Safety of baclofen versus tizanidine for older adults with musculoskeletal pain.

BACKGROUND: Baclofen and tizanidine are both muscle relaxants that carry the risk for neuropsychiatric events in older adults but there is a lack of data directly comparing their safety. This study aimed to investigate the relative risk between these two medications in causing injury and delirium in older adults. METHODS: This was a retrospective cohort study that was completed in an integrated healthcare system in the United States and included patients aged 65 years or older who started baclofen or tizanidine for the treatment of musculoskeletal pain from January 2016 through December 2018. Outcomes included new incidence of injury (concussion, contusion, dislocation, fall, fracture, or other injuries) and delirium. The cohort was followed from the initiation of therapy until the first occurrence of any of the following events: end of the index drug exposure, end of health plan membership, death, or the study end date of December 31st, 2019. Descriptive statistics were used to compare baseline patient characteristics between baclofen and tizanidine treatment groups. Cox proportional hazards model was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals. RESULTS: The final study cohort included 12,101 and 6,027 older adults in the baclofen and tizanidine group respectively (mean age 72.2 ± 6.2 years old, 59% female). Older adults newly started on baclofen had a greater risk of injury (HR = 1.54, 95% CI = 1.21-1.96, P = < 0.001) and delirium (HR = 3.33, 95% CI = 2.11-5.26, p = <0.001) compared to those started on tizanidine. CONCLUSION: The results of this study suggest that baclofen is associated with higher incidences of injury and delirium compared to tizanidine when used for the treatment of musculoskeletal pain. Future studies should investigate if these risks are dose-related and include a comparison group not exposed to either drug.

Real world outcomes related to providing an annual supply of short-acting hormonal contraceptives.

OBJECTIVE: To compare pregnancy rates among women provided a 12-month supply or less than a 12-month supply of short-acting hormonal contraceptives. STUDY DESIGN: This retrospective cohort study examined data from an integrated health plan in California, collected about people aged 10-50 years, who filled at least one contraceptive prescription between January 2017 and September 2018. We examined outcomes following index contraceptive prescriptions for up to 15 months, end of membership, initiation of a long-acting contraceptive, or death, whichever occurred first. We compared rates per 100 person years of observation of: pregnancy, receipt of emergency contraception (EC), and contraceptive refills more than 12 months after the index prescription. We used multivariable logistic regression to control for demographics and baseline clinical variables when comparing provision of a 12-month to a smaller supply. RESULTS: We identified 1689 members who received a 12-month supply of short-acting hormonal contraception and 352,624 women who received less than a 12-month supply. Those who received a 12-month supply were less likely to receive EC (1.3 vs 2.1 per 100 person years, p = 0.04) or have documentation of pregnancy (1.7 vs 2.7 per 100 person-years, p = 0.02), and more likely to refill the contraceptive more than 1 year after the index prescription (99.4% vs 63.9%, p < 0.01). Among new starts, the adjusted odds ratio (OR) of pregnancy was 0.50 (95% CI 0.27-0.94) among women who received a 12-month supply vs. those were not. CONCLUSION: Members of an integrated healthcare system who received a 12-month supply of short-acting hormonal contraceptives are less likely to become pregnant within the following year. IMPLICATIONS: Offering a 12-month supply of short-acting hormonal contraceptives may reduce rates of undesired pregnancy.

Retrospective Cohort Study Comparing Infliximab-dyyb and Infliximab in Biologic-Naive Patients With Inflammatory Bowel Disease in the United States.

Background: Real-world assessments of biosimilars are needed to understand their effectiveness and safety in practice settings that may differ from those seen in clinical trials or healthcare systems in different countries. To assess the effectiveness and safety of a biosimilar (infliximab-dyyb) and its reference product (infliximab) in patients with inflammatory bowel disease (IBD) in the United States. Methods: We conducted a retrospective cohort study of biologic-naive patients with IBD who started treatment with infliximab-dyyb or infliximab. The study included 3206 patients identified through electronic health records in a US integrated healthcare delivery system. The effectiveness outcome was a composite of IBD-related surgery, IBD-related emergency room visit, and IBD-related hospitalization within 12 months of initiation. Safety outcomes included incidence of any or serious infection, cancer, acute liver dysfunction, and tuberculosis. We used a non-inferiority test with an upper-limit margin of 10% to analyze effectiveness. Doubly robust methods incorporating Cox proportional hazard regression with standardized inverse probability of treatment weighting were used to analyze both effectiveness and safety outcomes. Results: The composite effectiveness outcome occurred in 107 of 870 patients (12.3%) in the infliximab-dyyb and 379 of 2336 patients (16.2%) in the infliximab groups. Infliximab-dyyb was non-inferior (P < .01) and was not different (hazard ratio [HR] 0.81; confidence interval [CI] 0.65-1.01; P = .06) to infliximab. Safety outcomes were not different between infliximab-dyyb and infliximab for any infections (HR 1.01; CI 0.86-1.17; P = .95), serious infections (HR 0.83; CI 0.54-1.26; P = .38), cancers (HR 0.83; CI 0.44-1.54; P = .55), and tuberculosis (HR 0.59; CI 0.10-3.55; P = .57). Conclusions: Initiation of infliximab-dyyb was non-inferior to infliximab among biologic-naive patients with IBD in an US integrated healthcare delivery system.

Risk of complete atypical femur fracture with Oral bisphosphonate exposure beyond three years.

