Sarah N Hilmer
David G Le Couteur
Medicines in older patients have the potential to provide great gains as well as significant harms.
To provide an ethically sound, evidence based discussion of the benefits and harms of medications commonly used in primary care among older patients.
Appropriate prescribing and deprescribing (drug withdrawal) for older patients requires a thorough understanding of the individual, their therapeutic goals, the benefits and risks of all of their medicines, and medical ethics. There is very limited evidence on the safety and efficacy of medicines in older adults, particularly in the frail, who often have multiple comorbidities and functional impairments. In robust older patients, therapy usually aims to delay or cure disease and to minimise functional impairment. In frail older patients, symptom control, maintaining function and addressing end-of-life issues become the main priorities. Optimising medicines is a time-consuming, multidisciplinary process that requires extensive communication, frequent monitoring and review, and has a major clinical impact.
People aged more than 65 years take more medicines than any other group, with over 90% taking at least one prescription medicine, and nearly half using five or more drugs (polypharmacy).1
The prevalence of chronic disease increases with age, and older people have much to gain from medicines that delay disease, cure disease or manage symptoms. However, older people are also at increased risk of adverse drug events. With increasing age, comes increasing inter- and intra-individual variability. Therapeutic aims, pharmacokinetics, pharmacodynamics, safety and efficacy vary significantly between individuals of the same age and change over time in older patients. Therefore, it is important to review all medicines appropriately in older patients to achieve relevant outcomes.1
Robust and frail older adults
In considering the potential benefits of medicines, it is important to differentiate robust from frail older adults. There are several objective definitions for frailty, such as the frailty phenotype (≥3 of unintentional weight loss, exhaustion, weakness, slow walking, low physical activity) and accumulation of medical, functional or social deficits.2–4 Robust older people are usually mobile and functionally independent, and medications are used to prevent and treat illness, alleviate symptoms and delay functional decline and mortality. In contrast, frail older people have reduced resilience to external stressors, are often less mobile, more functionally dependent, and may reside in a residential aged care facility. In frail older people, medical therapy may be predominantly aimed at relieving symptoms and maintaining function.5
Risks from medicines in older adults include adverse drug reactions, hospitalisation, functional impairment, geriatric syndromes (eg. confusion, falls, incontinence, frailty) and mortality.6 These risks increase with patient characteristics such as age, multiple comorbidities, low body weight, frailty and impaired hepatic or renal function. Risks are also associated with specific medicines exposures such as polypharmacy, drug-drug interactions, drug-disease interactions, drug-geriatric syndrome interactions,7 drugs with anticholinergic and sedative properties,8 anticoagulants, and antiplatelet and hypoglycaemic agents.9
Optimising medication use
Assessment of an older patient's medical therapy requires clear understanding by the doctor and patient of the therapeutic aims, and the potential and actual benefits and risks of the patient's medications. Key steps in optimising therapy in the older patient are outlined in Figure 1. Treatment guidelines are often based on clinical trials in young or robust older patients and must be applied with caution to frail older adults. Furthermore, guidelines rarely provide recommendations for patients with comorbidities.10
Figure 1. Key steps in optimising an older patient's medical therapy11,35
Understanding the available evidence
There is little evidence that many drug classes commonly prescribed for older patients reduce mortality.11 This may be due to multiple 'competing risks' for mortality,12 changes in pathophysiology, pharmacology and the increasing impact of adverse events of medicines.11
There is robust evidence to show major risks from polypharmacy and adverse drug reactions in old age.6,9,13 The limited evidence on deprescribing in older people suggests that it can be done safely.14–18 While efficacy is best assessed by randomised controlled trials (RCTs), adverse drug events are better assessed by observational studies and are more frequent in clinical practice than in RCTs.19
Estimates of benefits and risks of commonly used drug classes in general practice are summarised in Table 1 and described below.
