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The American Journal of Managed Care July 2010
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Development and Pilot Testing of Guidelines to Monitor High-Risk Medications in the Ambulatory Setting
Jennifer Tjia, MD, MSCE; Terry S. Field, DSc; Lawrence D. Garber, MD; Jennifer L. Donovan, PharmD; Abir O. Kanaan, PharmD; Marsha A. Raebel, PharmD; Yanfang Zhao, MA; Jacquelyne C. Fuller, MPH; Shawn J. Gagne, BA; Shira H. Fischer, AB; and Jerry H. Gurwitz, MD
US Cost Burden of Ischemic Stroke: A Systematic Literature Review
Bart M. Demaerschalk, MD, MSc, FRCP(C); Ha-Mill Hwang, PharmD; and Grace Leung, MPH
Cost Analysis Review of Stroke Centers, Telestroke, and rt-PA
Bart M. Demaerschalk, MD, MSc, FRCP(C); Ha-Mill Hwang, PharmD; and Grace Leung, MPH
Can Outpatient Pharmacy Data Identify Persons With Undiagnosed COPD?
Douglas W. Mapel, MD, MPH; Hans Petersen, MS; Melissa H. Roberts, MS; Judith S. Hurley, MS; Floyd J. Frost, PhD; and Jeno P. Marton, MD
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Ateev Mehrotra, MD; Melony E. S. Sorbero, PhD, MS, MPH; and Cheryl L. Damberg, PhD
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Joanna Campbell, PhD; Lisa J. McGarry, MPH; Scott A. Shikora, MD; Brent C. Hale, RPh; Jeffrey T. Lee, PhD; and Milton C. Weinstein, PhD
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Bruce Y. Lee, MD, MBA; Ann E. Wiringa, MPH; Rachel R. Bailey, MPH; Vishal Goyal, MPH; G. Jonathan Lewis, DO, MPH; Becky Y. K. Tsui, MPH; Kenneth J. Smith, MD, MS; and Robert R. Muder, MD
Diabetes Disease Management in Medicare Advantage Reduces Hospitalizations and Costs
James L. Rosenzweig, MD; Michael S. Taitel, PhD; Gordon K. Norman, MD, MBA; Tim J. Moore, MD, MS; Wendy Turenne, MS; and Pei Tang, MS, MA
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Howard S. Friedman, PhD, MMS; Eduardo Urdaneta, MD; John M. McLaughlin, PhD; and Prakash Navaratnam, RPh, MPH, PhD

Development and Pilot Testing of Guidelines to Monitor High-Risk Medications in the Ambulatory Setting

Jennifer Tjia, MD, MSCE; Terry S. Field, DSc; Lawrence D. Garber, MD; Jennifer L. Donovan, PharmD; Abir O. Kanaan, PharmD; Marsha A. Raebel, PharmD; Yanfang Zhao, MA; Jacquelyne C. Fuller, MPH; Shawn J. Gagne, BA; Shira H. Fischer, AB; and Jerry H. Gurwitz, MD

Pilot testing of guidelines for the laboratory monitoring of high-risk medications shows that monitoring is highly variable and that there is room for improvement.

Objectives: To develop guidelines to monitor high-risk medications and to assess the prevalence of laboratory testing for these medications among a multispecialty group practice.


Study Design: Safety intervention trial.


Methods: We developed guidelines for the laboratory monitoring of high-risk medications as part of a patient safety intervention trial. An advisory committee of national experts and local leaders used a 2-round Internet-based Delphi process to select guideline medications based on the importance of monitoring for efficacy, safety, and drug–drug interactions. Test frequency recommendations were developed by academic pharmacists based on a literature review and local interdisciplinary consensus. To estimate the potential effect of the planned intervention, we determined the prevalence of high-risk drug dispensings and laboratory testing for guideline medications between January 1, 2008, and July 31, 2008.


Results: Consensus on medications to include in the guidelines was achieved in 2 rounds. Final guidelines included 35 drugs or drug classes and 61 laboratory tests. The prevalence of monitoring ranged from less than 50.0% to greater than 90.0%, with infrequently prescribed drugs having a lower prevalence of recommended testing (P <.001 for new dispensings and P <.01 for chronic dispensings, nonparametric test for trend). When more than 1 test was recommended for a selected medication, monitoring within a medication sometimes differed by greater than 50.0%.


Conclusions: Even among drugs for which there is general consensus that laboratory monitoring is important, the prevalence of monitoring is highly variable. Furthermore, infrequently prescribed medications are at higher risk for poor monitoring.


