High Utilization of CYP2D6 Substrate Prescriptions Among Long-Term Care Residents With Overactive Bladder
Abstract
Overactive bladder (OAB) is highly prevalent among adults in long-term care (LTC) facilities and is associated with substantial comorbidity and polypharmacy, which increases the likelihood of drug-drug interactions and detrimental adverse effects. This retrospective cohort analysis of LTC facility residents identified prescription claims for cytochrome P450 2D6 (CYP2D6) substrates and mirabegron, a moderate CYP2D6 inhibitor approved for the treatment of OAB. CYP2D6 substrate prevalence was assessed between May 1, 2013, and May 31, 2018, in a cohort of residents with OAB and a subset of residents with OAB receiving mirabegron. During the analysis period, >90% of residents in both cohorts received CYP2D6 substrates, approximately 66% of which were used for depression/psychiatric diseases. Within the OAB and mirabegron cohorts, 84% and 78% of residents, respectively, received CYP2D6 substrates that are associated with QT prolongation; 91% and 86% received CYP2D6 substrates with anticholinergic properties. One-third and one-quarter of residents received CYP2D6 substrates with narrow therapeutic index and box warning/contraindication for coadministration with CYP2D6 inhibitors, respectively. High prevalence of CYP2D6 substrates among LTC residents increases risk of drug-drug interactions and adverse effects.
Key words: adverse drug reaction, antimuscarinics, cytochrome P450, urinary bladder overactive, urinary incontinence
Citation: Ann Longterm Care. Published online October 7, 2022.
DOI: 10.25270/altc.2022.10.001
Overactive bladder (OAB) is defined as urinary urgency and frequency with or without urge urinary incontinence,1 and symptoms of OAB have been shown to increase with age.2,3 The prevalence of OAB among adults aged ≥65 years has been reported to range between 5.5% and >30%.4,5 Among long-term care (LTC) facilities, 66% of residents aged 65 to 74 years lack complete control of bladder function (ie, experience symptoms of OAB such as urinary incontinence) compared with 74% of residents aged 75 to 84 years old and 79% of residents aged ≥85 years old.3
Older adults with OAB have a higher incidence of comorbidities (eg, hypertension, psychiatric disorders, urinary tract infections) than older adults without OAB.6-8 As a result, older adults with OAB have a greater number of concomitant medications than those without OAB, increasing the risks for drug-drug interactions (DDIs).6 Such polypharmacy increases anticholinergic burden when multiple anticholinergics are prescribed, which is particularly relevant in patients with OAB because anticholinergics have been the mainstay of treatment.1 Increased anticholinergic burden is generally recommended to be avoided in older adults owing to an increased risk of falls, fractures, cognitive decline, and incident dementia.9-11 Drugs associated with QT prolongation risk are additionally relevant in patients with OAB given the high proportion with comorbid cardiovascular disorders.7
Compared with adults aged ≥65 years visiting general practitioners or hospitals, older adults in LTC facilities are more likely to have potentially inappropriate prescriptions as identified by the American Geriatrics Society (AGS) Beers Criteria® guidelines.12 In addition to inappropriate prescribing practices, cytochrome P450 (CYP)–mediated interactions can lead to DDIs and adverse events. Among LTC facilities, residents with OAB have a significantly greater number of prescription claims for CYP2D6 substrates (drugs metabolized by the CYP2D6 enzyme) than residents without OAB (73.8% vs 67.3%, respectively).13 Because some drugs inhibit the CYP2D6 enzyme, concomitant prescribing of CYP2D6 inhibitors with CYP2D6 substrates may increase serum concentrations of the substrate. This resultant rise in substrate serum concentration may be associated with increased risk for potentially serious adverse drug events related to the substrate’s pharmacologic properties. Concomitant use of mirabegron—a β3-adrenergic receptor agonist approved for the treatment of OAB that is a moderate CYP2D6 inhibitor—with a CYP2D6 substrate inhibits substrate metabolism and leads to a rise in substrate serum concentrations.14 Treatment of OAB with mirabegron and anticholinergics that are CYP2D6 substrates (ie, darifenacin, fesoterodine, tolterodine) may lead to increased anticholinergic burden.
Safe prescribing practices may mitigate the risk of potentially harmful DDIs in older populations, and such practices could reduce scenarios of increased exposure to drugs that have risk of QT prolongation, have anticholinergic properties, or have a narrow therapeutic index. This study aims to describe the prevalence of CYP2D6 substrate use among LTC residents with OAB and among a subset of residents with OAB receiving mirabegron.