BACKGROUND: Bisphosphonate (BP) therapy has been associated with atypical femur fracture (AFF). However, the threshold of treatment duration leading to increased AFF risk is unclear. In a retrospective cohort of older women initiating BP, we compared the AFF risk associated with treatment for at least three years to the risk associated with treatment less than three years. METHODS: We used observational data from a large population of female members of an integrated healthcare system who initiated oral BP during 2002-2014. Women were retrospectively followed for incident AFF confirmed by radiologic adjudication. Demographic data, pharmacologic exposures, comorbidity, bone density, and fracture history were ascertained from electronic health records. Inverse probability weighting was used to estimate risk differences comparing the cumulative incidence (risk) of AFF if women discontinued BP within three years to the cumulative incidence of AFF if women continued BP for three or more years, adjusting for potential time-dependent confounding by the aforementioned factors. RESULTS: Among 87,820 women age 45-84 years who initiated BP (mean age 68.6, median T-score - 2.6, 14% with prior major osteoporotic fracture), 16,180 continued BP for three or more years. Forty-six confirmed AFFs occurred during follow-up in the two groups. AFF-free survival was greater for BP treatment < 3 years compared to treatment ≥3 years (p = 0.004 comparing areas under survival curves). At five years, the risk of AFF was 27 per 100,000 (95% confidence interval, CI: 8-46) if women received BP treatment < 3 years and 120 per 100,000 (95% CI: 56-183) if women received BP treatment ≥3 years (risk difference 93 per 100,000, 95% CI: 30-160). By ten years, the risks were 27 (95% CI: 8-46) and 363 (95% CI: 132-593) per 100,000 for BP treatment < 3 and ≥ 3 years, respectively (risk difference 336 per 100,000, 95% CI: 110-570). CONCLUSIONS: Bisphosphonate treatment for 3 or more years was associated with greater risk of AFF than treatment for less than 3 years. Although AFFs are uncommon among BP-treated women, this increased risk should be considered when counseling women about long-term BP use. Future studies should further characterize the dose-response relationship between BP duration and incident AFF and identify patients at highest risk.

Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older Women.

Importance: Clinical trials have demonstrated the antifracture efficacy of bisphosphonate drugs for the first 3 to 5 years of therapy. However, the efficacy of continuing bisphosphonate for as long as 10 years is uncertain. Objective: To examine the association of discontinuing bisphosphonate at study entry, discontinuing at 2 years, and continuing for 5 additional years with the risk of hip fracture among women who had completed 5 years of bisphosphonate treatment at study entry. Design, Setting, and Participants: This cohort study included women who were members of Kaiser Permanente Northern and Southern California, 2 integrated health care delivery systems, and who had initiated oral bisphosphonate and completed 5 years of treatment by January 1, 2002, to September 30, 2014. Data analysis was conducted from January 2018 to August 2020. Exposure: Discontinuation of bisphosphonate at study entry (within a 6-month grace period), discontinuation at 2 years (within a 6-month grace period), and continuation for 5 additional years. Main Outcomes and Measures: The outcome was hip fracture determined by principal hospital discharge diagnoses. Demographic, clinical, and pharmacological data were ascertained from electronic health records. Results: Among 29 685 women (median [interquartile range] age, 71 [64-77] years; 17 778 [60%] non-Hispanic White individuals), 507 incident hip fractures were identified. Compared with bisphosphonate discontinuation at study entry, there were no differences in the cumulative incidence (ie, risk) of hip fracture if women remained on therapy for 2 additional years (5-year risk difference [RD], -2.2 per 1000 individuals; 95% CI, -20.3 to 15.9 per 1000 individuals) or if women continued therapy for 5 additional years (5-year RD, 3.8 per 1000 individuals; 95% CI, -7.4 to 15.0 per 1000 individuals). While 5-year differences in hip fracture risk comparing continuation for 5 additional years with discontinuation at 2 additional years were not statistically significant (5-year RD, 6.0 per 1000 individuals; 95% CI, -9.9 to 22.0 per 1000 individuals), interim hip fracture risk appeared lower if women discontinued after 2 additional years (3-year RD, 2.8 per 1000 individuals; 95% CI, 1.3 to 4.3 per 1000 individuals; 4-year RD, 9.3 per 1000 individuals; 95% CI, 6.3 to 12.3 per 1000 individuals) but not without a 6-month grace period to define discontinuation. Conclusions and Relevance: In this study of women treated with bisphosphonate for 5 years, hip fracture risk did not differ if they discontinued treatment compared with continuing treatment for 5 additional years. If women continued for 2 additional years and then discontinued, their risk appeared lower than continuing for 5 additional years. Discontinuation at other times and fracture rates during intervening years should be further studied.

Correction to: Effectiveness of Switching from Reference Product Infliximab to Infliximab-Dyyb in Patients with Inflammatory Bowel Disease in an Integrated Healthcare System in the United States: A Retrospective, Propensity Score-Matched, Non-Inferiority Cohort Study.

The article Effectiveness of Switching from Reference Product Infliximab to Infliximab-Dyyb in Patients with Inflammatory Bowel Disease in an Integrated Healthcare System in the United States: A Retrospective, Propensity Score-Matched, Non-Inferiority Cohort Study, written by Stephanie L. Ho, Fang Niu, Suresh Pola, Fernando S. Velayos, Xian Ning and Rita L. Hui, was originally published electronically on 26 February 2020 without open access.

Effectiveness of Switching from Reference Product Infliximab to Infliximab-Dyyb in Patients with Inflammatory Bowel Disease in an Integrated Healthcare System in the United States: A Retrospective, Propensity Score-Matched, Non-Inferiority Cohort Study.

