"One size does not fit all" and other lessons learned from grants for implementation of the AHRQ medication assisted treatment for opioid use disorder in rural primary care.

Purpose: This article summarizes lessons learned from five AHRQ grants to implement Medication for Opioid Use Disorder (MOUD) in rural primary care practices. Methods: Lessons learned were extracted from quarterly and annual grantee progress reports, minutes from quarterly virtual meetings, and minutes and notes from annual grantee in-person meetings. The lessons learned were drafted by the authors and reviewed by the grantees for accuracy. Results: The experience of these projects suggest that recruiting providers in rural areas and engaging them to initiate and sustain provision of MOUD is very difficult. Innovative approaches and providing supports are required for supporting providers to overcome barriers. Implications: Implementation of MOUD in rural primary care is challenging but success is more likely if implementers are attentive to the needs of individual providers, are flexible and tailor implementation to the local situation, and provide on-going support.

Developing AHRQ's Feasibility Assessment Criteria for Wide-Scale Implementation of Patient-Centered Outcomes Research Findings.

BACKGROUND: The Agency for Healthcare Research and Quality's (AHRQ) Patient-Centered Outcomes Research (PCOR) Dissemination and Implementation (D&I) Initiative identifies and prioritizes PCOR findings that could improve health care if widely implemented. To inform PCOR implementation investments, AHRQ sought to assess feasibility of widely implementing impactful PCOR findings with good strength of evidence in clinical practice. OBJECTIVE: To develop criteria to assess the feasibility of widely implementing nominated PCOR findings. METHODS: We reviewed literature and interviewed thirteen D&I experts to identify factors affecting feasibility of implementing PCOR findings. We grouped similar factors into themes. Fourteen technical expert panel (TEP) members discussed the face-validity and relative merits of the themes and additional factors, applied themes to fictional case studies, and prioritized themes for assessing feasibility. We developed criteria and guiding questions with a 3-point Likert scale. Seven D&I experts pilot-tested the criteria using sample nominations of PCOR findings. Experts represented diverse views of implementation from federal and state government agencies, research institutions, and quality improvement and advocacy organizations. KEY RESULTS: We developed a set of three essential criteria for AHRQ to assess feasibility of widely implementing PCOR findings to be widely implementable: (1) acceptability to the implementers; (2) generalizability, adaptability, and ease of implementing with fidelity; and (3) alignment with external policies and incentives. Two supplemental criteria, (1) the presence of a plan or toolkit supporting implementation, or (2) evidence supporting implementation outside the research setting, can enhance reviewers' confidence in the intervention's feasibility. Each criterion includes "guiding questions" to parse out specific components that could be more readily assessed. CONCLUSIONS: The criteria and guiding questions are a valuable tool for informing AHRQ's investment decisions regarding implementing PCOR findings. Although developed for AHRQ's needs, the criteria may help other funders and health care organizations determine the feasibility of implementing evidence-based practices.

Prioritizing Evidence-based Interventions for Dissemination and Implementation Investments: AHRQ's Model and Experience.

BACKGROUND: The Agency for Healthcare Research and Quality (AHRQ) is mandated to implement patient-centered outcomes research (PCOR) to promote safer, higher quality care. With this goal, we developed a process to identify which evidence-based PCOR interventions merit investment in implementation. We present our process and experience to date. MATERIALS AND METHODS: AHRQ developed and applied a systematic, transparent, and stakeholder-driven process to identify, evaluate, and prioritize PCOR interventions for broad dissemination and implementation. AHRQ encouraged public nominations, and assessed them against criteria for quality of evidence, potential impact, and feasibility of successful implementation. Nominations with sufficient evidence, impact, and feasibility were considered for funding. RESULTS: Between June 2016 and June 2018, AHRQ received 35 nominations from researchers, nonprofit corporations, and federal agencies. Topics covered diverse settings, populations, and clinical areas. Twenty-eight unique PCOR interventions met minimum criteria; 16 of those had moderate to high evidence/impact and were assessed for feasibility. Fourteen topics either duplicated other efforts or lacked evidence on implementation feasibility. Two topics were prioritized for funding (cardiac rehabilitation after myocardial infarction and screening/treatment for unhealthy alcohol use). CONCLUSIONS: AHRQ developed replicable criteria, and a transparent and stakeholder-driven framework that attracted a diverse array of nominations. We identified 2 evidence-based practice interventions to improve care with sufficient evidence, impact, and feasibility to justify an AHRQ investment to scale up practice. Other funders, health systems or institutions could use or modify this process to guide prioritization for implementation.

