Daniel S. Budnitz, MD, MPH; Nadine Shehab, PharmD; Scott R. Kegler, PhD; Chesley L. Richards, MD, MPH
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agencies.
Acknowledgment: The authors thank Margie Goulding, PhD, of CDC, for insights in study design; Benjamin Kupronis, MPH, and Katherine Ellingson, PhD, of CDC, for programming assistance; Kelly Weidenbach, MPH, of CDC, and Cathy Irish, BS, and Joel Friedman, BA, of the U.S. Consumer Product Safety Commission, for assistance with data collection; and Daniel Pollock, MD, and Lee Annest, PhD, of CDC, for thoughtful review of the manuscript. No individuals named herein received compensation for their contributions.
Grant Support: This work was implemented using CDC funding and was supported in part by an appointment to the CDC Research Participation Program administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and CDC (Dr. Shehab).
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Daniel S. Budnitz, MD, MPH, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Mailstop A-24, Atlanta, GA 30333; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Budnitz, Shehab, and Richards: Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Mailstop A-24, Atlanta, GA 30333.
Dr. Kegler: Coordinating Center for Environmental Health and Injury Prevention, Centers for Disease Control and Prevention, 4770 Buford Highway NE, Mailstop E-19, Atlanta, GA 30341.
Author Contributions: Conception and design: D.S. Budnitz, C.L. Richards.
Analysis and interpretation of the data: D.S. Budnitz, N. Shehab, S.R. Kegler, C.L. Richards.
Drafting of the article: D.S. Budnitz, N. Shehab, C.L. Richards.
Critical revision of the article for important intellectual content: D.S. Budnitz, N. Shehab, S.R. Kegler.
Final approval of the article: D.S. Budnitz, N. Shehab, S.R. Kegler.
Provision of study materials or patients: D.S. Budnitz, N. Shehab.
Statistical expertise: D.S. Budnitz, S.R. Kegler.
Obtaining of funding: D.S. Budnitz.
Administrative, technical, or logistic support: D.S. Budnitz, N. Shehab.
Collection and assembly of data: D.S. Budnitz, N. Shehab.
The Beers criteria identify inappropriate use of medications in older adults. The number of and risk for adverse events from these medications are unknown.
To estimate the number of and risk for emergency department visits for adverse events involving Beers criteria medications compared with other medications.
Nationally representative, public health surveillance of adverse drug events and a cross-sectional survey of outpatient medical visits.
National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance System, 2004–2005; National Ambulatory Medical Care Survey, 2004; and National Hospital Ambulatory Medical Care Survey, 2004.
Persons 65 years of age or older seeking emergency department and outpatient care.
Estimated number of and risks for emergency department visits for adverse drug events involving Beers criteria medications and other medications.
Among U.S. patients 65 years of age or older, an estimated 177 504 emergency department visits (95% CI, 100 155 to 254 854 visits) for adverse drug events occurred both years. An estimated 3.6% (CI, 2.8% to 4.5%) of these visits were for adverse events medications considered to be always potentially inappropriate, according to the Beers criteria, and 33.3% (CI, 27.8% to 38.7%) of visits were for adverse events from 3 other medications (warfarin [17.3%], insulin [13.0%], and digoxin [3.2%]). Accounting for outpatient prescription frequency, the risk for emergency department visits for adverse events due to these 3 medications was 35 times (CI, 9.6 to 61) greater than that for medications considered to be always potentially inappropriate.
Adverse events were identified only in emergency departments.
Compared with other medications, Beers criteria medications caused low numbers of and few risks for emergency department visits for adverse events. Performance measures and interventions targeting warfarin, insulin, and digoxin use could prevent more emergency department visits for adverse events.
Emergency department visits by older adults are often due to adverse drug events, but the proportion of these visits that are the result of drugs designated as inappropriate for use in this population is unknown.