PURPOSE: The aim was to compare outcomes in adult patients with inflammatory bowel disease (IBD) who switched to infliximab-dyyb with those who remained on reference product (RP) infliximab in the United States (US) in a retrospective, propensity score-matched, non-inferiority cohort trial. METHODS: This study was a retrospective, non-inferiority study conducted within a US integrated healthcare system and included adult patients with a confirmed diagnosis of Crohn's disease or ulcerative colitis. A 1:1 propensity score matching was utilized to match patients who switched to infliximab-dyyb during the period April 2016-March 2018 to patients who remained on RP infliximab. The non-inferiority margin was set at + 10% of the upper limit. The primary outcome was a composite measure of disease worsening requiring acute care after the index date of switching to infliximab-dyyb or continuing RP infliximab. Disease worsening requiring acute care was defined as any IBD-related emergency room visit, hospitalization, or surgery. The secondary outcome was the composite measure of disease worsening requiring acute care or treatment failure. A switch to another biologic or tofacitinib was a proxy for treatment failure. All patients were followed for up to 9 months. RESULTS: After propensity score matching, the matched cohort included 1409 patients in the infliximab-dyyb group and 1409 patients in the RP infliximab group. The overall mean age (± standard deviation) was 47.7 ± 17.0 years, 50.9% of patients were of male gender, and 51.8% of patients had Crohn's disease, while the remainder of the cohort had ulcerative colitis. There were 144 patients (10.2%) in the infliximab-dyyb group and 245 patients (17.4%) in the RP infliximab group who experienced disease worsening requiring acute care (P < 0.01 for non-inferiority). There were 347 patients (24.6%) in the infliximab-dyyb group who experienced disease worsening requiring acute care or treatment failure compared to 375 patients (26.6%) who remained on RP infliximab (P < 0.01 for non-inferiority). CONCLUSION: There was no increased risk of (1) disease worsening requiring acute care or (2) disease worsening requiring acute care or treatment failure in patients with IBD who switched from RP infliximab to infliximab-dyyb when compared to patients who remained on RP infliximab in this US population. Infliximab-dyyb is an option for patients with IBD who need to use RP infliximab.

Evaluation of Dipeptidyl Peptidase-4 Inhibitors versus Thiazolidinediones or Insulin in Patients with Type 2 Diabetes Uncontrolled with Metformin and a Sulfonylurea in a Real-World Setting.

BACKGROUND: Guidelines do not make clear recommendations for third add-on agents to metformin plus a sulfonylurea. This study compared the effectiveness and safety of dipeptidyl peptidase-4 inhibitors (DPP4is) to thiazolidinedione (TZD) or insulin as a third add-on agent to metformin plus a sulfonylurea in an integrated health care setting. METHODS: This retrospective database cohort study included adults with type 2 diabetes not at goal hemoglobin A1C (HbA1C) who initiated DPP4i, TZD, or insulin as a third add-on agent to metformin plus a sulfonylurea from January 2006 to June 2016. Primary outcomes were the proportion of patients who achieved goal HbA1C after starting the third add-on agent and change in HbA1C. Subgroup analysis was performed for patients with baseline HbA1C greater than 9%. RESULTS: In this study, 2080 patients started on a DPP4i were matched to 8320 patients started on TZD and to 8320 patients taking insulin. A significantly higher percentage of patients taking TZD reached goal HbA1C (31.0% versus 23.6%; p < 0.05) and had a significantly larger HbA1C reduction (-0.94% ± 1.34% versus -0.79% ± 1.23%; p < 0.01) compared to patients taking a DPP4i. No difference in the percentage of patients meeting goal HbA1C nor in change in HbA1C was demonstrated between insulin versus DPP4i regimens. For patients with baseline HbA1C greater than 9%, insulin or TZD resulted in a significantly higher proportion of patients achieving goal HbA1C compared to DPP4i (17.3% and 19.0% versus 12.4%, respectively; p < 0.01). CONCLUSION: TZD was more effective than DPP4i but DPP4i was as effective as insulin as a third add-on agent in the overall study population. Insulin was more effective than DPP4i only in the subgroup analysis of patients with baseline HbA1C greater than 9%.

Evaluation of a Pharmacist-Managed Antidiabetic Deprescribing Program in an Integrated Health Care System.