Methods
Study Design and Database
This was a retrospective cohort analysis of an LTC pharmacy claims database from IQVIA, a health information technology company with an integrated data warehouse. The database is compliant with the Health Insurance Portability and Accountability Act. Deidentified claims from residents of LTC facilities were linked to IQVIA’s New Data Warehouse. Details regarding the claims database have been previously published.13 Briefly, the New Data Warehouse includes professional fee claims, prescription claims, and hospital charge master data for >500 hospitals and approximately 165 pharmacies representing >3000 clinics.
Eligibility and Treatment Groups
OAB cohort: To be eligible for consideration, as a proxy for continuous enrollment, residents were required to have ≥1 office visit in the diagnosis database and ≥1 prescription claim in the prescription or LTC database during the 12-month pre- and post-index periods. To be included in the OAB cohort, residents were required to have ≥2 non‒same-day prescription claims for medications indicated for the treatment of OAB and pharmacy stability (consistent data reporting and ≥80% coverage for each month in the 12-month pre- and post-index periods) during the selection window between May 1, 2013, and May 31, 2018. Data quality issues such as invalid birth year, sex, or region were exclusionary.
Mirabegron cohort: Residents who met inclusion criteria for the OAB cohort and had ≥1 prescription claim for mirabegron between May 1, 2013, and May 31, 2018, were included in the mirabegron cohort.
Outcomes Assessment and Analysis
Within the OAB and mirabegron cohorts, prescription claims for CYP2D6 substrates were identified using IQVIA’s New Data Warehouse. CYP2D6 substrates were selected based on those included in a previous publication15 that identified CYP2D6 substrates via US prescribing prevalence, degree of CYP2D6 metabolism, consequences of increased exposure (eg, serotonin syndrome, QT prolongation, torsades de pointes [TdP]), and the associated risks of the drug itself (eg, narrow therapeutic index). CYP2D6 substrates were then classified based on primary treatment indication, risk of QT interval prolongation, anticholinergic properties, narrow therapeutic index, and black box warning/contraindication for coadministration with CYP2D6 inhibitors, as identified in the previous publication.15
Treatment indications of interest included OAB and lower urinary tract symptoms and common comorbid diseases associated with OAB (ie, depression, psychotic disorder, or other psychiatric disease; hypertension and cardiovascular disease; neurologic disorder; pain and supportive care; other conditions). Substrates associated with risk of QT prolongation were classified into 3 risk categories: (1) known risk (drug prolongs QT intervals and has a risk of TdP when used as directed in labeling); (2) possible risk (drug can cause QT prolongation, but there is insufficient evidence that the drug, when used as directed in labeling, has a risk of causing TdP); and (3) conditional risk (drug prolongs QT and has a risk of developing TdP but only under certain known conditions such as DDIs).16 Substrates with any anticholinergic properties were identified by Hanlon et al,17 and those with strong anticholinergic properties were identified from the AGS Beers Criteria® guidelines.11 Narrow therapeutic index medications of interest were those that were prohibited in a phase 4 study of mirabegron in older adults with OAB (aripiprazole, desipramine, donepezil, flecainide, imipramine, propafenone, thioridazine, tramadol, and venlafaxine).18
The number and percentage of adults within the OAB and mirabegron cohorts with a relevant prescription at any time during the 5-year analysis window was recorded. Medication use is reported individually (ie, not mutually exclusive) and in aggregate. Data are presented descriptively.
Results
Resident Cohorts and CYP2D6 Substrate Prevalence
The OAB cohort included 159,785 residents, and the mirabegron cohort included 25,115 residents. Demographic data for the OAB cohort have been previously published.13 Within the OAB and mirabegron cohorts, 95.4% and 92.5% of residents, respectively, received a CYP2D6 substrate during the analysis period. The 3 most frequently prescribed substrates in both cohorts were metoprolol, hydrocodone, and tramadol (Table 1). Exposure to CYP2D6 substrates was generally similar between groups, with the exception of tolterodine (16.1% in the OAB cohort vs 4.2% in the mirabegron cohort). Donepezil, tamsulosin, duloxetine, and escitalopram were prescribed at slightly higher rates in the mirabegron cohort compared with the OAB cohort.
