Saturday 18th October – Day 4 Saturday 18th October – Day 4 Australian Lung Cancer Conference Day in Review Australian Lung Cancer Conference OPTIMAL LUNG CANCER CARE right care – right time - right place Session S5: Looking forward Chairs: Emily Stone and Bill Musk What is new in EBUS for the management
Www3.lhl.uab.eduORIGINAL INVESTIGATION Updating the Beers Criteria for Potentially
Inappropriate Medication Use in Older Adults
Results of a US Consensus Panel of Experts
Donna M. Fick, PhD, RN; James W. Cooper, PhD, RPh; William E. Wade, PharmD, FASHP, FCCP;Jennifer L. Waller, PhD; J. Ross Maclean, MD; Mark H. Beers, MD Background: Medication toxic effects and drug-
Results: This study identified 48 individual medica-
related problems can have profound medical and safety tions or classes of medications to avoid in older adults consequences for older adults and economically affect the and their potential concerns and 20 diseases/conditions health care system. The purpose of this initiative was to and medications to be avoided in older adults with these revise and update the Beers criteria for potentially inap- conditions. Of these potentially inappropriate drugs, 66 propriate medication use in adults 65 years and older in were considered by the panel to have adverse outcomes the United States.
of high severity.
Methods: This study used a modified Delphi method, a
Conclusions: This study is an important update of pre-
set of procedures and methods for formulating a group judg- viously established criteria that have been widely used ment for a subject matter in which precise information is and cited. The application of the Beers criteria and other lacking. The criteria reviewed covered 2 types of state- tools for identifying potentially inappropriate medica- ments: (1) medications or medication classes that should tion use will continue to enable providers to plan inter- generally be avoided in persons 65 years or older because ventions for decreasing both drug-related costs and over- they are either ineffective or they pose unnecessarily high all costs and thus minimize drug-related problems.
risk for older persons and a safer alternative is available and(2) medications that should not be used in older personsknown to have specific medical conditions.
Arch Intern Med. 2003;163:2716-2724 tions and drug-related prob- 2000, it is estimated that medication- lems can have profound related problems caused 106 000 deaths medical and safety conse- annually at a cost of $85 billion.6 Others quences for older adults and have calculated the cost of medication- economically effect the health care sys- related problems to be $76.6 billion to am- tem. Thirty percent of hospital admissions bulatory care, $20 billion to hospitals, and in elderly patients may be linked to drug- $4 billion to nursing home facilities.2,7,8 If related problems or drug toxic effects.1 Ad- medication-related problems were ranked verse drug events (ADEs) have been linked as a disease by cause of death, it would be From the Department of to preventable problems in elderly pa- the fifth leading cause of death in the Medicine, Center for Health tients such as depression, constipation, falls, United States.9 The prevention and rec- Care Improvement (Drs Fick immobility, confusion, and hip frac- ognition of drug-related problems in el- and Maclean); and Office of tures.1,2 A 1997 study of ADEs found that derly patients and other vulnerable popu- Biostatistics (Dr Waller),Medical College of Georgia, 35% of ambulatory older adults experi- lations is one of the principal health care Augusta; Department of enced an ADE and 29% required health care quality and safety issues for this decade.
Veterans Affairs Medical services (physician, emergency depart- Center, Augusta (Dr Fick); ment, or hospitalization) for the ADE.1 Some CME course available at
Department of Clinical and two thirds of nursing facility residents have ADEs over a 4-year period.3 Of these ADEs, College of Pharmacy, 1 in 7 results in hospitalization.4 The aforementioned IOM report has University of Georgia, Athens, Recent estimates of the overall hu- focused increased attention on finding so- (Drs Cooper and Wade); and man and economic consequences of medi- lutions for unsafe medication practices, Merck & Co Inc, West Point, cation-related problems vastly exceed the polypharmacy, and drug-related problems Pa (Dr Beers). The authorshave no relevant financial findings of the Institute of Medicine (IOM) in the care of older adults. There are many interest in this article. on deaths from medical errors, estimated ways to define medication-related prob- ARCH INTERN MED/ VOL 163, DEC 8/22, 2003 Association. All rights reserved.
(REPRINTED WITH CORRECTIONS) lems in elderly patients, including the use of lists contain-ing specific drugs to avoid in the elderly and appropriate- Below are the Beers criteria published in 1997. In parts 1 and 2, we are first asking you to rate your level of agreement on these 1997 criteria.
ness indexes applied by pharmacists or clinicians.1,10,11 Please answer the following questions regarding the use of medications in adults Systematic review of the evidence-based literature on medi- 65 years or older: cation use in elderly patients is another approach to de- Please give one of the following answers: fining the problem, but the number of controlled studies 1=Strongly Agree 2=Agree 3=Unsure 4=Disagree 5=Strongly Disagree
on medication use in elderly patients is limited.
0=Unable to offer an opinion
The use of consensus criteria for safe medication use 1) Propoxyphene (Darvon) and combination products (Darvon with ASA, in elderly patients is one approach to developing reliable Darvon-N, and Darvocet-N) should be avoided.
and explicit criteria when precise clinical information is lacking. The two most widely used consensus criteria formedication use in older adults are the Beers criteria and Sample survey question.
the Canadian criteria.12-14 The Beers criteria are based onexpert consensus developed through an extensive litera- facility populations older than 65 years in the United ture review with a bibliography and questionnaire evalu- States. There were 3 main aims: (1) to reevaluate the ated by nationally recognized experts in geriatric care, 1997 criteria to include new products and incorporate clinical pharmacology, and psychopharmacology using a new information available from the scientific literature, modified Delphi technique to reach consensus. The (2) to assign or reevaluate a relative rating of severity Beers criteria have been used to survey clinical medica- for each of the medications, and (3) to identify any new tion use, analyze computerized administrative data sets, conditions or considerations not addressed in the 1997 and evaluate intervention studies to decrease medication problems in older adults. The Beers criteria were alsoadopted by the Centers for Medicare & Medicaid Ser- vices (CMS) in July 1999 for nursing home regulation.
