Abstract
The increasing burden of harm resulting from the use of multiple drugs in older patient populations represents a major health problem in developed countries. Approximately 1 in 4 older patients admitted to hospitals are prescribed at least 1 inappropriate medication, and up to 20% of all inpatient deaths are attributable to potentially preventable adverse drug reactions. To minimize this drug-related iatrogenesis, we propose a quality use of medicine framework that comprises 10 sequential steps: 1) ascertain all current medications; 2) identify patients at high risk of or experiencing adverse drug reactions; 3) estimate life expectancy in high-risk patients; 4) define overall care goals in the context of life expectancy; 5) define and confirm current indications for ongoing treatment; 6) determine the time until benefit for disease-modifying medications; 7) estimate the magnitude of benefit versus harm in relation to each medication; 8) review the relative utility of different drugs; 9) identify drugs that may be discontinued; and 10) implement and monitor a drug minimization plan with ongoing reappraisal of drug utility and patient adherence by a single nominated clinician. The framework aims to reduce drug use in older patients to the minimum number of essential drugs, and its utility is demonstrated in reference to a hypothetic case study. Further studies are warranted in validating this framework as a means for assisting clinicians to make more appropriate prescribing decisions in at-risk older patients.
Keywords
SEE RELATED EDITORIAL p. 523
Older patients (aged ≥70 years) are often frail, suffer several chronic diseases, and receive multiple medications on an ongoing basis. In the United States, 60% of older patients receive 5 or more drugs and approximately 20% receive 10 or more drugs.
1
Although many patients have a genuine need for multiple drugs, the downside is an increased risk of serious adverse drug reactions as a result of drug interactions and altered pharmacokinetic and pharmacodynamic responses.2
Approximately 1 in 3 older persons who are living in the community and taking at least 5 medications will experience an adverse drug reaction during a 12-month period,3
with serious adverse drug reactions involved in up to 17%4
of hospital presentations. Many of these adverse drug reactions—one quarter of those involving community-living patients4
and 30% to 55% of those causing hospitalization5
, 6
—are preventable by avoiding inappropriate medications (ie, those for whom the likelihood of adverse drug reactions outweighs therapeutic benefits).7
Up to 20% of older patients living in the community receive at least 1 inappropriate medication,8
as do one third of hospitalized patients9
and as many as 50% of those living in residential aged care facilities.10
Clinical Significance
- •A 10-step drug minimization framework that aims to assist prescribing physicians in determining which drugs are essential for older patients is described.
- •The framework features an individualized appraisal of drug-related risk, expected life span, care goals, verification of diagnoses, likely time to benefit, and benefit–risk thresholds of individual drugs and their relative utility.
- •A hypothetic case study is used to demonstrate the framework's impact on prescribing decisions.
Among patients presenting acutely to emergency departments, the risk of an adverse drug reaction contributing to the presentation increases from 13% for those prescribed 2 drugs to 38% for those prescribed 4 drugs and 82% for those prescribed 7 drugs or more.
11
Among admitted patients, the risk of serious in-hospital adverse drug reactions is increased by 58% in patients receiving 5 to 7 drugs compared with those receiving less than 5 drugs and by 4-fold if they are taking 8 or more drugs.12
Patients taking 5 or more medications also are 3 times more likely to be taking inappropriate medications compared with those taking less than 5 drugs.11
These findings, combined with expert consensus,13
support the need to critically appraise the indications and expected net benefits of individual drugs in patients at high risk for adverse drug reactions. A conceptual framework that prompts clinicians to consider in a logical fashion all relevant factors in making prescribing decisions may assist in minimizing the number of inappropriate drugs in older patients.A drug minimization framework confronts the therapeutic momentum to prescribe more medications on the basis of disease-specific clinical guidelines that ignore the increasing risk of drug-drug and drug-disease interactions in older patients with multiple comorbidities.
14
, 15
As an example, although a sentinel trial showed that treatment of hypertension reduced mortality in healthy persons aged more than 80 years,16
a systematic review of all relevant trials (including the sentinel trial) showed no benefit when less healthy individuals were included.17
Most older patients favor taking fewer drugs and avoiding any drug that is likely to cause side effects severe enough to affect functioning, irrespective of its efficacy in preventing future morbid events.18
, 19
, 20
This is in keeping with formal decision analyses showing that the total benefit of multiple drugs tends to be less than the sum of the projected benefits of individual drugs.21
Reducing the number of currently prescribed drugs may be difficult in many individuals and may inadvertently increase the risk of morbid events or decrease quality of life unless performed with care and under close expert supervision. In addition, there may be logistic constraints in busy clinical settings in trying to apply a framework that requires time and access to data, especially if there is no financial reimbursement for doing this. However, we contend that a conceptual framework that considers important decision steps may still be of value to clinicians confronted with older patents receiving multiple medications, particularly those at high risk of adverse drug reactions and who have themselves expressed a desire to receive fewer drugs.
Proposed Multi-Step Framework for Optimizing Prescribing Quality
We propose a 10-step framework for optimizing medication prescribing in individual older patients that addresses the decision-making needs of clinicians identified in other studies (Table 1).
