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Ulcickas Yood M.,EpiSource LLC | Ulcickas Yood M.,Boston University | Bortolini M.,Roche Holding AG | Casso D.,EpiSource LLC | And 5 more authors.
Pharmacoepidemiology and Drug Safety | Year: 2015

Purpose: Using liver laboratory tests (LLTs), Hy's law is a method used to identify drug-induced liver injury (DILI), after excluding other causes. Elevated LLTs in chemotherapy-exposed patients may result from tumor effects or comorbidities. This study evaluated incidence of Hy's law in chemotherapy-treated cancer patients. Methods: We identified breast, colorectal, and lung cancer patients diagnosed in 1 January 2000 to 31 December 2007 at a Midwestern health system. Using automated data, potential Hy's law (PHL) cases were defined by patterns of elevated LLTs suggestive of DILI. Among those treated with chemotherapy, we excluded PHL patients with pre-existing conditions that could cause liver injury, producing a cohort meeting Hy's law criteria, according to automated data. Medical record review, conducted among these automated data-derived Hy's law patients, further excluded those with causes of liver injury other than chemotherapy. Results: Using automated data, among chemotherapy-exposed patients (N=2788), 91 (3.3%) met PHL criteria using LLTs and 64 (2.3%) met Hy's law after excluding underlying liver injury using the International Classification of Diseases, 9th Revision codes. After a medical record review, 62 of 64 patients qualifying as Hy's law through automated data had other potential causes, leaving two patients (0.07%; 95%CI: 0.01-0.24%) with chemotherapy as a likely alternative cause of liver injury. Conclusions: Abnormal LLTs are common in chemotherapy-treated patients. Medical record review showed that the incidence of Hy's law events is rare. These data provide context for evaluating DILI in clinical trials and postmarketing surveillance of anticancer therapies, understanding that automated data alone may substantially overestimate the number of Hy's law cases. © 2015 John Wiley & Sons, Ltd.


Rugo H.S.,University of California at San Francisco | Brufsky A.M.,University of Pittsburgh | Yood M.U.,EpiSource LLC | Yood M.U.,Boston University | And 7 more authors.
Breast Cancer Research and Treatment | Year: 2013

Data characterizing demographics, treatment patterns, and clinical outcomes in black patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) are limited. registHER is a large, observational cohort study of patients (n = 1,001) with HER2-positive MBC diagnosed ≤6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up of 27 months). Demographics, treatment patterns, and clinical outcomes were described for black (n = 126) and white patients (n = 793). Progression-free survival (PFS) following first-line therapy and overall survival (OS) were examined. Multivariate analyses adjusted for baseline and treatment factors. Black patients were more likely than white patients to be obese (body mass index ≥30), to have diabetes, and to have a history of cardiovascular disease; they were also less likely to have estrogen receptor or progesterone receptor positive disease. In patients treated with trastuzumab, the incidence of cardiac safety events (grade ≥3) was higher in black patients (10.9 %) than in white patients (7.9 %). Unadjusted median OS and PFS (months) were significantly lower in black patients than in white patients (OS: black: 27.1, 95 % confidence interval [CI] 21.3-32.1; white: 37.3, 95 % CI 34.6-41.1; PFS: black: 7.0, 95 % CI 5.7-8.2; white: 10.2, 95 % CI 9.3-11.2). The adjusted OS hazard ratio (HR) for black patients compared with white patients was 1.29 (95 % CI 1.00-1.65); adjusted PFS HR was 1.29 (95 % CI 1.05-1.59). This real-world evaluation of a large cohort of patients with HER2-positive MBC shows poorer prognostic factors and independently worse clinical outcomes in black versus white patients. Further research is needed to identify potential biologic differences that could have predictive impact for black patients or that could explain these differences. © 2013 The Author(s).


Tripathy D.,University of Southern California | Kaufman P.A.,Dartmouth Hitchcock Medical Center | Kaufman P.A.,University of Southern New Hampshire | Brufsky A.M.,University of Pittsburgh | And 7 more authors.
Oncologist | Year: 2013

Background. Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting. Methods. registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors. Results. HER2-positive, HR-positive patients receiving firstline trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22-0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27-1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42-0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36- 0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54-1.21; adjusted OS HR: 0.48, 95% CI: 0.26- 0.89). Conclusions. These real-world data in patients with HER2-positive/ HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting ofHRsandHER2receptors is associated with significantly prolonged PFS and OS times. ©AlphaMed Press 2013.