Previous studies have shown these criteria to be useful There were 5 phases in the data collection for this study: (1) in decreasing problems in older adults.15-19 These crite- the review of the literature, (2) creation and mailing of the round1 questionnaire, (3) creation of the second-round question- ria, though controversial at times, have been widely used naire based on round 1 and expert panel feedback, (4) con- over the past 10 years for studying prescribing patterns vening of the expert panel and panel responses to the second- within populations, educating clinicians, and evaluating round questionnaire, and (5) completion and analysis of a third health outcomes, cost, and utilization data.20-23 and final mailed questionnaire that measured the severity rat- A recently published study of potentially inappro- ings of the PIMs to create the final revised list.
priate medication (PIM) use with the Beers criteria in a The criteria reviewed covered 2 types of statements: (1) Medicare-managed care population found a PIM preva- medications or medication classes that should generally be lence of 23% (541/2336). Those receiving a PIM had sig- avoided in persons 65 years or older because they are either nificantly higher total, provider, and facility costs and a ineffective or they pose unnecessarily high risk for older per- higher mean number of inpatient, outpatient, and emer- sons and a safer alternative is available and (2) medicationsthat should not be used in older persons known to have spe- gency department visits than comparisons after control- cific medical conditions. The 2 statements each used a 5-point ling for sex, Charlson Comorbidity Index, and total num- Likert scale and ask respondents to rate their agreement or dis- ber of prescriptions.20 Other studies have found that specific agreement with the statement from strongly agree (1) to PIMs such as nonsteroidal anti-inflammatory drugs strongly disagree (5), with the midpoint (3) expressing equivo- (NSAIDs) and benzodiazepines have been associated with cation. The second type of question asked the respondents to adverse outcomes and increased costs.18 In contrast, a re- evaluate the medication appropriateness given certain condi- cent study on the relationship between inappropriate drug tions or diagnoses (Figure). All questions included an option
use, functional status decline, and mortality in 3234 pa- to not answer if the respondent did not feel qualified to tients from the Duke cohort did not find an association answer. This methodology was similar to that used by Beers et with mortality and inappropriate drug use as determined al13 in the creation of the first 2 iterations of the criteria. Themethodology used in the third iteration of the Beers criteria by the Beers criteria after controlling for covariates.24 only differed in the number of panelists (13 in 1991; 6 in In summary, these criteria have been used exten- 1997; and 12 in 2002) and the use of a third-round survey for sively for evaluating and intervening in medication use the severity ratings, which was done (in person) in the 1997 in older adults over the past decade. However, with the update of the criteria.
continuous arrival of new drugs on the market, in-creased knowledge about older drugs, and removal of older drugs from the market, these criteria must be up-dated on a regular basis to remain useful. Since the cri- The modified Delphi method is a technique to arrive at a group teria were published in 1997, there has been an increase consensus regarding an issue under investigation that was origi- in the number of scientific studies addressing drug use nally developed at the RAND Corporation (Santa Monica, Calif)by Olaf Helmer and Norman Dalkey.25 The Delphi method is a and appropriateness in older adults, but there is still a set of procedures and methods for formulating a group judg- lack of controlled studies in the older population and par- ment for a subject matter in which precise information is lack- ticularly in patients older than 75 years and patients with ing (such as medication use in older adults). The Delphi method provides a means to reach consensus within a group of ex- The purpose of this initiative was to revise and perts. The method relies on soliciting individual (often anony- update the Beers criteria for ambulatory and nursing mous) answers to written questions by survey or other type of ARCH INTERN MED/ VOL 163, DEC 8/22, 2003 Association. All rights reserved.
(REPRINTED WITH CORRECTIONS) communication. A series of iterations provides each indi- years and older. The second-round survey included the state- vidual with feedback on the responses of the others in the group.
ments included from round 1 and any statements added by the The final responses are evaluated for variance and means to de- experts from the first round. In the second round and the face- termine which questions the group has reached consensus about, to-face meeting, the respondents were given information about either affirmatively or negatively.
their answers and the anonymous answers of the other mem-bers of the group and were given the opportunity to recon- sider their previous response.
After analyzing the responses from the first round of the The selection of articles for formulating the survey involved 3 survey, we examined each question for inclusion or exclusion steps and was phase 1 of the study. First, we identified litera- in the revised criteria or for further consideration in the sec- ture published since January 1994 in English, describing or ond round of the survey. We calculated the mean rating and analyzing medication use in community-living (ambulatory) corresponding 95% confidence interval (CI) of each state- older adults and older adults living in nursing homes. From ment or dosing question collected from the first round of the that, we created a table and bibliography. We used MEDLINE, survey. Those statements whose upper limit of the 95% CI searching with the following key terms adverse drug reactions, was less than 3.0 were included in the updated criteria. Those adverse drug events, medication problems, and medications and statements or dosing questions whose lower limit of the 95% elderly for all relevant articles published between January 1994 CI was greater than 3.0 were excluded from the updated cri- and December 2000. Second, we hand searched and identified teria. Statements whose 95% CI included the value of 3.0 were additional references from the bibliographies of relevant included for further determination in the second-round face- articles. Third, all the panelists were invited to add references to-face meeting.
and articles after the first survey to add to the literature review.
The face-to-face meeting was convened on December 10, Each study was systematically reviewed by 2 investigators 2001, in Atlanta, Ga. Each panel member was given the re- using a table to outline the following information: type of sults of the first-round survey and the added medications (from study design; sample size; medications reviewed; summary of the other panel members) to review approximately 10 days be- results and key points; quality, type and category of medica- fore the meeting. For statements that needed further exami- tion addressed; and severity of the drug-related problem.
nation (neither included or excluded during round 1), each raterwas given his or her previous rating and the mean rating of the EXPERT PANEL SELECTION
group of experts in the second survey.
Any additional statements or dosing questions that had The panel of members were invited to participate via letter by been made on the open-ended portion of the first round of the the 4 investigators and a consultant and represented a variety of survey by any expert was included in the survey for the sec- experience and judgment including extensive clinical practice, ond round. Forty-four questions were added by expert panel- extensive publications in this area, and/or senior academic rank.
ists during round 1 of the survey, and 9 questions were added They were also chosen to represent acute, long-term, and com- during the round 2 in-person survey and voted on during the munity practice settings with pharmacological, geriatric medi- in-person meeting. These questions/medications made up part cine, and psychiatric expertise. Lastly, they were selected from 5 of the survey. Twenty-four questions from parts 3 and 4 had geographically diverse parts of the United States. We initially in- 95% CIs greater than 3.0 after the round 1 survey. During the vited (via regular mail) 16 potential participants with nation- second-round face-to-face meeting, the group debated these re- ally and/or internationally recognized expertise in psychophar- maining statements and then rerated them using the same Likert macology, pharmacoepidemiology, clinical geriatric scale. The mean rating and 95% CI were calculated. The tech- pharmacology, and clinical geriatric medicine to complete our nique used for the first round for inclusion or exclusion of the survey. Our response rate for the initial invitation to participate statement or dosing question in the updated criteria was used.
as a panelist was 75% (12/16). Our final panel thus consisted of Those statements whose 95% CI included 3.0 were excluded 12 experts who completed all rounds of the survey.
from the updated criteria. Lastly, in January 2002, we sur-veyed panelists on a 5-point scale for the severity of the poten- tial medication problem.
