Common ED Medication Errors: Polypharmacy

Author: Kristin E. Fontes, MD (Emergency Physician, Aspirus Iron River Hospital, Santa Barbara Cottage Hospital) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

Case presentation

A 78-year-old man with a history of advanced dementia, hypertension, and coronary artery disease is brought to the emergency department (ED) by ambulance from a skilled nursing facility after an unwitnessed fall. Facility staff state that he was found on his bedroom floor sitting against his bed, unable to get himself up. He typically ambulates unassisted. He has been having increasing issues with nighttime agitation recently, so the facility physician started him on quetiapine 50 milligrams at bedtime one week ago. His medication list also includes low dose aspirin, lisinopril, metoprolol, donepezil, and tamsulosin.

Initial vitals are as follows: T 98.8F, HR 70, BP 130/90, RR 16, SpO2 98% on room air

He is oriented to self only (which is his baseline, per facility staff). The remainder of his physical examination and workup are unremarkable. On attempting an ambulation trial, the patient is unable to stand without assistance.

Repeat vital signs while standing are as follows: HR 70, BP 90/50

Introduction

In the United States, patients older than 65 years of age accounted for 15% (19.6 million) of ED visits between 2009 and 2010, and the average visit rate increased with advancing age^[1]. Common reasons for visiting the ED include altered mental status, falls, syncope, dizziness, and generalized weakness. These presenting problems are often representative of the functional loss that accompanies an inability to endure an underlying illness, otherwise known as frailty^[2]. Arguably overlooked is polypharmacy being a contributing factor in many ED presentations. Polypharmacy (commonly defined as taking more than 5-10 drugs per day^[3]) is essentially a geriatric issue. Older patients are generally sicker and require more medical therapy than younger patients, but polypharmacy is often inappropriate^[4]. Furthermore, many patients struggle with managing multiple medications due to cognitive and functional decline, and discrepancies between patients and providers are common^{[5] [6] 19}.

This is a rapidly growing and important demographic of which to have an understanding of pharmacokinetic and pharmacodynamic principles. It may seem surprising that an age disparity actually exists among drug clinical trial participants, but the elderly are consistently underrepresented in this arena^[7]. A recent review of randomized controlled trials involving therapy with pioglitazone, rosuvastatin, risedronate, and valsartan demonstrated poor representation of patients over age 65 when compared to the numbers of patients in this age group prescribed these drugs in clinical practice^[8]. A potential consequence of this information gap is limited knowledge and recommendations about proper dosing.

Another factor to be mindful of is the concept of aging being a complex and unique process for every individual. We tend to group older patients by age, but a 75-year-old with multiple comorbid conditions and the same-aged healthy patient will metabolize drugs differently, and as a result, will experience variable therapeutic and adverse effects^[9]. There are some unique pharmacokinetic features to keep in mind when prescribing medication to an older (especially if chronically ill) patient^{[10] [11]}:

Note that pharmacogenetic polymorphism (e.g. robust or poor CYP450 isozyme activity) may be an important risk factor for hospitalization in polymedicated elders^[12]. While a comprehensive review of the literature on polypharmacy and associated adverse events is beyond the scope of this article, there are two areas that deserve special attention. Falls and delirium are among the most common polypharmacy-associated ED presentations for older patients, and these will be the focus of this discussion.

Falls:

After age, polypharmacy may be the most common risk factor for falls in older adults presenting to the ED^[13]. A cross-sectional analysis of 873 ED patients age 65 or older found acid-related disorder drugs, analgesics, anti-Parkinson drugs, nasal drugs, ophthalmologic drugs, antipsychotics, and antidepressants to be statistically significantly associated with ED visits due to recurrent fall^[14]. Fall-risk increasing drugs (FRIDs) were also shown to be more associated with recurrent falls in frail elderly patients admitted to the hospital after a fall as compared to more robust patients^[15].

Delirium:

Delirium, an acute mental status change that occurs in the context of an underlying illness or intoxication, is a multifactorial process. With regard to medications, polypharmacy is an independent risk factor for delirium in elderly patients after admission from the ED, with the relative risk being up to twofold^[16]. One pharmacological hypothesis is that vulnerable patients may have reduced hepatic esterase enzyme activity, consequently altering drug metabolism and potentiating the risk for delirium^[17].

Error considerations

There is no standardized way to measure the severity of prescribing errors^[18], but they are nonetheless prevalent among older patients. The term “prescribing error” should be distinguished from “potentially inappropriate medication,” as the former is typically a factor (such as prescriber knowledge) that may lead to the latter^[19]. The following are examples of both types of errors and should be considered when evaluating all elderly patients.

Dosing

Drug dose adjustments for age-related renal impairment are inconsistent and often inappropriate. This may be, in part, due to inaccurate estimation of renal function. Serum creatinine changes likely underestimate the true drop in glomerular filtration rate (GFR), whereas creatinine clearance (CrCl) is a more accurate reflection^[20],[21]. Generally speaking, dose adjustments are necessary when CrCl is less than 60.

Take home point

Avoid using the serum creatinine value to make decisions about drug dosing in older patients. Use GFR or calculate CrCl.