Kaufman P.A.,Dartmouth Hitchcock Medical Center | Brufsky A.M.,University of Pittsburgh | Mayer M.,Patient Advocate | Rugo H.S.,University of California at San Francisco | And 7 more authors.
Breast Cancer Research and Treatment | Year: 2012

Limited data exist regarding treatment patterns and outcomes in elderly patients with HER2-positive metastatic breast cancer (MBC). registHER is an observational study of patients (N = 1,001) with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up 27 months). Outcomes were analyzed by age at MBC diagnosis: younger (<65 years), older (65-74 years), elderly (≥75 years). For progression-free survival (PFS) and overall survival (OS) analyses of first-line trastuzumab versus nontrastuzumab, older and elderly patients were combined. Cox regression analyses were adjusted for baseline characteristics and treatments. Estrogen receptor/ progesterone receptor status was similar across age groups. Underlying cardiovascular disease was most common in elderly patients. In patients receiving trastuzumab-based first-line treatment, elderly patients were less likely to receive chemotherapy. In trastuzumab-treated patients, incidence of left ventricular dysfunction (LVD) and congestive heart failure (CHF) (grades ≥3) were highest in elderly patients (LVD: elderly 4.8 %, younger 2.8 %, older 1.5 %; CHF: elderly 3.2 %, younger 1.9 %, older 1.5 %). Unadjusted median PFS (months) was significantly higher in patients treated with first-line trastuzumab than those who were not (<65 years: 11.0 vs. 3.4, respectively; ≥65 years: 11.7 vs. 4.8, respectively). In patients <65 years, unadjusted median OS (months) was significantly higher in trastuzumab-treated patients; in patients ≥65 years, median OS was similar (<65 years: 40.4 vs. 25.9; ≥65 years: 31.2 vs. 28.5). In multivariate analyses, first-line trastuzumab use was associated with significant improvement in PFS across age. For OS, significant improvement was observed for patients <65 years and nonsignificant improvement for patients ≥65 years. Elderly patients with HER2-positive MBC had higher rates of underlying cardiovascular disease than their younger counterparts and received less aggressive treatment, including less first-line trastuzumab. These real-world data suggest improved PFS across all age groups and similar trends for OS. © The Author(s) 2012.


Yardley D.A.,Sarah Cannon Research Institute Tennessee Oncology PLLC | Tripathy D.,University of Southern California | Brufsky A.M.,University of Pittsburgh | Rugo H.S.,University of California at San Francisco | And 7 more authors.
British Journal of Cancer | Year: 2014

Background:Data characterising long-term survivors (LTS) with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) are limited. This analysis describes LTS using registHER observational study data.Methods:A latent class modelling (LCM) approach was used to identify distinct homogenous patient groups (or classes) based on progression-free survival (PFS), overall survival, and complete response. Demographics, clinicopathologic factors, first-line treatment patterns, and clinical outcomes were described for each class. Class-associated factors were evaluated using logistic regression analysis.Results:LCM identified two survivor groups labelled as LTS (n=244) and short-term survivors (STS; n=757). Baseline characteristics were similar between groups, although LTS were more likely to be white (83.6% vs 77.8%) with oestrogen receptor-positive (ER+) or progesterone receptor-positive (PgR+) disease (59.4% vs 50.9%). Median PFS in LTS was 37.2 (95% confidence interval (CI): 32.9-40.5) vs 7.3 months (95% CI: 6.8-8.0) in STS. Factors associated with long-term survival included ER+ or PgR+ disease, metastasis to node/local sites, first-line trastuzumab use, and first-line taxane use.Conclusions:Prognostic variables identified by LCM define a HER2-positive MBC patient profile and therapies that may be associated with more favourable long-term outcomes, enabling treatment selection appropriate to the patient's disease characteristics. © 2014 Cancer Research Uk.


