Sarah N. Hilmer

Polypharmacy cutoff and outcomes: five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes

OBJECTIVE This study aimed to determine an optimal discriminating number of concomitant medications associated with geriatric syndromes, functional outcomes, and mortality in community-dwelling older men. STUDY DESIGN AND SETTING Older men aged ≥ 70 years (n=1,705), enrolled in the Concord Health and Aging in Men Project were studied. Receiver operating characteristic curve analysis using the Youden Index and the area under the curve was performed to determine discriminating number of medications in relation to each outcome. RESULTS The highest value of the Youden Index for frailty was obtained for a cutoff point of 6.5 medications compared with a cutoff of 5.5 for disability and 3.5 for cognitive impairment. For mortality and incident falls, the highest value of Youden Index was obtained for a cutoff of 4.5 medications. For every one increase in number of medications, the adjusted odds ratios were 1.13 (95% confidence interval [CI]=1.06-1.21) for frailty, 1.08 (95% CI=1.00-1.15) for disability, 1.09 (95% CI=1.04-1.15) for mortality, and 1.07 (95% CI=1.03-1.12) for incident falls. There was no association between increasing number of medications and cognitive impairment. CONCLUSION The study supports the use of five or more medications in the current definition of polypharmacy to estimate the medication-related adverse effects for frailty, disability, mortality, and falls.

Reducing Inappropriate Polypharmacy: The Process of Deprescribing

Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application.

Clinical pharmacology in the geriatric patient

Geriatric patients are a subset of older people with multiple comorbidities that usually have significant functional implications. Geriatric patients have impaired homeostasis and wide inter‐individual variability. Comprehensive geriatric assessment captures the complexity of the problems that characterize frail older patients and can be used to guide management, including prescribing. Prescribing for geriatric patients requires an understanding of the efficacy of the medication in frail older people, assessment of the risk of adverse drug events, discussion of the harm:benefit ratio with the patient, a decision about the dose regime and careful monitoring of the patients response. This requires evaluation of evidence from clinical trials, application of the evidence to frail older people through an understanding of changes in pharmacokinetics and pharmacodynamics, and attention to medication management issues. Given that most disease occurs in older people, and that older people are the major recipients of drug therapy in the Western world, increased research and a better evidence base is essential to guide clinicians who manage geriatric patients.

The Effects of Polypharmacy in Older Adults

An assessment of the safety and efficacy of multiple medications in older adults requires clinically relevant objective outcomes and pharmacological measures of medication exposure. Important outcomes include geriatric syndromes and objective measures of physical function. Measurements of medication exposure have evolved from merely counting the drugs to a consideration of pharmacologic principles such as drug class, dose response, and maximal effect. Emerging evidence regarding the effects of cumulative medication exposure on functions critical for independence may provide guidance for prescribers.

High‐Risk Prescribing and Incidence of Frailty Among Older Community‐Dwelling Men

Evidence about the association between treatment with high–risk medicines and frailty in older individuals is limited. We investigated the relationship between high–risk prescribing and frailty at baseline, as well as 2–year incident frailty, in 1,662 men ≥70 years of age. High–risk prescribing was defined as polypharmacy (≥5 medicines), hyperpolypharmacy (≥10 medicines), and by the Drug Burden Index (DBI), a dose–normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69–3.84) for polypharmacy, 5.80 (95% CI: 2.90–11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58–3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42–4.23) for polypharmacy, 2.50 (95% CI: 0.76–8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25–3.64) for DBI exposure. High–risk prescribing may contribute to frailty in community–dwelling older men.

Associations Between Drug Burden Index and Falls in Older People in Residential Aged Care

OBJECTIVES: To evaluate the association between the Drug Burden Index (DBI), a measure of a persons total exposure to anticholinergic and sedative medications that includes principles of dose‐response and maximal effect and is associated with impaired physical function in community‐dwelling older people, and falls in residents of residential aged care facilities (RACFs).

Physical and Cognitive Performance and Burden of Anticholinergics, Sedatives, and ACE Inhibitors in Older Women

Polypharmacy, common in older people, confers both risk of adverse outcomes and benefits. We assessed the relationship of commonly prescribed medications with anticholinergic and sedative effects to physical and cognitive performance in older individuals. The study population comprised 932 moderately to severely disabled community‐resident women aged 65 years or older who were participants in the Womens Health and Aging Study I. A scale based on pharmacodynamic principles was developed and utilized as a measure of drug burden. This was related to measures of physical and cognitive function. After adjusting for demographics and comorbidities, anticholinergic drug burden was independently associated with greater difficulty in four physical function domains with adjusted odds ratios (95% confidence interval (CI)) of 4.9 (2.0–12.0) for balance difficulty; 3.2 (1.5–6.9) for mobility difficulty; 3.6 (1.6–8.0) for slow gait; 4.2 (2.0–8.7) for chair stands difficulty; 2.4 (1.1–5.3) for weak grip strength; 2.7 (1.3–5.4) for upper extremity limitations; 3.4 (1.7–6.9) for difficulty in activities of daily living; and 2.4 (95% CI, 1.1–5.1) for poor performance on the Mini‐Mental State Examination. Sedative burden was associated only with impaired grip strength (3.3 (1.5–7.3)) and mobility difficulty (2.4 (1.1–5.3)). The burden of multiple drugs can be quantified by incorporating the recommended dose regimen and the actual dose and frequency of drug taken. Anticholinergic drug burden is strongly associated with limitations in physical and cognitive function. Sedative burden is associated with impaired functioning in more limited domains. The risk associated with exposure of vulnerable older women to drugs with anticholinergic properties, and to a lesser extent those with sedative properties, implies that such drugs should not be used in this patient group without compelling clinical indication.