22
, 23
Each step in the framework is based on a search of relevant literature and captures, in a logical sequence, issues that have been raised in other frameworks24
, 25
but that, to date, have not been synthesized into one integrated schema. The aim of the framework is to rationalize drug use and reduce the number of inappropriate drugs prescribed. For patients receiving, for example, 10 to 15 drugs, reducing that number to 7 or 8 might represent a significant improvement. The sequential decision steps described below are grouped into 3 key prescribing domains. In recognition of patient complexity, limitations in the available evidence pertaining to several steps, and various logistic constraints, the framework is not intended as a normative decision aid but more a conceptual checklist, with some caveats, that may prompt clinicians to more critically examine factors that influence their prescribing.Table 1Framework Steps and Operational Strategies with Caveats
| Framework Step | Operational Strategies | Caveats |
|---|---|---|
| Ask patients to disclose all medications they are taking; apply the “brown paper bag” method of ascertainment; seek collateral information on adherence, side effects, out-of-pocket expenses, and administration burden from family, caregivers and prescribing primary care doctors. | Ensure patients understand that over-the-counter, herbal, and other nonprescription complementary medicines are included. |
| Identify all relevant risk factors. | Risk prediction rules vary in their predictive accuracy and applicability. |
| Apply risk prediction tools where appropriate. | ||
| Apply a validated survival prediction rule that best fits patient characteristics. | Estimates of life expectancy based on survival prediction rules are average or median survivals for whole populations and may not be accurate in individuals; actuarial life tables may be more accurate but may not be easily accessible and may still not be applicable to the individual patient. |
| Ascertain limitations of physical and social function and quality of life. | Care goals may not be easily assigned if a profile of needs and prospects is complicated and likely to frequently change, or where there are unrealistic expectations on the part of patient or caregivers. They also may change over time, as patients transition in and out of disease states, and patients or caregivers alter their care priorities. |
| Integrate life expectancy, functional limitations, and quality of life into an overall individual profile of need and prospects. | ||
| Elicit patient and caregiver perceptions as to what constitute care priorities. | ||
| On the basis of the needs and prospects profile and patient/caregiver priorities, define care goals as being directed primarily toward prolonging survival (survival prolongation), preventing major morbid events (event prevention), improving or maintaining functional capacity (capacity enhancement), or relieving symptoms (symptom relief). | ||
| Reconcile current medications with all listed diagnoses in identifying obvious mismatches. | This step may prove time-consuming and impractical in gathering all the primary evidence to support or refute specific diagnoses. It also may entail challenging diagnostic labels applied by other specialists or on which patients and caregivers have become particularly fixated. |
| Verify diagnostic labels and ascertain current level of disease activity and response to specific therapies. | ||
| Review all disease-specific medications aimed at event prevention and compare time to benefit with estimated life expectancy. | Accessing time to benefit data for every preventive medication in a time-efficient manner may not be feasible in busy clinical settings, and, when available, represent trial averages and may not be applicable to individuals. |
| Estimate the disease-specific absolute risk of events based on patient characteristics (using validated risk prediction rules where appropriate). | Accessing disease-specific risk prediction rules (or risk stratification data) and benefit–harm data for every preventive medication in a time-efficient manner may not be feasible in busy clinical settings and, when available, represent trial averages and may not be applicable to individuals. |
| Estimate the potential treatment-specific reduction in absolute event risk.Estimate the treatment-specific absolute risk of harm. | ||
| Determine the appropriate threshold for continuing or discontinuing treatment. | ||
| By using information derived from preceding steps where relevant, apply a utility grid to all current medications and classify them according to level of decreasing utility as follows: | Gathering all the data required and classifying medications according to drug utility may take more time than is available in busy clinical settings. |
| class A: very effective and minimal toxicity; | The classification system also involves a degree of subjective judgment that may result in considerable variation in drug classification between clinicians. | |
| class B: reasonably effective but some concerns about toxicity; | ||
| class C: concerns about both effectiveness and toxicity; and | ||
| class D: minimal effectiveness and considerable potential for toxicity in most circumstances. | ||
| By using information derived from the preceding steps, especially step 8, identify drugs associated with a strong case for discontinuation or modification of dose. | Patients, caregivers, and clinicians may experience difficulty in labeling nonspecific symptoms as drug side effects. Information on rarely encountered drug toxicity may be difficult to locate. |
| Where decisions to discontinue specific drugs are, or could be, highly sensitive to patient/caregiver preferences, elicit their opinions. | Patients and caregivers may be unable to understand benefit–harm tradeoffs or have a fixation on continuing a particular drug despite low utility. | |
| Devise and implement a regimen of drug de-prescribing associated with close monitoring for disease or symptom recrudescence. | Unacceptable demands may be placed on clinicians, especially clinical pharmacists, in making ongoing alterations to medication and monitoring for adverse effects of de-prescribing. |
| Implement strategies to maximize patient adherence to clearly indicated drugs and observe for instances of persistent nonadherence that may call for drug discontinuation. |
| |
| Reappraise therapeutic plan in light of changed patient circumstances and care goals. | ||
| Maintain oversight of therapeutic plan by a single nominated clinician. |
ADR=adverse drug reaction.
Gathering Information in Constructing a Patient Profile
1) Ascertain Current Drug Use
All the medications a patient is currently taking should be ascertained as accurately as possible, avoiding undue reliance on proffered medication lists. A “brown paper bag” review in which patients (or caregivers) are asked to bring in all current medications is probably the most reliable method of medication reconciliation
26
and affords an opportunity to ask patients how they self-administer their drugs and what adherence problems they may be encountering, including any out-of-pocket expenses incurred in procuring drugs.2) Identify Patients at High Risk of or Experiencing Adverse Drug Reactions
Multiple factors independently predict an increased risk for adverse drug reactions in older patients (Table 2).