We used the systematic review of the literature to construct thefirst round questionnaire. The first-round survey contained The final criteria are listed in Table 1 and Table 2. Table
4 sections. Parts 1 and 2 reviewed the latest 1997 criteria. Parts 1 contains 48 individual medications or classes of medi- 3 and 4 were medications added for the 2002 update for medi-cations alone (part 3) and medications considering diagnoses cations to avoid in older adults and their potential con- and conditions. Parts 3 and 4 included 29 new questions about cerns. Table 2 lists 20 diseases or conditions and medi- medications or medication classes and conditions. The last ques- cations to be avoided in older adults with these conditions.
tion in part 4 asked panel members to add medications to the Sixty-six of these potentially inappropriate drugs were list. The panel was then surveyed via Delphi technique to de- considered by the panel to have adverse outcomes of high termine concordance/consensus with the round 1 survey and severity. New conditions and diagnoses that were ad- invited to add additional medications prior to and during the dressed this time included depression, cognitive impair- ment, Parkinson disease, anorexia, and malnutrition, syn- We created the second and third questionnaires (severity drome of inappropriate antidiuretic hormone secretion, ratings) from panel input and the results of the previous round and obesity.
survey. We completed all mailed and face-to-face rounds be-tween October 2001 and February 2002. We constructed the A total of 15 medications/medication classes were questionnaire statements according to the original Beers cri- dropped or modified from the 1997 to the 2002 update from teria published in 1991 and the updated criteria published in the round 1 survey. Most of the medications dropped since 1997. The instructions accompanying the survey asked the re- 1997 were those that were associated with diagnoses or con- spondents to consider the use of medications only in adults 65 ditions. The following medications were voted to be dropped ARCH INTERN MED/ VOL 163, DEC 8/22, 2003 Association. All rights reserved.
(REPRINTED WITH CORRECTIONS) Table 1. 2002 Criteria for Potentially Inappropriate Medication Use in Older Adults: Independent of Diagnoses or Conditions
(High or Low)
Propoxyphene (Darvon) and combination products Offers few analgesic advantages over acetaminophen, yet has the adverse (Darvon with ASA, Darvon-N, and Darvocet-N) effects of other narcotic drugs.
Indomethacin (Indocin and Indocin SR) Of all available nonsteroidal anti-inflammatory drugs, this drug produces the most CNS adverse effects.
Pentazocine (Talwin) Narcotic analgesic that causes more CNS adverse effects, including confusion and hallucinations, more commonly than other narcoticdrugs. Additionally, it is a mixed agonist and antagonist.
One of the least effective antiemetic drugs, yet it can cause extrapyramidal adverse effects.
Muscle relaxants and antispasmodics: methocarbamol Most muscle relaxants and antispasmodic drugs are poorly tolerated by (Robaxin), carisoprodol (Soma), chlorzoxazone (Paraflex), elderly patients, since these cause anticholinergic adverse effects, metaxalone (Skelaxin), cyclobenzaprine (Flexeril), and sedation, and weakness. Additionally, their effectiveness at doses oxybutynin (Ditropan). Do not consider the extended-release tolerated by elderly patients is questionable.
Flurazepam (Dalmane) This benzodiazepine hypnotic has an extremely long half-life in elderly patients (often days), producing prolonged sedation and increasing theincidence of falls and fracture. Medium- or short-actingbenzodiazepines are preferable.
Amitriptyline (Elavil), chlordiazepoxide-amitriptyline (Limbitrol), Because of its strong anticholinergic and sedation properties, amitriptyline and perphenazine-amitriptyline (Triavil) is rarely the antidepressant of choice for elderly patients.
Doxepin (Sinequan) Because of its strong anticholinergic and sedating properties, doxepin is rarely the antidepressant of choice for elderly patients.
Meprobamate (Miltown and Equanil) This is a highly addictive and sedating anxiolytic. Those using meprobamate for prolonged periods may become addicted and mayneed to be withdrawn slowly.
Doses of short-acting benzodiazepines: doses greater than Because of increased sensitivity to benzoadiazepines in elderly patients, lorazepam (Ativan), 3 mg; oxazepam (Serax), 60 mg; smaller doses may be effective as well as safer. Total daily doses should alprazolam (Xanax), 2 mg; temazepam (Restoril), 15 mg; rarely exceed the suggested maximums.
and triazolam (Halcion), 0.25 mg Long-acting benzodiazepines: chlordiazepoxide (Librium), These drugs have a long half-life in elderly patients (often several days), producing prolonged sedation and increasing the risk of falls and clidinium-chlordiazepoxide (Librax), diazepam (Valium), fractures. Short- and intermediate-acting benzodiazepines are preferred quazepam (Doral), halazepam (Paxipam), and chlorazepate if a benzodiazepine is required.
Disopyramide (Norpace and Norpace CR) Of all antiarrhythmic drugs, this is the most potent negative inotrope and therefore may induce heart failure in elderly patients. It is also stronglyanticholinergic. Other antiarrhythmic drugs should be used.
Digoxin (Lanoxin) (should not exceed ⬎0.125 mg/d except when Decreased renal clearance may lead to increased risk of toxic effects.
treating atrial arrhythmias) Short-acting dipyridamole (Persantine). Do not consider the May cause orthostatic hypotension.
long-acting dipyridamole (which has better properties than theshort-acting in older adults) except with patients with artificialheart valves Methyldopa (Aldomet) and methyldopa-hydrochlorothiazide May cause bradycardia and exacerbate depression in elderly patients.
Reserpine at doses ⬎0.25 mg May induce depression, impotence, sedation, and orthostatic hypotension.
It has a prolonged half-life in elderly patients and could cause prolonged hypoglycemia. Additionally, it is the only oral hypoglycemic agent thatcauses SIADH.