BACKGROUND: In the elderly, use of medications may increase the propensity for adverse drug events due to alterations in pharmacokinetic and pharmacodynamic profiles from normal aging processes. Deprescribing is the planned and supervised process of dose reduction or discontinuation of medications that may lead to harm or are no longer beneficial. While there are studies detailing strategies to deprescribe medications such as benzodiazepines and antipsychotics in nursing homes or for patients with dementia, there is a lack of guidance to safely deprescribe chronic medications, such as antidiabetics, for older patients in the community setting. OBJECTIVE: To evaluate the risk of hypoglycemia and other outcomes of pharmacist-managed deprescribing on selected antidiabetic medications under the guidance of a standardized program compared with usual care within an integrated health care system. METHODS: This was a retrospective propensity score-matched cohort study. The pharmacist-managed deprescribing group included patients who were enrolled in the deprescribing program between July 1, 2016, and June 30, 2017. The usual care group included eligible patients who did not receive the deprescribing intervention and were matched to the deprescribing group using propensity score matching (PSM). Baseline demographics and clinical variables were used for matching. Patients were followed for 6 months or the end of membership or death, whichever occurred first. Primary outcome was the risk of hypoglycemia. Secondary outcomes included risk of hyperglycemia, proportion of patients at goal (A1c), change in A1c, change in monthly antidiabetic drug cost, and all-cause mortality. Outcomes were analyzed using descriptive statistics and multivariant regression or Cox proportional hazard models when appropriate. RESULTS: After PSM, 685 patients in the deprescribing group and 2,055 patients in the usual care group were similar in age, gender, weight, and comorbidity burden (mean [SD] age 82.4 [5.4] years, 48% female, mean [SD] weight 81.7 [19.2] kg, mean [SD] Charlson Comorbidity Index score 3.2 [1.6]). Compared with the usual care group, the deprescribing group had a lower risk of hypoglycemia (1.5% vs. 3.1%, P < 0.02; adjusted odds ratio 0.42, P < 0.01). As for the secondary outcomes, the deprescribing group had a greater change (SD) in A1c (0.3 [0.6] vs. 0.2 [0.7] P < 0.01) and lower all-cause mortality (2.3% vs 5.6%, P < 0.01; adjusted hazard ratio 0.35, P < 0.01). There were no differences observed in the risk of hyperglycemia, proportion of patients at goal A1c < 7%, and change in monthly antidiabetic drug costs between the 2 groups. CONCLUSIONS: There are currently no studies to our knowledge that evaluate the outcomes of a pharmacist-managed deprescribing program targeting antidiabetic medications. The results of our study showed that deprescribing of selected antidiabetics reduced the risk of hypoglycemia and may have mortality benefit in elderly patients with well-controlled type 2 diabetes, who are taking medications that can cause hypoglycemia. Further and longer studies are needed to validate these benefits. DISCLOSURES: No outside funding was provided to support this research study. The authors of this study have no actual or potential conflicts of interest to report. Parts of this study were presented in a nonreviewed resident poster at the Academy of Managed Care Pharmacy Managed Care and Specialty Pharmacy Annual Meeting; April 23-26, 2018; Boston, MA.

Evaluation of Outcomes After Initiating Triple Antidiabetic Therapy with a GLP-1 RA in an Integrated Health Care System.

BACKGROUND: Type 2 diabetes (T2D) is characterized by chronic hyper-glycemia and can lead to life-threatening complications if not treated. A stepwise and patient-centered approach is recommended when managing patients with T2D. Metformin is the preferred first-line agent, while sulfonylureas (SU) are often chosen as second-line agents. If a patient's hemoglobin A1c (A1c) goal is not achieved despite 3 months of treatment with dual therapy, then triple therapy is recommended. However, due to the lack of head-to-head trials for different triple antidiabetic regimens, the recommendations are unclear for selection of an optimal third-line agent. OBJECTIVE: To evaluate the comparative effectiveness of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) compared with a thiazolidinedione (TZD) or insulin as a third-line add-on therapy in patients who have not achieved A1c goals while receiving metformin and SU dual therapy in the real-world setting within an integrated health care system. METHODS: This is a retrospective cohort study of adult patients with T2D who were not at goal A1c while on dual therapy with metformin and an SU and initiated triple antidiabetic therapy. The primary outcome was the proportion of patients who achieved goal A1c within 3-7 months after starting triple therapy with a GLP-1 RA compared with a TZD or insulin. Goal A1c was defined as an A1c of < 7% for patients aged less than 65 years and A1c of < 8% for patients aged 65 years or older. Secondary outcomes included mean change in A1c, mean change in weight, and the proportion of patients with an emergent health care encounter due to a hypoglycemic event. Propensity score matching was used to select comparison groups from the insulin and TZD groups with similar baseline characteristics to the GLP-1 RA group in a 4:1 ratio. RESULTS: 274 patients initiated a GLP-1 RA in addition to dual therapy with metformin and an SU. A propensity matched group of 1,096 patients who initiated insulin and 1,096 patients who initiated a TZD were selected as the control groups. Addition of a GLP-1 RA resulted in a significantly lower proportion of patients achieving goal A1c (23.0%) compared with the addition of a TZD (30.8%, P = 0.011). There was no significant difference with the addition of a GLP-1 RA when compared with insulin (24.1%, P = 0.704). CONCLUSIONS: This study reflects data from real-world practice in a large integrated health care system. Significantly less patients achieved goal A1c with the addition of a GLP-1 RA as a third-line add-on option to dual therapy with metformin and an SU compared with the addition of a TZD. Providers and patients should carefully weigh the risks and benefits of different antidiabetic agents when choosing triple therapy regimens. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. Part of this study was presented as a nonreviewed resident poster at the Academy of Managed Care & Specialty Pharmacy Annual Meeting 2017 in Denver, CO, on March 27-29, 2017.

Trends in bisphosphonate initiation within an integrated healthcare delivery system.

In the setting of changing temporal trends in the management of osteoporosis, we examined how select characteristics of new oral bisphosphonate (BP) initiators changed over time among 94,073 women within a large, integrated healthcare organization during the period 2004 to 2012. In the earlier era (2004-2007), approximately half of women younger than 65 years initiating BP therapy (47%-54%) had osteoporosis by bone mineral density (BMD) criteria, but this proportion increased sharply in the later era (2008-2012), with 55% to 81% having osteoporosis. This trend was not evident in older women (≥65 years). The proportion of younger women with prior fracture increased from 15% in 2008 to 32% in 2012, after remaining relatively stable (10%-15%) during the earlier era. Again, this trend was not observed among older women. Thus, among women younger than 65 years, we observed a marked temporal shift in initiation of BP treatment toward women at high risk (including those with prior fracture and those with osteoporosis by BMD testing) and away from those at lower risk (such as those with osteopenia and/or no prior fracture).