Although several definitions of polypharmacy appear in the literature, we argue that a number>5 is associated with significant increase in ADR risk and is the number most commonly used in published literature.
27
, 28
Risk prediction tools for calculating individual adverse drug reactions risk are now emerging,12
, 29
although their predictive accuracy remains suboptimal. However, the prescribing of 8 or more drugs is one of the most predictive risk factors and serves as an easily ascertainable starting point in identifying patients at high risk.Table 2Patient Characteristics Predictive of Higher Risk of Adverse Drug Reactions
26
, 27
| No. of drugs |
| ≥8 drugs=high risk |
| 5-7 drugs=intermediate risk |
| Previous ADR |
| ≥4 medical comorbidities |
| Liver disease |
| Heart failure |
| Renal disease |
| Receiving high-risk drugs |
| Anticoagulants |
| Insulin or oral hypoglycemic drugs |
| Psychotropic medications |
| Sedatives/hypnotics |
| Cardiovascular drugs (especially digoxin, nitrates, and vasodilators) |
| Nonsteroidal anti-inflammatory drugs |
| Cognitive impairment |
| Living alone |
| History of nonadherence |
| Known psychologic disorders or substance abuse |
ADR=adverse drug reaction.
12
, 13
3) Estimate Life Expectancy in High-Risk Patients
Increasing age combined with multisystem chronic disease and disability combine with individual diseases in lowering life expectancy. Consequently, the potential benefits of disease-modifying treatments in some individuals may never be realized during the patient's remaining life span.
30
Bedside prognostication tools that estimate life expectancy may be generic31
, 32
(combining age, various comorbidities, and global measures of functional status) or disease-specific33
, 34
, 35
(in cases where a single chronic disease exerts the predominant influence on survival). While noting that these estimates are subject to various qualifications,36
this estimate proves useful before performing steps 4 and 6.4) Define Overall Care Goals with Reference to Estimated Life Expectancy
The estimated life expectancy is then integrated with an assessment of current level of irreversible disability, quality of life, and personal life priorities in defining overall care goals. Simple bedside surveys of functional assessment and quality of life
37
provide just as much key information as more formal, time-consuming questionnaires.38
In patients with a long life expectancy (eg, 15 years) and no significant functional impairment, the priority may be to prevent disease progression and maintain excellent function as long as possible. In those with significant functional limitations, poor quality of life, and life expectancy less than 12 months, the priority may be toward symptomatic relief and minimally intrusive treatment.39
Synthesizing Diagnostic and Medication Data in Making Treatment Decisions
5) Define and Confirm Current Indications for Ongoing Treatment
After establishing overall care goals, the existence of diseases or conditions that may require pharmacologic intervention needs to be verified and an assessment made as to whether drugs linked to such diagnoses are conferring and will continue to confer benefits. Each of the patient's medical conditions should be matched with medications being taken in identifying mismatches that suggest overuse (no indication), underuse (clear indication but no suitable drug being offered), and misuse (clear indication but an alternative dosing schedule or mode of administration of the current drug, or administration of a different drug, may be more effective and less toxic).
Diagnoses of ischemic heart disease, heart failure, epilepsy, Parkinson's disease, and depression are highly prevalent among older populations but, in many cases, cannot be confirmed using formal diagnostic criteria.
40
, 41
Failure of disease-specific medication to alter the natural history or ameliorate symptoms raises 2 possibilities: The diagnosis is wrong or the treatment is ineffective. Currently prescribed medications could be discontinued if the original diagnosis-specific indications no longer exist or the drugs are having little or no therapeutic effect.6) Determine the Time Until Benefit of Disease-Specific Medication
This step is most relevant to medications aimed at primary or secondary disease prevention rather than symptom relief or control of currently active disease. After estimating life expectancy, verifying disease diagnoses, and ascertaining risk factors, disease-modifying treatments should be reviewed with the aim of selecting only those likely to realize a benefit within the expected life span. Drugs used to prevent future adverse events should be assessed in regard to the time from initiation at which benefits start to appear on the basis of relevant data (eg, time to event curves) from clinical trials. A life span less than this time to benefit would argue against treatment initiation or continuation. For example, where life expectancy is less than 12 months, medications that usually take longer than this to prevent a morbid event may be inappropriate, such as bisphosphonate therapy (to prevent osteoporotic fractures)
42
or statins (to prevent cardiovascular events),43
more so if they possess potential for short-term toxicity (reflux esophagitis or myopathy, respectively). Beyond a certain age, some medications in some patients have no proven benefit irrespective of the number of remaining years of life. For example, no protective effects of bisphosphonates on hip or wrist fractures have been noted in women aged more than 80 years with no prior hip or vertebral fractures.44
, 45
, 46
7) Determine Disease-Specific Benefit–Risk Thresholds That May Support Treatment Discontinuation
Recent studies question the benefits and safety in older populations of disease-specific criteria for initiating therapies and disease-specific physiologic thresholds used to determine disease control that in turn influence dose titration of individual drugs. For example, given the U-shaped relation between blood pressure and mortality in older populations, achieving “optimal” systolic blood pressure values (<140 mm Hg) at the expense of low diastolic readings places patients at risk.
