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CLINICAL INVESTIGATION

American Geriatrics Society 2019 Updated AGS Beers Criteria®

for Potentially Inappropriate Medication Use in Older Adults By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel*

The American Geriatrics Society (AGS) Beers Criteria®

(AGS Beers Criteria®) for Potentially Inappropriate Medica- tion (PIM) Use in Older Adults are widely used by clini- cians, educators, researchers, healthcare administrators, and regulators. Since 2011, the AGS has been the steward of the criteria and has produced updates on a 3-year cycle. The AGS Beers Criteria® is an explicit list of PIMs that are typi- cally best avoided by older adults in most circumstances or under specific situations, such as in certain diseases or con- ditions. For the 2019 update, an interdisciplinary expert panel reviewed the evidence published since the last update (2015) to determine if new criteria should be added or if existing criteria should be removed or undergo changes to their recommendation, rationale, level of evidence, or strength of recommendation. J Am Geriatr Soc 00:1– 21, 2019.

Key words: medications; drugs; older adults; Beers list; Beers Criteria

The American Geriatrics Society (AGS) Beers Criteria ®

(AGS Beers Criteria®) for Potentially Inappropriate Medication (PIM) Use in Older Adults are widely used by clinicians, educators, researchers, healthcare administrators, and regulators. Since 2011, the AGS has been the steward of the criteria and has produced updates on a 3-year cycle that began in 2012.1,2 The AGS Beers Criteria® are an explicit list of PIMs that are typically best avoided by older adults in most circumstances or under specific situations, such as in certain diseases or conditions.

For the 2019 update, an interdisciplinary expert panel reviewed the evidence published since the last update (2015) to determine if new criteria should be added or if existing criteria should be removed or undergo changes to their recommendation, rationale, level of evidence, or strength of recommendation. Each of the five types of cri- teria in the 2015 update were retained in this 2019 update: medications that are potentially inappropriate in most older adults, those that should typically be avoided in older adults with certain conditions, drugs to use with caution, drug-drug interactions, and drug dose adjustment based on kidney function.

OBJECTIVES

The specific aim was to update the 2015 AGS Beers Criteria®

using a comprehensive, systematic review and grading of the evidence on drug-related problems and adverse events in older adults. The strategies to achieve this aim were to:

• Incorporate new evidence on PIMs included in the 2015 AGS Beers Criteria® and evidence regarding new criteria or modifi- cations of existing criteria being considered for the 2019 update.

• Grade the strength and quality of each PIM statement based on the level of evidence and strength of recommendation.

• Convene an interdisciplinary panel of 13 experts in geriatric care and pharmacotherapy who would apply a modified Delphi method, informed by the systematic review and grading, to reach consensus on the 2019 update.

• Incorporate exceptions in the AGS Beers Criteria® that the panel deemed clinically appropriate. These exceptions would be designed to make the criteria more individualized to clinical practice and be more relevant across settings of care.

INTENT OF CRITERIA

The primary target audience for the AGS Beers Criteria®

is practicing clinicians. The criteria are intended for use in adults 65 years and older in all ambulatory, acute, and institutionalized settings of care, except for the hospice and palliative care settings. Consumers, researchers, phar- macy benefits managers, regulators, and policymakers also widely use the AGS Beers Criteria®. The intention of the AGS Beers Criteria® is to improve medication selection;

From the *American Geriatrics Society, New York, New York.

Address correspondence to Mary Jordan Samuel, American Geriatrics Society, 40 Fulton St, 18th Floor, New York, NY 10038. E-mail: [email protected]

See related editorial by Michael Steinman et al.

DOI: 10.1111/jgs.15767

JAGS 00:1–21, 2019 © 2019 The American Geriatrics Society 0002-8614/18/$15.00

educate clinicians and patients; reduce adverse drug events; and serve as a tool for evaluating quality of care, cost, and patterns of drug use of older adults.

As with previously published AGS Beers Criteria®, the goal of the 2019 update continues to be improving the care of older adults by reducing their exposure to PIMs that have an unfavorable balance of benefits and harms com- pared with alternative treatment options. This is accom- plished by using the AGS Beers Criteria® as both an educational tool and a quality measure—two uses that are not always in agreement—and the panel considered and vigorously deliberated both. The AGS Beers Criteria® are not meant to be applied in a punitive manner. Prescribing decisions are not always clear-cut, and clinicians must con- sider multiple factors, including discontinuation of medica- tions no longer indicated. Quality measures must be clearly defined, easily applied, and measured with limited informa- tion and, thus, although useful, cannot perfectly distinguish appropriate from inappropriate care. The panel’s review of evidence at times identified subgroups of individuals who should be exempt from a given criterion or to whom a spe- cific criterion should apply. Such a criterion may not be eas- ily applied as a quality measure, particularly when such subgroups cannot be easily identified through structured and readily accessible electronic health data. As an exam- ple, the panel thought that a criterion should not be expanded to include all adults 65 years and older when only certain subgroups have an adverse balance of benefits vs harms for the medication, or conversely when a sizable subgroup of older adults may be appropriate candidates for a medication that is otherwise problematic.