Table 1. Estimates of benefits and risks of commonly used medication classes in older people
|Medication||Benefit||Study population*||RR, OR, HR (95% CI)||NNT||NNH|
||Secondary prevention of all cause mortality
||28 to prevent death over 5 years
||10–20 to experience myalgia
||Secondary prevention of all cause mortality
||84 to prevent death over a mean time of 4.5 years
||Two to experience any overall adverse events over a mean time of 4.5 years
||Secondary prevention of
||Primary prevention of all cause mortality
||Mean age of 57 years20
||120 to prevent one cardiovascular event over 6 years
||73 to experience a non-trivial bleed over 6 years
||Zoledronic acid after hip fracture prevention of mortality
||≥50 years (84% of participants aged over 65 years)38
||27 to prevent death over 3 years
||18 to experience pyrexia, 45 for myalgia, 45 for bone pain and 53 for musculoskeletal pain over 3 years
||Zoledronic acid after hip fracture prevention of mortality in nursing home subgroup
||A sub-study of: ≥50 years (84% of participants aged over 65 years)38
|RR = relative risk. The risk of developing an outcome in the group receiving the trial medication compared to the group not receiving the medication. RR <1, the outcome is less likely to occur in the medication group than in the control.
RR >1, the outcome is more likely to occur in the medication group
OR = odds ratio. The OR measures the ratio of the odds of an event (disease or death) occurring from specific causative agent to the odds of the event not occurring. The OR gives an idea of how strongly dependant the outcome is on the supposed causative agent. OR <1 suggests that the agent reduced the odds of the event occurring
HR = hazard ratio. The ratio of the chance of events (usually death) occurring in the treatment group as a ratio of the hazard occurring in the control group of a trial. HR <1 means that death is less likely to occur in a given time period in the treatment group than in the control
CI = confidence interval. This is a calculated range of the margin of error
NNT = number needed to treat. The number of patients who need to be treated for the stated time period for one patient to experience the stated benefit
NNH = number need to harm. The number of patients who need to be treated for the stated time period for one patient to experience the stated adverse event
* Most data is from robust older participants in randomised trials. When available, data from nursing home patients is included separately
Antiplatelets and antithrombotics
Data from RCTs suggests that when prescribing aspirin for primary prevention of cardiovascular disease, we need to treat 120 people for 6 years to prevent one event (number needed to treat [NNT] = 120). However, there will be one major bleed among 73 people over the same time (number needed to harm [NNH] = 73).20 Similar NNH are observed in RCTs of aspirin in patients with atrial fibrillation.21 However, an observational study of warfarin use in frail adults over 70 years of age with atrial fibrillation found a higher likelihood of harm: for every six people treated for 6 months one had a major bleed.22
Lipid lowering drugs are taken by over 40% of Australians aged over 65 years.23 In older patients, the best evidence for statins is for secondary prevention of cardiovascular events and death in patients with coronary heart disease.24,25 In this setting, a doctor would need to treat 28 patients for 5 years to prevent one death (NNT=28). The cost per quality associated life year (QALY) in secondary prevention are $15 000 to 24 000 for all age groups (45–85 years). However, for primary prevention of coronary heart disease, cost per QALY increases from $26 000 to 90 000 at 65 years to $56 000 to 169 000 at 85 years.26
General practitioners may consider withdrawal of statins when potential benefits are no longer clinically relevant. In patients with severe physical or cognitive impairments or those in their last year of life, reducing the risk of vascular events or mortality may no longer be important. Statins may also be withdrawn if frail older patients have significant symptoms or signs consistent with adverse effects in a temporal pattern associated with statin use.27
A recent Cochrane review of antihypertensive (mainly thiazides) use in adults over 60 years of age with moderate to severe systolic or diastolic hypertension, showed reduction in overall mortality, cardiovascular mortality and cardiovascular morbidity in healthy people aged 60–80 years. However, among patients 80 years of age or over, there was limited data showing no reduction in total mortality.28 Several prospective, open label studies of withdrawal of antihypertensives in patients over 65 years of age found that this can be done safely without withdrawal effects. Overall, 20–85% of subjects remained normotensive 6 months to 5 years after cessation, with no increase in mortality.14
The best evidence that sulfonylureas reduce microvascular complications of diabetes mellitus comes from the 20 year United Kingdom Prospective Diabetes Study (UKPDS), which recruited patients with a median age of 53 (+/– 8.6) years at baseline.29 Risks of hypoglycaemia increase with age and national guidelines recommend higher target blood sugar levels for older patients.30
Detection and treatment of infection is important and clinically effective in older patients. Infections are a major cause of death in old age, and not only affect the infected site, but also precipitate geriatric syndromes such as confusion and falls. Dosing of antibiotics, and all medicines, in frailty is complicated by reduced lean body weight, impaired hepatic and renal function31 and pharmacodynamic factors (increased risk of adverse events, impaired immune responses).5,11 Dose adjustment, monitoring of drug levels or clinical response may be required. Frail older adults in a pre-terminal state may choose not to treat infections with antibiotics.