Specific drug associations

Older patients commonly use at least one drug that affects the central nervous system (CNS) including opioids, benzodiazepines, antidepressants, and antipsychotics. A longitudinal cohort study of more than 3,000 American adults aged 70-79 with good baseline physical function demonstrated a significantly increased risk of recurrent falls in patients taking 2 or more drugs from any of the four classes listed above (adjusted OR 1.95, 95% CI 1.35-2.81, p=0.0004)^[22]. Opioids alone appear to be driving recent increases in CNS polypharmacy^[23].

It should come as no surprise that CNS medications can also induce and exacerbate delirium. However, anticholinergics are quite possibly the worst offenders^[24]. While there is currently no reliable laboratory method for quantifying anticholinergic burden^[25], providers may be able to estimate anticholinergic load in a patient taking multiple medications by summing the risk associated with each drug^[26]. Consider this carefully when treating acute delirium with antipsychotics, which may paradoxically worsen delirium^[27].

Take home point

When prescribing to older adults, minimize the number of CNS medications and their cumulative anticholinergic burden as much as possible.

Drug-drug interactions

Common adverse drug events related to drug-drug interactions (DDIs) in older patients include increased bleeding with warfarin when co-administered with antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), and proton pump inhibitors (PPIs)^[28]. Whereas most clinically important DDIs likely result from pharmacodynamic mechanisms, PPIs in particular should be used cautiously in patients taking vitamin K antagonists (e.g. warfarin) and clopidogrel due to inactivation of the CYP2C19 isoenzyme, leading to a pharmacokinetic-mediated increased bleeding and thrombosis, respectively.^[29]

Regarding falls and delirium, there are specific DDIs that deserve special attention:

Hypoglycemics: Two important drug-drug interactions with antidiabetic agents may lead to severe hypoglycemia – beta blockers and antibiotics (trimethoprim/sulfamethoxazole^[30] and fluoroquinolones²⁹). Unfortunately, despite efforts to curtail DDIs for elderly outpatients, Raschi et al demonstrated a near 8% increase in beta blocker-antidiabetic agent DDIs over a 2-year interventional period²⁹. A possible explanation for this prevalent combination is that the individual drugs are accepted first-line agents for their respective diseases.

Calcium channel blockers (CCBs): Any patient on antihypertensive therapy is at risk for relative or true hypotension which may lead to orthostasis and falls. CCBs (both dihydropyridine and non-dihydropyridine) are cytochrome P450 3A4 substrates and, when taken with macrolide antibiotics (CYP3A4 inhibitors), patients may develop hypotension requiring hospital admission. A case-crossover study of 176 admitted hypotensive patients taking a CCB and a macrolide antibiotic found the strongest association of hypotension with erythromycin (OR 5.8, 95% CI 2.3-15.0) and clarithromycin (OR 3.7, 95% CI 2.3-6.1); there was no association found with azithromycin (OR 1.5, 95% CI 0.8-2.8)^[31]. Note, however, that azithromycin does not inhibit CYP3A4.

Serotonin augmenters: Increased serotonin activity leading to altered mental status and falls, among other complications, due to concomitant use of SSRIs with psychotropics, antithrombotics, and diuretics may affect the elderly disproportionately^[32].

In recent years, pharmacogenetic polymorphism has gathered more attention as an explanation for DDIs and adverse events in individual patients. Precision medicine through pharmacogenomic testing identifies patients who are “poor” and “rapid” metabolizers of certain cytochrome P450 isozymes, which will affect drug bioavailability and, in polymedicated patients, potentiate DDIs^[33]. Below is a summary of specific isozymes and their associated drug interaction complications. Note that these complications are largely based on case reports.

Take home point

Use caution when prescribing new medications to elderly patients already taking antidiabetic agents, calcium channel blockers, and selective serotonin reuptake inhibitors, as drug-drug interactions with these agents can lead to falls and delirium.

How do we improve? Questions to ask yourself and tools to consider…

While many interventions to reduce inappropriate polypharmacy should take place in the primary care setting, emergency providers should consider the following when treating acute problems in older and, in particular, polymedicated patients. 

What medications is the patient taking?

This might seem like an obvious and simple question, but medication discrepancies in older patients are extremely prevalent. One study of close to 800 patients taking a median of 15 medications found that every individual had at least one medication discrepancy such as missing medications and dosing/frequency discrepancies when comparing medication lists created by referring providers and home healthcare nurses⁶. Not surprisingly, a consequence of discrepant medication records is potential adverse drug events (ADE). While we may intuit that information exchange through electronic health records (EHR) mitigates this risk, a study of nearly 500 patients in both Veterans Affairs (VA) and non-VA facilities found no difference in the occurrence of medication discrepancies (mean difference 0.02; 95% CI -0.8-0.85) or resultant ADEs (OR 0.96, 95% CI 0.18-5.01) at the time of transfer between facilities, regardless of the presence of EHRs (albeit the overall number of ADEs was small)^[39].

Is the drug I want to prescribe appropriate for use in older patients?

