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INTRODUCTION

Each year in the United States, approximately 2.1 million prescriptions produce adverse drug reactions (ADRs).¹ An ADR is “harms directly caused by a drug at normal doses.”² Adverse drug events (ADE), or “injury resulting from medical intervention related to a drug,”³ were among the top 10 common causes of death in 2017.⁴ The incidence of drug-drug interactions continues to rise.⁵ Studies suggest that approximately 15.1% of older adults were at risk for a potential major drug-drug interaction in 2017 compared with an estimated 8.4% in 2005–06.⁵ In addition, an estimated 350,000 ADEs occur in the United States nursing homes annually and are experienced by 40% of hospitalized older adults.^6,7

In this program, the reasons for these high numbers of ADRs and ADEs are examined and actions pharmacists can take in addressing these causes discussed. Deprescribing is a recently developed tool for intervening in polypharmacy, and its use in this process by pharmacists is described using case examples. Drug therapy in older adults is emphasized, since those aged 65 years or older use a disproportionate proportion of medications.

PREVALENCE AND CONTRIBUTING FACTORS TO POLYPHARMACY

Polypharmacy is the concomitant use of several drugs by a single individual.⁸ This often occurs because of presence of various health problems, including chronic diseases, acute conditions, and symptoms, which accumulate with age. When applied to individuals with multiple conditions, evidence-based prescribing guidelines designed for the management of single diseases can produce complex drug regimens.⁹

These factors result in a higher number of concomitantly used medications in older adults than among younger people.¹⁰ The use of multiple drug treatments can be clinically appropriate if they improve health and quality of life.¹¹ However, polypharmacy presents significant challenges to clinicians because many older adults are exposed to medication burden past the point where drug therapy is efficacious.¹²

Age-Related Contributors to Polypharmacy

Patients 65 years of age or older consume more than 30% of all prescriptions.¹³ Of these patients, approximately 50% take 5 or more medications regularly, and 12% take at least 10 medications regularly, according to a study conducted in 2003.¹⁴ A cohort study of Medicare enrollees in the ambulatory clinic setting demonstrated an adverse drug event rate of 50.1 per 1,000 person–years, with 38% of the events categorized as severe, life threatening, or fatal.¹⁵ Furthermore, each ADE in ambulatory patients older than 65 years is estimated to cost an average of $1,300 in additional health care expenditures.¹⁶ Key factors predisposing older patients to ADEs include age-related changes in physiology and drug metabolism; polypharmacy; number of comorbidities; and visits to multiple physicians. The use of 5 to 7 medications regularly doubles the risk for an ADE; use of 8 or more medications regularly triples this risk.¹⁷

Prescribing Cascades

Prescribing cascades occur when signs and symptoms of a patient are inaccurately assessed and an adverse drug reaction is misinterpreted as a new condition, resulting in a new medication being prescribed.¹⁸ Prescribing cascades are an additional contributor to polypharmacy, especially in older adults. Polypharmacy is also a risk factor for ADRs, which are cited as factors in 12% of all hospital admissions.¹⁹ Limiting prescribing cascades could therefore help to prevent ADRs.²⁰ A symptom misinterpreted as a new health problem can lead to prescribing of additional but inappropriate medications. In Figure 1, Tylenol PM contains diphenhydramine, which has the side effect of constipation; when this occurs, clinicians or patients may inappropriately add a new medication, leading to a yet another side effect, and the sequence continues. Potentially, the patient or a caregiver can initiate over the counter (OTC) products in response to side effects; when these are not reported to the provider, the cascade is likely to continue.

DEPRESCRIBING

The use of the term “deprescribing” is relatively recent. The word first appeared in the literature in 2003 due to a growing concern about the overuse of certain medications.^21,22Deprescribing has been defined as the process of withdrawal or dose reduction of medications that are considered inappropriate in an individual. To emphasize the need for provider oversight, deprescribing can also be defined as the process of withdrawal of an inappropriate medication, supervised by a health care professional with the goal of managing polypharmacy and improving health care outcomes.²² The aim is to reduce medication burden and harm while maintaining or improving quality of life. This can include reducing medication safely to address changes in the patient’s health status.

Patient Case:

RT, a 73-year-old man, presents with chronic pain, feeling of dizziness, and recent falls; he believed that the adverse effects were related to some of his medicines, and this resulted in part in nonadherence. He was referred to the integrated care clinical pharmacist (ICP) for medication review.