Predicting Adherence and Persistence with Oral Bisphosphonate Therapy in an Integrated Health Care Delivery System.

BACKGROUND: Examining drug exposure is essential to pharmacovigilance, especially for bisphosphonate (BP) therapy. OBJECTIVE: To examine differences in 4 measures of oral BP exposure: treatment discontinuation, adherence, persistence, and nonpersistence. METHODS: Among women aged ≥ 50 years who initiated oral BP therapy during 2002-2007 with at least 3 years of health plan membership follow-up, discontinuation was defined by evidence of no further treatment during the study observation period. Among those with at least 2 filled BP prescriptions during the study period, adherence was calculated for each year of follow-up using the (modified) proportion of days covered (mPDC) metric that allows for stockpiling of prescription/refills overlap ≤ 30 days supply. Persistence was quantified by treatment duration, allowing a gap of up to 60 days between prescription/refill days covered. Nonpersistence was quantified by the periods without drugs outside this allowable gap. Multivariable logistic regression was used to compare age and race groups and the relationships of early adherence (adherence during the first year) with subsequent adherence. RESULTS: Among 48,390 women initiating oral BP therapy and followed for 3 years, 26.7% discontinued in year 1, and 14.7% of the remaining 35,456 women discontinued in year 2. Discontinuation rates were slightly higher (29.4%, P < 0.001) for women aged ≥ 75 years and somewhat lower (21.1%, P < 0.001) for Asian women. During the first year, 60.4% of the women achieved an mPDC of ≥ 75%, with demographic differences in adherence similar to that seen for treatment discontinuation. Over the 3 years, the median mPDC levels for BP therapy were 86%, 84%, and 85% in years 1, 2, and 3, respectively, for those receiving treatment. Cumulative persistence was 2.3 years (median, IQR = 1.0-3.0) overall and slightly greater for Asian versus white women and lower for older women. There were 18,174 (42.9%) women with at least 1 period of nonpersistence during 3 years follow-up in excess of the 60-day allowable gap between prescription/refills (median cumulative nonpersistence = 0.65, IQR = 0.30-1.25 years). Women with mPDC ≥ 75% during the first year had a 12-fold and 6-fold increased odds of mPDC ≥ 75% during year 2 and year 3, respectively. CONCLUSIONS: BP discontinuation rates are highest for women during the first year. Among those continuing treatment in subsequent years, adherence rates were relatively stable. Persistence and adherence varied slightly by age and was somewhat higher in Asians, contributing to differences in cumulative BP exposure. We also found evidence that optimal adherence in the first year was highly predictive of optimal adherence in the subsequent 1-2 years. Hence, subgroups of patients receiving oral BP drugs may require different levels of support and monitoring to maximize treatment benefit, especially based on early patterns of use. DISCLOSURES: This study was supported by grants from the Kaiser Permanente Northern California Community Benefit Program and the National Institutes of Health, 1R01AG047230-01A1. The opinions expressed in this publication are solely the responsibility of the authors and do not represent the official views of Kaiser Permanente or the National Institutes of Health. Hui, Yi, and Chandra have received past research funding from Amgen not related to the current study. Adams has received research funding from Amgen, Merck, and Otsuka not related to the current study. Niu has received research funding from Bristol-Myers Squibb not related to the current study. Ettinger has received past legal fees in litigation involving Fosamax. Lo has received past research funding from Amgen and current research funding from Sanofi not related to the current study. The data from this study were presented at the Academy of Managed Care Pharmacy Annual Meeting; April 19-22, 2016; San Francisco, California. Study concept and design were contributed primarily by Hui and Lo, along with Adams, Niu, Yi, and Ettinger. Hui took the lead in data collection, along with Chandra, and data interpretation was performed by Niu, Yi, and Lo, along with the other authors. The manuscript was written by Hui, Adams, and Lo, along with Niu, Yi, and Ettinger, and revised by Ettinger, Hui, Lo, and Niu, along with the other authors.

