpatients and 702.21–40273.08 euro for outpatients.13) The calculated costs in our study, although fairly close to those reported previously, are somewhat lower, which is potentially due to differences in age groups and adverse reactions that were investigated. In our study, costs for only days on which a health care provider performed treatment for an adverse reaction were included in the calculations; this may also have contributed to the lower estimates.
The extra cost for treatment of adverse reactions in patients who used drugs listed in the BCJV and GL2015 was estimated to range from 497 to 13371 yen per patient, which corresponds to a national cost of 2.18–381.42 billion yen per year. This is the first report to provide data on per-patient costs as well as on the overall national expense incurred due to adverse drug reactions. The costs calculated in our study are higher than the 23.9 trillion yen currently spent for treatment/care of elderly individuals aged 65 years or older. Therefore, the BCJV and GL2015 indices appear to be useful for reducing medical costs.
Limitations of this study include the fact that this study was limited to patients at one general hospital in one specific region and that this was a retrospective study using electronic medical records. Not all adverse drug reactions were evaluated, unlike prospective monitoring of adverse drug reactions using BCJV and GL2015. In the future, doctors and pharmacists need to prospectively monitor elderly patients according to the BCJV and GL2015 and need to evaluate the incidence of adverse drug reactions and associated medical costs.
In conclusion, this study demonstrates that appropriate use of drugs based on the BCJV and GL2015 can help prevent adverse reactions; this would help in reducing the overall medical costs. Based on the kinds of drugs used and types/severities of the adverse drug reactions observed in this study, doctors need to carefully prescribe drugs to elderly patients by referring to the BCJV and GL2015, and pharmacists need to actively suggest prescriptions according the BCJV and GL2015.
Conflict of Interest
The authors declare no conflict of interest.
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