Korea has recently attained the aged society status and the growth rate of the aging population will be among the most rapid worldwide. The objective of this study was to develop a credible list of potentially inappropriate medications (PIMs) for Korean older adults.
A new Korean PIMs list was produced through a comprehensive structured expert survey (modified Delphi method). To generate an expert panel, we invited the nomination of experts in geriatric medication from the Korean Geriatric Society, the Korean Academy of Clinical Geriatrics, the Korean Academy of Family Medicine, the Korean Association for Geriatric Psychiatry, and the Korean Association of Geriatric Hospitals. Based on their recommendation, the expert panel consisted of 14 geriatric specialists, including 10 geriatricians (7 family medicine doctors and 3 internal medicine doctors), 3 geriatric psychiatrists, and 1 clinical pharmacist. After 4 rounds, the new Korean PIMs list was finalized.
Sixty-two drugs were classified as PIMs for older adults irrespective of comorbidities, including antipsychotics, tricyclic antidepressants, benzodiazepines, non-steroidal anti-inflammatory drugs, and first-generation antihistamines. Forty-eight drugs or drug categories were classified as PIMs for 18 specific conditions that older adults encounter frequently. The expert panel presented the rationale and comments including preferred therapeutic alternatives and exceptional situations for each item.
We presented a “user-friendly” PIMs list for Korean older adults. Further prospective studies to validate its usefulness in clinical settings and regular updating of the list are required. It is also important to disseminate this list to doctors who prescribe medication to older people.
In January 2018, approximately 7.4 million Koreans (14.3% of the total population) were ≥65 years of age.
Older patients generally use more drugs than younger people. Changes in pharmacokinetics and pharmacodynamics, poor homeostatic reserves, and increased frailty significantly increase the risk of adverse drug events (ADEs) in older populations.
Medications whose risk of ADEs outweighs their expected clinical benefit when they are administered to older persons are considered potentially inappropriate medications (PIMs), especially when there are better-tolerated alternatives.
A research steering team was formed to recruit experts and prepare and circulate the content of the Delphi rounds. The team comprised 2 geriatricians, a family physician, a Delphi method expert, and a public health researcher. The final PIMs list was produced through 4 rounds of comprehensive structured expert surveys distributed through email (modified Delphi method).
To generate an expert panel, we invited nomination of experts in geriatric medication from the Korean Geriatric Society, the Korean Academy of Clinical Geriatrics, the Korean Academy of Family Medicine, the Korean Association for Geriatric Psychiatry and the Korean Association of Geriatric Hospitals. All nominees were provided information regarding the study objectives and design and the commitment required for participation. Finally, the expert panel consisted of 14 geriatric specialists, including 10 geriatricians (7 family medicine doctors and 3 internal medicine doctors), 3 geriatric psychiatrists, and 1 clinical pharmacist.
The questionnaire for the first-round survey consisted of open-ended questions about the recommendations of preexisting PIMs screening tools published in English or Korean that the new Korean PIMs list should refer to, the appropriate number of items on the new list, and general opinions and comments regarding the research process.
According to the response of the first-round survey and literature review, a preliminary list was produced based on the 2015 Beers criteria,
In the questionnaire for the second-round survey, the research steering team provided summarized information from the responses to the first round and the process of developing the preliminary list. The expert panel was asked to score with 5-point Likert scales the frequency (1, very rare; 2, rare; 3, average; 4, common; 5, very common) and severity (1, trivial; 2, mild; 3, average; 4, severe; 5, very severe) of the ADEs that are potentially caused by each item in the preliminary list. The panelists were allowed a “cannot judge” option and asked to state the reason why each item was inappropriate, preferred therapeutic alternatives, methods to minimize the risk, and other general comments. To help the expert panel evaluate the items, the reference and major rationale of each item and representative brand names of the drugs were included in the questionnaire.