The ethical principles of beneficence, nonmaleficence, autonomy and justice can be considered in guiding medication use in older adults, both on an individual and a population scale.32
The effectiveness of medicines can be considered a marker of beneficence, the duty to do good. Only a small proportion of medications, such as analgesics, can be monitored clinically in individual patients. For other drugs, individual assessment of benefit is limited to surrogate markers or is not possible. Therefore assessment may rely instead on the likelihood of doing good, which is derived from the results of clinical trials that may not be generalisable to frail older people.19 Adverse drug reactions are good examples of avoidable (nonmaleficence) harm, they increase with frailty and age, and may present atypically as geriatric syndromes.5 There is also increased harm from polypharmacy6 and the 'prescribing cascade', where drugs are prescribed to treat the side effects of others.33
Respect for autonomy may be a challenge when patients are not competent to consent to treatment due to cognitive impairment. Carers – acting as decision makers – may be in conflicted positions. For example, the treatment of behavioural disturbances in dementia arguably accrues the risks of adverse events from medications to the patient, while the benefits reside chiefly with the carers. Consideration of numbers needed to treat and harm from research trials may be helpful so that patients can weigh up the risks in keeping with their personal priorities.34
The principle of justice denotes fair, unbiased treatment on the basis of medical need. In Australia, age-based economic rationing of medicines does not occur directly on a population level. However, some individuals and communities of older patients on multiple medications may not be able to afford them despite government subsidies.35
General practitioners are best able to understand the complete medical, functional and social issues that are in play when optimising medications. A multidisciplinary approach involving doctors (GPs and specialists), pharmacists and nurses, is the common feature of successful interventions to reduce polypharmacy.36,37 Nevertheless, this is a time-consuming, ongoing activity.
General practitioners may consider a medication review after significant transitions such as moving into residential aged care, hospitalisation or a new diagnosis. Medication review by a pharmacist, or a structured interview performed by the practice nurse during which the patient (or carer) brings all their medications, will assist the GP in compiling information from multiple sources.
General practitioners may also need to liaise with specialists to ensure agreement on therapeutic goals. Where reaching concordance is difficult, a second opinion from another GP or a geriatrician may help.
Patients and their families need to be reassured that medicines are being changed to achieve their therapeutic goals. It must be clear that if drugs are ceased it is because they are causing harm or are of no benefit, and not because the patient is 'not worth treating'. Close monitoring of, and discussion with, the patient throughout the period of medication change will determine whether goals are being met, detect any adverse events, and demonstrate to the patient that the change is part of an active treatment plan.
- Individual therapeutic goals and priorities influence the choice to continue or commence medications in primary care.
- Polypharmacy and drug related adverse effects may cause significant harm to older patients.
- GPs can safely deprescribe medications with patient and multidisciplinary support.
Conflict of interest: none declared.
- Le Couteur DG, Hilmer SN, Glasgow N, Naganathan V, Cumming RG. Prescribing in older people. Aust Fam Physician 2004;33:777–81.
- Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146–56.
- Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci 2007;62:722–7.
- Hilmer SN, Perera V, Mitchell S, et al. The assessment of frailty in older people in acute care. Australas J Ageing 2009;28:182–8.
- Hubbard RE, O'Mahony MS, Woodhouse KW. Medication prescribing in frail older people. Eur J Clin Pharmacol 2012 Sep 11 [Epub ahead of print].
- Hilmer SN, Gnjidic D. The effects of polypharmacy in older adults. Clin Pharmacol Ther 2009;85:86–8.
- Gnjidic D, Hilmer SN, Blyth FM, et al. High-risk prescribing and incidence of frailty among older community-dwelling men. Clin Pharmacol Ther 2012;91:521–8.
- Hilmer SN, Mager DE, Simonsick EM, et al. A drug burden index to define the functional burden of medications in older people. Arch Intern Med 2007;167:781–7.
- Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011;365:2002–12.
- Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA 2005;294:716–24.