Analyses of a national surveillance study of adverse drug events and a national outpatient survey estimate that Americans age 65 years or older have more than 175 000 emergency department visits for adverse drug events yearly. Three commonly prescribed drugs accounted for more than one third of visits: warfarin, insulin, and digoxin.
The study was limited to adverse events in the emergency department.
Strategies to decrease adverse drug events among older adults should focus on warfarin, insulin, and digoxin.
Data sources and descriptions.
NAMCS = National Ambulatory Medical Care Survey (36); NEISS-CADES = National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance System (5, 33–35); NHAMCS = National Hospital Ambulatory Medical Care Survey (37). *The NEISS-CADES is a 63-hospital national probability sample, but 5 pediatric hospitals were not included in this analysis.
Table 1. Potentially Inappropriate Medications for Individuals Age 65 Years or Older
Table 2. Cases and Annual National Estimates of Emergency Department Visits for Adverse Drug Events in Individuals Age 65 Years or Older, by Patient Characteristic
Table 3. Cases and National Estimates of Emergency Department Visits for Adverse Drug Events in Persons Age 65 Years or Older, by Medication
National estimates of emergency department (ED) visits for adverse drug events (ADEs) (top), outpatient prescription visits (middle), and risk (bottom) for persons age 65 years or older.
Data are from the 2004–2005 National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance System (top) and the 2004 National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey (middle), Centers for Disease Control and Prevention. Risks for adverse events (bottom) are estimated by dividing the estimated number of ED visits for ADEs (top) by the estimated number of outpatient visits at which implicated medications were prescribed (middle). Medications are identified as potentially inappropriate on the basis of the updated Beers criteria, 2003 (12) (Table 1). For medications considered potentially inappropriate only in certain circumstances, all ED visits for ADEs attributed to those medications were included regardless of the dose, frequency, or duration of use. Commonly implicated agents include the 3 medications (warfarin, insulin, and digoxin) and 3 medication classes (oral anticoagulant or antiplatelet, antidiabetic, and narrow therapeutic index agents) that most commonly caused ED visits for ADEs (Table 3). Oral anticoagulant or antiplatelet agents, other than warfarin, included aspirin, clopidogrel, ticlopidine, and cilostazol. Antidiabetic agents, other than insulin, included oral hypoglycemics. Narrow therapeutic index agents, other than digoxin, included phenytoin, carbamazepine, primidone, valproic acid, lithium, theophylline, and l-thyroxine. Bars represent 95% CIs.
Appendix Table. Emergency Department Visits for Adverse Events from Warfarin, Insulin, and Digoxin in Individuals Age 65 Years or Older, by Adverse Event Manifestation
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Department of Internal Medicine, Easton Hospital
December 4, 2007
Adverse Drug Events in the Elderly - Time to reiterate "Primum Non Nocere"
One of the principal precepts taught to all medical students is the principle of "Primum Non Nocere", a Latin phrase translated as "First, do no harm" (1). Budnitz et al in their article have appropriately identified that some of the commonly used medications are the most common cause of adverse reactions in elderly patients (2). As the human body ages, there are significant changes in metabolism. Hence risk-benefit analyses that apply to the healthy middle aged adult population (on whom most clinical studies are focused) do not translate to the elderly. It therefore follows that pharmacokinetics, pharmacodynamics, dosing guidelines and safety profiles of medications are different in older adults. Also, there are other significant psychosocial issues that are unique to the elderly population. Drug interactions due to polypharmacy, medication substitutions due to non coverage by prescription plans, vision problems leading to wrong medication use and improper understanding of doses due to memory issues leading to either over or under dosing are just some examples of how adverse drug reactions can occur. Without adequate knowledge of these, we might be causing more harm than good to the elder population by prescribing the medications.