The clinical significance score (CSS) of the medications was defined as the product of the frequency and severity scores. According to the expert panel’s suggestion that the appropriate number of PIMs items would be <90, items with a CSS <9 were excluded from the first draft of the Korean PIMs list. The draft included 49 medications that should be avoided by most older adults, regardless of co-morbid conditions, and 45 medications to be avoided by older adults with specific conditions. Based on the experts’ opinions and literature review, the research steering team described the rationale and comments for each medicine on the PIMs list, including preferred therapeutic alternatives and exceptional situations. In the third-round survey, the expert panel was asked to state whether they agreed with the inclusion or exclusion of each item and if not, to present their rationale and supporting evidence.
Reflecting the experts’ opinions in the third-round survey, the second draft of Korean PIMs list was produced. The second draft, including changes and their rationale, was submitted to the expert panel for approval. The final version of the Korean PIMs list was generated, with minor modifications of the second draft, to reflect the response to the fourth-round survey. Items for which no consensus was achieved in the fourth round were excluded from the final version.
The present study protocol was reviewed and approved by the Research Committee of Seoul Medical Center and the study was conducted in accordance with the principles of the Declaration of Helsinki.
The final PIMs list is presented in
A total of 62 drugs were classified as PIMs for older adults irrespective of comorbidities, most of which were antipsychotics, tricyclic antidepressants (TCA), benzodiazepines, first-generation antihistamines, and nonsteroidal anti-inflammatory drugs (NSAID). Some antiparkinsonian drugs (benztropine, trihexyphenidyl), antispasmodics (clidinium-chlordiazepoxide, scopolamine), skeletal muscle relaxants (methocarbamol, orphenadrine), and oxybutynin were included in this list due to their strong anticholinergic properties. Among cardiovascular drugs, some antiarrhythmics (dronedarone, amiodarone, and flecainide), digoxin, and ticlopidine were included due to their worse clinical outcomes or higher risk of adverse events compared to those of available alternatives.
A total of 48 drugs or drug categories were classified as PIMs for 18 specific conditions that older adults encounter frequently. The panel agreed that anticholinergics are especially inappropriate for older adults with cognitive problems, higher fall risk, constipation, lower urinary tract symptoms, or glaucoma, which includes first-generation antihistamines, bladder antimuscarinics, tricyclic antidepressants, and some antipsychotics. Benzodiazepine and zolpidem were also classified as PIMs for older patients with cognitive problems and higher fall risk. Antipsychotics and metoclopramide should be avoided in patients with Parkinson disease whenever possible. The panel agreed that NSAID use requires special precautions in older adults with heart failure, hypertension, chronic kidney disease, history of peptic ulcer, or concurrent bleeding disorders. The use of aspirin in older adults aged ≥80 years for cardiovascular primary prevention and the use of aspirin plus clopidogrel for stroke secondary prevention are discouraged except in special situations because they could increase bleeding risk without definite benefit. Hyponatremic older patients are recommended to avoid diuretics, some antidepressants and antipsychotics.
We present a new PIMs list for Korean older adults that was developed in collaboration with major geriatric academic societies in Korea. The list was generated with the modified Delphi method referring to recently published international screening tools such as the 2015 Beers criteria and the revised STOPP.
A prospective, observational cohort study showed that the self-reported history of falls (odds ratio, 1.23; 95% confidence interval [CI], 1.04–1.45) and hospital admission (hazard ratio, 1.16; 95% CI, 1.08–1.24) were independently associated with the use of PIMs in community-dwelling older men.
As there is no official geriatric training system in Korea, many Korean doctors might be unfamiliar with PIMs for older adults. For this reason, the expert panel agreed to provide a concise rather than exhaustive list, which can be easily adopted by doctors who treat older people, including primary care physicians and surgeons. To reduce the number of PIMs items, the research steering team excluded items with CSS <9 points, with the possibility of re-entry in further Delphi rounds. We also merged some conditions sharing similar PIMs; for example, dementia with delirium, and history of falls with syncope and postural hypotension. Finally, we were able to produce a concise list including 62 general PIMs and 48 PIMs for 18 specific conditions compared to the 2015 Beers criteria, which included 113 general PIMs, 68 PIMs for 12 specific conditions, and 16 PIMs with caution. Despite the small number of items, the new list addresses common ADEs in the older population such as falls and cognitive problems,
Some panelists were skeptical about the inclusion of antipsychotics in this list because nonpharmacological options such as behavioral intervention for Behavioral and Psychological Symptoms of Dementia management are rarely available in Korean hospitals and long-term care facilities. However, with increasing evidence of harm associated with antipsychotics
This study has several limitations. Because of limited resources, we generated the preliminary list without evidence review for each item but rather from the review of existing criteria, which could result in the omission of recently introduced items. However, in view of the limited number of methodologically high-quality studies of older patients, the Delphi method based on existing criteria has been acknowledged as an acceptable way to generate a domestic PIMs list.