Despite past and current efforts to translate the cri- teria into practice, some controversy and myths about their use in practice and policy continue to prevail. The panel addressed these concerns and myths by writing a companion article to the 2015 update of the AGS Beers Criteria® and an updated 2019 short piece, which remains the best way to advise patients, providers, and health sys- tems on how to use (and not use) the 2019 AGS Beers Criteria®.3

METHODS

Methods used for the 2019 update of the AGS Beers Criteria®

were similar to those used in the 2015 update, with additional emphasis on extending the rigor of the evidence review and synthesis process.2 These methods were based on the Grading of Recommendations Assessment, Development and Evalua- tion (GRADE) guidelines for clinical practice guideline devel- opment and are consistent with recommendations from the National Academy of Medicine.4,5

Panel Composition

The AGS Beers Criteria® expert update panel comprised 13 clinicians and included physicians, pharmacists, and nurses, each of whom had participated in the 2015 update. Panelists had experience in different practice settings, including ambulatory care, home care, acute hospital care, skilled-nursing facility, and long-term care. In addition, the panel included ex-officio representatives from the Cen- ters for Medicare and Medicaid Services, the National

Committee for Quality Assurance, and the Pharmacy Quality Alliance. Potential conflicts of interest were dis- closed at the beginning of the process and before each full panel call and are listed in the disclosures section of this article. Panelists were recused from discussion in areas in which they had a potential conflict of interest.

Literature Review

Literature searches were conducted in PubMed and the Cochrane Library from January 1, 2015, to September 30, 2017. Search terms for each criterion included individ- ual drugs, drug classes, specific conditions, and combina- tions thereof, each with a focus on “adverse drug events” and “adverse drug reactions.” Medications believed to have low utilizations (eg, meprobamate and central α-agonist antihypertensives other than clonidine) or no longer avail- able in the United States were excluded from the literature search. Searches targeted controlled clinical trials, observa- tional studies, and systematic reviews and meta-analyses, with filters for human participants, 65 years and older, and English language. Clinical reviews and guidelines were also included to provide context. Case reports, case series, letters to the editor, and editorials were excluded.

Searches identified 17,627 references; 5403 abstracts were sent to panelists for review, of which 1422 references were selected for full-text review. Among these, 377 articles were abstracted into evidence tables, including 67 systematic reviews and/or meta-analyses, 29 controlled clinical trials, and 281 observational studies.

Development Process

Between February 2016 and May 2018, the full panel con- vened for a series of conference calls and 1 full-day, in- person meeting. In addition, the panel divided into four work groups, each assigned a subset of the criteria. Each work group led the review and synthesis of evidence for its subset of the criteria, convening via conference calls and electronically via e-mail.

The development process began by soliciting ideas from the panelists about criteria that should be explored for addi- tion, modification, or removal. Suggestions from others were also welcomed. To guide the evidence selection, review, and synthesis process, each work group then under- took an exercise to identify a priori which clinical out- comes, indications, and comparison groups were most relevant when considering evidence for each criterion (ie, the “desired evidence” for reviewing each criterion). These discussions were not considered binding but provided guidance for keeping the evidence review and synthesis focused on what was most clinically relevant.

Each work group reviewed abstracts from the literature searches for the criteria in its purview and collectively selected a subset for full-text review. This selection process considered the methodologic quality of each study, its rele- vance to older adults, and its concordance with the desired evidence noted above. After reviewing the full text of each selected article, the work group then decided by consensus which articles represented the best available evidence, based on a balance of these same three key criteria (methodologic quality, relevance to older adults, and concordance with

2 2019 AGS BEERS CRITERIA® UPDATE EXPERT PANEL MONTH 2019–VOL. 00, NO. 00 JAGS

desired evidence). Special emphasis was placed on selecting systematic reviews and meta-analyses when available, because resource constraints precluded the panel from con- ducting these types of comprehensive analyses. In general, a study was considered relevant to older adults if the mean or median age of participants was older than 65 years, and especially relevant if most or all participants were older than this age threshold.