The Institute of Healthcare Improvement as one of its primary objectives in the "5 million lives campaign" wants to reiterate the goal of "Prevent Harm from High Alert Medications" (3). This list includes anticoagulants, insulin, sedatives and hypnotics and closely mirrors the study conclusions of Budnitz et al. (2). Antiplatelet agents (aspirin, clopidogrel) and drugs with narrow therapeutic index like digoxin are certainly other major culprits in terms of adverse events. These take a huge toll in terms of patient suffering, patient outcomes, healthcare utilization and healthcare costs. The solution probably lies in better understanding the homeostasis of an aging body, having reasonable expectations and individualizing goals in the elderly patients. It is necessary to understand, identify and discuss these risks with them and their families. These would result in prudent prescribing and less adverse drug events. As America is aging rapidly these problems would become more frequent if not addressed. Therefore, last but not least, we need to tweak our medical education system and emphasize geriatrics more comprehensively to our medical students and residents, the physicians of tomorrow (4). And also, help them better understand "Primum Non Nocere".
1.Smith CM. Origin and uses of primum non nocere--above all, do no harm! Clin Pharmacol. 2005 Apr; 45(4):371-7.
2.Budnitz DS, Shebab N, Kegler SR, Richards CL. Medication Use Leading to Emergency Department Visits for Adverse Drug Events in Older Adults Ann Intern Med, December 4, 2007; 147(11): 755 - 765
3.http://www.ihi.org/IHI/Programs/Campaign/HighAlertMedications.htm (Accessed December 4, 2007)
4.Hazzard WR. General Internal Medicine and Geriatrics: Collaboration To Address the Aging Imperative Can't Wait. Ann Intern Med, October 7, 2003; 139(7): 597 - 598.
Adam G. Golden
Miami VA Medical Center/GRECC, University of Miami Miller School of Medicine
December 8, 2007
Doubts About the Conclusions of This Study
Budnitz et al recently reported in The Annals on ER visits attributed to adverse drug reactions in the elderly (1). While the authors identified medications that represent an important safety risk to the elderly, we disagree with their conclusion that the "Beers' Criteria medications caused low numbers of and few risks for emergency visits for adverse events." Their method of identifying attribution of risk may be severely flawed for several reasons.
The authors required that the ER physician explicitly attribute the diagnosis to use of medication. Most ER physicians would not miss that hypoglycemia or hyperglycemia was related to insulin use; they would not miss that bleeding with an elevated INR was related to warfarin use. Elevated digoxin levels are easily measured as well. However, these physicians would likely far less reliably recognize that an antihistamine contributed to a fall-related injury, delirium, or urinary retention. Indeed, they might not even have known that the patient was using that drug. Without a chart review, the investigators may have significantly underestimated the contribution of drugs listed in the Beers' Criteria. We are surprised that this limitation was not even discussed.
We are also perplexed that the authors seem to have ignored the other 5.3% of cases listed in Table 3 that are part of the Beers' Criteria (digoxin, short-acting benzodiazepines, NSAIDs and other medications). In Table 3 they also calculated that 3 of the 4 most commonly implicated medications (warfarin, aspirin and clopidogrel) accounted for 27.7% of the cases. The authors chose not to use the part of the Beers' criteria that identifies additional medications as potentially inappropriate if they are prescribed to patients who have certain preexisting conditions (2). However, this section of the Beers' Criteria lists aspirin as inappropriate in patients with gastric ulcers. Both aspirin and clopidogrel are listed as inappropriate for older adults receiving anticoagulant therapy. Without knowing the patients' medications and comorbid illnesses, they could not determine if drugs in the Beers' Criteria were involved in many of the cases. We believe that the conclusions of this study are flawed by poor study design.
1.Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med 2007;147:755-765.
2.Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH. Updating the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Arch Intern Med. 2003;163:2716-2724.