Computerized decision support, where electronic alerts are produced to guide the prescriber, is an effective intervention in improving medication prescription in older adults.
We hope that this explicit PIMs list helps Korean physicians to make individualized therapeutic decisions for their older patients and improve medication safety. Further prospective studies to validate its usefulness in various clinical setting and regular updating of the list are required.
The authors thank Rho SY (Seoul Women’s University, Seoul) for advice regarding the Delphi process; Hwang HJ (Catholic Kwandong University College of Medicine, Incheon), Park YM (National Health Insurance Service Ilsan Hospital, Ilsan), Rho YK (Hallym University Medical Center, Seoul), Lee EJ (Asan Medical Center, Seoul), Kim ST (Seocho Cham Convalescence Hospital, Seoul), Lee HW (Seoul Medical Center, Seoul), and Park SH (Seoul Medical Center, Seoul) for their participation in the Delphi process; the Korean Geriatric Society, the Korean Academy of Clinical Geriatrics, the Korean Academy of Family Medicine, the Korean Association for Geriatric Psychiatry, and the Korean Association of Geriatric Hospitals for expert nominations. This study was supported by an internal research grant from the Seoul Medical Center (16-C11).
The researchers claim no conflicts of interest.
Potentially inappropriate medications in older adults
Organ system, drug category, drugs | Rationale | Comments |
---|---|---|
Central nervous system | ||
| ||
Antipsychotics | Increased mortality and stroke risk in dementia patients | Exceptions: schizophrenia, bipolar disorder |
(1st generation) | ||
Chlorpromazine | ||
(2nd generation) | ||
Haloperidol | ||
Risperidone, Olanzapine, Clozapine, Quetiapine | ||
| ||
Antidepressants | Highly anticholinergic, sedating, and cause orthostatic hypotension | Possible alternatives: SSRIs, SNRIs or mirtazapine |
Amitriptyline | ||
Amoxapine | ||
Clomipramine | ||
Doxepin (>6 mg/day) | ||
Nortriptyline | ||
Imipramine | ||
| ||
Benzodiazepines | High risk of dependence |
Exceptions: seizure disorders, rapid eye movement sleep disorders, myoclonus, benzodiazepine withdrawal, ethanol withdrawal, severe generalized anxiety disorder, and periprocedural anesthesia |
(Short- and intermediate-acting) | ||
Alprazolam | ||
Lorazepam | ||
Temazepam | ||
Triazolam | ||
(Long-acting) | ||
Chlordiazepoxide | ||
Clonazepam | ||
Diazepam | ||
Flurazepam | ||
Bromazepam | ||
Clobazam | ||
Flunitrazepam | ||
| ||
Zolpidem | Similar safety profile to benzodiazepines | If prescription is inevitable, prescribe medication for a short duration |
| ||
Antiparkinsonian agents | Risk of anticholinergic side effects such as confusion, dry mouth, constipation, etc. | Possible alternatives: levodopa for the treatment of Parkinson's disease |
Benztropine | ||
Trihexyphenidyl | ||
| ||
First-generation antihistamines | Risk of anticholinergic side effects such as confusion, dry mouth, constipations, etc. | Possible alternatives: second-generation antihistamines |
Chlorpheniramine | ||
Dimenhydrinate | ||
Diphenhydramine | ||
Hydroxyzine | ||
Triprolidine | ||
| ||
Cardiovascular system | ||
| ||