CYP2D6 Substrate Use by Indication
Overall, 66.2% of residents in the OAB cohort received CYP2D6 substrates indicated for the treatment of depression, psychotic disorder, or other psychiatric diseases; 58.8% received CYP2D6 substrates for pain and supportive care (Table 2). Prevalence of CYP2D6 substrate use in the mirabegron cohort was generally similar to the OAB cohort when classified by indication; however, the largest disparity in prescribing prevalence between cohorts was seen among medications for OAB and lower urinary tract disorders (31.6% of residents in the OAB cohort vs 20.1% in the mirabegron cohort).
CYP2D6 Substrates With Risk of QT Prolongation
During the analysis period, 84.0% of residents in the OAB cohort and 78.3% in the mirabegron cohort received ≥1 CYP2D6 substrate with any risk of QT prolongation. Within the OAB cohort, 38.1%, 58.5%, and 46.5% of residents received CYP2D6 substrates with known, possible, and conditional risk of QT prolongation, respectively (Table 3). Within the mirabegron cohort, 37.1%, 47.6%, and 43.1% of residents received CYP2D6 substrates with known, possible, and conditional risk of QT prolongation, respectively. In both cohorts, donepezil and hydrocodone were the most frequently prescribed medication with a known and possible risk for QT prolongation, respectively. Trazodone was the most frequently prescribed medication with a conditional risk for QT prolongation in both cohorts.
CYP2D6 Substrates With Anticholinergic Properties
Overall, 90.6% of residents in the OAB cohort and 85.7% in the mirabegron cohort received ≥1 CYP2D6 substrate with any anticholinergic properties (Table 4). When classified by treatment indication, 66.0% of residents in the OAB cohort and 64.6% in the mirabegron cohort received a CYP2D6 substrate with any anticholinergic properties indicated for the treatment of depression or other psychiatric disease (ie, anxiety, bipolar disorder, schizophrenia) during the analysis period; 56.6% of residents in the OAB cohort and 49.7% in the mirabegron cohort received ≥1 CYP2D6 substrate with any anticholinergic properties for pain and supportive care.
CYP2D6 Substrates With Narrow Therapeutic Index or Black Box Warning/Contraindication With CYP2D6 Inhibitor
In the OAB and mirabegron cohorts, 38.3% and 37.6% of residents, respectively, received ≥1 CYP2D6 substrate of interest with a narrow therapeutic index during the analysis period (Table 5), and 24.0% and 21.3% of residents, respectively, received a CYP2D6 substrate with a black box warning or contraindication when prescribed with a CYP2D6 inhibitor (Table 6). Tramadol was the most frequently prescribed CYP2D6 substrate meeting these criteria in both cohorts.
Discussion
Approximately 25% of all drugs are CYP2D6 substrates, and a substantial percentage of these medications are highly prescribed in the United States.19 In this analysis, almost all residents of LTC facilities with OAB had ≥1 prescription claim for a CYP2D6 substrate during the 5-year analysis window. Within the OAB and mirabegron cohorts, most residents had a prescription claim for a CYP2D6 substrate with varying degrees of anticholinergic properties. Approximately one-third of residents in both cohorts had a prescription claim for a CYP2D6 substrate with a known risk of QT prolongation or with a narrow therapeutic index. Additionally, nearly one-quarter of residents with OAB receiving mirabegron had ≥1 claim for a CYP2D6 substrate with a boxed warning and/or a contraindication for use with CYP2D6 inhibitors. Although using CYP2D6 substrates is unavoidable and generally safe in most instances, providers should be cognizant of the risks associated with coprescribing CYP2D6 substrates with CYP2D6 inhibitors.
The risks of DDIs are amplified in older adults, especially those in LTC facilities, given the higher prevalence of polypharmacy.20 Although we are unable to determine whether potential DDIs may have been raised by consultant pharmacists and subsequently revised by the prescriber, the high proportion of older adults in LTC facilities exposed to CYP2D6 substrates in our analyses highlights the need for health care providers to monitor resident medication regimens. Multiple studies have shown that older adults may have clinically significant adverse reactions (ie, renal dysfunction and/or dehydration, sedation, hypotension, bradycardia) from DDIs,21 which may lead to hospital admissions.22 Thus, proactively identifying DDIs may lead to improved patient safety.