47
Likewise, the chances of fatal hypoglycemia may be unduly increased by aggressive diabetic treatment without any offsetting reductions in cardiovascular risk.48
, 49
In older patients with relatively short life spans, any benefit conferred by stringent “treat-to-target” regimens may be offset by treatment harm. Although the absolute risk of morbid disease-related events often increases with age, and along with it absolute risk reduction due to therapy, the absolute harm of treatment also may increase with age. For example, in older patients with atrial fibrillation the annual risk of embolic stroke increases according to the number of risk factors (as measured by the Congestive heart failure, Hypertension, Age≥75 years, Diabetes, previous Stroke score, in which a patient's age is itself a predictor variable),50
but so might the risk of major warfarin-induced bleeding (as measured by the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score, which also includes age).- Rietbrock S.
- Heeley E.
- Plumb J.
- van Staa T.
Chronic atrial fibrillation: incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme.
Am Heart J. 2008; 156: 57-64
51
Where available, and applicable to individual patient circumstances (including extreme age or residence in nursing homes), tools for calculating the absolute risk of disease or treatment-related events may provide values more precise than intuitive estimates. Examples of tools that perform such functions and that include risk thresholds that warrant therapeutic intervention include the World Health Organization Fracture Risk Assessment Tool (FRAX tool) for osteoporotic fracture,- Lip G.Y.H.
- Frison L.
- Halperin J.L.
- Lane D.A.
Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation The HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) Score.
J Am Coll Cardiol. 2011; 57: 173-180
52
the QRISK2 tool for cardiovascular events,53
and the chronic obstructive pulmonary disease Prognostic Index for exacerbations of chronic obstructive pulmonary disease.54
8) Review the Relative Utility of Individual Drugs in Older Patients
The utility of a drug is a composite measure of likely clinical benefit, potential for harm, and burden of administration and ongoing monitoring of drug effects. The utility of specific drugs spans a spectrum between 2 poles. At one pole will be drugs of high utility associated with proven and sizeable benefit in virtually all eligible patients and little potential for harm; at the opposite pole will be drugs of low utility with questionable indications and high risk of harm in most patients and that should consequently be withheld in virtually all cases. This dipolar concept is captured in the STOP/START screening tool for appropriate drug use that defines clinical scenarios in which specific drugs should, in most cases, be administered or ceased. This tool has been shown in clinical trials to predict adverse events and improve medication use.
Wehling M. Multimorbidity and polypharmacy: How to reduce the classification: fit for the aged. J Am Geriatric Soc. 2009;57:560-561.
55
, 56
Between these 2 poles will be drugs where the balance between benefit and harm and burden of administration, or relative utility, is determined on a case-by-case consideration of patient characteristics and treatment indications and targets defined in steps 5 to 7. Such an approach is more flexible and responsive to individual patient needs than more rigid drug safety criteria57
and where the prescribing clinician selects or deselects drugs on the basis of all available information. Table 3 provides a matrix that may assist in ranking drugs according to their relative utility.58
Table 3Proposed Classification of Drug Utility
| Class | Description | Examples |
|---|---|---|
| A | Clear-cut benefit with large absolute effect size with no or minimal toxicity for a given indication and few drug–drug and drug–disease interactions. Mortality and morbidity data for older populations consistent and favorable. | ACEIs or calcium antagonists for hypertension with systolic blood pressure>160 mm Hg; ACEIs or β-blockers for severe systolic heart failure. Paracetamol for relief of chronic pain. |
| B | Proven efficacy in older patients but limited or inconsistent data on absolute effects or safety concerns relating to side effects or drug–drug and drug–disease interactions. Could be omitted in case of side effects or under pressure of>5 class A drugs. | Diuretics and β-blockers in hypertension; bisphosphonates in osteoporosis. |
| C | Questionable efficacy and safety profiles in older patients. Should be omitted if indications are in doubt, any side effects or clinically significant potential for interactions, or under pressure of>5 class A drugs. | Amiodarone in atrial fibrillation; spironolactone in hypertension; ezetimibe for cholesterol lowering. |
| D | Avoid in older patients because likelihood of side effects or interactions outweighs realizable benefit in virtually all cases; delete first. | Benzodiazepines, nonsteroidal anti-inflammatory drugs, promethazine, anticholinergic drugs. |
ACEI=angiotensin-converting enzyme inhibitor.
9) Identify Drugs That May Be Discontinued or Reduced in Dose
Drugs that patients are currently receiving should be reconciled against care goals, treatment targets, and clinical utility criteria as already described. Several questions assist in identifying drugs that might be reduced in dose or discontinued (Table 4).
As defined in Table 3.