Antiarrhythmics | Worse clinical outcomes or higher adverse events than those of other antiarrhythmics | Rate control (with beta blockers or calcium channel blockers) is preferred over rhythm control in atrial fibrillation of older patients unless patients have heart failure or substantial left ventricular hypertrophy |
Dronedarone | ||
Amiodarone | ||
Flecainide | ||
| ||
Digoxin | May be associated with increased mortality in older adults with atrial fibrillation or heart failure | Avoid as a first-line therapy for atrial fibrillation or heart failure |
| ||
Ticlopidine | Altered blood counts and weak evidence | Possible alternatives: aspirin, clopidogrel |
| ||
Gastro-intestinal system | ||
| ||
Metoclopramide | Extrapyramidal effects including tardive dyskinesia | Short-term use might be appropriate |
| ||
Cimetidine | Can cause confusion and delirium | Possible alternatives: proton pump inhibitors(short-term) |
| ||
Antispasmodics | Risk of anticholinergic side effects such as confusion, dry mouth, constipation, etc. |
|
Clidinium-chlordiazepoxide | ||
Scopolamine | ||
| ||
Kidney and urinary tract | ||
| ||
Peripheral alpha-1 blockers | High risk of orthostatic hypotension |
Not recommended as routine treatment for hypertension |
Doxazosin | ||
Prazosin | ||
Terazosin | ||
| ||
Desmopressin | High risk of hyponatremia | Exception: diabetes insipidus |
| ||
Oxybutynin | Risk of anticholinergic side effects such as confusion, dry mouth, constipation, etc. | |
| ||
Endocrine system | ||
| ||
Estrogens±progestins | Evidence of carcinogenic potential (breast and endometrium) |
Especially contraindicated for patients with a history of breast cancer or venous thromboembolism |
| ||
Growth hormone | Impact on body composition is small and associated with edema, arthralgia, carpal tunnel syndrome, gynecomastia, and impaired fasting glucose | Exception: hormone replacement after pituitary gland removal |
| ||
Insulin, sliding scale | Higher risk of hypoglycemia without improvement in glucose control | Refers to the sole use of short- or rapid-acting insulins to manage or avoid hyperglycemia in the absence of basal or long-acting insulin |
Glibenclamide | Increased risk of hypoglycemia | Possible alternatives: other oral hypoglycemic agents such as metformin |
| ||
Musculoskeletal system | ||
| ||
Opioid analgesics | More commonly causes adverse CNS effects than other opioid analgesics | Possible alternatives: acetaminophen, oxycodone, buprenorphine patch |
Pethidine | ||
Pentazocine | ||
| ||
NSAIDs | Increased risk of GI bleeding, peptic ulcer disease and kidney injury |
This drug list is not exhaustive and other NSAIDs are also inappropriate for older patients |
Aspirin (>325 mg/day) | ||
Diclofenac | ||
Indomethacin | ||
Ibuprofen, Dexibuprofen | ||
Ketorolac, includes parenteral | ||
Mefenamic acid | ||
Naproxen | ||
Piroxicam | ||
Sulindac | ||
| ||
Skeletal muscle relaxants | Poorly tolerated by older adults because of sedation and increased risk of fractures |
|
Methocarbamol | ||
Orphenadrine |
BPH, benign prostatic hyperplasia; CNS, central nervous system; COX, cyclooxygenase; GI, gastrointestinal; HbA1c, glycated hemoglobin; NSAID, nonsteroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitors; SNRI, serotonin-norepinephrine reuptake inhibitors.