Computerized physician order entry (CPOE) systems and electronic health record (EHR) databases are intended to assist physicians and pharmacists in monitoring patient medication regimens and clinical results, minimize occurrence of adverse drug reactions or DDIs, and provide medication safety alerts and decision-making support when potential DDIs are encountered. However, some CPOE databases may increase the likelihood of prescribing errors,23 and a lack of EHR database standardization may create disparities among safety performance scores.24 Furthermore, an analysis of a CPOE system at a community hospital showed that only 0.7% of 466,311 prescriptions were considered true medication errors after discussions between pharmacy staff and the prescriber.25 A prospective study showed that pharmacists considered 62% of medication alerts unhelpful and 50% unimportant.26 A retrospective database analysis found that the most common reasons for DDI override were as follows: the interaction was deemed not clinically significant (21.6%), the interaction was currently or previously tolerated by the patient (21.6% and 12.3%, respectively), and one of the offending agents was no longer prescribed to the patient (8.0%).27 Constant override of medication alerts puts both pharmacists and clinicians at risk for alert fatigue, which may increase the likelihood of inappropriate prescribing.
Genetic variability of the CYP2D6 gene can lead to altered metabolism of CYP2D6 substrates. Approximately 6.4% of Americans are classified as poor and/or intermediate CYP2D6 metabolizers28,29 who would experience increased CYP2D6 substrate exposure and increased risk of adverse reactions. Patients with OAB receiving mirabegron, a moderate CYP2D6 inhibitor, may also experience increased CYP2D6 substrate exposure.30 Pharmacokinetic studies of CYP2D6 substrates commonly prescribed with mirabegron (eg, tolterodine, metoprolol, desipramine) have shown increases in maximum plasma concentration and area under the curve of the substrate.14,31 This increased substrate exposure resulting from coadministration of a CYP2D6 substrate and inhibitor is similar to the increased exposure seen in poor and intermediate CYP2D6 metabolizers. A meta-analysis32 showed that intermediate and poor CYP2D6 metabolizers had increases in maximum plasma concentration after a single oral dose of metoprolol. Poor metabolizers displayed a greater change in exercise-induced heart rate compared with extensive metabolizers in these analyses.32 Thus, residents who are reduced CYP2D6 metabolizers and are prescribed a CYP2D6 inhibitor have a compounded risk of experiencing potentially harmful adverse drug reactions.
Recent systematic reviews showed that advanced age, hypertension, heart failure, electrolyte abnormalities, bradycardia, cardiovascular medications such as loop diuretics, and receipt of multiple QT-prolonging drugs were strongly associated with QT prolongation.33,34 These risk factors are common in individuals with OAB and in residents of LTC facilities, many of whom present with cardiovascular comorbidities.35 Thus, a large portion of the LTC residents in our analysis may be at additional risk for QT prolongation owing to factors beyond CYP2D6 substrate interactions. QT prolongation, if left unmanaged, can progress into dangerous arrhythmia, such as TdP. When used alone at maximum approved dosage, both tolterodine and mirabegron cause an increase from baseline in QTc interval relative to placebo.30,36 Increased tolterodine exposure in poor metabolizers was associated with greater increases in QT interval.36 Although small increases in QT interval will generally not result in adverse cardiovascular effects, coadministration of drugs with risk of QT prolongation may lead to additive effects on cardiac ion channels.37 In an analysis38 of patients admitted to a cardiac intensive care unit with QT prolongation, almost half had a causally related pharmacokinetic DDI responsible for their admission, many of which included CYP2D6 substrates and inhibitors.
Because anticholinergics are generally recommended to be avoided in older adults,11 anticholinergic burden, which is a function of both dose and duration, was of interest in our analyses. Inhibited metabolism of anticholinergics that are CYP2D6 substrates leads to increased exposure and, subsequently, higher anticholinergic burden. Increased anticholinergic burden is associated with a significantly increased rate of falls and fractures among older adults with OAB9 and an increased risk of dementia.10 Despite recommendations to reduce use of anticholinergics in older adults, our analysis showed that a high percentage of older adults in LTC facilities received CYP2D6 substrates that had some level of anticholinergic properties. These results are in line with other studies that showed a significant association between polypharmacy and anticholinergic burden39 and relatively high rates of prescriptions for medications with very high (Anticholinergic Drug Scale >3) anticholinergic burden in older adults in nursing homes.40
CYP2D6 substrates with a narrow therapeutic index present a substantial risk in the LTC population, especially if the substrate is coadministered with a CYP2D6 inhibitor such as mirabegron. In our analyses, we assessed the prevalence of CYP2D6 substrates that were specifically prohibited in a phase 4 clinical trial of mirabegron in older adults with OAB.18 Tramadol was the most commonly prescribed CYP2D6 substrate with a narrow therapeutic index in our analyses in the OAB and mirabegron cohorts. Although we are unable to confirm that tramadol was coprescribed with mirabegron, these results illuminate a potential lack of prescriber knowledge with respect to potential DDIs and highlight the need for health care providers to carefully review pharmacologic interventions to avoid high-risk medications in LTC communities.
