Development of an algorithm to detect methotrexate wrong frequency error using computerized health care data.

PURPOSE: We validated an algorithm to detect frequency errors in computerized healthcare data and estimated the incidence of these errors in an integrated healthcare system. METHODS: We applied Sentinel System analytic tools on the electronic health records of Kaiser Permanente, Northern California, January 1, 2010, through May 30, 2015,to identify rheumatoid arthritis (RA) patients with new use of methotrexate (365-day baseline period). We identified potential methotrexate frequency errors using ICD-9 code 995.20 (adverse drug event), Current Procedural Terminology (CPT) code 96409 for injection of leucovorin and prescription refill patterns. We performed chart review to confirm the frequency errors, assessed performance for detecting frequency errors, and estimated the incidence of chart-confirmed errors. RESULTS: The study included 24,529 methotrexate dispensings among 3,668 RA patients. Among these, 722 (3%) had one dispensing and 23,807 (97.1%) had ≥2 dispensings during 1-year follow-up period. We flagged 653 (2.7%) with a potential medication error (46 with one dispensing and 607 with ≥2 dispensings). We sampled 94 for chart review, and confirmed three methotrexate errors. All three confirmed frequency errors involved a first methotrexate dispensing followed by injected rescue therapy, leucovorin, (positive predictive value, 60%; 95% confidence interval [CI], 15-95%). No potential errors were found among patients with ≥2 dispensings. We estimated the frequency error incidence among one methotrexate dispensing to be 0.4% (95%CI, 0.1% to 1.2%). CONCLUSION: Rescue therapy is a specific indicator of methotrexate overdose among first methotrexate dispensings. This method is generalizable to other medications with serious adverse events treated with antidotes.

Understanding Nonadherence with Hydroxychloroquine Therapy in Systemic Lupus Erythematosus.

OBJECTIVE: Hydroxychloroquine (HCQ) is a cornerstone to managing systemic lupus erythematosus (SLE), yet adherence to medication is poor. We sought to measure the association of adherence with 5 "dimensions of adherence" as articulated by the World Health Organization for chronic conditions: the patient's socioeconomic status, and patient-, condition-, therapy-, and healthcare system-related factors. Our longterm goal is to generate evidence to design effective interventions to increase adherence. METHODS: The retrospective cohort study included Kaiser Permanente Northern California patients ≥ 18 years old during 2006-2014, with SLE and ≥ 2 consecutive prescriptions for HCQ. Adherence was calculated from the medication possession ratio and dichotomized as < 80% versus ≥ 80%. Predictor variables were obtained from the electronic medical record and census data. We used multivariable logistic regression to estimate adjusted OR and 95% CI. RESULTS: The study included 1956 patients. Only 58% of patients had adherence ≥ 80%. In adjusted analyses, socioeconomic variables did not predict adherence. Increasing age (65-89 yrs compared with ≤ 39 yrs: OR 1.44, 95% CI 1.07-1.93), white race (p < 0.05), and the number of rheumatology visits in the year before baseline (≥ 3 compared with 0 or 1: OR 1.47, 95% CI 1.18-1.83) were positively associated with adherence. The rheumatologist and medical center providing care were not associated with adherence. CONCLUSION: At our setting, as in other settings, about half of patients with SLE were not adherent to HCQ therapy. Differences in adherence by race/ethnicity suggest the possibility of using tailored interventions to increase adherence. Qualitative research is needed to elucidate patient preferences for adherence support.

An Observational Study of Cardiovascular Risks Associated with Rheumatoid Arthritis Therapies: A Comparison of Two Analytical Approaches.