Treatment Patterns and Overall Survival Associated with First-Line Systemic Therapy for Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: A variety of regimens are used as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC), which may include combination regimens and single agents, depending on histology, molecular profile, and performance status. OBJECTIVE: To describe the types of first-line therapies and compare overall survival between therapies used for patients with advanced NSCLC in an integrated health care system. METHODS: This retrospective cohort study included patients aged 18 years or older from Kaiser Permanente California with a diagnosis of stage IIIB/IV NSCLC. First systemic treatment date occurred from January 1, 2008, through September 30, 2013. Overall survival was measured as the number of months from initial treatment until death, end of enrollment, or September 30, 2014. Treatment regimens were categorized into 6 mutually exclusive groups: platinum doublets; pemetrexed-based, bevacizumab-based, and pemetrexed + bevacizumab-based combinations; singlets; and tyrosine-kinase inhibitors (TKIs). Survival was compared using Kaplan-Meier curves and adjusted Cox proportional hazard models. Subgroup analyses were performed by age group and by nonsquamous histology. RESULTS: Of 2,081 patients, approximately half (52.3%) received platinum doublets, followed by TKIs (19.0%), pemetrexed-based regimens (13.4%), bevacizumab-regimens (8.0%), singlets (5.5%), and pemetrexed + bevacizumab-based combinations (1.8%). Median survival was longest for pemetrexed + bevacizumab-based combinations (18.5 months), followed by bevacizumab-based regimens (14.5), TKIs (12.7), pemetrexed-based regimens (10.4), doublets (9.2), and singlets (5.3). There was a significantly reduced risk of mortality for pemetrexed + bevacizumab-based combinations (HR = 0.64; 95% CI = 0.42-0.94) and TKIs (HR = 0.83; 95% CI = 0.73-0.94) compared with doublets. Singlets were associated with an increased risk of mortality (HR = 1.50; 95% CI = 1.22-1.84). Subgroup analysis among patients aged 65 years and over found no significant differences among treatment groups, with the exception of singlets, which were associated with an increased risk of mortality compared with doublets (HR = 1.51; 95% CI = 1.20-1.90). Among patients under aged 65 years, pemetrexed + bevacizumab-based combinations (HR = 0.36; 95% CI = 0.21-0.64) and TKIs (HR = 0.76; 95% CI = 0.59-0.97) were associated with a reduced risk of mortality, and singlets were associated with an increased risk (HR = 1.85; 95% CI = 1.17-2.92). CONCLUSIONS: In this cohort of patients with advanced NSCLC, patients received a platinum agent with or without bevacizumab or pemetrexed, a TKI, or a single agent. Younger patients (aged < 65 years) receiving bevacizumab + pemetrexed-based combinations had a survival advantage over those receiving platinum doublets, and this finding merits further investigation. Younger patients receiving TKIs also had longer survival. Compared with platinum doublets, we found no survival advantage for older patients receiving bevacizumab or pemetrexed, which suggests that combination therapy of a platinum agent and taxane, such as carboplatin and paclitaxel, could be a reasonable option for older patients who are not candidates for targeted therapy. DISCLOSURES: No outside funding supported this study. Rashid has received past funding from Bristol-Myers Squibb, Astellas, Novartis, and Pfizer. No other authors report any potential financial conflicts of interest. Study concept and design were primarily contributed by Spence and Hui, with input from the other authors. Hui, Spence, and Rashid took the lead in data collection, and data interpretation was performed by Schottinger, Millares, and Spence, assisted by the other authors. The manuscript was written primarily by Spence, along with Chang, and revised by Spence, with input from the other authors.

The Risk of Pneumonia in Older Adults Using Nonbenzodiazepine Hypnotics.

BACKGROUND: Previous studies have shown an increased risk of pneumonia with benzodiazepines (BZD) and an increased risk of any infection with non-BZD hypnotics, but no analysis has specifically investigated the risk of pneumonia with non-BZD hypnotic use. OBJECTIVE: To evaluate the risk of pneumonia associated with non-BZD hypnotic use in the elderly. METHODS: This was a retrospective case-control study of members aged 65 years and older enrolled in an integrated health care system. Cases were identified as patients aged 65 years and older with a diagnosis of pneumonia from January 2011 to December 2012. Controls were matched in a 4:1 ratio to cases based on age, gender, and active enrollment. Non-BZD hypnotic exposure was evaluated for all cases and controls 1 year before the index date. Proximity of exposure to index date and duration of use were analyzed. Conditional logistic regression adjusted for covariates was performed. RESULTS: We identified 51,029 cases with pneumonia and matched 188,391 controls without pneumonia. Of the cases with pneumonia, 5.5% (2,790) of cases had exposure to a non-BZD hypnotic, compared with 3.4% (6,345) of controls. Non-BZD hypnotic exposure was associated with an increased risk of pneumonia (OR = 1.14; 95% CI = 1.08-1.20). When exposure was stratified by proximity to index date, only current exposure was associated with an increased risk of pneumonia (OR = 1.27; 95% CI = 1.18-1.36). Short-term exposure was associated with a relatively higher risk of pneumonia (OR = 1.57; 95% CI = 1.39-1.77) compared with long-term use (OR = 1.16; 95% CI = 1.06-1.25). CONCLUSIONS: Current use of non-BZD hypnotics in older adults is associated with an increased risk of pneumonia. The findings of this study provide additional support for reducing the use of non-BZD hypnotics in older adults and for pursuing safer alternatives for treating insomnia. DISCLOSURES: No outside funding supported this study. At the time of this study, Jung was a PGY2 resident in drug information at Kaiser Permanente Drug Information Services. All authors are employed by Kaiser Permanente and report no other potential financial conflicts of interest. Study concept and design were contributed by Jung, Spence, Lee, and Gibbs. Jung, Spence, and Hui were responsible for data collection, and data interpretation was performed by Jung and Spence, with assistance from Escasa, Lee, and Hui. The manuscript was primarily written by Jung, along with Spence and Escasa, and revised by Spence, Escasa, and Lee, along with the other authors.

Risk of Injury in Older Adults Using Gastrointestinal Antispasmodic and Anticholinergic Medications.

OBJECTIVES: To determine the risk of injury associated with gastrointestinal (GI) antispasmodic and anticholinergic use in elderly adults. DESIGN: Retrospective case-control study. SETTING: Integrated healthcare system. PARTICIPANTS: Healthcare system members aged 65 and older (N = 260,010; 54,152 cases, 205,858 controls). MEASUREMENTS: Cases were identified as individuals with an injury resulting in a hospitalization, emergency department, or urgent care visit (index date) from January 2009 through December 2010. Cases and controls were matched in a 1:4 ratio based on age and sex. GI antispasmodic and anticholinergic current and past exposure for cases and controls was evaluated. Individuals were classified as current users if the days' supply of the GI prescription overlapped the index date and past users if the days' supply ended more than 60 days before the index date. Duration of use for current users was analyzed for short- and long-term use. Conditional logistic regression produced adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Of the total population, 1,068 (0.4%) had current exposure to a GI antispasmodic or anticholinergic (302 (0.6%) cases, 766 (0.4%) controls). Current users had a small but significantly greater risk of injury than nonusers (OR = 1.16, 95% CI = 1.01-1.34, P = .03). Past use was not significantly different from no use. Short-term users had a significantly greater risk of injury (OR = 1.31, 95% CI = 1.01-1.70, P = .04) than nonusers. Long-term use was associated with greater risk, but the difference was not statistically significant. CONCLUSION: Older adults using GI antispasmodic and anticholinergic drugs have greater risk of injury. These findings support recommendations to limit the prescribing of GI antispasmodics and anticholinergics in elderly adults.