(Am J Manag Care. 2010;16(7):489-496)

This article adds to the existing literature and informs clinical decisions in the following ways:


  • By describing a process to develop guidelines for the laboratory monitoring of high-risk medications within a multispecialty group practice. 
  • By estimating the potential effect of an intervention to improve laboratory testing of high-risk medications by reporting the use frequency of high-risk medications requiring monitoring in 2008 and the prevalence of test completion for high-risk drugs in 2008. 
  • By demonstrating that infrequently used medications have lower rates of recommended laboratory test monitoring.
Drug-induced injury is common. Independent risk factors for adverse drug events in the ambulatory setting include advanced age, multiple comorbid conditions, and the use of high-risk medications requiring close monitoring. For example, failure to appropriately monitor older patients receiving drug therapy accounts for 36% of preventable adverse drug events in the ambulatory setting.1

Efforts to improve monitoring within organizations are hampered by a lack of comprehensive and specific guidelines for the laboratory monitoring of high-risk medications.2 Monitoring guidelines for selected drugs exist in recommendations of organizations such as the American Heart Association guidelines to manage heart failure,3 the American Geriatrics Society Assessing Care of Vulnerable Elders medication quality indicators,4 and the National Quality Forum–endorsed measures.5 A nationwide baseline monitoring assessment study6 developed more comprehensive guidelines for medications used through 2000, among which a subset of 14 were updated and adopted for an intervention trial between 2002 and 2003 within a single health maintenance organization.7,8

We sought to develop an updated and comprehensive list of drugs requiring laboratory monitoring for an electronic medical record–embedded clinical decision support intervention at a multispecialty group practice for medications in clinical use during 2008. The intent of the updated guidelines was to include drugs introduced to the market since December 2000, the date of the literature review for the original drug and laboratory monitoring recommendations published by Raebel et al6 in 2005, as well as to update laboratory test and frequency recommendations based on 2007 changes in monitoring recommendations.9 Herein, we describe the development of guidelines to monitor high-risk medications in the ambulatory setting using a 2-step consensus-based approach, including a national expert advisory panel and local leaders to select candidate medications for monitoring and to determine the frequency of laboratory monitoring. To estimate the potential effect of our guidelines on actual practice, we determined the use frequency of the guideline drugs and the prevalence for each of the recommended laboratory tests. The specific objectives of this study were (1) to develop recommendations to guide the monitoring of high-risk medications in the ambulatory setting, (2) to assess the use prevalence of candidate medications for monitoring, and (3) to determine completion of recommended testing for medications dispensed among the patient population.
Study Setting and Population

This study was conducted in a large multispecialty group practice that provides most medical care to members of a closely associated health plan based in the New England area of the United States. The group practice employs 250 outpatient clinicians at 30 ambulatory clinic sites. The practice uses the EpicCare Ambulatory (Epic, Verona, WI) electronic medical record system and provides medical care to approximately 180,000 individuals. For this analysis, we included patients if they received care from the multispecialty group practice, were 18 years or older, and obtained insurance coverage from the health plan between January 1, 2007, and July 31, 2008. Patients had to be continuously enrolled during the observation period and not residing in a long-term care facility. Data about medication exposure were derived from the prescription drug claims of the health plan. Data about laboratory test completion were derived from the multispecialty group practice electronic medical record.

Determination of High-Risk Drugs and Laboratory Monitoring Guidelines

Laboratory monitoring guidelines for high-risk drugs were developed using a sequential process adapted from an approach created and tested for a study6 conducted within the Health Maintenance Organization Research Network Center for Education and Research on Therapeutics. This approach used an advisory committee of national experts and local health plan leaders, including practicing clinicians and pharmacists and experts in patient safety and geriatric pharmacotherapy. The charge for this group was as follows: (1) to review a comprehensive initial list of medications requiring monitoring; (2) to assess the importance of including monitoring recommendations to evaluate efficacy, safety, and clinically relevant drug–drug interactions; and (3) to determine the need to include infrequently prescribed medications in the guidelines. The initial list of high-risk drugs included those commonly implicated in adverse events among patients in the ambulatory setting1 and those associated with adverse events leading to emergency department visits,10 as well as drugs with low monitoring rates,6,11 drugs included in national quality guidelines,4 and drugs with black box warnings.12

We asked panel members to participate in an Internet-based questionnaire administered in a 2-round modified Delphi process13 between August and October 2008. Panelists were asked whether electronic monitoring alerts should be sent to primary care physicians, specialists, or both and whether monitoring alerts should be generated for infrequently dispensed or effectively obsolete medications. Panelists were also asked to rate the importance of monitoring each candidate medication for efficacy, toxic effects, and drug–drug interactions. Each question was answered based on a 5-point Likert-type scale to evaluate agreement or disagreement with statements concerning the importance of monitoring each medication or medication class for the domain assessed. The scale ranged from 1 (indicating “strongly agree”) to 5 (indicating “strongly disagree”).