Articles comprising the best available evidence were abstracted by AGS staff into evidence tables. These tables summarized the design, population, and findings of each study, and identified markers of methodologic quality highlighted by the GRADE criteria for clinical trials and observational studies and by A MeaSurement Tool to Assess Systematic Reviews (AMSTAR).6–8 Each work group then synthesized evidence for each criterion from the 2015 to 2017 literature reviews based on GRADE guidelines and the American College of Physicians’ evidence grading framework (Table 1).6,9

Using evidence from the 2015 to 2017 literature review, evidence findings from previous updates in 2012 and 2015, and clinical judgment, each work group pre- sented to the full panel its findings and suggestions for changes (or no change) to the criteria, with ensuing discus- sion. For most criteria, a consensus emerged, to leave an existing criterion from the 2015 update unchanged, to mod- ify it, to remove it entirely, or to add a new criterion. Poten- tial modifications included the drug(s) included in the criterion, the recommendation, the rationale, the quality of evidence, and the strength of recommendation. As noted in the GRADE guidelines, strength of recommendation ratings incorporate a variety of considerations, including expert opinion and clinical judgment and context, and thus do not always align with quality of evidence ratings.

After discussion of proposed changes, an anonymous Del- phi process was used to ascertain panel consensus, using a five-point Likert scale with anchors of “strongly disagree” and “strongly agree.” As a general rule, criteria receiving “agree” or strongly agree ratings from more than 90% of panelists were included. The remainder were brought back for group discussion, with final decisions resolved through consensus.

In addition to changes made on the basis of evidence, the panel decided on several modifications to improve clar- ity and usability of the AGS Beers Criteria®. These included removing a number of medications that are used only rarely. These removals should not be interpreted as condon- ing use of these medications but rather are intended to “declutter” the AGS Beers Criteria® and not distract from information on more commonly used medications. In selected cases, the panel changed the wording of certain cri- teria, recommendations, and rationale statements to improve clarity and avoid potential misinterpretations.

The final set of criteria was reviewed by the AGS Exec- utive Committee and Clinical Practice and Models of Care Committee and subsequently released for public comment. Comments were solicited from the general public and sent to 39 organizations. Comments were accepted over a 3-week period from August 13, 2018, until September 4, 2018. A total of 244 comments were received from 47 individuals (79 comments), 6 pharmaceutical companies (10 comments), and 22 peer organizations (155 comments). All comments were reviewed and discussed by the panel

cochairs. All comments along with proposed changes to the criteria were shared with the entire panel for final approval.

RESULTS

Noteworthy Changes to PIMs for Older Adults

Tables 2 through 6 show the 2019 criteria. Table 7 lists those drugs with strong anticholinergic properties that are sometimes referenced in Tables 2 through 6. Compared with the 2015 criteria, several drugs were removed from Table 2 (medications that are potentially inappropriate in most older adults), Table 3 (medications that are potentially inappropriate in older adults with certain conditions), and Table 4 (medications that should be used with caution). These removals are summarized in Table 8 and include removal of drugs no longer available in the United States (ticlopidine, oral pentazocine). In other cases, the recom- mendation was removed entirely because the panel decided the drug-related problem was not sufficiently unique to older adults (eg, using stimulating medications in patients with insomnia or avoiding medications that can lower the seizure threshold in patients with a seizure disorder). These removals do not imply that these medications are now con- sidered safe for older adults; rather, they were made to help keep the AGS Beers Criteria® streamlined and focused on medications particularly problematic for older adults.

The H2-receptor antagonists were removed from the “avoid” list in patients with dementia or cognitive impair- ment. This is because evidence for adverse cognitive effects in these conditions is weak, and because the panel expressed concern that the intersection of this criterion with another criterion that discourages chronic use of proton- pump inhibitors in the absence of strong indications would overly restrict therapeutic options for older adults with dementia who have gastroesophageal reflux or similar issues. However, H2-receptor antagonists remain on the cri- teria as “avoid” in patients with delirium. In addition, wording of this criterion was modified to affirm that non- benzodiazepine, benzodiazepine receptor agonist hypnotics (ie, the “Z drugs”: zolpidem, eszopiclone, and zaleplon) should be avoided in older adults with delirium.

Two drugs with strong anticholinergic properties, pyri- lamine and methscopolamine, were added to the list of anti- cholinergic drugs to avoid. Changes to criteria on cardiovascular drugs include minor updates to the rationale and a minor change to clarify the recommendation for avoiding digoxin as first-line therapy for atrial fibrillation and heart failure (Table 2). The rationale to avoid sliding- scale insulin has been revised to clarify its meaning and intent (Table 2). Glimepiride has been added to the list of sulfonylureas with a greater risk of severe prolonged hypo- glycemia (Table 2). The duration of use of metoclopramide has been added to be consistent with US Food and Drug Administration labeling (Table 2).