The incident user design in comparative effectiveness research.

Comparative effectiveness research includes cohort studies and registries of interventions. When investigators design such studies, how important is it to follow patients from the day they initiated treatment with the study interventions? Our article considers this question and related issues to start a dialogue on the value of the incident user design in comparative effectiveness research. By incident user design, we mean a study that sets the cohort's inception date according to patients' new use of an intervention. In contrast, most epidemiologic studies enroll patients who were currently or recently using an intervention when follow-up began. We take the incident user design as a reasonable default strategy because it reduces biases that can impact non-randomized studies, especially when investigators use healthcare databases. We review case studies where investigators have explored the consequences of designing a cohort study by restricting to incident users, but most of the discussion has been informed by expert opinion, not by systematic evidence.

Study design for a comprehensive assessment of biologic safety using multiple healthcare data systems.

BACKGROUND: Although biologic treatments have excellent efficacy for many autoimmune diseases, safety concerns persist. Understanding the absolute and comparative risks of adverse events in patient and disease subpopulations is critical for optimal prescribing of biologics. PURPOSE: The Safety Assessment of Biologic Therapy collaborative was federally funded to provide robust estimates of rates and relative risks of adverse events among biologics users using data from national Medicaid and Medicare plus Medicaid dual-eligible programs, Tennessee Medicaid, Kaiser Permanente, and state pharmaceutical assistance programs supplementing New Jersey and Pennsylvania Medicare programs. This report describes the organizational structure of the collaborative and the study population and methods. METHODS: This retrospective cohort study (1998-2007) examined risks of seven classes of adverse events in relation to biologic treatments prescribed for seven autoimmune diseases. Propensity scores were used to control for confounding and enabled pooling of individual-level data across data systems while concealing personal health information. Cox proportional hazard modeling was used to analyze study hypotheses. RESULTS: The cohort was composed of 159,000 subjects with rheumatic diseases, 33,000 with psoriasis, and 46,000 with inflammatory bowel disease. This report summarizes demographic characteristics and drug exposures. Separate reports will provide outcome definitions and estimated hazard ratios for adverse events. CONCLUSION: This comprehensive research will improve understanding of the safety of these treatments. The methods described may be useful to others planning similar evaluations.

Rhabdomyolysis reports show interaction between simvastatin and CYP3A4 inhibitors.

PURPOSE: To assess spontaneous reports of rhabdomyolysis associated with simvastatin (SV) and pravastatin (PV) for evidence of CYP3A4 interaction. Clinical trial results advocate cholesterol lowering in high-risk patients including diabetics and the elderly. Given the association between advancing age, metabolic, and cardiovascular disease, many patients are treated with concomitant medications upon statin initiation. Although statins are generally safe, minor and severe adverse reactions arise, especially when given to patients taking concomitant medications that inhibit the statin clearance and lead to increased statin plasma concentration. METHODS: We conducted a comparative case series of rhabdomyolysis reports associated with SV and PV. Domestic spontaneous reports were obtained from the FDA's Adverse Event Reporting System (AERS). Drug utilization data were obtained from IMS HEALTH and the National Ambulatory Medical Care Survey (NAMCS). Adverse event reporting rates (AER) and ratios (AERR) of rhabdomyolysis associated with SV and PV-with and without stratification by CYP3A4 inhibitor concomitancy were determined. RESULTS: Stratification by CYP3A4 inhibitor concomitancy did not change the rhabdomyolysis AER for PV with or without a CYP3A4 inhibitor (2.4 cases and 3.1 cases per 10 million Rx, respectively). However, stratification of SV reports with or without a concomitant CYP3A4 inhibitor resulted in a rhabdomyolysis AER (38.4 and 6.0 cases per 10 million Rx, respectively). The corresponding AERR with or without a CYP3A4 inhibitor were 0.77 for PV and 6.43 for SV. CONCLUSIONS: Spontaneous adverse event reports provide evidence of increased risk for rhabdomyolysis based on interaction between SV and selected CYP3A4 inhibitors.

Emergency department visits attributed to selected analgesics, United States, 2004-2005.