BACKGROUND AND OBJECTIVES: Comparative safety studies typically use hierarchical treatment categories that lump monotherapy and combination therapy. The consequence of this approach on study results is not clear. For example, studies of tumor necrosis factor inhibitors usually lump users regardless of whether they are using the drug alone or in combination with other agents. This study explored the importance of lumping vs splitting users of monotherapy and combination therapy. We also explored whether the timing of disenrollment from Health Plan membership was informative as an outcome variable when interpreting unmeasured, time-varying confounding. METHODS: This observational cohort study included Kaiser Permanente Northern California 2003 to 2013 members with rheumatoid arthritis who started methotrexate. The study end point was a major cardiovascular event. In Cox proportional hazards analysis, we compared treatment classifications using five lumped categories with treatment classification using nine split categories. We also studied disenrollment as an outcome. RESULTS: Among 5885 patients, 238 experienced serious cardiovascular events during an average follow-up of 4.25 years. Analysis of drug treatments using 5 lumped categories was difficult to interpret because treatment effects and drug users were mixed. In contrast, analysis of 9 drug categories that split monotherapies from combination therapy was easier to interpret, although confidence intervals were wider. Analysis of drug treatment in relation to disenrollment provided useful information with which to assess study validity, although the power of the analysis was limited. CONCLUSION: In comparative safety studies, we recommend greater transparency in classifying treatment and evaluating disenrollment.

A Pharmacist-Staffed, Virtual Gout Management Clinic for Achieving Target Serum Uric Acid Levels: A Randomized Clinical Trial.

CONTEXT: Relatively few patients with gout receive appropriate treatment. OBJECTIVE: To determine whether a pharmacist-staffed gout management program is more effective than usual care in achieving target serum uric acid (sUA) levels in gout patients. DESIGN: A parallel-group, randomized controlled trial of a pharmacist-staffed, telephone-based program for managing hyperuricemia vs usual care. Trial duration was 26 weeks. MAIN OUTCOME MEASURES: Primary outcome measure was achieving sUA levels at or below 6 mg/dL at the 26-week visit. Secondary outcome was mean change in sUA levels in the control and intervention groups. Participants were adults with recurrent gout and sUA levels above 6.0 mg/dL. Participants were randomly assigned to management by a clinical pharmacist following protocol or to monitoring of sUA levels but management of their gout by their usual treating physician. RESULTS: Of 102 patients who met eligibility criteria, 77 subjects obtained a baseline sUA measurement and were entered into the trial. Among 37 participants in the intervention group, 13 (35%) had sUA levels at or below 6.0 mg/dL at 26 weeks, compared with 5 (13%) of 40 participants in the control group (risk ratio = 2.8, 95% confidence interval [CI] = 1.1 to 7.1, p = 0.03). The mean change in sUA levels among controls was +0.1 mg/dL compared with -1.5 mg/dL in the intervention group (sUA difference = -1.6, 95% CI = -0.9 to -2.4, p < 0.001). CONCLUSIONS: A structured pharmacist-staffed program was more effective than usual care for achieving target sUA levels. These results suggest a structured program could greatly improve gout management.

Risk of Serious Infection for Patients with Systemic Lupus Erythematosus Starting Glucocorticoids with or without Antimalarials.

OBJECTIVE: To compare serious infection risk for systemic lupus erythematosus (SLE) patients starting glucocorticoids (GC), antimalarials (AM), or their combination. METHODS: We conducted a new-user, historical cohort study, Kaiser Permanente Northern California, 1997-2013. Cox proportional hazards analysis was used to calculate adjusted HR and 95% CI. RESULTS: The study included 3030 patients with SLE followed an average of 4 years. Compared with patients starting AM without GC (9 infections/1461 patient-yrs), the HR for the risk of infection was 3.9 (95% CI 1.7-9.2) for those starting GC ≤ 15 mg/day without AM (14 infections/252 patient-yrs), while it was 0.0 (0 infections/128 patient-yrs) for those starting the combination. We split the 14 patients with a serious infection and with GC < 15 mg/day into 2 groups: < 7.5 and ≥ 7.5-15 mg/day. The HR for < 7.5 mg/day was 4.6 (95% CI 1.8-11.4) and for ≥ 7.5-15 mg/day, 3.1 (95% CI 1.0-9.7). For patients starting GC > 15 mg/day (reflecting more severe SLE), the risk of infection was nearly the same for the combination of GC and AM (9 infections/135 patient-yrs) and GC alone (41 infections/460 patient-yrs), but the combination users had evidence of more severe disease. Patients with SLE had a 6- to 7-fold greater risk of serious infection than the general population. CONCLUSION: Our findings suggest that the benefits of AM treatment for SLE may extend to preventing serious infections. Although the study included > 3000 patients, the statistical power to examine GC dosages < 15 mg/day was poor.