Gastrointestinal antispasmodic drugs: dicyclomine (Bentyl), GI antispasmodic drugs are highly anticholinergic and have uncertain hyoscyamine (Levsin and Levsinex), propantheline effectiveness. These drugs should be avoided (especially for (Pro-Banthine), belladonna alkaloids (Donnatal and others), long-term use).
and clidinium-chlordiazepoxide (Librax) Anticholinergics and antihistamines: chlorpheniramine All nonprescription and many prescription antihistamines may have potent (Chlor-Trimeton), diphenhydramine (Benadryl), hydroxyzine anticholinergic properties. Nonanticholinergic antihistamines are (Vistaril and Atarax), cyproheptadine (Periactin), promethazine preferred in elderly patients when treating allergic reactions.
May cause confusion and sedation. Should not be used as a hypnotic, and when used to treat emergency allergic reactions, it should be used inthe smallest possible dose.
Ergot mesyloids (Hydergine) and cyclandelate (Cyclospasmol) Have not been shown to be effective in the doses studied.
Ferrous sulfate ⬎325 mg/d Doses ⬎325 mg/d do not dramatically increase the amount absorbed but greatly increase the incidence of constipation.
All barbiturates (except phenobarbital) except when used to Are highly addictive and cause more adverse effects than most sedative or hypnotic drugs in elderly patients.
ARCH INTERN MED/ VOL 163, DEC 8/22, 2003 Association. All rights reserved.
(REPRINTED WITH CORRECTIONS) Table 1. 2002 Criteria for Potentially Inappropriate Medication Use in Older Adults: Independent of Diagnoses or Conditions (cont)
(High or Low)
Meperidine (Demerol) Not an effective oral analgesic in doses commonly used. May cause confusion and has many disadvantages to other narcotic drugs.
Ticlopidine (Ticlid) Has been shown to be no better than aspirin in preventing clotting and may be considerably more toxic. Safer, more effective alternativesexist.
Ketorolac (Toradol) Immediate and long-term use should be avoided in older persons, since a significant number have asymptomatic GI pathologic conditions.
Amphetamines and anorexic agents These drugs have potential for causing dependence, hypertension, angina, and myocardial infarction.
Long-term use of full-dosage, longer half-life, Have the potential to produce GI bleeding, renal failure, high blood non–COX-selective NSAIDs: naproxen (Naprosyn, Avaprox, pressure, and heart failure.
and Aleve), oxaprozin (Daypro), and piroxicam (Feldene) Daily fluoxetine (Prozac) Long half-life of drug and risk of producing excessive CNS stimulation, sleep disturbances, and increasing agitation. Safer alternatives exist.
Long-term use of stimulant laxatives: bisacodyl (Dulcolax), May exacerbate bowel dysfunction.
cascara sagrada, and Neoloid except in the presence of opiateanalgesic use Amiodarone (Cordarone) Associated with QT interval problems and risk of provoking torsades de pointes. Lack of efficacy in older adults.
Orphenadrine (Norflex) Causes more sedation and anticholinergic adverse effects than safer Guanethidine (Ismelin) May cause orthostatic hypotension. Safer alternatives exist.
Guanadrel (Hylorel) May cause orthostatic hypotension.
Lack of efficacy.
Isoxsurpine (Vasodilan) Lack of efficacy.
Potential for renal impairment. Safer alternatives available.
Doxazosin (Cardura) Potential for hypotension, dry mouth, and urinary problems.
Methyltestosterone (Android, Virilon, and Testrad) Potential for prostatic hypertrophy and cardiac problems.
Thioridazine (Mellaril) Greater potential for CNS and extrapyramidal adverse effects.
Mesoridazine (Serentil) CNS and extrapyramidal adverse effects.
Short acting nifedipine (Procardia and Adalat) Potential for hypotension and constipation.
Clonidine (Catapres) Potential for orthostatic hypotension and CNS adverse effects.
Potential for aspiration and adverse effects. Safer alternatives available.
Cimetidine (Tagamet) CNS adverse effects including confusion.
Ethacrynic acid (Edecrin) Potential for hypertension and fluid imbalances. Safer alternatives Desiccated thyroid Concerns about cardiac effects. Safer alternatives available.
Amphetamines (excluding methylphenidate hydrochloride CNS stimulant adverse effects.
Estrogens only (oral) Evidence of the carcinogenic (breast and endometrial cancer) potential of these agents and lack of cardioprotective effect in older women.
Abbreviations: CNS, central nervous system; COX, cyclooxygenase; GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; SIADH, syndrome of inappropriate antidiuretic hormone secretion.
or modified from the criteria by the panelists since the 1997 that are off the market. The expert panelists could not publication: phenylbutazone, oxybutynin chloride, ␤-block- reach consensus about adding questions regarding set- ers, corticosteroids with persons with diabetes; sedative- ting maximum dosages for sedative-hypnotics, antipsy- hypnotics in persons with chronic obstructive pulmonary chotics, selective serotonin reuptake inhibitors, and tri- disease; ␤-blockers in persons with asthma; ␤-blockers in cyclic antidepressants that do not have specific persons with peripheral vascular disorder; ␤-blockers in recommendations from the manufacturer, though there persons with syncope and falls; narcotics in persons with was agreement that consideration of changes in pharma- bladder outflow obstruction; and theophylline sodium gly- cokinetics were important in older patients in prevent- cinate in persons with insomnia (Table 3). Oxybutinin
ing problems caused by excessive dosages and usage.
was modified by not including the extended-release for- This update also includes several medications that have mula, which the panel believed had fewer adverse new information or have come to market since the last study effects. Reserpine was changed to be avoided only at of the Beers criteria was published (1997), including se- doses greater than 0.25 mg, and disopyramide phosphate lective serotonin reuptake inhibitors, amiodarone, and avoidance now only refers to the non–extended release fluoxetine hydrochloride. The panel also voted to add me- formulation. New information about ␤-blockers in thyltestosterones, amphetamines, and bupropion hydro- elderly patients led the panel to drop this class of drugs chloride to the list of medications to be avoided in older from the list. The other criteria dropped involved use of adults. Tables 1 and 2 state why medications were added drugs in the setting of a comorbid condition or drugs since 1997, and Table 3 summarizes all the changes to the ARCH INTERN MED/ VOL 163, DEC 8/22, 2003 Association. All rights reserved.
(REPRINTED WITH CORRECTIONS) Table 2. 2002 Criteria for Potentially Inappropriate Medication Use in Older Adults: Considering Diagnoses or Conditions
Disease or Condition
(High or Low)
Disopyramide (Norpace), and high sodium content drugs Negative inotropic effect. Potential to promote (sodium and sodium salts [alginate bicarbonate, fluid retention and exacerbation of heart biphosphate, citrate, phosphate, salicylate, and sulfate]) Phenylpropanolamine hydrochloride (removed from the May produce elevation of blood pressure market in 2001), pseudoephedrine; diet pills, and secondary to sympathomimetic activity.