Ulcickas Yood M.,EpiSource LLC | Ulcickas Yood M.,Boston University | DeLorenze G.N.,Kaiser Permanente | Quesenberry Jr C.P.,Kaiser Permanente | And 8 more authors.
BMC Psychiatry | Year: 2011

Background: The benefits of some second-generation antipsychotics (SGAs) must be weighed against the increased risk for diabetes mellitus. This study examines whether the association between SGAs and diabetes differs by dose.Methods: Patients were ≥18 years of age from three US healthcare systems and exposed to an SGA for ≥45 days between November 1, 2002 and March 31, 2005. Patients had no evidence of diabetes before index date and no previous antipsychotic prescription filled within 3 months before index date.49,946 patients were exposed to SGAs during the study period. Person-time exposed to antipsychotic dose (categorized by tertiles for each drug) was calculated. Newly treated diabetes was identified using pharmacy data to determine patients exposed to anti-diabetic therapies. Adjusted hazard ratios for diabetes across dose tertiles of SGA were calculated using the lowest dose tertile as reference.Results: Olanzapine exhibited a dose-dependent relationship for risk for diabetes, with elevated and progressive risk across intermediate (diabetes rate per 100 person-years = 1.9; adjusted Hazard Ratio (HR), 1.7, 95% confidence interval (CI), 1.0-3.1) and top tertile doses (diabetes rate per 100 person-years = 2.7; adjusted HR, 2.5, 95% CI, 1.4-4.5). Quetiapine and risperidone exhibited elevated risk at top dose tertile with no evidence of increased risk at intermediate dose tertile. Unlike olanzapine, quetiapine, and risperidone, neither aripiprazole nor ziprasidone were associated with risk of diabetes at any dose tertile.Conclusions: In this large multi-site epidemiologic study, within each drug-specific stratum, the risk of diabetes for persons exposed to olanzapine, risperidone, and quetiapine was dose-dependent and elevated at therapeutic doses. In contrast, in aripiprazole-specific and ziprasidone-specific stratum, these newer agents were not associated with an increased risk of diabetes and dose-dependent relationships were not apparent. Although, these estimates should be interpreted with caution as they are imprecise due to small numbers. © 2011 Yood et al; licensee BioMed Central Ltd.


Yood M.U.,EpiSource LLC | Oliveria S.A.,EpiSource LLC | Cziraky M.,HealthCore Inc. | Hirji I.,Bristol Myers Squibb | And 2 more authors.
Current Medical Research and Opinion | Year: 2012

Background and objective: Previous studies have shown that long-term outcomes are more favorable for patients newly diagnosed with chronic myeloid leukemia (CML) if a complete cytogenetic response is achieved within ≤12months of diagnosis. Because continuous and adequate dosing is important to achieve this outcome, it is important to understand treatment adherence as part of managing long-term CML therapy. While studies regarding imatinib suggest that adherence varies widely, data addressing adherence to newer breakpoint cluster regionAbelson (BCR-ABL) inhibitors (dasatinib and nilotinib) are sparse. This study evaluates real-world adherence in patients diagnosed with CML receiving dasatinib or nilotinib as second-line therapy. Research design and methods: Using the HealthCore Integrated Research Database (HIRD SM), patients with ≥1 International Classification of Diseases, 9th edition/revision, Clinical Modification (ICD-9-CM) code for CML (205.1x) and ≥1 prescription for imatinib from January 1, 2001 to June 30, 2010 were identified. Analysis was limited to patients who switched to second-line dasatinib or nilotinib. Dasatinib exposure was stratified by dose (≤100mg/day or ≥140mg/day) to account for dasatinib label changes. Main outcome measures: Medication possession ratio (MPR) was used to calculate adherence and Cox proportional hazard models were used to quantify poor rates of adherence (i.e. MPR <85%). Results: Of 2064 imatinib-exposed patients, 197 received dasatinib (≤100mg/day, n=112; ≥140mg/day, n=85) and 53 received nilotinib (400mg BID, n=46; 400mg QD, n=7) as second-line therapy. Mean exposure durations were 276days for dasatinib (≤100mg, 275days; ≥140mg, 276days) and 170days for nilotinib. Cox proportional hazard models quantifying rates of poor adherence (MPR<85%) comparing nilotinib with dasatinib (adjusted for age, sex, duration of previous imatinib exposure, number of concomitant medications, presence of cardiovascular disease or diabetes) calculated hazard ratios of 1.6 (95% confidence interval [CI], 1.02.4) for nilotinib versus dasatinib overall, 1.9 (95% CI, 1.23.0) for nilotinib versus dasatinib ≥100mg, and 1.2 (95% CI, 0.72.0) for nilotinib versus dasatinib ≥140mg. Conclusions: While this study is limited by use of claims data to identify CML and adherence, claims based data have been widely used to evaluate the association between treatment use and clinical outcomes. When stratified by dose, patients receiving second-line nilotinib were almost two times more likely to have poor adherence compared with patients receiving second-line dasatinib at the current approved dose of 100mg once daily. © 2012 Informa UK Ltd.