PURPOSE: To estimate the rate of emergency department (ED) visits attributed to selected analgesic-containing medications. METHODS: We used a nationally representative public health surveillance system to provide estimates of adverse events identified in EDs, and a national telephone survey to provide estimates of selected analgesic-containing medication usage in the US population, 2004-2005. Analysis was restricted to products containing acetaminophen, aspirin, ibuprofen, or naproxen. Types of adverse events and outcomes were compared. Estimated numbers and rates of ED visits were calculated by analgesic groupings and patient age groups. RESULTS: The estimated overall rate of ED visits attributed to analgesic-containing medications was 1.6 visits /100,000 users per week. The very old and very young had the highest rates; there were minimal differences in rates by patient gender. Acetaminophen was the attributed drug with the most estimated ED visits and generally had the highest rates of ED visits. The highest estimated rate for a specific product group was among subjects 18-64 years of age taking narcotic-acetaminophen products (8.9 ED visits /100,000 users per week). Overall, 12% of patients presenting to EDs with analgesic-attributed events were hospitalized. CONCLUSIONS: Rates of ED visits due to analgesics vary depending on the age of the patient and the product; most do not result in hospitalization. Although the rate of emergency visits is relatively low, because of the wide use of the analgesics, public health impact is considerable.

Drug-risk communication to pharmacists: assessing the impact of risk-minimization strategies on the practice of pharmacy.

OBJECTIVES: To gain insight on the knowledge, opinions, barriers, and practices of pharmacists regarding drug risk-minimization tools. DESIGN: Descriptive, nonexperimental, cross-sectional survey. SETTING: 20 states in the United States, fall 2004. PARTICIPANTS: 2,052 randomly selected licensed pharmacists employed in a position requiring an active pharmacist license at the time of the survey and who responded to the survey. INTERVENTION: Participants completed a four-page survey regarding their experience with different types of risk-minimization tools. MAIN OUTCOME MEASURE: Univariate distributions for each question were analyzed. RESULTS: 50% of survey recipients responded to the mailing; 88% of respondents had an active pharmacist license. Of respondents, 18% reported never having received a Dear Healthcare Professional letter and 29% stated that they were not familiar with Medication Guides. Patient package inserts were thought to be somewhat effective by 53% of respondents. Of pharmacists who dispensed a drug with programs for special stickers to be affixed on prescriptions to indicate that the labeled risk had been addressed by the prescriber, 41% reported receiving a prescription without a sticker; 45% dispensed the prescription when stickers were missing. Sixty percent of pharmacists stated that risk-minimization programs have a negative impact on the daily practice of pharmacy; nevertheless, many acknowledged that it was a necessary duty. CONCLUSION: Pharmacists might benefit from additional training on risk-minimization strategies. The successful implementation and impact of risk-minimization programs on the practice of pharmacy should be carefully considered by drug manufacturers and regulators.

Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action.

BACKGROUND: Warfarin sodium is widely used and causes bleeding; a review might suggest the need for regulatory action by the US Food and Drug Administration (FDA). METHODS: We accessed warfarin prescriptions from the National Prescription Audit Plus database of IMS Health (Plymouth Meeting, Pennsylvania), adverse event reports submitted to the FDA, deaths due to therapeutic use of anticoagulants from vital statistics data, and warfarin bleeding complications from national hospital emergency department data. RESULTS: The number of dispensed outpatient prescriptions for warfarin increased 45%, from 21 million in 1998 to nearly 31 million in 2004. The FDA's Adverse Event Reporting System indicated that warfarin is among the top 10 drugs with the largest number of serious adverse event reports submitted during the 1990 and 2000 decades. From US death certificates, anticoagulants ranked first in 2003 and 2004 in the number of total mentions of deaths for drugs causing "adverse effects in therapeutic use." Data from hospital emergency departments for 1999 through 2003 indicated that warfarin was associated with about 29 000 visits for bleeding complications per year, and it was among the drugs with the most visits. These data are consistent with literature reports of major bleeding frequencies for warfarin as high as 10% to 16%. CONCLUSIONS: Use of warfarin has increased, and bleeding from warfarin use is a prevalent reaction and an important cause of mortality. Consequently, a "black box" warning about warfarin's bleeding risk was added to the US product labeling in 2006. Physicians and nurses should tell patients to immediately report signs and symptoms of bleeding. A Medication Guide, which is required to be provided with each prescription, reinforces this message.

Deaths attributed to X-ray contrast media on U.S. death certificates.