Gastric or duodenal NSAIDs and aspirin (⬎325 mg) (coxibs excluded) May exacerbate existing ulcers or produce Seizures or epilepsy Clozapine (Clozaril), chlorpromazine (Thorazine), May lower seizure thresholds.
thioridazine (Mellaril), and thiothixene (Navane) Blood clotting disorders Aspirin, NSAIDs, dipyridamole (Persantin), ticlopidine May prolong clotting time and elevate INR (Ticlid), and clopidogrel (Plavix) values or inhibit platelet aggregation, anticoagulant therapy resulting in an increased potential forbleeding.
Anticholinergics and antihistamines, gastrointestinal May decrease urinary flow, leading to urinary antispasmodics, muscle relaxants, oxybutynin (Ditropan), flavoxate (Urispas), anticholinergics,antidepressants, decongestants, and tolterodine (Detrol) Stress incontinence ␣-Blockers (Doxazosin, Prazosin, and Terazosin), May produce polyuria and worsening of anticholinergics, tricyclic antidepressants (imipramine hydrochloride, doxepin hydrochloride, and amitriptylinehydrochloride), and long-acting benzodiazepines Tricyclic antidepressants (imipramine hydrochloride, Concern due to proarrhythmic effects and ability doxepin hydrochloride, and amitriptyline hydrochloride) to produce QT interval changes.
Decongestants, theophylline (Theodur), methylphenidate Concern due to CNS stimulant effects.
(Ritalin), MAOIs, and amphetamines Parkinson disease Metoclopramide (Reglan), conventional antipsychotics, and Concern due to their antidopaminergic/ Cognitive impairment Barbiturates, anticholinergics, antispasmodics, and muscle Concern due to CNS-altering effects.
relaxants. CNS stimulants: dextroAmphetamine(Adderall), methylphenidate (Ritalin), methamphetamine(Desoxyn), and pemolin Long-term benzodiazepine use. Sympatholytic agents: May produce or exacerbate depression.
methyldopa (Aldomet), reserpine, and guanethidine(Ismelin) CNS stimulants: DextroAmphetamine (Adderall), Concern due to appetite-suppressing effects.
methylphenidate (Ritalin), methamphetamine (Desoxyn),pemolin, and fluoxetine (Prozac) Short- to intermediate-acting benzodiazepine and tricyclic May produce ataxia, impaired psychomotor antidepressants (imipramine hydrochloride, doxepin function, syncope, and additional falls.
hydrochloride, and amitriptyline hydrochloride) SSRIs: fluoxetine (Prozac), citalopram (Celexa), May exacerbate or cause SIADH.
fluvoxamine (Luvox), paroxetine (Paxil), and sertraline(Zoloft) Bupropion (Wellbutrin) May lower seizure threshold.
Olanzapine (Zyprexa) May stimulate appetite and increase weight gain.
Long-acting benzodiazepines: chlordiazepoxide (Librium), CNS adverse effects. May induce respiratory depression. May exacerbate or cause clidinium-chlordiazepoxide (Librax), diazepam (Valium), quazepam (Doral), halazepam (Paxipam), andchlorazepate (Tranxene). ␤-blockers: propranolol Chronic constipation Calcium channel blockers, anticholinergics, and tricyclic May exacerbate constipation.
antidepressant (imipramine hydrochloride, doxepinhydrochloride, and amitriptyline hydrochloride) Abbreviations: CNS, central nervous systems; COPD, chronic obstructive pulmonary disease; INR, international normalized ratio; MAOIs, monoamine oxidase inhibitors; NSAIDs, nonsteroidal anti-inflammatory drugs; SIADH, syndrome of inappropriate antidiuretic hormone secretion; SSRIs, selective serotonin reuptakeinhibitors.
Beers criteria since 1997, including medications that were cited.16,20,22,23,26-29 The application of the Beers criteria and added, dropped, or modified.
other tools for identifying PIM use will continue to en-able providers to plan interventions for decreasing both drug-related costs and overall costs and thus minimizedrug-related problems.9,30 Such tools are also vitally im- This study is an important update of previously estab- portant to managed care organizations, pharmacy ben- lished criteria that have been widely used and efit plans, and both acute and long-term health care in- ARCH INTERN MED/ VOL 163, DEC 8/22, 2003 Association. All rights reserved.