While no gold standard currently exists, there are several validated tools to identify potentially inappropriate medication therapy in older patients. The Beers’ criteria is a widely available resource for potentially inappropriate medications. Important to the discussion of polypharmacy is the most recent update which includes a selective list of harmful drug-drug interactions, notably an increased risk of falls when taking 3 or more central nervous system-active drugs concomitantly^[40]. The Norwegian General Practice (NORGEP) criteria also lists potentially inappropriate medications as well as potentially pharmacologically inappropriate drug combinations^[41]. The Medication Appropriateness Index (MAI) is a 10-question tool regarding a drug’s indication, efficacy, dosing, and pharmacologic properties and assigns a numerical value to its appropriateness (with 0 being completely appropriate, and a maximum score of 18 being completely inappropriate). A comprehensive tool known as the Screening Tool of Older Person’s Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) provides specific prescribing considerations for potentially inappropriate medications and medications to consider starting in patients age 65 years and over, respectively. It was updated in 2015 and lists recommendations by organ system^[42]. As mentioned previously, we should strongly consider cumulative anticholinergic burden as a risk factor for delirium. The Anticholinergic Risk Scale (ARS) is a simple tool that assigns 1-3 points per anticholinergic drug used. Higher point values are associated with more anticholinergic adverse effects, suggesting a dose-response relationship^[43].

Links to screening tools:

Beers’ criteria (2015 update)

Medication Appropriateness Index (MAI)

STOPP/START

Anticholinergic Risk Scale (ARS)

The most recent Cochrane review analyzing appropriate polypharmacy (as measured by the MAI, Beers’ criteria, and STOPP/START) found that, while the number of inappropriate prescriptions to older patients decreased when using these tools, did not demonstrate whether this results in improved clinical outcomes^[44].

Take home point:

Consider using a validated screening tool to identify and avoid potentially inappropriate medications and drug combinations in older patients (MAI and STOPP/START may be more appropriate to the ED setting).

What ancillary support is available to identify and reduce polypharmacy?

Proper medication reconciliation is important but often incomplete. Pharmacist-driven medication review may prove to be a critical patient care application. A recent randomized controlled trial of such a program for patients 70 years of age and older taking 8 or more medications in which changes were recommended to the physician resulted in significantly fewer prescriptions per patient as well as greater numbers of dose adjustments and substitutions compared to control group. However, there was no difference in number of ED visits, admissions, or deaths^[45]. Electronic health records (EHRs) should also play a role. With the recent federal mandate for healthcare providers and organizations to adopt EHRs and achieve meaningful use (http://www.healthit.gov/), clinical decision support has the potential to improve quality of care and patient safety with regard to polypharmacy^[46]. One recent study examined re-hospitalization and ED visits after randomizing patients age 50 and over to receive pharmacogenetic testing and medication screening for potential drug interactions using an electronic clinical decision support tool (versus the control group who underwent no testing and received medication review through a standard drug information resource and pharmacist guidance). It found the intervention group had a significant decrease in both re-hospitalization (relative risk, RR 0.48, 95% CI 0.27-0.82, P=0.007) and ED visits (RR 0.58, 95% CI 0.34-0.99, P=0.045) at 60 days^[47]. Another study, which implemented an adjusted STOPP list and pharmacist-led medication review, also demonstrated a trend toward fewer ED visits in the intervention group (versus usual geriatric care), in addition to improved quality of life^[48].

Conclusion

Older adults frequently require multiple medications to manage chronic conditions, and these patients at risk for complications due to inappropriate polypharmacy. In fact, the “iatrogenic triad” of polypharmacy, drug-drug interactions, and potentially inappropriate medications is prevalent among elderly, and in particular frail, patients^[49]. Reducing prescribing errors and avoiding potentially inappropriate medications begins with provider education, which should include clinical decision support and pharmacist expertise. Pharmacogenetic testing may assist with optimizing medication appropriateness for individual patients. Furthermore, with an actively growing geriatric population, it is imperative that undergraduate and postgraduate medical curricula include training in good prescribing practices^19,[50],[51]. Recognizing frailty syndromes including (but not limited to) falls and delirium, as potential harbingers of polypharmacy, may be a critical opportunity to improve clinical and functional outcomes. Clinical operations should include comprehensive medication reconciliation, especially when prescribing new medications. A “bigger picture” solution will involve improving policy to consistently include older adults in drug clinical trials to optimize our ability to safely and effectively treat this unique and vulnerable patient population^[52].

Take home points

1. Avoid using the serum creatinine value to make decisions about drug dosing in older patients. Use GFR or calculate creatinine clearance (CrCl).
2. When prescribing to older adults, minimize the number of CNS medications and their cumulative anticholinergic burden as much as possible.
3. Use caution when prescribing new medications to elderly patients already taking antidiabetic agents, calcium channel blockers, and selective serotonin reuptake inhibitors, as drug-drug interactions with these agents can lead to falls and delirium.
4. Consider using a validated screening tool to identify and avoid potentially inappropriate medications and drug combinations in older patients (MAI and STOPP/START may be more appropriate to the ED setting).

References/Further Reading:

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