- Hilmer SN, McLachlan AJ, Le Couteur DG. Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol 2007;21:217–30.
- Berry SD, Ngo L, Samelson EJ, Kiel DP. Competing risk of death: an important consideration in studies of older adults. J Am Geriatr Soc 2010;58:783–7.
- Beer C, Hyde Z, Almeida OP, et al. Quality use of medicines and health outcomes among a cohort of community dwelling older men: an observational study. Br J Clin Pharmacol 2011;71:592–9.
- Iyer S, Naganathan V, McLachlan AJ, Le Couteur DG. Medication withdrawal trials in people aged 65 years and older: a systematic review. Drugs Aging 2008;25:1021–31.
- Garfinkel D, Mangin D. Feasibility study of a systematic approach for discontinuation of multiple medications in older adults: addressing polypharmacy. Arch Intern Med 2010;170:1648–54.
- Hardy JE, Hilmer SN. Deprescribing in the final year of life. Journal of Pharmacy Practice and Research 2011;411:148–51.
- Beer C, Loh P, Peng YG, Potter K, Millar A. A pilot randomised controlled trial of deprescribing. Ther Adv Drug Saf 2011;2:37–43.
- Le Couteur DG, Banks E, Gnjidic D, McLachlan AJ. Deprescribing. Aust Prescr 2011;34:182–5.
- Hilmer SN, Gnjidic D, Abernethy DR. Pharmacoepidemiology in the postmarketing assessment of the safety and efficacy of drugs in older adults. J Gerontol A Biol Sci Med Sci 2012;67:181–8.
- Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med 2012;172:209–16.
- Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527–39.
- Perera V, Bajorek BV, Matthews S, Hilmer SN. The impact of frailty on the utilisation of antithrombotic therapy in older patients with atrial fibrillation. Age Ageing 2009;38:156–62.
- Morgan TK, Williamson M, Pirotta M, Stewart K, Myers SP, Barnes J. A national census of medicines use: a 24-hour snapshot of Australians aged 50 years and older. Med J Aust 2012;196:50–3.
- Roberts CG, Guallar E, Rodriguez A. Efficacy and safety of statin monotherapy in older adults: a meta-analysis. J Gerontol A Biol Sci Med Sci 2007;62:879–87.
- Sontheimer D. Review: statins reduce all-cause mortality in elderly patients with coronary heart disease. ACP J Club 2008;148:3.
- National Institute for Health and Clinical Excellence. Statins for the prevention of cardiovascular events. 2006.
- Hilmer SN, Gnjidic D. Statins in older adults. Aust Prescr 2012; in press.
- Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. Cochrane Database Syst Rev 2009(4):CD000028.
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837–53.
- eTG complete [Internet]. Melbourne: Therapeutic Guidelines Limited, 2012. Available at www.tg.org.au/etg_demo/ tgc/about/5a57c76.htm.
- Hilmer SN, Tran K, Rubie P, et al. Gentamicin pharmacokinetics in old age and frailty. Br J Clin Pharmacol 2011;71:224–31.
- Le Couteur DG, Kendig H, Naganathan V, McLachlan AJ. The ethics of prescribing medications to older people. In: Koch S, editor. Medication management in older adults: a concise guide for clinicians. Springer Science + Business Media 2010;29–42.
- Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: the prescribing cascade. BMJ 1997;315:1096–9.
- Tinetti ME, McAvay GJ, Fried TR, et al. Health outcome priorities among competing cardiovascular, fall injury, and medication-related symptom outcomes. J Am Geriatr Soc 2008;56:1409–16.
- Kemp A, Roughead E, Preen D, Glover J, Semmens J. Determinants of self-reported medicine underuse due to cost: a comparison of seven countries. J Health Serv Res Policy 2010;15:106–14.
- Gnjidic D, Le Couteur DG, Kouladjian L, Hilmer SN. Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes. Clin Geriatr Med 2012;28:237–53.
- Patterson SM, Hughes C, Kerse N, Cardwell CR, Bradley MC. Interventions to improve the appropriate use of polypharmacy for older people. Cochrane Database Syst Rev 2012;5:CD008165.
- Colon-Emeric CS, Mesenbrink P, Lyles KW, et al. Potential mediators of the mortality reduction with zoledronic acid after hip fracture. J Bone Miner Res 2009;25:91–7.