59
, 60
, 61
In older patients, physical frailty, forgetfulness, heightened sensitivity to even mild side effects, psychologic illness, and demands of everyday life may push nonadherence rates as high as 84%.62
Rates of nonadherence increase in proportion with the number of drugs prescribed.63
Probing patients' beliefs as to the benefit and burden of a drug can uncover legitimate reasons for nonadherence that may justify discontinuation. Although common side effects should be sought, those of a sensitive nature (effects on sexual, cognitive, and emotional function) should not be overlooked.64
Table 4Questions Used to Identify Drugs That May Be Discontinued or Decreased in Dose
59
, 60
, 61
| Are treatment targets and care goals being achieved by the use of a specific drug? |
| Is there an ongoing indication that justifies continued use of a specific drug based on evidence of effectiveness? |
| Does a non-drug therapy exist that may substitute for≥1 drugs? |
| Does a drug fail to meet class A criteria as being a clinically useful drug (ie, a drug has a low benefit–risk ratio)? |
| Is a drug consistently associated with nonadherence as a result of side effects or lack of effect, burden of cost or inconvenience, or complexity of dosing schedules? |
| Is there another drug that may be superior to the one in question for the same indication? |
| Are there duplications in drug therapy (ie, ≥2 drugs from the same class)? |
| Is a combination pill being used in which one of the medications is inappropriate? |
| Is a drug being used that carries a risk of addiction or accumulation over the medium- to long-term? |
| Are there lower effective doses for specific drugs, particularly in the presence of more conservative treatment targets? |
| Are≥1 drugs being prescribed to counter side effects or ADR of another drug? If so, can the drug that caused the ADR be withdrawn or substituted with another less troublesome agent? |
| Can a drug be withdrawn or have its dose reduced with no significant risk? |
ADR=adverse drug reaction.
Once a drug has been selected for discontinuation, a de-prescribing schedule of ceasing or weaning the drug follows, combined with close patient monitoring for any adverse effects. Drugs with indeterminate indications can be safely discontinued in many, if not most, cases,
65
although with more caution in the case of cardiovascular or neurologic drugs.66
In one study of 70 community-living patients with a mean age of 83 years subjected to critical medication review, an average of 4.4 drugs per patient were successfully discontinued in 81% of patients, with no clinical events or deaths attributable to discontinuation.61
In other studies, approximately 40% of older subjects remained normotensive after withdrawal of antihypertensive agents;67
patients receiving bisphosphonates for at least 5 years had no increase in fractures after cessation;68
patients with dementia in whom antipsychotic drugs were discontinued had lower mortality than similarly affected individuals who continued medication;69
and cessation or dose reduction of drugs, such as benzodiazepines, led to fewer falls over subsequent months.70
Monitoring and Reviewing Treatment Decisions
10) Implement and Monitor Revised Therapeutic Plan with Ongoing Reappraisal of Drug Utility and Patient Adherence
On the basis of the preceding steps, a regimen of drug de-prescribing is developed and implemented combined with close monitoring for recrudescence or deterioration of disease or symptoms. Strategies should be implemented to maximize patient adherence to clearly indicated drugs (Table 5).
71
The drug minimization plan may need to be revised because patient circumstances and care goals, and thus treatment indications, change over time. This may best be performed by a single nominated clinician (general internist or geriatrician or clinical pharmacologist with general medicine interests) working in a polypharmacy clinic with assistance from a clinical pharmacist, both of whom have the time and resources to become fully familiar with the patient's circumstances and are committed to providing regular review over the long-term. These clinicians would liaise with primary care providers and specialists in working through the framework and seeking consensus in developing the drug minimization plan.Table 5Methods for Maximizing Patient Adherence
71
| Regularly scheduled patient follow-up visits |
| Multi-compartment dose administration aids |
| Pharmacist-mediated medication reviews |
| Group education |
| Simplification of drug regimens |
| Single daily dosing of slow release, long-acting preparations |
| Combination formulations when appropriate (ie, the indications for, and dose of, each component drug are clinically appropriate and titration of individual drugs using different formulations is possible) |
| Medication calendars |
| Diaries and reminder cues |
| Telephone support |
| Self-monitoring |
Conclusions
Our framework encourages a systematic approach to medication use aimed at selecting the right drug at the right dose for clear-cut clinical indications determined on a case-by-case basis. This framework draws attention to the dangers of therapeutic inertia, whereby drugs continue to be prescribed in the absence of any periodic review of continuing indication or net benefit, and therapeutic momentum, where more drugs are added in response to new but questionable indications, including treatment of unrecognized side effects arising from preexisting medications.
Although prescribing decisions in older patients will always be constrained by limited data on treatment effects in individuals with diverse characteristics,
23
we contend the framework has face validity in minimizing inappropriate drug use, as exemplified by its application to a hypothetic case study (Appendix E1).72
Clinicians may have to rely on intuitive estimates in the absence of “plug-and-play” computerized risk and survival prediction tools, benefit–risk equations, and time to benefit data applicable to individual patients. It is hoped such decision support tools will become increasingly available in the future in response to clinician demand.The effectiveness and safety of the framework in routine care need to be evaluated in formal trials that measure patient-important outcomes and involve prescribers trained in applying the framework to a wide range of commonly encountered clinical scenarios. The potential reduction in risk of adverse drug reactions as a result of drug minimization needs to be balanced against the potential increase in risk of death, complications, or loss of function pursuant to less than aggressive treatment of multiple chronic diseases.
73
However, multiple trials of drug optimization in elderly populations demonstrate that cessation of inappropriate medications occurs more frequently than initiation of new medications.56
, 74
, 75
, 76
Eliminating inappropriate drugs has the potential to realize savings in the cost of drugs and management of iatrogenic illness, funds that could be channeled toward reimbursing clinicians for the time and effort spent in applying the framework. In Australia, primary care practitioners are given incentive payments for quality prescribing,77
and pharmacists are paid for undertaking medication reviews as often as every 6 months as requested by the primary care practitioner,78
an activity associated with evidence of reduced medication duplication and smaller total number of prescribed medications.79
This conceptual framework offers a systematic and individualized approach to medication prescribing in older patients with the aim of identifying and discontinuing medications that are of little or no benefit or indeed potentially harmful. Further development of tools and resources that may assist clinicians in applying the framework is warranted before real-world controlled studies of feasibility and effectiveness are performed.