(REPRINTED WITH CORRECTIONS) Table 3. Summary of Changes From 1997 Beers Criteria to New 2002 Criteria
Medicines Modified Since 1997 Beers Criteria
1. Reserpine (Serpasil and Hydropres)* 3. Iron supplements ⬎325 mg† 2. Extended-release oxybutynin (Ditropan XL)† 4. Short-acting dipyridamole (Persantine)‡ Medicines Dropped Since 1997 Beers Criteria
Independent of Diagnoses 1. Phenylbutazone (Butazolidin) 6. Metoclopramide (Reglan) with seizures or epilepsy Considering Diagnoses 7. Narcotics with bladder outflow obstruction and narcotics with constipation 2. Recently started corticosteroid therapy with diabetes 8. Desipramine (Norpramin) with insomnia 3. ␤-Blockers with diabetes, COPD or asthma, peripheral vascular 9. All SSRIs with insomnia disease, and syncope or falls 10. ␤-Agonists with insomnia 4. Sedative hypnotics with COPD 11. Bethanechol chloride with bladder outflow obstruction 5. Potassium supplements with gastric or duodenal ulcers Medicines Added Since 1997 Beers Criteria
Independent of Diagnoses 1. Ketorolac tromethamine (Toradol) 15. Desiccated thyroid 2. Orphenadrine (Norflex) 16. Ferrous sulfate ⬎325 mg 3. Guanethidine (Ismelin) 17. Amphetamines (excluding methylpenidate and anorexics) 4. Guanadrel (Hylorel) 18. Thioridazine (Mellaril) 5. Cyclandelate (Cyclospasmol) 19. Short-acting nifedipine (Procardia and Adalat) 6. Isoxsuprine (Vasodilan) 20. Daily fluoxetine (Prozac) 7. Nitrofurantoin (Macrodantin) 21. Stimulant laxatives may exacerbate bowel dysfunction (except in presence 8. Doxazosin (Cardura) of chronic pain requiring opiate analgesics) 9. Methyltestosterone (Android, Virilon, and Testrad) 22. Amiodarone (Cordarone) 10. Mesoridazine (Serentil) 23. Non–COX-selective NSAIDs (naproxen [Naprosyn], oxaprozin, and 11. Clonidine (Catapres) 24. Reserpine doses ⬎0.25 mg/d 13. Cimetidine (Tagamet) 25. Estrogens in older women 14. Ethacrynic acid (Edecrin) Considering Diagnoses 26. Long-acting benzodiazepines: chlordiazepoxide (Librium), 33. Decongestants with bladder outflow obstruction 34. Calcium channel blockers with constipation clidinium-chlordiazepoxide (Librax), diazepam (Valium), 35. Phenylpropanolamine with hypertension quazepam (Doral), halazepam (Paxipam), and chlorazepate 36. Bupropion (Wellbutrin) with seizure disorder (Tranxene) with COPD, stress incontinence, depression, and falls 37. Olanzapine (Zyprexa) with obesity 27. Propanolol with COPD/asthma 38. Metoclopramide (Reglan) with Parkinson disease 28. Anticholinergics with stress incontinence 39. Conventional antipsychotics with Parkinson disease 29. Tricyclic antidepressants (imipramine hydrochloride, doxepine 40. Tacrine (Cognex) with Parkinson disease hydrochloride, and amitriptyline hydrochloride) with syncope or 41. Barbiturates with cognitive impairment falls and stress incontinence 42. Antispasmodics with cognitive impairment 30. Short to intermediate and long-acting benzodiazepines with 43. Muscle relaxants with cognitive impairment 44. CNS stimulants with anorexia, malnutrition, 31. Clopidogrel (Plavix) with blood-clotting disorders receiving and cognitive impairment anticoagulant therapy 32. Tolterodine (Detrol) with bladder outflow obstruction Abbreviations: CNS, central nervous system; COPD, chronic obstructive pulmonary disease; COX, cyclooxygenase; NSAIDs, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors.
*Reserpine in doses ⬎0.25 mg was added to the list.
†Ditropan was modified to refer to the immediate-release formulation only and not Ditropan XL and iron supplements was modified to include only ferrous ‡Do not consider the long-acting dipyridamole, which has better properties than the short-acting dipyridamole in older adults (except with patients with artificial heart valves).
stitutions. However, to remain useful, criteria must be at times as too simplistic and limiting the freedom of phy- regularly updated and must take into account the ever- sicians to prescribe.31-35 However, we believe that thought- increasing, evidence-based literature in the area of medi- ful application of the updated 2002 Beers criteria and other cation use in older adults.
tools for identifying PIM use can enable providers and in- The argument in favor of using explicit criteria in pre- surers to plan interventions aimed at decreasing drug- scribing practice is overwhelming: improvements in thera- related costs and overall health care costs, while reducing peutic practices and reduction in medication-related ADEs ADE-related admissions in elderly patients9,30 and improv- will increase the quality of care and enhance patient out- ing care. The updated Beers criteria will enable everyone come at the same time as optimizing resource utilization from individual physicians to health care systems to in- and promoting fiscal prudence. These criteria, though tegrate the new criteria-based prescribing recommenda- widely used, have been controversial because of their adop- tions into their organic, mechanical, and electronic infor- tion by nursing home regulators and have been criticized mation systems.
ARCH INTERN MED/ VOL 163, DEC 8/22, 2003 Association. All rights reserved.
(REPRINTED WITH CORRECTIONS) The proponents of explicit criteria and evidence- clinical need remains a challenge for the information sys- based prescribing are among the biggest players in the tems and information technology engineer, the behav- health care industry: the IOM, the CMS, the Agency for ior change specialist, and the medical profession.42 Healthcare Research and Quality (AHRQ), and the Ameri-can Association of Health Plans (AAHP), to name but Accepted for publication March 28, 2003. four.36,37 Indeed, finding a voice of dissent is challeng- This research was supported by a grant from the Medi- ing. In "Crossing the Quality Chasm" the IOM38 pre- cal College of Georgia (Augusta) and University of Geor- sents a template for the future, when the traditional val- gia (Athens) Combined Intramural Grant Program. ues of physician integrity, altruism, knowledge, skill, and We thank Judy Johnson, MAT, R. C. Robinson, BS, and dedication to lifelong patient care are seamlessly inte- Alison Maclean, BA, for assistance with data management grated into an information era of point-of-care, comput- and manuscript preparation. We acknowledge the follow- erized decision support that facilitates appropriate care ing individuals for contributing their expertise to this study using the available resources. The updated Beers crite- as panel members: Maude Babington, PharmD (Babington ria are one component of that movement, enabling all Consulting, LLC, Boulder, Colo); Manju T. Beier, PharmD parties, from providers to insurers, to integrate our rec- (The University of Michigan, Ann Arbor); Richard W. Be- ommendations into their clinical information systems.
sdine, MD (Brown University, Providence, RI); Jack Fin- Given the aforementioned, there appears to be a po- cham, PhD (University of Kansas, Lawrence); F. Michael tential niche for the Beers criteria in fulfilling the mis- Gloth III, MD (Johns Hopkins University School of Medi- sions of the IOM, CMS, AHRQ, and AAHP. However, cine, Baltimore, Md); Thomas Jackson, MD (Medical Col- translating research into measurable quality improve- lege of Georgia, Augusta); John E. Morley, MD (Saint Louis ment may be more challenging. In the first instance, de- University Health Sciences Center, St Louis, Mo); Becky spite the much-lauded public statements about quality Nagle, PharmD, BCPC (Medco Health Solutions, Franklin by many (including the above organizations), there is Lakes, NJ); Todd Semla, PharmD, MS (Evanston North- widespread recognition that perhaps cost containment western Healthcare, Evanston, Ill); Mark A. Stratton, is the principal driver of change in the health care world.39 PharmD (University of Oklahoma, Oklahoma City); An- Individual health care providers and organizations will drew D. Weinberg, MD (Emory University School of Medi- demand objective evidence that implementation of the cine, Atlanta, Ga). updated Beers criteria (or, indeed, other inappropriate Corresponding author and reprints: Donna M. Fick, medication guides) will result in objective, quantifiable PhD, RN, Center for Health Care Improvement, Depart- improvements in the clinical effectiveness and cost- ment of Medicine, Medical College of Georgia, HB 2010, 1467 effectiveness of health care services. To date, despite ex- Harper St, Augusta, GA 30912 (e-mail: email@example.com). tensive literature demonstrating association—based onretrospective studies on administrative data—there is an absence of rigorous, prospective research in this field. We(D.M.F., J.L.W., and J.R.M.) are completing a random-ized controlled study among a Medicare managed care 1. Hanlon JT, Schmader KE, Kornkowski MJ, et al. Adverse drug events in high risk older outpatients. J Am Geriatr Soc. 1997;45:945-948.
