Rita L. Hui

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.

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

To evaluate clinical and safety outcomes among transplant recipients whose tacrolimus was converted from the brand‐name formulation to a generic formulation.

Differential Association Between Statin Exposure and Elevated Levels of Creatine Kinase

BACKGROUND: Although hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are generally well tolerated, myopathy can be a serious adverse event. The association among different statins, doses, and related risk factors is not well understood. Objective: To determine the prevalence of elevated creatine kinase (CK) levels in patients taking statins, specific doses of these drugs, and other factors. Simvastatin and lovastatin were the drugs of primary interest. METHODS: In a modified prevalence (cross-sectional) study, prescriptions and laboratory data for 215 191 patients exposed to a statin in 2002 were reviewed. A log-linear Poisson regression model was used to determine the statistical relationship of an elevated CK level to other independent variables. RESULTS: Prevalence of high elevation of CK levels (ie, n of cases/1000 pts. exposed to statins) was 1.6; prevalence of mild to moderate elevation of CK levels was 6.4. For high elevations, the prevalence ratios were lower for low doses of lovastatin than for high doses of simvastatin. A higher prevalence ratio was associated with elevated serum creatinine (SCr) levels (2.44), exposure to interacting drugs (1.62), male gender (1.48), and evidence of diabetes (1.34). For mild to moderate elevation, a higher prevalence ratio was associated with elevated SCr (1.45), exposure to interacting drugs (1.21), male gender (3.19), age ≤65 years (1.35), and evidence of diabetes (1.34). Lower prevalence ratios were associated with all doses of lovastatin compared with those of high doses of simvastatin. CONCLUSIONS: Compared with simvastatin, lovastatin was generally associated with a lower prevalence of high elevation and mild to moderate elevation of CK levels. An elevated SCr level, exposure to interacting drugs, male gender, evidence of diabetes, and age ≤65 years were associated with higher prevalence ratios.

Risk of Skeletal-Related Events in Patients with Advanced Prostate Cancer Treated with Pamidronate or Zoledronic Acid

Background: Pamidronate and zoledronic acid are used for the prevention of skeletal-related events (SREs) in patients with advanced solid tumors, particularly breast and prostate cancers. There have been no head-to-head clinical trials comparing Pamidronate and zoledronic acid among patients with advanced prostate cancer. Objective: To estimate the risk of developing an SRE among men with metastatic prostate cancer after being treated with either pamidronate or zoledronic acid. Methods: A retrospective cohort study was conducted, using data from Kaiser Permanentes Southern California Region. The cohort included men aged ≥18 years diagnosed with prostate cancer from 1998 to 2004 who received at least 1 infusion of either Pamidronate or zoledronic acid after their cancer diagnosis. Patients receiving both drugs and those with a documented SRE prior to diagnosis were excluded. The primary outcome of SREs was defined using diagnosis codes for fractures, spina) cord compression, radiation to bone, and hypercalcemia of malignancy. Secondary outcomes were deterioration in renal function, based on serum creatinine laboratory results, and mortality. Multivariate logistic regression was used to predict SREs and mortality risk for Pamidronate compared to zoledronic acid. The proportion of patients with renal function deterioration was analyzed using χ2 tests. Results: The cohort included 118 patients treated with Pamidronate and 274 treated with zoledronic acid. Results showed no significant difference in risk of SREs for Pamidronate versus zoledronic acid (OH 0.99; 95% CI 0.59 to 1.67; p = 0.98). No significant difference was found in renal function deterioration (χ2 2.08; p = 0.15) or mortality (OR 0.71; 95% CI 0.43 to 1.17; p = 0.18). Conclusions: For patients with prostate cancer, the choice between these 2 bisphosphonates must be balanced between the shorter infusion time of zoledronic acid versus its increased costs. We found no evidence for a difference in outcomes; therefore, pamidronate is an effective choice where clinic capacity permits.

Identifying Subsequent Therapies in Patients with Advanced Non–Small Cell Lung Cancer and Factors Associated with Overall Survival

To identify subsequent therapies used after first‐line therapies in patients with advanced non–small cell lung cancer (NSCLC), compare overall survival (OS) associated with subsequent therapies, and evaluate factors associated with OS in these patients.

Risk of injury in older adults using gastrointestinal antispasmodic and anticholinergic medications

To determine the risk of injury associated with gastrointestinal (GI) antispasmodic and anticholinergic use in elderly adults.

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.

Changing Patterns in Oral Bisphosphonate Initiation in Women between 2004 and 2012

To the Editor: Recent studies examining trends in bisphosphonate (BP) therapy for fracture prevention show declining numbers of prescriptions starting 2007–2008 through 2012, possibly ascribed in part to media reports regarding rare adverse effects. This overall decline may reflect both trends in treatment discontinuation and lower rates of BP initiation. Treatment paradigms have also shifted towards primary and secondary fracture prevention in higher-risk patients, with increasing focus on integrated fracture risk. This study examines oral BP initiation patterns between 2004-2012 within an integrated healthcare delivery system.

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.