The serotonin-norepinephrine reuptake inhibitors (SNRIs) have been added to the list of drugs to avoid in patients with a history of falls or fractures (Table 3). Fol- lowing a principle that applies to all criteria, the panel rec- ognizes there may be situations when SNRIs, other antidepressants, and other medications listed in this crite- rion may be appropriate for people with a history of falls

JAGS MONTH 2019–VOL. 00, NO. 00 2019 AGS BEERS CRITERIA® UPDATE EXPERT PANEL 3

or fractures, based on potential benefits and the lack of availability of safer alternatives. After reviewing and dis- cussing the evidence on antipsychotics to treat psychosis in patients with Parkinson disease, the panel decided to remove aripiprazole as preferred and add pimavanserin. Thus, the 2019 AGS Beers Criteria® recognize quetiapine, clozapine, and pimavanserin as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson disease (Table 3). However, none of these three excepted drugs is close to ideal in either efficacy or safety, each having its own limitations and concerns.

The criteria on drugs to avoid in older adults with heart fail- ure were reorganized to add clinical nuance based on evidence, other guideline recommendations, and clinical considerations. The updated recommendations are that nondihydropyridine cal- cium channel blockers should be avoided in older adults who have heart failure with reduced ejection fraction; that nonsteroi- dal anti-inflammatory drug (NSAIDs), cyclooxygenase-2 inhibi- tors, thiazolidinediones (“glitazones”), and dronedarone should

be used with caution in older adults with heart failure who are asymptomatic (ie, excellent control of heart failure signs and symptoms, with or without use of medications) and avoided in older adults who are symptomatic; and that cilostazol should continue to be avoided in older adults with heart failure of any type.

Drugs To Be Used With Caution

Table 4 contains drugs to be used with caution in older adults. The purpose of this table is to identify drugs for which there is some cause for concern, but for which the evidence and/or clinical context is as of yet insufficient to merit inclusion in the main tables. Compared with the pre- vious update, the following changes and additions were made:

• The age threshold beyond which extra caution is advised for using aspirin for primary prevention of cardiovascular disease

Table 1. Designations of Quality of Evidence and Strength of Recommendationsa

Quality of Evidence Quality of evidence ratings for each criterion are based on synthetic assessment of two complementary approaches to evaluating the quality of evidence.

ACP-based approach9 GRADE-based approach4

High-quality evidence “Evidence…obtained from 1 or more well- designed and well-executed randomized, controlled trials (RCTs) that yield consistent and directly applicable results. This also means that further research is very unlikely to change our confidence in the estimate of effect.”

Consider the following five factors for the studies that comprise the best-available evidence for a given criterion: 1. Risk of bias: Severity of threats to studies’

internal validity (eg, randomized vs observational design, potential for confounding, bias in measurement)

2. Inconsistency: Do different studies provide similar or different estimates of effect size

3. Indirectness: How relevant are the studies to the clinical question at hand (eg, nature of study of population, comparison group, type of outcomes measured)

4. Imprecision: Precision of estimates of effect 5. Publication bias: Risk of bias due to selective

publication of results

Moderate-quality evidence “Evidence…obtained from RCTs with important limitations…. In addition, evidence from well- designed controlled trials without randomization, well-designed cohort or case-control analytic studies, and multiple time series with or without intervention are in this category. Moderate- quality evidence also means that further research will probably have an important effect on our confidence in the estimate of effect and may change the estimate.”

Low-quality evidence “Evidence obtained from observational studies would typically be rated as low quality because of the risk for bias. Low-quality evidence means that further research is very likely to have an important effect on our confidence in the estimate of effect and will probably change the estimate. However, the quality of evidence may be rated as moderate or even high, depending on circumstances under which evidence is obtained from observational studies.”

# # # # # Overall quality of evidence that supports a given criterion: high, moderate, low

Strength of Evidence Strength of evidence ratings for each criterion are based on synthetic integration of the quality of evidence, the frequency and severity of potential adverse events and relationship to potential benefits, and clinical judgment. Strong Harms, adverse events, and risks clearly outweigh benefits. Weak Harms, adverse events, and risks may not outweigh benefits.

Abbreviations: ACP, American College of Physicians; GRADE, Grading of Recommendations Assessment, Development and Evaluation. aAdapted from: Qaseem A, Snow V, Owens DK, et al. The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann Intern Med. 2010;153:194-–199. Guyatt G, Oxman AD, Sultan S, et al. GRADE guidelines,: 11.: making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. J Clin Epidemiol. 2013;66(2):151-–157. Andrews JC, Schünemann HJ, Oxman AD, et al. GRADE guidelines,: 15.: going from evidence to recommendation-determinants of a recommendation’s direction and strength. J Clin Epi- demiol. 2013;66(7):726–735.

4 2019 AGS BEERS CRITERIA® UPDATE EXPERT PANEL MONTH 2019–VOL. 00, NO. 00 JAGS

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