population at this time, using the 1997 medication cri- 2. Bootman JL, Harrison DL, Cox E. The health care cost of drug-related morbidity teria for older adults. Well-controlled studies are needed and mortality in nursing facilities. Arch Intern Med. 1997;157:2089-2096.
that show prospectively that using these criteria make a 3. Cooper JW. Probable adverse drug reactions in a rural geriatric nursing home difference in patient outcomes.31 population: a four-year study. J Am Geriatr Soc. 1996;44:194-197.
These criteria have some limitations, however, and 4. Cooper JW. Adverse drug reaction-related hospitalizations of nursing facility pa- tients: a 4-year study. South Med J. 1999;92:485-490.
must be regularly updated to remain useful to both cli- 5. Kohn L, Corrigan J, Donaldson M, eds. To Err Is Human: Building a Safer Health nicians, health care administrators, and researchers. These System. Washington, DC: National Academy Press; 1999. Available at: http: criteria are meant to apply to the general population of //books.nap.edu/html/to_err_is_human/. Accessed March 14, 2001.
patients 65 years and older, thus some that are not ap- 6. Perry DP. When medicine hurts instead of helps. Consultant Pharmacist. 1999; propriate for significantly older or more frail persons do 7. Bates DW, Spell N, Cullen DJ, et al, the Adverse Drug Events Prevention Study not appear in this list. These criteria are not meant to regu- Group. The costs of adverse drug events in hospitalized patients. JAMA. 1997; late practice in a manner to which they supersede the clini- cal judgment and assessment of the physician or practi- 8. Johnson JA, Bootman JL. Drug-related morbidity and mortality: a cost-of- tioner. In addition, defining inappropriate medications illness model. Arch Intern Med. 1995;155:1949-1956.
9. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospi- by specific lists of medications rather than other mecha- talized patients: a meta-analysis of prospective studies. JAMA. 1998;279:1200-1205.
nisms may miss some problems such as the underuse and 10. Hanlon JT, Landsman PB, Cowan K, et al. Physician agreement with pharmacist- interactions of drugs in older people.26,40 A true meta- suggested drug therapy changes for elderly outpatients. Am J Health Syst Pharm.
analysis was not conducted for this study. Lastly, this study has the same limitations previously documented regard- 11. Hanlon JT, Schmader KE, Samsa GP, et al. A method for assessing drug therapy appropriateness. J Clin Epidemiol. 1992;45:1045-1051.
ing the use of the Delphi technique.25,41 12. Beers MH. Explicit criteria for determining potentially inappropriate medication A further challenge to adoption of the Beers crite- use by the elderly. Arch Intern Med. 1997;157:1531-1536.
ria will come from the information systems and infor- 13. Beers MH, Ouslander JG, Rollingher J, Reuben DB, Beck JC. Explicit criteria for mation technology sector. Despite phenomenal ad- determining inappropriate medication use in nursing home residents. Arch In-tern Med. 1991;151:1825-1832.
vances in hardware and software, decision support systems 14. McLeod JP, Huang AR, Tamblyn RM. Defining inappropriate practices in pre- continue to have significant limitations, and presenting scribing for elderly people: a national consensus panel. CMAJ. 1997;156:385- the right information to the right person at the point of ARCH INTERN MED/ VOL 163, DEC 8/22, 2003 Association. All rights reserved.
(REPRINTED WITH CORRECTIONS) 15. Doucet J, Chassagne P, Trivalle C, et al. Drug-drug interactions related to hos- ate prescribing before and after nursing home admission. J Am Geriatr Soc. 2002; pital admissions in older adults: a prospective study of 1000 patients. J Am Geri- atr Soc. 1996;44:944-948.
29. Sloane P, Zimmerman S, Brown L, Ives T, Walsh J. Inappropriate medication 16. Golden AG, Preston RA, Barnett SD, Liorente M, Hamdan K, Silverman MA. In- prescribing in residential care/assisted living facilities. J Am Geriatr Soc. 2002; appropriate medication prescribing in homebound older adults. J Am Geriatr Soc.
30. Cooper JW, Wade WE. Repeated unnecessary NSAID-associated hospitaliza- 17. Mort JR, Aparasu RR. Prescribing potentially inappropriate psychotropic medi- tions in an elderly female: a case report. Geriatr Drug Ther. 1997;12:95-97.
cations to the ambulatory elderly. Arch Intern Med. 2000;160:2825-2831.
31. Avorn J. Improving drug use in elderly patients: getting to the next level. JAMA.
18. Smalley WE, Griffin MR. The risks and costs of upper gastrointestinal disease attributable to NSAIDs. Gastroenterol Clin North Am. 1996;25:373-396.
32. Ruscin JM, Page RL II. Inappropriate prescribing for elderly patients. JAMA. 2002; 19. Thapa PB, Gideon P, Cost TW, Milam AB, Ray WA. Antidepressants and the risk of falls among nursing home residents. N Engl J Med. 1998;339:875-882.
33. Slater EJ. Polypharmacy in skilled-nursing facilities [letter]. Ann Intern Med. 1993; 20. Fick DM, Waller JL, Maclean JR, et al. Potentially inappropriate medication use in a Medicare managed care population: association with higher costs and uti- 34. Ashburn PE. Polypharmacy in skilled-nursing facilities [letter]. Ann Intern Med.
lization. J Managed Care Pharm. 2001;7:407-413.
21. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent pat- 35. Terplan M. Polypharmacy in skilled-nursing facilities [letter]. Ann Intern Med.
terns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287:337-344.
36. Centers for Medicare and Medicaid Services Web site. Available at: http://cms 22. Hanlon JT, Schmader KE, Boult C, et al. Use of inappropriate prescription drugs .hhs.gov/. Accessed April 8, 2002.
by older people. J Am Geriatr Soc. 2002;50:26-34.
37. American Association of Health Plans Web site. Available at: http://www.aahp 23. Morley JE. Drugs, aging, and the future [editorial]. J Gerontol A Biol Sci Med .org/. Accessed April 8, 2002.