Donato B.M.K.,Bristol Myers Squibb | Burns L.,Bristol Myers Squibb | Willey V.,HealthCore | Cohenuram M.,Yale University | And 2 more authors.
Clinical Therapeutics | Year: 2010

Objective: The aim of this work was to analyze chemotherapy treatment patterns in patients with advanced breast cancer who had been previously exposed to an anthracycline, a taxane, and capecitabine.Methods: This retrospective cohort study used medical and pharmacy administrative claims with health-plan enrollment data and medical-record review from a large, US-based health insurer database, the HealthCore Integrated Research Database. Women were included if they were aged ≥18 years at the initial breast cancer diagnosis between January 1999 and July 2005 and had received all 3 drug classes of interest, as well as an initial diagnosis of American Joint Committee on Cancer stage I to III breast cancer with metastatic recurrence or an initial diagnosis of stage IV disease. Information about demographics, clinical and pathologic characteristics, survival, and treatments were obtained from computerized data and medical record review. Descriptive analyses were conducted to characterize the treatment patterns.Results: One hundred forty-four women with advanced breast cancer were identified. Patients ranged in age from 28 to 76 years, with a mean (SD) age of 48.2 (9.1) years, and with 54 patients (37.5%) aged 40 to 49 years and 48 patients (33.3%) aged 50 to 59 years at the time of initial diagnosis. Ninety-three patients (64.6%) were white, 15 (10.4%) were black, 7 (4.9%) were Hispanic, and 4 (2.8%) were Asian. Overall, 89 patients (61.8%) received ≥1 additional chemotherapy regimen after exposure to all 3 chemotherapy agents of interest; 55 (38.2%) received ≥2 additional regimens. A variety of chemotherapeutic regimens were prescribed; 14 monotherapy regimens and 37 combination therapy regimens were used. The most common regimens (both as single agents and combination therapy) included gemcitabine, vinorelbine, or retreatment with a taxane. Of the 89 patients who received ≥1 retreatment, 7 (7.9%) were retreated with anthracycline, 12 (13.5%) with a taxane, and 9 (10.1%) with capecitabine. For first and second treatment after exposure to all 3 agents of interest, the most common single-agent regimens were gemcitabine (first: 17 patients [19.1%]; second: 9 patients [16.4%]) and vinorelbine (first: 14 patients [15.7%]; second: 9 patients [16.4%]). The most common combination therapies for first retreatment were carboplatin based (6 patients [6.7%]).Conclusions: Of these patients with advanced breast cancer, 61.8% received ≥1 additional chemotherapy regimen after previous treatment with an anthracycline, a taxane, and capecitabine. The variety of agents prescribed suggests a lack of standard of care. Rigorous clinical effectiveness studies of common regimens in heavily pretreated and chemotherapy-resistant populations with breast cancer are warranted. © 2010 Excerpta Medica Inc.