Impact of a Medicare MTM program: evaluating clinical and economic outcomes.

OBJECTIVES: To assess the impact of a Medicare Medication Therapy Management (MTM) program in a large integrated health plan on patient mortality, hospitalization and emergency department (ED) utilization, and daily prescription costs. STUDY DESIGN: Retrospective matched cohort study. METHODS: Patients who received MTM services between 2006 and 2010 were matched to control patients who were enrolled in Medicare but did not receive MTM services. They were matched in a 1:4 ratio based on age, gender, geographic location, and prospective diagnostic-cost-group (DxCG) risk score. Multivariate regressions were used to analyze the outcomes. Subgroup analyses were conducted for patients enrolled in 2010 because the Centers for Medicare & Medicaid Services lowered the drug-cost threshold for MTM eligibility and changed from opt-in to optout participation. RESULTS: We identified 34,532 members who received MTM services and 138,128 control members. The MTM group was found to have a significantly reduced mortality (hazard ratio 0.86, 95% confidence interval [CI], 0.84-0.88; P <.001), lower odds for hospitalization (odds ratio [OR] = 0.97, 95% CI, 0.94-0.99; P = .018), higher odds for emergency department visits (OR = 1.17, 95% CI, 1.14-1.20; P <.001), and no differences in change in daily medication costs when compared to the matched group. The subgroup analysis of the 2010 cohort found similar results with better outcomes than the overall cohort. CONCLUSIONS: Medicare MTM services resulted in lower mortality and odds for hospitalization for enrolled patients compared with matched controls. This study observed an increase in ED visits and no differences in change in daily medication costs in MTM services.

Evaluation of clinical and safety outcomes associated with conversion from brand-name to generic tacrolimus in transplant recipients enrolled in an integrated health care system.

STUDY OBJECTIVE: To evaluate clinical and safety outcomes among transplant recipients whose tacrolimus was converted from the brand-name formulation to a generic formulation. DESIGN: Retrospective analysis. DATA SOURCE: Clinical databases and electronic records from a large, integrated health care system in California. PATIENTS: A total of 234 clinically stable, adult transplant recipients (renal, liver, and heart) whose tacrolimus was converted from the brand-name formulation to a generic formulation between October 1, 2010, and December 31, 2010, according to a physician-approved protocol. MEASUREMENTS AND MAIN RESULTS: For each patient, pre- and postconversion tacrolimus trough concentrations and serum creatinine concentrations were analyzed. Data were also collected on the percentage of patients who required dosage titration, drug cost savings, and rates of reversion to brand-name tacrolimus, biopsy-proved acute allograft rejections, and mortality. No significant differences were noted in mean ± SD pre- and postconversion tacrolimus trough levels (6.74 ± 1.61 vs 6.96 ± 2.31 ng/ml, p=0.137) or serum creatinine concentrations (1.33 ± 0.48 vs 1.36 ± 0.82 mg/dl, p=0.302). The mean ± SD percent change in tacrolimus trough concentration was 5.63 ± 32.95%. Thirty-six patients (15.4%) required dosage titration. Six patients (2.6%) reverted back to brand-name tacrolimus. No deaths or acute rejections occurred. Use of the generic product saved each patient an average of $45/month in drug acquisition cost and $26/prescription copayment. CONCLUSION: Clinical experience as well as research data show that use of generic tacrolimus results in trough concentrations that are comparable to the brand-name drug. Given the lack of adverse events reported and the cost savings recognized, conversion from brand-name tacrolimus to generic tacrolimus should be encouraged. Since dosage titration may be required, close therapeutic drug monitoring is recommended.

Treatment of vitamin D deficiency within a large integrated health care delivery system.