Sam F Carter
Murfreesboro Medical Clinic
December 23, 2007
Beers List Not a Patient-Centered Approach
It is appropriate that a study questioning the utility of the Beers list of potentially inappropriate medications for older adults(1) was published in the same issue as a position paper supporting patient- centered performance measures(2). The widespread use of the Beers criteria as a quality measure appears to me an example of premature adoption, without adequate validation, of a measure which is easily administered but not patient-centered. While these medications are not usually first choices for older patients (and the Beers list has educational value in that regard), they remain useful in many circumstances, contrary to the incorrect statement in the article summary on page I-5 that they "should never be prescribed." As a primary care internist with a mostly geriatric practice, I encounter patients on a regular basis who find that the benefits exceed the adverse effects of Beers list drugs, such as amitriptyline for chronic headaches, hyoscyamine for irritable bowel syndrome, estrogen for persistent hot flashes, clonidine for hypertension (when multiple other drugs have failed), diphenhydramine or hydroxyzine for itching or hives, doxepin for chronic urticaria, promethazine for nausea, propoxyphene for pain (when alternatives are poorly tolerated or less effective). In many cases the medications were initiated at younger ages, and the recipients continue to find them effective and well tolerated past age 65. For me to stop Beers list drugs under these circumstances, in order to look better on a quality measure, would be a disservice to my patients. The provision and measurement of good comprehensive patient care are much more complex than adherence to a checklist of medications compiled by a small panel of experts.
1. Butnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Int Med. 2007;147:755-765.
2. Snyder L, Neubauer RL. Pay-for-performance principles that promote patient-centered care: an ethics manifesto. Ann Int Med. 2007;147:792-794.
Daniel S. Budnitz
Centers for Disease Control and Prevention
December 31, 2007
Re: Doubts About Conclusions of This Study and Time to Reiterate "Primum Non Nocere"
We thank Dr. Golden and colleagues for their "rapid response" to our recent article in The Annals (1,2). Dr. Golden and colleagues raised several interesting issues, but we believe the critical issue for patient safety is identified by Dr. Krishnamurthy in his "rapid response" -- "Primum Non Nocere", first, do no harm (3). An estimated 59,000 emergency visits each year caused by adverse events from the therapeutic use of insulin, warfarin and digoxin are harms that should be addressed (1). We stand by our conclusions that performance measures and interventions targeting the use of warfarin, insulin, and digoxin could prevent more emergency department visits for adverse events than measures targeting the use of "potentially inappropriate" medications.
Dr. Golden and colleagues suggest that by relying on emergency department physician diagnoses we likely did not identify all adverse events, such as falls for which a (sedating) antihistamine might have been a contributing factor, that could have been identified if we had performed complete chart reviews. We indeed acknowledged the limitations that adverse events "diagnosed and treated in other settings (for example, in primary care offices, in urgent care centers, or during hospitalizations) or not treated in any health care facility were not included", and that our surveillance methodology is "probably less sensitive than research studies involving chart review" (1). The data we present are not based on epidemiologic associations, but rather on counts of physician diagnoses and treatments rendered. Exhaustive chart review to identify antihistamine use in a patient who has fallen and then designate the antihistamine as a contributing factor post hoc is problematic. In fact, a recent review of prescribing for the elderly concluded that the evidence that potentially inappropriate prescribing is associated with adverse patient outcomes is "mixed and contradictory" (4).
Performance measures and interventions to improve medication safety for our older patients are important. These should be based on scientific soundness, feasibility, and relevance, particularly the ability to improve measurable patient outcomes (5). The estimated 5.3% of emergency department visits attributed to medications potentially inappropriate in certain circumstances and the fraction of emergency department visits from antiplatelet agents among patients with gastric ulcers or concomitant anticoagulation represent important subsets of patients. The Beers criteria provide useful guidance for optimizing medication selection and may identify safety issues for further study. But with limited resources available for medication safety, national public health surveillance data on numbers and risks of emergency visits provide useful information to help focus and prioritize safety efforts and measure impact in the future.
1. Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med 2007;147:755-765.
2. Golden AG, Beers MH, Fick DM. Doubts about the conclusions of this study [rapid response]. Accessed at: http://www.annals.org/cgi/eletters/147/11/755 on 13 December 2007.