38. Institute of Medicine. Crossing the Quality Chasm. Washington, DC: Institute of 24. Hanlon J, Fillenbaum G, Kuchibhatla M, et al. Impact of inappropriate drug use Medicine Press; 2001.
on mortality and functional status in representative community dwelling elders.
39. DesHarnais SI, Fortham MT, Homa-Lowry JM, Wooster LD. Risk-adjusted clini- Med Care. 2002;40:166-176.
cal quality indicators: indices for measuring and monitoring rates of mortality, 25. Dalkey N, Brown B, Cochran S. The Delphi Method, III: Use of Self Ratings to complications, and readmissions. Qual Manag Health Care. 2000;9:14-22.
Improve Group Estimates. Santa Monica, Calif: Rand Corp; November 1969. Pub- 40. Hanlon JT, Schmader K, Ruby C, Weinberger M. Suboptimal prescribing in older inpatients and outpatients. J Am Geriatr Soc. 2001;49:200-209.
26. Rochon P, Gurwitz J. Prescribing for seniors. JAMA. 1999;282:113-115.
41. Hasson F, Keeney S, Mckenna H. Research guidelines for the Delphi survey tech- 27. Aparasu RR, Fliginger SE. Inappropriate medication prescribing for the elderly nique. J Adv Nurs. 2000;32:1008-1015.
by office-based physicians. Ann Pharmacother. 1997;31:823-829.
42. Coiera E. When conversation is better than computation. J Am Med Inform As- 28. Dhalla I, Anderson G, Mandani M, Bronskill S, Sykora K, Rochon P. Inappropri- ARCH INTERN MED/ VOL 163, DEC 8/22, 2003 Association. All rights reserved.
(REPRINTED WITH CORRECTIONS) 19. Thomas C, Kelman HR, Kennedy GJ, Ahn C, Yang C. Depressive symptoms and 30. Unutzer J, Patrick DL, Marmon T, Simon GE, Katon WJ. Depressive symptoms mortality in elderly persons. J Gerontol. 1992;47(suppl):S80-S87.
and mortality in a prospective study of 2,558 older adults. Am J Geriatr Psychia- 20. Gatz M, Hurwicz M-L. Are old people more depressed? cross-sectional data on Center for Epidemiological Studies Depression Scale factors. Psychol Aging. 1990; 31. Williams JW Jr, Noel PH, Cordes JA, Ramirez G, Pignone N. Is this patient clini- cally depressed? JAMA. 2002;287:1160-1170.
21. Kaplan GA, Roberts RE, Camacho TC, Coyne JC. Psychosocial predictors of de- 32. Sauer WH, Berlin JA, Kimmel SE. Selective serotonin reuptake inhibitors and myo- pression: prospective evidence from the human population laboratory studies.
cardial infarction. Circulation. 2001;104:1894-1898.
Am J Epidemiol. 1987;125:206-220.
33. Writing Committee for the ENRICHD Investigators. Effects of treating depres- 22. Bush DE, Ziegelstein RC, Tayback M, et al. Even minimal symptoms of depres- sion and low perceived social support on clinical events after myocardial infarc- sion increase mortality risk after acute myocardial infarction. Am J Cardiol. 2001; tion: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Ran- domized Trial. JAMA. 2003;289:3106-3116.
23. Whooley MA, Browner WS, Study of Osteoporotic Fractures Research Group.
34. Haft JI. Cardiovascular injury induced by sympathetic catecholamines. Prog Car- Association between depressive symptoms and mortality in older women. Arch diovasc Dis. 1974;17:73-86.
Intern Med. 1998;158:2129-2135.
35. Fielding R. Depression and acute myocardial infarction: a review and reinterpre- 24. Knekt P, Raitasalo R, Heliovaara M, et al. Elevated lung cancer risk among per- tation. Soc Sci Med. 1991;32:1017-1028.
sons with depressed mood. Am J Epidemiol. 1996;144:1096-1103.
36. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial in- 25. Barefoot JC, Schroll M. Symptoms of depression, acute myocardial infarction, farction: impact on 6-month survival. JAMA. 1993;270:1819-1825.
and total mortality in a community sample. Circulation. 1996;93:1976-1980.
37. Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis 26. Ferkeitch A, Schwartzbaum J, Frid D, Moeschberger M. Depression as an ante- after myocardial infarction. Circulation. 1995;91:999-1005.
cedent to heart disease among women and men in the NHANES I study: Na- 38. O'Connor CM, Gurbel PA, Serebruany VL. Depression and ischemic heart dis- tional Health and Nutrition Examination Survey. Arch Intern Med. 2000;160: ease. Am Heart J. 2000;140:63-69.
39. Kliks BR, Burgess MJ, Abildskov JA. Influence of sympathetic tone on ventricu- 27. Ariyo AA, Haan M, Tangen CM, et al, Cardiovascular Health Study Collaborative lar fibrillation threshold during experimental coronary occlusion. Am J Cardiol.
Research Group. Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Circulation. 2000;102:1773-1779.
40. Musselman DL, Tomer A, Manatunga AK, et al. Exaggerated platelet reactivity in 28. Hybels CF, Pieper CF, Blazer DG. Sex differences in the relationship between sub- major depression. Am J Psychiatry. 1996;153:1313-1317.
threshold depression and mortality in a community sample of older adults. Am 41. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive pro- J Geriatr Psychiatry. 2002;10:283-291.
tein and low-density lipoprotein cholesterol levels in the prediction of first car- 29. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug diovascular events. N Engl J Med. 2002;347:1557-1565.
treatment in older persons with isolated systolic hypertension: final results of the 42. Rothermundt M, Arolt V, Peters M, et al. Inflammatory markers in major depres- Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-3264.
sion and melancholia. J Affect Disord. 2001;63:93-102.
Error in "Results" Section. In the Original Investigation by Fick et al titled
"Updating the Beers Criteria for Potentially Inappropriate Medication Use in
Older Adults," published in the December 8/22 issue of the ARCHIVES (2003;
163:2716-2724), an error occurred in the "Results" section on page 2720. The
second full sentence in the left column should have read "Reserpine was changed
to be avoided only at doses greater than 0.25 mg, and disopyramide phosphate
avoidance now only refers to the non–extended release formulation." This cor-
rection was made previously to online versions of this article.
(REPRINTED) ARCH INTERN MED/ VOL 164, FEB 9, 2004 2004 American Medical Association. All rights reserved.
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