PubMed | EpiSource LLC
Type: Journal Article | Journal: Current medical research and opinion | Year: 2012

Previous studies have shown that long-term outcomes are more favorable for patients newly diagnosed with chronic myeloid leukemia (CML) if a complete cytogenetic response is achieved within 12months of diagnosis. Because continuous and adequate dosing is important to achieve this outcome, it is important to understand treatment adherence as part of managing long-term CML therapy. While studies regarding imatinib suggest that adherence varies widely, data addressing adherence to newer breakpoint cluster region-Abelson (BCR-ABL) inhibitors (dasatinib and nilotinib) are sparse. This study evaluates real-world adherence in patients diagnosed with CML receiving dasatinib or nilotinib as second-line therapy.Using the HealthCore Integrated Research Database (HIRD(SM)), patients with 1 International Classification of Diseases, 9th edition/revision, Clinical Modification (ICD-9-CM) code for CML (205.1x) and 1 prescription for imatinib from January 1, 2001 to June 30, 2010 were identified. Analysis was limited to patients who switched to second-line dasatinib or nilotinib. Dasatinib exposure was stratified by dose (100mg/day or 140mg/day) to account for dasatinib label changes.Medication possession ratio (MPR) was used to calculate adherence and Cox proportional hazard models were used to quantify poor rates of adherence (i.e., MPR <85%).Of 2064 imatinib-exposed patients, 197 received dasatinib (100mg/day, n=112; 140mg/day, n=85) and 53 received nilotinib (400mg BID, n=46; 400mg QD, n=7) as second-line therapy. Mean exposure durations were 276days for dasatinib (100mg, 275days; 140mg, 276days) and 170days for nilotinib. Cox proportional hazard models quantifying rates of poor adherence (MPR<85%) comparing nilotinib with dasatinib (adjusted for age, sex, duration of previous imatinib exposure, number of concomitant medications, presence of cardiovascular disease or diabetes) calculated hazard ratios of 1.6 (95% confidence interval [CI], 1.0-2.4) for nilotinib versus dasatinib overall, 1.9 (95% CI, 1.2-3.0) for nilotinib versus dasatinib 100mg, and 1.2 (95% CI, 0.7-2.0) for nilotinib versus dasatinib 140mg.While this study is limited by use of claims data to identify CML and adherence, claims based data have been widely used to evaluate the association between treatment use and clinical outcomes. When stratified by dose, patients receiving second-line nilotinib were almost two times more likely to have poor adherence compared with patients receiving second-line dasatinib at the current approved dose of 100mg once daily.


The benefits of some second-generation antipsychotics (SGAs) must be weighed against the increased risk for diabetes mellitus. This study examines whether the association between SGAs and diabetes differs by dose.Patients were 18 years of age from three US healthcare systems and exposed to an SGA for 45 days between November 1, 2002 and March 31, 2005. Patients had no evidence of diabetes before index date and no previous antipsychotic prescription filled within 3 months before index date.49,946 patients were exposed to SGAs during the study period. Person-time exposed to antipsychotic dose (categorized by tertiles for each drug) was calculated. Newly treated diabetes was identified using pharmacy data to determine patients exposed to anti-diabetic therapies. Adjusted hazard ratios for diabetes across dose tertiles of SGA were calculated using the lowest dose tertile as reference.Olanzapine exhibited a dose-dependent relationship for risk for diabetes, with elevated and progressive risk across intermediate (diabetes rate per 100 person-years = 1.9; adjusted Hazard Ratio (HR), 1.7, 95% confidence interval (CI), 1.0-3.1) and top tertile doses (diabetes rate per 100 person-years = 2.7; adjusted HR, 2.5, 95% CI, 1.4-4.5). Quetiapine and risperidone exhibited elevated risk at top dose tertile with no evidence of increased risk at intermediate dose tertile. Unlike olanzapine, quetiapine, and risperidone, neither aripiprazole nor ziprasidone were associated with risk of diabetes at any dose tertile.In this large multi-site epidemiologic study, within each drug-specific stratum, the risk of diabetes for persons exposed to olanzapine, risperidone, and quetiapine was dose-dependent and elevated at therapeutic doses. In contrast, in aripiprazole-specific and ziprasidone-specific stratum, these newer agents were not associated with an increased risk of diabetes and dose-dependent relationships were not apparent. Although, these estimates should be interpreted with caution as they are imprecise due to small numbers.

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