OBJECTIVE: The objectives of our study were to determine the number, rate, and types of deaths attributed to specific X-ray contrast media on the basis of U.S. death certificates and to attempt to assess the comparative safety of commonly used diagnostic X-ray contrast agents using death certificate information. CONCLUSION: From 1999 through 2001, deaths attributed to the International Classification of Diseases (ICD) code for contrast media occurred at the rate of 1.1-1.2 per million contrast media packages distributed. An analysis of 1999 death certificates indicated that most deaths attributed to contrast media predictably were associated with renal failure or nephropathy and anaphylaxis or allergic reactions. Risk assessment of the comparative safety of classes or agents was limited by lack of specific contrast media names. Names of administered contrast agents should be recorded in patients' medical records and communicated to primary care physicians and certifiers of death in the event of serious sequelae after an identified recent radiologic procedure.

Estimates of acetaminophen (Paracetomal)-associated overdoses in the United States.

OBJECTIVE: To estimate the number of acetaminophen-associated overdoses in the United States and identify possible risk factors for intervention. METHODS: The investigators obtained estimates of acetaminophen-associated overdoses using different national databases. Two emergency room databases, a hospital discharge database, a national mortality file, and a poison surveillance database were used to identify cases. The FDA's spontaneous reporting system was searched to identify possible root causes for overdoses. RESULTS: Analysis of national databases show that acetaminophen-associated overdoses account for about 56,000 emergency room visits and 26,000 hospitalizations yearly. Analysis of national mortality files shows 458 deaths occur each year from acetaminophen-associated overdoses; 100 of these are unintentional. The poison surveillance database showed near-doubling in the number of fatalities associated with acetaminophen from 98 in 1997 to 173 in 2001. AERS data describe a number of possible causes for unintentional acetaminophen-associated overdoses. CONCLUSIONS: Each year a substantial numbers of Americans experience intentional and unintentional acetaminophen-associated overdoses that, in severe cases, lead to serious illness and possible death. This summary of a series of analyses highlights the need for strategies to reduce this public health burden.

Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey.

BACKGROUND: QT interval prolongation can lead to torsades de pointes, a potentially fatal arrhythmia. Although research exists on the relationship between QT prolongation and clinical outcome, few studies have described risk factors for prolonged QT interval in the general population. METHODS: The Third National Health and Nutrition Examination Survey (NHANES III) collected electrocardiogram interval data on 8561 subjects over 40 years of age and projected results to the US population. QT was corrected for heart rate using Fridericia's formula. Logistic regression analyses were performed to identify factors independently associated with prolonged QTc interval, defined as being in the upper 5% of the population QTc interval distribution. Analyses were conducted separately for women and men as a result of differences in the QT distribution between the sexes and also because of potential effect modification. Analytical variables included age, race/ethnicity, electrolyte measurements, body mass index, the recent use of QT-prolonging drugs and past medical histories of stroke, thyroid disease, hypertension, diabetes and myocardial infarction. RESULTS: Age, female sex, hypocalcemia (men), hypokalemia (women), and a history of thyroid disease and myocardial infarction (men) were associated with a prolonged QTc interval. In addition, taking QT-prolonging medications in the past month was associated with more than a twofold increase in the odds of prolonged QTc interval in both men and women. CONCLUSIONS: Healthcare practitioners should be aware that a prolonged QTc interval is a potential indicator of cardiovascular risk, and should exercise caution in prescribing potentially QT-prolonging medications to certain patients.

Trends in adherence to a revised risk management program designed to decrease or eliminate isotretinoin-exposed pregnancies: evaluation of the accutane SMART program.