3. Krishnamurthy M. Adverse Drug Events in the Elderly - Time to reiterate "Primum Non Nocere" [rapid response]. Accessed at: http://www.annals.org/cgi/eletters/147/11/755 on 13 December 2007.
4. Spinewine A, Schmader KE, Barber N, Hughes C, Lapane KL, Swine C, Hanlon JT. Appropriate prescribing in elderly people: how well can it be measured and optimised? Lancet 2007;370:173-184.
5. Desirable attributes of HEDIS. Washington, DC. National Committee on Quality Assurance, 2007. Accessed at: http://web.ncqa.org/tabid/415/Default.aspx on 13 December 2007.
Cork University Hospital, Wilton, Cork, Ireland
February 25, 2008
Potentially inappropriate medications and adverse drug events in older adults admitted to hospital
Budnitz et al. reported that Beers' criteria medications cause low numbers of and few risks for emergency department visits for adverse drug events (ADEs) (1). However, many of Beers' criteria, particularly those considering diagnosis, were not applied to the data principally because of limited clinical information owing to the retrospective nature of the study. Furthermore, identification of ADEs was reliant on physicians recognising and reporting such events. ADEs often present with non- specific symptoms in older people e.g. confusion, falls, constipation and may be under-reported by physicians and by hospital coding systems. A prospective study would increase the likelihood of capturing such ADEs.
We have prospectively evaluated the performance of Beers' criteria (2) and a recently validated set of prescribing criteria called STOPP (Screening Tool of Older Persons' potentially inappropriate Prescriptions) (3) in detecting potentially inappropriate medicines and related ADEs in 715 non-selected, consecutive older patients admitted with acute illness to a university teaching hospital in Ireland. Beers' criteria medications (both independent of and considering diagnosis) were identified in 177 patients (25%). STOPP criteria medications were detected in 247 patients (35%). Ninety patients (13%) presented with symptoms that were clearly attributable to ADEs, the most common being falls and cognitive deterioration secondary to inappropriately prescribed psychotropic medications and upper gastrointestinal bleeds and renal failure secondary to inappropriate use of non-steroidal anti-inflammatory drugs (NSAIDs). Of these 90 ADE-related admissions, 43 cases were attributable to Beers' criteria medications (48% ADE detection) compared to 82 cases being attributable to STOPP criteria medications (91% ADE detection).
These prospective data show that Beers' criteria medications cause a significantly lower rate of admissions through the emergency department because of ADEs (6% of admissions) than STOPP criteria medications (12% of admissions). Perhaps this is because many of Beers' criteria medications are redundant in modern day geriatric clinical practice, e.g. meprobamate and amphetamines. We agree with Budnitz et al that the value of using Beers' criteria as a safety intervention is uncertain and that monitoring of medications such as warfarin, insulin and digoxin is important to minimise risk of ADEs. However, many other potentially harmful drugs such as long-acting benzodiazepines, opiates and NSAIDs continue to be inappropriately prescribed for older people and should also be the focus of preventive strategies. There is a role for clinically relevant drug utilisation review tools such as STOPP in detecting potentially inappropriate medications and preventing related ADEs in older people.
1. Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007;147:755-765.
2. Fick DM, Cooper JW, Wade W, Waller JL, Maclean JR, Beers MH. Updating the Beers criteria for potentially inappropriate medication use in older adults "“ results of a US consensus panel of experts. Arch Intern Med 2003;163:2716-24.
3. Gallagher P, Ryan C, Byrne S, Kennedy J, O'Mahony D. STOPP (Screening Tool of Older Persons' potentially inappropriate Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus Validation. Int J Clin Pharm Ther 2008;46(2):72-83.
Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication Use Leading to Emergency Department Visits for Adverse Drug Events in Older Adults. Ann Intern Med. 2007;147:755–765. doi: 10.7326/0003-4819-147-11-200712040-00006
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Published: Ann Intern Med. 2007;147(11):755-765.
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