Medical history:

• Type 2 diabetes (insulin dependent)
• Diabetic retinopathy, right eye
• Diabetic neuropathy
• Erectile dysfunction
• Hypertension
• Incontinence
• History of urinary tract infection
• History of falls
• Cataracts
• Chronic obstructive pulmonary disease
• Memory impairment

Social History:

• Alcohol consumption is 28 drinks/week
• Smokes 20 cigarettes/day; failed treatment with varenicline
• Lives alone in third floor apartment
• Private caretaker visits 2–3 times/week to assist with meal preparation and cleaning
• Mobile and active

Labs:

• Glomerular filtration rate (GFR) = 55 mL/min
• Body mass index (BMI) = 22.53 kg/m²
• Blood pressure (BP) = 110/62 mm Hg
• Hemoglobin A1c (A1c) = 7.9%
• Mini mental state examination (MMSE) = 16/30

Current medications:

Are any of RT’s medications dosed at a suboptimal level? Answer: The gabapentin dose is suboptimal for neuropathic pain, which should be initiated at 300 mg on day 1 and increased as needed for pain relief to between 600 and 1800 mg daily in three divided doses, if eGFR is 50–80 mL/min/1.73 m2. Are there any drug interactions? Answer: Amlodipine & simvastatin or quinine & simvastatin: can result in increased blood levels of simvastatin. Quinine & vardenafil: increased risk of QT prolongation

1. NPH human insulin (rDNA origin) isophane suspension 100 units/mL — 5 units SC every morning
2. Metformin 500 mg tablets — 2 twice a day
3. Vardenafil 20 mg tablets — as directed if needed
4. Oxybutynin 2.5 mg tablets — 1 twice a day
5. Gabapentin 100 mg capsules — 1 three times a day
6. Acetaminophen 500 mg tablets — 2 tablets as needed
7. OTC pain relief gel — when required to applicable areas for pain
8. Quinine sulfate 200 mg tablets — 1 at night
9. Lansoprazole 30 mg capsules — 1 once a day
10. Amlodipine 10 mg — 1 every morning
11. Ramipril 5 mg capsules — 1 twice a day
12. Simvastatin 40 mg tablets — 1 at night
13. Salbutamol 100 mcg chlorofluorocarbon (CFC)–free inhaler — as needed
14. Fluticasone/salmeterol hydrofluoroalkane (HFA) inhaler, oral — 1–2 puffs twice a day
15. Tiotropium 18 mcg caps for inhalation — once a day
16. Lancets and testing strips for self-monitoring of blood glucose

Overview of a Deprescribing Process

   (1) Collect a Complete and Comprehensive Medication History

The first step in deprescribing is to understand in detail which medications the patient takes as well as how and when they are taken.^24,25

The ICP visited RT in his home to conduct an in-depth assessment of his medication-related needs. Reconciliation of medicines involved review of a recent hospital discharge summary list, general practitioner brief summary, and the patient's own medications present in the home.23

Produce a thorough medication list: This should include scheduled, intermittent, and "as needed" prescriptions, and also nonprescription medications, other over-the-counter products, and dietary supplements. To elicit information about vitamins and herbal supplements, additional questioning is often needed to ensure complete reporting. All identified medications should include the dose, dosing frequency, duration (how long they have been taking it), and indication (why they are taking it). If there is any uncertainty, additional follow-up with the prescriber may be needed to provide a full and accurate picture of the patient's medication history. The patient should also be asked about their perceptions of the effectiveness of each medication. Relevant laboratory results should be reviewed to corroborate efficacy, when applicable and available.

RT is experiencing gastrointestinal (GI) symptoms, leg cramps, swollen ankles, dizziness, and falls.23

Identify possible adverse drug reactions: There are many factors to consider in assessing potential ADRs. Tools such as the Naranjo algorithm can be used to determine the likelihood that a new sign or symptom was caused by a medication.²⁶ To establish a high probability of an ADR, a temporal relationship should be established between starting the drug and the appearance of the symptom, alternative causes ruled out, and objective evidence reviewed (i.e., blood concentrations of drug).

RT was usually adherent with his morning doses, omitted the afternoon doses, and took some of his evening doses. Poor dexterity and poor vision are affecting his ability to draw up syringe doses from vials. Memory impairment is also an important factor to consider in determining his medication regimen.23

Assess adherence: Many potential methods can be used to assess medication adherence. This may include direct methods such as blood levels or indirect methods such as refill records or self-report. A questionnaire or diary can be helpful in measuring medication adherence. If there is nonadherence, ask patients to indicate the reasons why they missed doses. Explanations might include side effects, perceived lack of efficacy, costs, confusion, or time constraints.