Population Variations in Rheumatoid Arthritis Treatment and Outcomes, Northern California, 1998-2009.

OBJECTIVE: To assess variations in rheumatoid arthritis treatment and outcomes at the community level from 1998 through 2009. METHODS: The study used computerized data from 16 Kaiser Permanente Northern California Medical Centers. Mixed modeling was used to assess patterns across time and clinic. The analysis accounted for patient demographics, clustering of patients within Medical Centers, and repeated measures of patients over time. The metric used to measure drug use, months of use per patient per year, included both users and nonusers in the denominator, to account for both prevalence and duration of use. RESULTS: Assessment was performed of 28,601 patients with rheumatoid arthritis, with all levels of severity. From 1998 through 2009, methotrexate use doubled in the typical patient to include 23% of the time they were observed; sulfasalazine and hydrochloroquine use declined. By 2008 through 2009, leflunomide and antitumor necrosis factor agents were used by the typical patient 4% and 9% of the time, respectively. Between 1998 and 2009, disease-modifying antirheumatic drug use increased in the typical patient from 38% to 63% of the time, and oral prednisone use declined from 23% to 15% of the time, whereas opioid use initially rose but then fell to 23% of the time. No variations over time were observed for the rate of hospitalized pneumonia or opportunistic infection. Variation across clinics, measured by the difference in drug use between clinics at the 75th and 25th percentiles, was lowest for opioids (25% vs 20% of the time) and greatest for infliximab (< 1% to 3%). CONCLUSION: Increased use of disease-modifying antirheumatic drugs and declines in prednisone are encouraging. Opioid use may need intervention.

Effectiveness of a pharmacist-based gout care management programme in a large integrated health plan: results from a pilot study.

OBJECTIVES: The study objective was to determine the feasibility of using a pharmacist-staffed, protocol-based structured approach to improving the management of chronic, recurrent gout. SETTING: The study was carried out in the outpatient clinic of a single Kaiser Permanente medical centre. This is a community-based clinic. PARTICIPANTS: We report on 100 consecutive patients between the ages of 21 and 94 (75% men) with chronic or recurrent gout, referred by their primary physicians for the purpose of management of urate-lowering therapy. Patients with stage 5 chronic kidney disease or end-stage kidney disease were excluded. INTERVENTIONS: The programme consisted of a trained clinical pharmacist and a rheumatologist. The pharmacist contacted each patient by phone, provided educational and dietary materials, and used a protocol that employs standard gout medications to achieve and maintain a serum uric acid (sUA) level of 6 mg/dL or less. Incident gout flares or adverse reactions to medications were managed in consultation with the rheumatologist. PRIMARY OUTCOME MEASURE: The primary outcome measure was the achievement and maintenance of an sUA of 6 or less for a period of at least 3 months. RESULTS: In 95 evaluable patients enrolled in our pilot programme, an sUA of 6 mg/dL or less was achieved and maintained in 78 patients with 4 still in the programme to date. Five patients declined to participate after referral, and another 13 patients did not complete the programme. (The majority of these were due to non-adherence.) CONCLUSIONS: A structured pharmacist-staffed programme can effectively and safely lower and maintain uric acid levels in a high percentage of patients with recurrent gout in a primary care setting. This care model is simple to implement, efficient and warrants further validation in a clinical trial.