Potentially inappropriate medications in older adults with specific conditions
Organ system, disease, syndrome or condition | Drug category, drugs | Rationale | Comments |
---|---|---|---|
Central nervous system | |||
Delirium, dementia or cognitive impairment | Anticholinergics |
Potential of inducing or deteriorating delirium, dementia and cognitive impairment | Short-term and low-dose antipsychotic use might be appropriate for delirium or dementia if non-pharmacological options (e.g., behavioral interventions) have failed or are not possible and the older adult is threatening substantial harm to self or others |
History of falls, fractures, syncope or postural hypotension | Anticholinergics |
May cause ataxia, impaired psychomotor function, syncope, or additional falls | Exceptions for anticonvulsants: seizure, mood disorders Short-term opioid use with caution might be appropriate for moderate to severe pain management |
Insomnia | Caffeine |
CNS stimulant effects | |
Parkinson disease | Antipsychotics Metoclopramide | Potential to worsen Parkinsonian symptoms | Exceptions: aripiprazole, quetiapine, clozapine (less likely to worsen Parkinson disease) |
Cardiovascular system | |||
Heart failure | Verapamil |
Potential to worsen heart failure | Verapamil and diltiazem can be used in mild heart failure with caution |
Arrhythmia | TCAs | Pro-arrhythmic effects | |
Hypertension | NSAIDs | Risk of exacerbation of hypertension | Short-term use might be appropriate for mild hypertension (<160/90 mmHg) |
Primary prevention in adults ≥80 years of age | Aspirin | Lack of evidence of benefit versus risk in this age group | Use with caution in adults ≥80 years of age |
Secondary stroke prevention | Aspirin plus clopidogrel | Lack of evidence of added benefit over clopidogrel monotherapy | Exceptions: coronary stent(s) inserted in the previous 12 months, concurrent acute coronary syndrome, or high- grade symptomatic carotid arterial stenosis |
Gastro-intestinal system | |||
History of gastric or duodenal ulcers | Aspirin (>325 mg/day) |
Exacerbate existing ulcers or cause new ulcers | If other alternatives are not effective, gastroprotective agents (i.e., PPI or misoprostol) should be coprescribed |
Chronic constipation | Anticholinergics |
Exacerbate constipation | Short-term (<2 weeks) opioid use with laxatives might be appropriate for moderate to severe pain management |
Kidney and urinary tract | |||
Chronic kidney disease (CrCl <30 mL/min) | NSAIDs |
Increased risk of acute kidney injury and further decline of renal function | Possible alternatives: acetaminophen, corticosteroids |
Lower urinary tract symptoms, BPH | Anticholinergics |
Decreased urinary flow and cause urinary retention | Exceptions: antimuscarinics for urinary incontinence |
SIADH or hyponatremia | Diuretics | May exacerbate hyponatremia | Antipsychotics, antidepressants |
Chronic obstructive pulmonary disease | Theophylline as monotherapy | More effective agents (inhaler) are available | Theophylline is generally considered as a third-line bronchodilator after inhaled anticholinergics and beta- 2 agonists |
Concurrent bleeding disorder or high bleeding risk situation | Aspirin |
Increased bleeding risk | High bleeding risk includes uncontrolled severe hypertension, bleeding diathesis, or recent non- trivial spontaneous bleeding |
Diabetes | Beta-blockers | Masking of hypoglycemic symptoms | Exceptions: heart failure, ischemic heart disease |
Corticosteroids | May worsen diabetes | Avoid long-term use | |
Glaucoma | Anticholinergics |
Risk of acute exacerbation of glaucoma | If other alternatives are not available, discuss with ophthalmologists |
BPH, benign prostatic hyperplasia; COX, cyclooxygenase; COPD, chronic obstructive pulmonary disease; CrCl, creatinine clearance; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton-pump inhibitor; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TCA, tricyclic antidepressant.
Anticholinergics include first-generation antihistamines, bladder antimuscarinics, antidepressants (tricyclic antidepressants and paroxetin), antipsychotics (chlorpromazine, clozapine, olanzapine, perphenazine), antispasmodics (belladonna alkaloid, clidinium-chlordiazepoxide, dicyclomine, scopolamine), antiparkinsonian agents (benztropine, trihexyphenidyl), skeletal muscle relaxants (cyclobenzaprine, orphenadrine), etc.
Antidepressants include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, mirtazapine, and bupropion.
Some other drugs include carbamazepine, oxcarbazepine, carboplatin, cyclophosphamide, cisplatin and vincristine.
Direct oral anticoagulants include dabigatran, rivaroxaban, apixaban, and edoxaban.