Drug Burden Index Score and Functional Decline in Older People

BACKGROUND The Drug Burden Index (DBI), a measure of exposure to anticholinergic and sedative medications, has been independently associated with physical and cognitive function in a cross-sectional analysis of community-dwelling older persons participating in the Health, Aging and Body Composition study. Here we evaluate the association between DBI and functional outcomes in Health, Aging and Body Composition study participants over 5 years. METHODS DBI was calculated at years 1 (baseline), 3, and 5, and a measure of the area under the curve for DBI (AUCDB) over the whole study period was devised and calculated. Physical performance was measured using the short physical performance battery, usual gait speed, and grip strength. The association of DBI at each time point and AUCDB with year 6 function was analyzed in data from participants with longitudinal functional measures, controlling for sociodemographics, comorbidities, and baseline function. RESULTS Higher DBI at years 1, 3, and 5 was consistently associated with poorer function at year 6. On multivariate analysis, a 1-unit increase in AUCDB predicted decreases in short physical performance battery score of .08 (P=.01), gait speed of .01 m/s (P=.004), and grip strength of .27 kg (P=.004) at year 6. CONCLUSION Increasing exposure to medication with anticholinergic and sedative effects, measured with DBI, is associated with lower objective physical function over 5 years in community-dwelling older people.

A Systematic Review of Amnestic and Non-Amnestic Mild Cognitive Impairment Induced by Anticholinergic, Antihistamine, GABAergic and Opioid Drugs

BackgroundMild cognitive deficits are experienced by 18% of community-dwelling older adults, many of whom do not progress to dementia. The effect of commonly used medication on subtle impairments in cognitive function may be under-recognized.ObjectiveThe aim of the review was to examine the evidence attributing amnestic or non-amnestic cognitive impairment to the use of medication with anticholinergic, antihistamine, GABAergic or opioid effects.MethodsMEDLINE and EMBASE were searched for randomized, doubleblind, placebo-controlled trials of adults without underlying central nervous system disorders who underwent detailed neuropsychological testing prior to and after oral administration of drugs affecting cholinergic, histaminergic, GABAergic or opioid receptor pathways. Seventy-eight studies were identified, reporting 162 trials testing medication from the four targeted drug classes. Two investigators independently appraised study quality and extracted relevant data on the occurrence of amnestic, non-amnestic or combined cognitive deficits induced by each drug class. Only trials using validated neuropsychological tests were included. Quality of the evidence for each drug class was assessed based on consistency of results across trials and the presence of a dose-response gradient.ResultsIn studies of short-, intermediate- and long-acting benzodiazepine drugs (n = 68 trials), these drugs consistently induced both amnestic and non-amnestic cognitive impairments, with evidence of a dose-response relationship. H1-antihistamine agents (n = 12) and tricyclic antidepressants (n = 15) induced non-amnestic deficits in attention and information processing. Non-benzodiazepine derivatives (n = 29) also produced combined deficits, but less consistently than benzodiazepine drugs. The evidence was inconclusive for the type of cognitive impairment induced by different bladder relaxant antimuscarinics (n = 9) as well as for narcotic agents (n = 5) and antipsychotics (n = 5). Among healthy volunteers >60 years of age, low doses of commonly used medications such as lorazepam 0.5 mg, oxybutynin immediate release 5 mg and oxycodone 10 mg produced combined deficits.ConclusionNon-amnestic mild cognitive deficits are consistently induced by first-generation antihistamines and tricyclic antidepressants, while benzodiazepines provoke combined amnestic and non-amnestic impairments. Risk-benefit considerations should be discussed with patients in order to enable an informed choice about drug discontinuation or substitution to potentially reverse cognitive adverse effects.

The impact of frailty on the utilisation of antithrombotic therapy in older patients with atrial fibrillation

OBJECTIVE to investigate the impact of frailty on the utilisation of antithrombotics and on clinical outcomes in older people with atrial fibrillation (AF). DESIGN prospective study of a cohort of 220 acute inpatients aged > or =70 years with AF, admitted to a teaching hospital in Sydney, Australia (April-July 2007), with 207 followed up over 6 months. RESULTS a total of 140 patients (64%) were identified as frail using a validated tool. Frail patients were less likely to receive warfarin than non-frail on hospital admission (P = 0.002) and discharge (P < 0.001). During hospitalisation, the proportion of frail participants prescribed warfarin decreased by 10.7% and that of non-frail increased by 6.3%. Over the 6-month follow-up, 43 major or severe haemorrhages (20.8%), 20 cardioembolic strokes (9.7%) and 40 deaths (19.2%) were reported. Compared to non-frail, frail participants were significantly more likely to experience embolic stroke (RR 3.5, 95% CI 1.0-12.0, P < 0.05), had a small non-significant increase in risk of major haemorrhage (RR 1.5, 95% CI = 0.7-3.0, P = 0.29) and had greater mortality (RR 2.8, 95% CI 1.2-6.5, P = 0.01). CONCLUSION frail older inpatients with AF are significantly less likely to receive warfarin than non-frail and appear more vulnerable to adverse clinical outcomes, with and without antithrombotic therapy.