These analyses are limited by the reliance on a claims database, which may have been incomplete or may have included residents without OAB who received OAB-related medications for other purposes. Although residents were prescribed the medication, the extent to which the prescription medication regimen was followed or the total number of prescriptions is unknown. Furthermore, our analyses accounted for prescription claims during a 5-year analysis window, but we are unable to determine whether medications were coprescribed at any one time or if negative health outcomes arose from such coprescribing. Future analyses should assess the effects of coprescribing and DDIs on health outcomes. Our analysis did not account for individual genetic data or CYP2D6 metabolism phenotype, nor were we able to determine OAB symptom severity. Furthermore, our analysis did not account for residents who received behavioral therapy for treatment of their OAB; because our focus was on medication prescribing patterns, such data would not impact the potential for inappropriate prescribing. Databases typically do not provide data on over-the-counter medications; however, in the LTC setting, over-the-counter medications should have been prescribed by the treating clinician and thus should be accounted for within our analyses with few exceptions (eg, diphenhydramine).
Conclusion
In this retrospective database analysis of LTC claims data, nearly all LTC facility residents with OAB had received ≥1 CYP2D6 substrate during the 5-year analysis period, and a similarly high percentage had received a CYP2D6 substrate with anticholinergic properties. Many residents had also received CYP2D6 substrates with risk of QT prolongation or narrow therapeutic index, which increases the risk for clinically significant adverse drug reactions when administered with CYP2D6 inhibitors. Most strikingly, nearly all residents with OAB who had a claim for mirabegron, a moderate CYP2D6 inhibitor, had also received a CYP2D6 substrate during the analysis period; in addition, many had received a CYP2D6 substrate with a specific black box warning or contraindication for coadministration with a CYP2D6 inhibitor. These results suggest that potentially inappropriate prescribing may be a common occurrence in LTC facilities and highlight the need for health care providers to mitigate drug risks through careful monitoring of prescribing practices. Future analyses with controlled definitions of OAB diagnosis should assess coprescribing of OAB medications with CYP2D6 substrates to determine if potentially inappropriate prescribing is associated with negative health outcomes in this population.
Affiliations, Disclosures, & Correspondence
Authors: Richard G. Stefanacci, DO1 • John R. Horn, PharmD2 • Jason Yeaw, MPH3 • Drishti Shah, PhD3 • Adam Carrera, PharmD4 • Noelia Goti, BS4 • Stacie Holland, PharmD4,* • Paul N. Mudd Jr, PharmD, MBA4,*
Affiliations:
1 Jefferson College of Population Health, Thomas Jefferson University, Philadelphia, PA
2School of Pharmacy, Department of Pharmacy, University of Washington, Seattle, WA
3 IQVIA, Falls Church, VA
4 Urovant Sciences, Irvine, CA
*At the time the work was conducted.
Acknowledgments:
Editorial support was provided by Connor Hunter, PharmD, and Krystina Neuman, PhD, CMPP, of The Curry Rockefeller Group, LLC (Tarrytown, NY), and was funded by Urovant Sciences (Irvine, CA).
Disclosures:
This study was funded by Urovant Sciences (Irvine, CA). Richard G Stefanacci is an advisor for Urovant Sciences. John R. Horn is a coauthor and publisher of The Top 100 Drug Interactions: A Guide to Patient Management and a consultant to Urovant Sciences and Seegnal US. Jason Yeaw and Drishti Shah are employees of IQVIA, which received funding for this study from Urovant Sciences. Adam Carrera and Noelia Goti are employees of Urovant Sciences. Stacie Holland and Paul N Mudd Jr were employees of Urovant Sciences at the time the study was conducted.
Address correspondence to:
Richard G. Stefanacci, DO
Jefferson College of Population Health, Thomas Jefferson University
901 Walnut Street
10th Floor
Philadelphia, PA 19107
Email: richard.stefanacci@jefferson.edu
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