   (2) Assess Overall Risk of Harm and Benefit

RT was prescribed 15 medications and a total of 19 doses per day, excluding topicals, inhalers and as needed doses. He had complaints of taking too many medications, felt some were not working and others were contributing to adverse effects. To remedy this, he took some medications less often than prescribed to minimize symptoms.23

A risk-to-benefit analysis of deprescribing that includes individual patient factors, which may affect adjustment of medications, is necessary.^24,25 Discuss patient values, preferences, beliefs, and goals of care surrounding continued medication use versus deprescribing. Drug-related factors could include polypharmacy, pill burden (how complex is the medication regimen), drug-drug interactions, and use of drugs that have a high risk of causing significant patient harm when used in error (high-risk medications). Other patient-related considerations include life expectancy, cognitive and functional impairments, fall risk, comorbidities, multiple prescribers, and goals of treatment based on patient characteristics (e.g., palliative care, years of expected life remaining for agents such as statins whose benefits would accrue over longer time periods).

   (3) Identify Potentially Inappropriate Medications

Which medications may be causing the side effects that RT is experiencing? Answer: simvastatin & leg cramps; oxybutynin & dizziness; amlodipine & swollen ankles; metformin & GI symptoms

Consider withdrawing, tapering, or reducing the dose of medications without an indication, those that are part of a prescribing cascade, and agents that are causing an adverse drug reaction or may cause future harm.^24,25 For example, medications can be discontinued if a patient’s condition has resolved, efficacy is unclear or questionable, or there is a risk of ADRs with concomitant medications or a suitable nonpharmacologic alternative. In older adults, the use of tools such as the Beers and STOPP criteria (discussed in detail in the next section) highlight medications that are inappropriate in older adults.^27,28 Algorithms such as Medication Appropriateness Index and Good Palliative–Geriatric Practice can also be used to determine drug appropriateness.^29,30

   (4) Decide on Medication Withdrawal

Use patient and prescriber input to guide which medications should be withdrawn or adjusted. If more than one medication is identified for withdrawal, it is important to prioritize order of drugs for discontinuation. Factors may include potential for harm or patient preference.^24,25

   (5) Plan Tapering or Withdrawal Process

Which medications would you recommend that RT taper or withdraw? Possible answers:   • Discontinue oxybutinin   • Reduce metformin dose, switch to extended release   • Reduce dose or stop lansoprazole   • Discontinue acetaminophen and the OTC pain gel       since patient’s pain is neuropathic   • Reduce amlodipine dose

The process should include a plan for monitoring with documentation and communication to all persons relevant to the patient's care as well as timing of withdrawal. A tapering plan should be developed if the medication is commonly associated with an adverse drug withdrawal event. Slow dose reduction prior to discontinuation can help to identify lowest effective dose and minimize the impact of return of symptoms if they do occur. If withdrawal symptoms are known to occur, it is important to create a symptom management plan. This could include symptoms to look out for, what to do when symptoms occur, determine monitoring frequency, and who to contact if symptoms occur.

   (6) Conduct Monitoring and Support

Monitor for withdrawal-related ADRs, return of condition, reversal of drug-drug and drug-disease interactions and resolution of ADRs. If applicable, use nonpharmacologic approaches to reduce reliance on medications when possible. ^24,25

   (7) Documentation

Documentation should include reasons for as well as the process and outcomes of deprescribing. This documentation should be shared with all relevant health care professionals on the patient’s care team.^24,25

USEFUL RESOURCES TO GUIDE DEPRESCRIBING

Screening Tool of Older Person’s Prescriptions and Screening Tool to Alert Doctors to Right Treatment (STOPP/START) Criteria

The STOPP/START criteria provide explicit, evidence-based rules of avoiding exposure to common but potentially inappropriate agents (STOPP) and for identifying potential prescribing omissions (START).²⁸ This list can be used as a tool to improve medication appropriateness, avoid ADEs, and subsequently reduce costs. Table 1 lists key STOPP/START recommendations by organ class.

The Beers Criteria®

The American Geriatrics Society (AGS) Beers Criteria® are a set of evidence-based recommendations tailored specifically for adults aged 65 years and older in all care settings except for hospice or palliative care.²⁷ This list provides guidance on how to optimize medication selection in older adults by helping to identify potentially inappropriate medications (PIMs). This list is updated every 3 years. Table 2 highlights the notable updates in the 2019 guidelines.