OBJECTIVE: To review adherence to selected procedures outlined in the System to Manage Accutane-Related Teratogenicity (SMART) program during the first year of implementation vs the procedures in effect in the year prior to initiation of the SMART program. DESIGN: Observational. SETTING: A novel pharmacy compliance survey and an ongoing, voluntary survey. PATIENTS: Female recipients of isotretinoin. INTERVENTION: In April 2002, Hoffmann-La Roche Inc, Nutley, NJ, manufacturer of Accutane brand isotretinoin and at that time the sole source of isotretinoin, revised earlier guidelines and instituted the SMART risk management program, which included the use of qualification stickers to affix to all prescriptions for Accutane to indicate, among other things, a negative pregnancy test just before the prescription was written. The goal of the SMART program was to decrease or eliminate isotretinoin-exposed pregnancies. MAIN OUTCOME MEASURES: Use and completion of prescription qualification stickers; changes in pretherapy pregnancy testing and birth control use. RESULTS: The results of the pharmacy compliance survey indicated high (>90%) use of prescription qualification stickers. Results of the patient survey suggested that 9% of prescription qualification stickers within the observed user cohort were issued without a pregnancy test. Furthermore, the pregnancy rate for patients participating in the survey was similar to that reported for cohorts recruited before the SMART program. CONCLUSIONS: The usefulness of the results derived from 2 surveys designed to evaluate the SMART program is limited by the lack of reliability and validity of the survey instruments and by questionable generalizability to all female recipients of isotretinoin. The presence of a qualification sticker may not have an impact on pregnancy testing or compliance with effective birth control behavior as outlined in the SMART program.

Factors associated with celecoxib and rofecoxib utilization.

BACKGROUND: The cyclooxygenase-2 (COX-2) selective nonsteroidal antiinflammatory drugs (NSAIDs) celecoxib and rofecoxib (before its removal) are marketed as having fewer gastrointestinal (GI)-related complications than nonselective NSAIDs. However, adverse reaction data suggest that the use of COX-2 selective NSAIDs is associated with clinically significant GI events. OBJECTIVE: To assess whether patients receiving celecoxib and rofecoxib have a greater underlying disease burden than patients prescribed nonselective NSAIDs. METHODS: The study population consisted of members of 11 health plans, aged >34 years, with a pharmacy claim for celecoxib or rofecoxib or a nonselective NSAID dispensed between February 1, 1999, and July 31, 2001, who had been continuously enrolled for >364 days before the dispensing date. Celecoxib and rofecoxib patients were randomly selected without replacement from a pool of eligible users in each of the 30 months. Nonselective NSAID users were randomly chosen without replacement within each month on a 2:1 ratio to cases; they could be chosen in more than one month. Univariate analyses comparing 9000 cases and 18 000 controls were performed, followed by a multiple logistic regression analysis conditioned on time. RESULTS: Increasing age, treatment by a rheumatologist or an orthopedic specialist, treatment with a high number of different medications in the past year, treatment with oral corticosteroids in the past year, and having had a previous GI bleed increased the likelihood of receiving celecoxib or rofecoxib, whereas treatment with a high number of nonselective NSAID prescriptions in the past year decreased it. Treatment with a high number of different medications was a predictor of increased prevalence of underlying diabetes mellitus and cardiovascular disease. CONCLUSIONS: Patients having a greater underlying disease burden were more likely to receive COX-2 selective NSAIDs than nonselective ones. Paradoxically, patients at higher risk for cardiovascular disease were channeled toward treatment with COX-2 selective NSAIDs, many of which may confer an increased risk of acute myocardial infarction and other adverse cardiovascular outcomes.

Troglitazone-induced liver failure: a case study.

BACKGROUND: Troglitazone was removed from the U.S. market because its use was associated with an increased risk of liver failure. We evaluated the clinical features of all cases reported to the Food and Drug Administration and estimated the duration and magnitude of the risk of liver failure associated with continued use of the drug. METHODS: Data from cases of liver failure associated with troglitazone use were abstracted and analyzed. The extent of troglitazone use was determined from national marketing data, and the duration of use was estimated with data from a large, multistate, health care company. Survival analysis was performed to estimate monthly incidence rates and the cumulative risk of liver failure. RESULTS: Ninety-four cases of liver failure (89 acute, 5 chronic) were reported. Of the acute cases, 58 (67%) were women and only 11 (13%) recovered without liver transplantation. Progression from normal hepatic functioning to irreversible liver injury occurred within 1 month in 19 patients who were indistinguishable clinically from the 70 patients who had an unknown time course to irreversibility, except for the post hoc observation that prior cholecystectomy was less common in those with rapid onset. The incidence of liver failure was elevated from the first through at least the 26th month of troglitazone use. Accounting for case underreporting, the number needed to harm from troglitazone use was between 600 to 1500 patients at 26 months. CONCLUSION: The progression to irreversible liver injury probably occurred within a 1-month interval in most patients, casting doubt on the value of monthly monitoring of serum aminotransferase levels as a means of preventing troglitazone-induced acute liver failure. The cumulative risk of hepatic failure increased with continued use.