Appendix E1 Case Study
Case 1
The case is an 81-year-old woman who has been hospitalized with an exacerbation of heart failure attributed to nonadherence with diuretic medication. Her listed medical problems include hypertension, ischemic heart disease with previous acute myocardial infarction 8 years ago, chronic heart failure, chronic atrial fibrillation, Parkinson's disease, osteoporosis with past Colles' fracture, depression, osteoarthritis, type 2 diabetes for 15 years with past episodes of hypoglycemia, mild renal insufficiency, cognitive impairment, and gastroesophageal reflux disease.
The patient lives in a “granny flat” in her daughter's house and is normally able to perform basic self-care, albeit slowly, with her daughter doing the shopping, cooking, and washing. She has limited mobility due to pain and stiffness in her hips and knees, and walks with a wheelie-walker. She has had 2 falls in the last 12 months when walking outside her flat on uneven ground. She has reasonable hearing, wears reading glasses, and is usually happy to engage in conversation.
Physical examination reveals a frail-looking woman with kyphosis, with a weight of 54 kg and body mass index of 18. Her pulse is 64 beats/min and irregular, with a blood pressure of 110/60 mm Hg sitting and 115/55 mm Hg standing. No cardiac murmurs are audible, and she has mild pedal edema with varicose veins. She demonstrates generalized increased tone but no cog-wheeling rigidity or tremor. Testing of muscle power in her upper and lower limbs is difficult because of osteoarthritic pain in hips, knees, wrists, and shoulders. Muscle bulk is generally reduced, and she has absent knee and ankle jerks with sensory impairment in a stocking and glove distribution. There is bony hypertrophy and crepitus in both knees with reduced flexion of knees and reduced rotation of hips, with Heberden's nodes in small joints of the fingers. The x-rays of her wrist at the time of her Colles' fracture revealed osteopenia. Her mini-mental state examination scores 21 of 30.
Her recent investigations reveal hemoglobin of 104 g/L with normal white cell and platelet counts, and biochemical abnormalities of decreased serum sodium (128 mmol/L), increased potassium (5.1 mmol/L), urea (13 mmol/L), and creatinine (160 mmol/L) with estimated glomerular filtration rate of 35 mL/min/m2, and reduced serum albumin (31 mmol/L). Her serum calcium, phosphate, magnesium, vitamin D, iron studies, B12, folate, and thyroid function test results are normal. Her HbA1c is 6.7% with average blood glucose concentrations noted in hospital between 7 and 9 mmol/L. Urinary creatinine-albumin ratio is 4.0 (normal range<0.5), and microurine shows no cells or casts. Fasting serum lipids reveal a total cholesterol of 3.2 mmol/L, low-density lipoprotein cholesterol 1.5 mmol/L, and triglycerides 2.1 mmol/L. Electrocardiography confirms atrial fibrillation, Q waves in leads V1-V4, and prolonged QRS 140 ms. Chest x-ray reveals moderate cardiomegaly with clear lung fields. Echocardiography shows anterior wall hypokinesis and mild hypertrophy of the left ventricle with systolic dysfunction (ejection fraction 30%).
Her 21 medications comprise the following: carvedilol 12.5 mg bd; perindopril 5 mg mane; frusemide 80 mg mane; amlodipine 5 mg mane; spironolactone 12.5 mg mane; isosorbide dinitrate 60 mg mane; pravastatin 40 mg mane; digoxin 62.5 μg nocte; warfarin 3 mg mane; carbidopa-benserazide 100/25 mg td; alendronate 75 mg weekly; cholecalciferol 1000 units/d; calcium carbonate 600 mg mane; sertraline 150 mg mane; omeprazole 20 mg bd; gliclazide 80 mg bd; donepezil 10 mg nocte; paracetamol-codeine 1 tablet td; stool softener 2 sachets bd; oxazepam 15 mg nocte; oxycodone 5 mg td prn (bd=2 times per day; td=3 times per day; prn=as needed; mane=morning; nocte=night).
Outcome of the Application of the Drug Minimization Framework
As a result of the framework and in accordance with patient and caregiver preferences, the decision is made to attempt the weaning and discontinuation of 13 of the patient's 18 prescription-only drugs. The 5 drugs selected for continuation are carvedilol, perindopril, frusemide, warfarin, and omeprazole. Nonprescription drugs to be continued include vitamin D, paracetamol-codeine, stool softener, and calcium carbonate. The need for warfarin will be subject to ongoing review according to whether the patient has any further falls or the burden of anticoagulant monitoring becomes too great. Whether calcium supplements are continued also rests on the emergence of more definitive evidence linking this medication to increased cardiovascular risk.