According to the Beers Criteria®, first-generation antihistamines (diphenhydramine, chlorpheniramine, promethazine, cyproheptadine, clemastine, doxylamine, and others) should be avoided because of their sedating and strongly anticholinergic properties. These properties can result in delirium, falls, urinary retention, dry mouth, and constipation. However, the use of diphenhydramine may be appropriate for acute treatment of severe allergic reactions. Antispasmodic agents (dicyclomine, hyoscyamine, immediate-release oxybutynin, scopolamine, belladonna alkaloids ,and clidinium–chlordiazepoxide), tricyclic antidepressants (amitriptyline, doxepin, imipramine, nortriptyline, and others), certain antiparkinsonian agents (benztropine, trihexyphenidyl) and muscle relaxants (, methocarbamol, carisoprodol, and others) also have anticholinergic properties, and can lead to similar side effects.²⁷

Benzodiazepines should generally be avoided in older adults. Whether used for control of delirium, sleep disorders, or agitation, older adults are more sensitive to benzodiazepine-associated delirium and mechanical falls. Use may be appropriate for some conditions such as alcohol withdrawal or benzodiazepine withdrawal. Nonbenzodiazepine hypnotics such as zolpidem can have similar effects. ²⁷

Sedating drugs may cause confusion and oversedation in older adults. Because of these ADRs, medications such as hydroxyzine should be started at low doses and patients observed closely. Alternatively, trazodone may be considered to treat insomnia in older adults since it has fewer anticholinergic effects.

Antipsychotic agents (haloperidol, thioridazine, olanzapine, quetiapine, risperidone, and others) should be avoided for behavioral problems in older adults unless nonpharmacologic measures have failed and the patient poses a risk to themselves or others. This recommendation is based on an increased risk of stroke and death associated with these agents.²⁷

Alpha-1 blockers (doxazosin, prazosin, terazosin) and alpha agonists (clonidine and methyldopa) can cause orthostatic hypotension and should be avoided for hypertension. Doses of digoxin higher than 0.125 mg daily increase risk of toxicity without added benefit. Reduced renal function may also increase risk of toxicity including headache, dizziness, and mental disturbances.²⁷

Long-term use of nonselective NSAIDs should be avoided, unless other measures fail, because of increased risk of gastrointestinal bleeding (GIB), reduced renal function, and exacerbation of heart failure. This includes aspirin at doses of more than 325 mg/day, ibuprofen, naproxen, piroxicam, indomethacin, and other NSAIDs.²⁷

Fall Risk Assessment Scales

Several fall risk assessment scales are available for use in hospitals, nursing homes, acute care settings, and the community. These tools help identify factors contributing to risk of patient falls, including some that include medications. The Morse Fall Scale,²⁹ Johns Hopkins Fall Risk Assessment Tool,³⁰ development and evaluation of evidence-based risk assessment tool (STRATIFY),³¹ and the Hendrich II Fall Risk Model³² are widely used.

The Morse Fall Scale was developed in 1995 by Janice Morse and includes only intravenous medications among key factors contributing to fall risk. The Johns Hopkins Fall Risk Assessment Tool was developed in 2005 by Johns Hopkins Medicine and includes a list of current medications as part of seven key factors. The STRATIFY Scale was developed in 1997 by Oliver et al.; it includes four key factors and does not include medications as one of the risk factors to falls. The Hendrich II Fall Risk Model was developed in 2003 by Ann Hendrich, and one of its eight key factors is whether the patient is receiving antiepileptic medications or benzodiazepines.

The U.S. Centers for Disease Control and Prevention (CDC) has most recently developed a fall risk assessment tool known as Stopping Elderly Accidents, Deaths, and Injuries (STEADI).³³ STEADI was developed in 2013 to offer a coordinated approach to implementing the American and British Geriatrics Societies’ Clinical Practice Guideline for fall prevention. It consists of three core elements: Screen, Assess, and Intervene. These elements are supported by several resources including screening options, conversation starters, medications linked to falls, and continuing education for providers. STEADI’s medications linked to falls include anticonvulsants, antidepressants (tricyclic antidepressants and selective serotonin reuptake inhibitors), antipsychotics, benzodiazepines, opioids, sedative-hypnotics (eszopiclone, zaleplon, and zolpidem), anticholinergics, antihistamines, muscle relaxants, and medications affecting blood pressure.³³

The CDC has also designed STEADI-Rx to facilitate collaboration between pharmacists and healthcare providers.³² STEADI-Rx helps guide pharmacists to screen pharmacy patients, assess their medications, and intervene to reduce fall risk. It offers several resources to pharmacists, including a provider consult form that can be submitted to recommend deprescribing.