After the first round of the survey, we eliminated questions for which there was agreement and readministered questions for which there was lack of consensus. Consistent with other modified Delphi methods, consensus for a question was defined by agreement on categorization by at least a majority (>50.0%) of respondents.13 We then administered a second questionnaire to participants. In this round, panelists were reminded of their original responses to individual questions and were given the group’s aggregated response to the questions in the first round. At this stage, each participant was given the opportunity to revise his or her response to increase consensus with the succeeding round. The results of the Delphi process informed the selection of the final high-risk drug list.

Determination of Laboratory Test Monitoring Frequency

After selection of the final high-risk drug list, 2 research pharmacists (JLD and AOK) reviewed the literature to determine the appropriate frequency of laboratory monitoring for each drug. The review included monitoring recommendations provided in manufacturer labeling information, nationally available published guidelines, and clinical guidelines from national organizations and initiatives (eg, American Heart Association guidelines3 and National Committee for Quality Assurance–developed measures and guidelines5). Because manufacturers’ warnings often describe a nonspecific frequency for monitoring such as “periodically,” we reviewed other authoritative sources that pharmacists and clinicians commonly use to guide decisions about the frequency of monitoring. These sources included the following: (1) the published literature; (2) the Micromedex Healthcare Series14 (Thomson Reuters [Healthcare] Inc, Greenwood Village, CO) database, which sources the primary case report and experimental literature; (3) UpToDate Inc15 (Waltham, MA), an online peer-reviewed reference database; and (4) the Pharmacist’s Letter16 (Therapeutic Research Center, Stockton, CA). The final list of laboratory monitoring tests and the associated monitoring frequencies were reviewed by a local panel of academic pharmacists, the clinical pharmacist for the multispecialty group practice, and the medical director of the multispecialty group practice to determine local acceptability and congruence with local quality standards.

Statistical Analysis

We used drug dispensing claims between January 1, 2007, and July 31, 2008, to identify the first dispensing of a high-risk medication for a patient after January 1, 2008. New drug use was defined as an initial dispensing on or after the index date of January 1, 2008, and no drug dispensing in the 6 months preceding the index date. Chronic (ongoing) drug use was defined as a dispensing on or after January 1, 2008, with evidence of drug dispensing in the 6 months before that date. Because clinicians might rely on laboratory test results for up to 6 months before initiation of a drug or might order a test within 2 weeks after initiation of a drug, we defined test completion for a new dispensing in 2008 as having occurred if there was at least 1 associated monitoring test completed 180 days before dispensing to 42 days after dispensing (test ordered <14 days after dispensing plus 28 days for test completion). Completion of a test of serum drug levels (eg, serum carbamazepine) for new prescriptions was measured from the day of dispensing to 30 days after initial dispensing. Test completion for chronic medication use was defined as having occurred if there was at least 1 recommended test for the drug test pair that occurred up to 365 days before the index dispensing in 2008 through 42 days after the dispensing if the test was indicated annually (or 180 days before to 42 days after index dispensing if the test was indicated every 6 months). For each drug–laboratory test combination, the proportion of completed recommended tests was determined for all index dispensings in the observation period. We used a nonparametric test for trend across ordered groups by Cuzick17 to examine whether more frequently dispensed drugs had a higher prevalence of recommended test completion. All analyses were conducted using commercially available software (SAS 9.2; SAS Institute Inc, Cary, NC). The study was approved by the institutional review boards of the University of Massachusetts Medical School, Worcester, and the participating group practice.
Consensus Panel Survey

A panel of 3 pharmacists and 6 physicians participated in the consensus survey. All physicians were certified by the American Board of Internal Medicine, 2 had an added qualification in geriatric medicine, and 3 had subspecialty board certifications. All respondents completed the 2 rounds of the survey. After the second round of the survey, consensus was achieved for all 40 medications with respect to parameters (ie, efficacy or toxic effects) for laboratory monitoring and for alerts to physicians (ie, primary care physician vs specialist). The consensus panel agreed that alerts for high-risk medications were indicated to monitor efficacy and toxic effects alone or in the presence of significant drug–drug interactions. The panel also agreed that alerts should be sent to specialists and primary care physicians and should be developed for medications that were frequently and infrequently prescribed. Because strict national prescribing policies already exist to guide the use and monitoring of isotretinoin, we did not include this medication in the newly developed guidelines. The resulting list of drugs included 39 drugs or drug classes.

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