BACKGROUND: In the past decade, increasing attention has focused on identification and treatment of vitamin D deficiency although repletion outcomes of pharmacologic vitamin D therapy have not been examined at a population level. OBJECTIVE: To investigate population trends and outcomes of pharmacologic treatment of vitamin D deficiency. METHODS: We conducted a retrospective cohort study using data from an integrated health system with approximately 3.2 million members. Automated laboratory and pharmacy databases were used to identify patients aged 18 years or older with hypovitaminosis D (defined as a 25-hydroxy-vitamin D [25(OH)D] serum level < 20 nanograms [ng] per mL) who newly initiated pharmacologic ergocalciferol (50,000 international units [IU] per week) during 2007-2010 and did not have a prescription for ergocalciferol in the prior 12 months. Patients were required to be continuously enrolled for 12 months before and 6 months after ergocalciferol initiation. Age, gender, race/ethnicity, body mass index, and 25(OH)D levels were obtained from health plan electronic medical records and administrative, laboratory, and pharmacy databases. Outcome and predictors of repletion among the subset who received 12 weekly doses of 50,000 IU ergocalciferol (total dose 600,000 IU) were examined using multivariable logistic regression. RESULTS: There were 72,093 vitamin D-deficient patients who newly initiated pharmacologic ergocalciferol. During the study period, the use of ergocalciferol increased nearly 8-fold from 161 per 100,000 adult members in 2007 to 1,241 per 100,000 adult members in 2010. One-fifth (n = 14,727) had severe vitamin D deficiency (25[OH]D level < 10 ng per mL). Among 23,322 patients receiving 50,000 IU ergocalciferol for 12 weeks in whom subsequent 25(OH)D levels were measured between 90 and 365 days after the index ergocalciferol prescription date, 74.0% achieved 25(OH)D of at least 20 ng per mL, and 35.8% achieved 25(OH)D of at least 30 ng per mL. Increasing age (adjusted odds ratio [OR] 1.02, 95% CI 1.02-1.02) and higher baseline 25(OH)D level (OR 1.11, 95% CI 1.10-1.12) were associated with greater odds of successful repletion. Asian race (OR 0.80, 95% CI 0.73-0.88), Hispanic ethnicity (OR 0.71, 95% CI 0.65-0.77), and increasing overweight/obesity (OR 0.78, 95% CI 0.72-0.85 for body mass index [BMI], 25.0-29.9 kg/m²; OR 0.66, 95% CI 0.60-0.71 for BMI 30.0-39.9 kg/m²; OR 0.53, 95% CI 0.48-0.60 for BMI ≥ 40 kg/m²) were associated with lower odds of repletion compared with BMI 18.5-24.9 kg/m². CONCLUSIONS: There is increasing recognition and treatment of vitamin D deficiency within the health care setting. Patients of younger age, Asian and Hispanic race/ethnicity, and those who are obese or with more severe vitamin D deficiency may be at greater risk for incomplete repletion using standard regimens and may require additional treatment to achieve optimal levels.

Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure.

PURPOSE: Osteonecrosis of the jaw (ONJ) is a serious complication associated with bisphosphonate therapy, but its epidemiology in the setting of oral bisphosphonate therapy is poorly understood. The present study examined the prevalence of ONJ in patients receiving chronic oral bisphosphonate therapy. MATERIALS AND METHODS: We mailed a survey to 13,946 members who had received chronic oral bisphosphonate therapy as of 2006 within a large integrated health care delivery system in Northern California. Respondents who reported ONJ, exposed bone or gingival sores, moderate periodontal disease, persistent symptoms, or complications after dental procedures were invited for examination or to have their dental records reviewed. ONJ was defined as exposed bone (of >8 weeks' duration) in the maxillofacial region in the absence of previous radiotherapy. RESULTS: Of the 8,572 survey respondents (71 +/- 9 years, 93% women), 2,159 (25%) reported pertinent dental symptoms. Of these 2,159 patients, 1,005 were examined and an additional 536 provided dental records. Nine ONJ cases were identified, representing a prevalence of 0.10% (95% confidence interval 0.05% to 0.20%) among the survey respondents. Of the 9 cases, 5 had occurred spontaneously (3 in palatal tori) and 4 occurred in previous extraction sites. An additional 3 patients had mandibular osteomyelitis (2 after extraction and 1 with implant failure) but without exposed bone. Finally, 7 other patients had bone exposure that did not fulfill the criteria for ONJ. CONCLUSIONS: ONJ occurred in 1 of 952 survey respondents with oral bisphosphonate exposure (minimum prevalence of 1 in 1,537 of the entire mailed cohort). A similar number had select features concerning for ONJ that did not meet the criteria. The results of the present study provide important data on the spectrum of jaw complications among patients with oral bisphosphonate exposure.

Association between exposure to topical tacrolimus or pimecrolimus and cancers.

BACKGROUND: The Food and Drug Administration has issued a public health advisory regarding cancer risk from topical calcineurin inhibitors. OBJECTIVE: To compare the rates of cancer among patients with common dermatologic conditions who were exposed or not exposed to topical calcineurin inhibitors. METHODS: A retrospective cohort observational study used data from an integrated healthcare delivery system on 953,064 subjects with diagnoses of atopic dermatitis or eczema between 2001 and December 2004. The main endpoint was initial cancer diagnosis. Chart review was performed to confirm cancer diagnosis in the subjects exposed to topical calcineurin inhibitors when any particular cancer rate was at least 3 times higher than that in unexposed subjects. Data were analyzed using the Cox proportional hazards model. RESULTS: Age- and sex-adjusted hazard ratios for all cancers were 0.93 (95% CI 0.81 to 1.07; p = 0.306) for tacrolimus-exposed versus -unexposed subjects and 1.15 (95% CI 0.99 to 1.31; p = 0.054) for pimecrolimus-exposed versus -unexposed subjects. T-cell lymphoma was the only cancer associated with a significantly increased risk among subjects exposed to tacrolimus (HR = 5.04, 95% CI 2.39 to 10.63; p < 0.001) or pimecrolimus (HR = 3.76, 95% CI 1.71 to 8.28; p = 0.010). Subsequent chart review of subjects in the exposed group with T-cell lymphoma found that 4 of 16 had skin lesions that were suspected to be the early lesions of T-cell lymphoma prior to exposure to tacrolimus or pimecrolimus. After these 4 cases were excluded, the age and sex hazard ratio for T-cell lymphoma was 5.44 (95% CI 2.51 to 11.79; p < 0.001) for tacrolimus and 2.32 (95% CI 0.89 to 6.07; p = 0.086) for pimecrolimus. There was no statistically significantly increased risk for other subgroups of cancer, including melanoma. CONCLUSIONS: Exposure to topical tacrolimus or pimecrolimus was not associated with an increase in the overall cancer rate. Use of topical tacrolimus may be associated with an increased risk of T-cell lymphoma.