Deprescribing Guidelines

Evidence-based deprescribing guidelines have been developed for 4 classes of medications.^37-40 The guidelines indicate when a medication should be continued, reduced or stopped, if it can cause harm when stopped, how to stop and associated monitoring or management.

Table 3 summarizes the clinical circumstances that necessitate deprescribing and when deprescribing should not be recommended for proton pump inhibitors, antihyperglycemic medications, antipsychotics and benzodiazepine receptor agonists. Additional information about dosage availability for each medication in the class, patient engagement strategies, side effects and non-pharmacologic management or conditions to help reduce reliance on medications is outlined in the deprescribing algorithms, available at deprescribing.org.

BARRIERS TO DEPRESCRIBING

Some obstacles to deprescribing include the lack of a complete and continuous medication list, multiple prescribers, patient new to a prescriber, patient or family members’ preference (i.e., patient afraid to discontinue medication that they have taken for many years or fear of withdrawal effects), provider feeling obligated to prescribe due to disease-specific guidelines, unclear duration of treatment, or provider uncomfortable to reduce or stop a medication initiated by another provider.³⁵

In the above scenarios, clear communication among prescribers, pharmacists, patient, and other health care professionals involved in the patient’s care is important to help achieve the desired outcome. Pharmacists are in an unparalleled position to make medication-related interventions, especially in those who see multiple prescribers; these patients are at a disadvantage if all involved providers are not aware of medications ordered by other prescribers. Pharmacists are also at the front line of medication-related care and have the opportunity to provide patient education and help ease patients’ concerns regarding medication adjustments.

COLLABORATIVE DEPRESCRIBING

Prescribers, pharmacists, and other health care professionals must collaborate in collecting as much information as possible in clarifying questions surrounding the patient’s medication history and usage. This could include when the therapy was initiated and why; if the diagnosis was confirmed; whether the drug was prescribed to treat adverse effects of another drug or could be part of a prescribing cascade; if the drug is still efficacious; and whether alternative nonpharmacologic therapies are available that could provide comparable efficacy.

Sometimes medications are continued for years on the assumption that they are conferring a benefit, and this is a key contributor to polypharmacy. At a minimum, an annual review of the patient’s medication list should be conducted to reevaluate the answers to these questions. Deprescribing decisions can be informed by a range of healthcare professionals. Community pharmacists have a valuable role with respect to deprescribing. For example, pharmacists should conduct medication-use reviews, conduct structured adherence-centered questioning upon dispensing a medication, and focus counseling on long-term conditions in patients at risk for polypharmacy.

The patient's perspective and involvement in the deprescribing process is important so that medications can be withdrawn safely and outcomes realized. The patient’s perception of side effects and efficacy is important, as is the pharmacist’s assessment of medication adherence. Reasons why patients do or do not take medications as prescribed also plays a pivotal role in determining how to modify the medication regimen. Pharmacists should use clear, plain language to inform and educate the patient about reasons and process for deprescribing. Pharmacists working within multidisciplinary teams can play an important role as lead clinicians in the deprescribing process, coordinating medication-related care and collaborating with patients and others involved.

Integrating deprescribing into medical culture begins when a medication is prescribed. Each time a medication is prescribed, the expected duration of therapy should be included with instructions for medications. Decisions to reduce or stop medications are complex, particularly since patients prescribed multiple medications often have a complex, long-term set of clinical conditions. The deprescribing process can be facilitated when pharmacists recognize potential barriers and systematically identify opportunities for discontinuing medications by engaging with patients and caregivers and other health care professionals.

CONCLUSION

Pharmacists have a unique opportunity to shift the clinical focus from prescribing, or starting new medications, to deprescribing. This is accomplished by working in collaboration with the patient’s care team to withdraw inappropriate medications, especially in older adults. Deprescribing is a clinically important part of the prescribing process that ensures medication efficacy, reduces harms, and mitigates polypharmacy. It involves reducing doses or stopping medications that are not useful, no longer indicated, or which may be causing harm. It may also involve changing to a safer agent or using nonpharmacologic approaches for care instead.

Several resources are available to help in identifying medications that may be causing patient harm and may warrant deprescribing. A recent CDC initiative, STEADI-Rx, is one tool pharmacists can be used to recommend deprescribing in the community setting.³² Evidence-based guidelines for deprescribing have been developed for 4 medication classes thus far. Other guidelines are needed to integrate deprescribing into routine practice through behavioral changes focused on providers, patients and their caregivers, and health care decision-makers.

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