Tabled
1Application of the Drug Minimization Framework
| Framework Step | Application to Case Study |
|---|---|
| All drugs ascertained. The patient self-administers her drugs from a dosette box delivered by her daughter; states she does not experience any drug-specific problems apart from mild dizziness after morning drugs; self-reports good adherence although does forget midday drugs on occasion; finds the hassle of filling prescriptions irksome, although her daughter gets most of them for her; and is concerned about out-of-pocket expenses incurred and increasing cost of living. |
| She is taking 21 different drugs; has up to 8 different comorbidities, including heart failure and renal disease; her medications include high-risk drugs of warfarin, oral hypoglycemic drugs, psychotropics, sedatives, opiate analgesics, digoxin, nitrates; she has cognitive impairment; and there is a history of partial nonadherence. Applying the risk prediction tool of Onder et al, 12 her risk of a major ADR over the next 6 months is estimated to be at least 1 in 3. |
| The tool of Carey et al 32 was derived and validated in a population of frail, community-living elderly patients. The median survival for our patient using this tool is 2 years 4 months. |
| She is able to perform simple activities of daily living but is incapable of instrumental activities of daily living, relying on her daughter to do these, and has mild cognitive impairment. She has limited mobility, has pain and stiffness in several weight-bearing joints, and has had previous falls. Both the patient and her daughter nominate relief of pain and the continued ability to perform simple activities of daily living as priorities for therapeutic management. They also desire a reduction in the number of drugs given recent problems with nonadherence (secondary to forgetfulness and recent embarrassing diuretic-related events with urinary incontinence during morning social outings) and the burden of monitoring of drug effects, particularly warfarin monitoring. |
| Given the patient's life expectancy, functional capacity, and declared care priorities, the overall care goals are defined as capacity enhancement and symptom relief. | |
| Medication-diagnosis reconciliation suggests no obvious mismatches. |
| The diagnoses of hypertension, ischemic heart disease, heart failure, chronic atrial fibrillation, diabetes, osteoarthritis, renal insufficiency, and gastroesophageal reflux disorder are validated by objective evidence. | |
| In assessing severity of her heart disease, she has no chest pain, palpitations, or syncope but is limited by exertional dyspnoea when doing anything strenuous. Her renal insufficiency, attributed to diabetic nephropathy, has not substantially worsened over the past 2 years. She has no symptoms referable to her diabetes, and her blood glucose is well controlled. Osteoarthritic pain is her main concern. | |
| The diagnoses of angina, Parkinson's disease, depression, dementia, and osteoporosis are less certain. | |
| The patient has no chest pain at rest or with exertion, and past electrocardiograms, while showing Q waves consistent with past myocardial infarction, have not revealed labile ST-T wave changes suggestive of myocardial ischemia. The indication for isosorbide dinitrate is in doubt. | |
| The patient has no signs diagnostic of Parkinson's disease, and anti-Parkinsonian treatment has made no difference to her level of mobility. The indication for carbidopa/benserazide is in doubt. | |
| Although she was depressed for some months after her husband's death 4 years ago, she has had no depressive symptoms subsequently. The indication for sertraline is in doubt. | |
| Although osteopenia was reported on past x-rays of the wrist, her Colles' fracture was sustained from a fall when she tried to protect herself with the outstretched hand. In the absence of vitamin D, calcium, or phosphate deficiencies, low-trauma fractures, high-risk factors for osteoporosis (eg, steroid use), and T score on bone mineral densitometry of −0.5, her risk of major osteoporotic fracture over the next 10 years as calculated by the FRAX tool 52 is low (12%). The continuing indication for alendronate, which has been prescribed for the last 7 years, is in doubt especially in light of studies that show no increased risk in fractures in women who cease bisphosphonates after 5 years compared with those who continue them.42 | |
| Event prevention is not seen as a care goal. The minimal time to benefit of alendronate in preventing osteoporotic fractures in this patient is on the order of 2 years but only in the case of established osteoporosis and no prior use of bisphosphonates. |
| In light of the patient's current lipid levels (low-density lipoprotein cholesterol<2.0 mmol/L), the time span required to predispose her to further coronary events if statins were to be discontinued would be at least 2 years. | |
| In light of her present blood glucose control, the time span required to see any impact on cardiovascular event risk or progression to end-stage renal failure is measured in decades. 49 | |
| The patient has confirmed heart failure with reduced systolic function and recent hospitalization for decompensation. The evidence for β-blockers and angiotensin-converting enzyme inhibitors in improving cardiac function and short-term survival is strong, and the patient has exertional dyspnoea. These medications should be continued. |
| Spironolactone is beneficial in reducing mortality and hospitalization in patients with advanced symptomatic heart failure (dyspnea at rest or with minimal exertion) and ejection fraction<30%. The patient has neither of these characteristics and also has renal insufficiency, which increases the risk of hyperkalemia. Spironolactone could be discontinued. | |
| Digoxin has no effect on survival or symptoms of heart failure and only reduces rates of hospitalization in severe cases. It is a frequent cause of iatrogenic toxicity, especially in the presence of renal insufficiency, may predispose to falls and functional/cognitive decline, and is not as effective for controlling heart rate as β-blockers, which our patient is already receiving. Digoxin could be discontinued. | |
| Amlodipine is being prescribed as an antihypertensive and frusemide as a diuretic in controlling symptoms of heart failure. The patient's blood pressure of 110/60 mm Hg is currently lower than 140/90 mm Hg, a threshold below which evidence shows no further reduction in cardiovascular events. Lower blood pressure values increase the risk of mortality, syncope, and renal failure. Amlodipine could be discontinued, and the dose of frusemide could be decreased. | |
| The patient is receiving warfarin for prophylaxis against thromboembolic stroke in the setting of chronic atrial fibrillation. By applying the Congestive heart failure, Hypertension, Age≥75 years, Diabetes, previous Stroke score rule, 50 she scores 4, which equates to a risk of stroke of 8.5% per year. However, she also is at risk of warfarin-induced bleeding. By applying the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly,
Chronic atrial fibrillation: incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme. Am Heart J. 2008; 156: 57-64 51 she scores 3, which equates to a major bleeding risk of 8.4% per year. The patient's and caregiver's risk aversion to stroke or major bleeding need to be ascertained and reconciled with the burden of warfarin monitoring in deciding whether warfarin should be discontinued.
Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation The HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) Score. J Am Coll Cardiol. 2011; 57: 173-180 | |
| The patient's HbA1c is 6.7%, which, in recent trials involving older patients, has been associated with increased risk of death and hypoglycemia while having no effect on short-term risk of macro- or microvascular complications. A more appropriate HbA1c may be closer to 8%. Gliclazide could be discontinued. | |
| Cholinesterase inhibitors have little evidence of efficacy in reducing cognitive decline and are associated with increased risk of syncope. Donepezil could be discontinued. | |
| Drugs associated with high potential for benefit and low potential for harm include the following: |
| β-blockers and angiotensin-converting enzyme inhibitors: proven short-term benefits in heart failure and low risk of side effects if titrated according to desirable pulse rate and blood pressure levels. | |
| Vitamin D: reducing risk of osteoporosis, emerging evidence of reducing risk of falls and retarding cognitive decline, and no significant side effects. | |
| Omeprazole: effective in treating gastroesophageal reflux and no side effects; small increased risk of community-acquired pneumonia. | |
| Paracetamol-codeine: paracetamol is just as effective in ameliorating osteoarthritic pain but without risk of constipation and sedation of codeine component of paracetamol-codeine combination, so the former is substituted for the latter. | |
| Drugs associated with potential for benefit but more potential for harm include the following: | |
| Frusemide: effective in relieving symptoms of heart failure, but side effects of inconvenient diuresis. Could be reduced in dose or even ceased in response to up-titration of β-blockers and angiotensin-converting enzyme inhibitors. | |
| Warfarin: competing benefits of stroke prevention versus risk of bleeding coupled with burden of monitoring. | |
| Oxycodone: effective in relieving pain but side effects of constipation, sedation, and predisposition to falls. Could be reduced in dose if simple analgesics, nonpharmacologic physical therapies, and intra-articular steroid injections decrease burden of joint pain. | |
| Drugs associated with limited potential for benefit and significant potential for harm include the following: | |
| Spironolactone: uncertain indication and significant risk of hyperkalemia in presence of renal insufficiency | |
| Pravastatin: minimal impact on short-term risk of cardiovascular death or morbidity. | |
| Gliclazide: already low HbA1c and risk of hypoglycemia. | |
| Drugs with no potential for benefit and considerable potential for toxicity include the following: | |
| Carbidopa-benserazide: diagnosis of Parkinsonism not verified, no therapeutic response, and proclivity to cause hypotension, dystonias, and psychotropic side effects. | |
| Isosorbide dinitrate: no indication and predisposition to hypotension and falls. | |
| Digoxin: no indication as patient has controlled heart rate and risk of side effects and toxicity in presence of renal insufficiency. | |
| Alendronate: no indication (in view of age and absence of past hip or vertebral fractures) and risk of toxicity in patient with past ulcerative esophagitis. | |
| Sertraline: no indication and risk of hypotension and interactions with β-blockers. | |
| Donepezil: no evidence of benefit from randomized trials and risk of syncope and interaction with β-blockers. | |
| Oxazepam: alternative nonpharmacologic strategies available for insomnia and drug predisposes to falls and withdrawal syndromes. | |
| All drugs of limited or no potential for benefit or significant potential for harm, as identified in step 8, should be considered for discontinuation. |
| Drugs associated with both significant potential for benefit and harm and that are sensitive to patient/caregiver preferences should be discussed. If not discontinued, the dose of frusemide should be down-titrated to the lowest dose that controls symptoms while up-titrating β-blockers and angiotensin-converting enzyme inhibitors, whereas the dose of warfarin, if continued, should aim to keep the international normalized ratio between 1.5 and 2.5. | |
| Digoxin, alendronate, and pravastatin are ceased immediately. A gradual weaning of spironolactone, isosorbide dinitrate, gliclazide, sertraline, donepezil, carbidopa-benserazide, oxazepam, and oxycodone is commenced. |
| Carvedilol administered as a twice-daily drug is changed to bisoprolol given as a once-daily drug. | |
| The dose of frusemide is taken at midday rather than the morning on days when the patient has morning outings. | |
| If hyperglycemia warrants the continuation of gliclazide, this will be changed to a once-daily, slow-release formulation. | |
| In maximizing adherence, the patient's daughter is asked to maintain a daily watch on her mother's dosette box and to be vigilant for any symptom suggesting disease relapse as a result of drug discontinuation. The prescribing doctor arranges regular follow-up visits to review patient progress during the drug discontinuation process combined with phone calls to and from the practice nurse and caregiver in regard to any inquiries or concerns. |
ADR=adverse drug reaction.
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Article Info
Publication History
Published online: March 02, 2012
Footnotes
Michael W. Rich, MD, Section Editor
Funding: None.
Conflict of Interest: None.
Authorship: All authors had access to the data and played a role in writing this manuscript.
Identification
Copyright
© 2012 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
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