Natural history of SCLC patients treated in third-line and beyond: A retrospective real world study.

OBJECTIVES: To describe treatment patterns and estimate outcomes among real-world small cell lung cancer (SCLC) patients in the US who received three or more lines of therapy. MATERIALS AND METHODS: We conducted a retrospective analysis of adult patients with SCLC who received a front-line platinum-based regimen and two additional lines of therapy (ie., a cohort of at least three lines of therapy). De-identified patients were selected from a United States Flatiron Health oncology database of electronic health records. Treatment patterns were captured by line of therapy. Outcomes evaluated by line of therapy included real-world overall survival (rwOS), real-world progression free survival (rwPFS), real-world response rate (rwRR) and real-world duration of response (rwDOR). RESULTS: The analysis included 326 3L SCLC patients, of which 103 (32 %) received 4L treatment, and 38 % (39/103) of 4L treated received 5L of therapy. Among the 3L cohort, the average age was 67 years, 49 % were male, and nearly all had a history of smoking (96 %). In the 3L setting, the median rwOS was 5.3 months (95 % Confidence Interval (CI): 4.5, 6.0), median rwPFS was 2.5 months (95 % CI: 2.1, 2.7), rwRR was 19.3 % (95 % CI: 15.2, 24.0) and median DOR was 3.4 months (95 % CI: 2.8, 4.4). No differences were seen in outcomes between the overall cohort and a subgroup of patients treated with front-line platinum-based regimen with an anti-programmed cell death ligand 1 (PD-L1) agent (atezolizumab or durvalumab), in each respective line of therapy. CONCLUSION: Results from this large, real-world study of US patients with SCLC in the 3L setting and beyond highlight the poor treatment outcomes in advanced SCLC patients with existing therapies and underscore the dire need for new therapies for SCLC patients.

Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC.

Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be immune cold and hence immunotherapy resistant tumors, and EA TNBC as inflamed tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes.

Systematic Literature Review of the Prevalence and Prognostic Value of Delta-Like Ligand 3 Protein Expression in Small Cell Lung Cancer.

BACKGROUND: Delta-like ligand 3 (DLL3), a member of the Notch pathway, has been identified as a potential therapeutic target as it is highly expressed in small cell lung cancer (SCLC), a subtype accounting for 15% of lung cancer cases. OBJECTIVE: A systematic literature review (SLR) was conducted to understand the prevalence and prognostic impact of DLL3 expression on survival of patients with SCLC and treatment response. PATIENTS AND METHODS: Systematic literature searches were conducted across multiple databases to capture studies of any SCLC population that evaluated DLL3 expression. Specific outcomes of interest included prevalence of DLL3 expression, method of expression analysis, and impact on outcome, including treatment response and survival (overall, progression-free, disease-free) according to varying levels of DLL3 expression/positivity. Standard risk of bias tools were used to evaluate study quality. RESULTS: Among the 30 included studies, the most common DLL3 testing method was immunohistochemistry (N = 26, 86.7%). For comparability, results focused on the 13 (22.3%) studies that used the Ventana DLL3 (SP347) immunohistochemistry assay. The prevalence of DLL3 positivity ranged from 80.0-93.5% for studies using a threshold of ≥ 1% of tumor cells (N = 4) and 58.3-91.1% for studies with a ≥ 25% threshold (N = 4). DLL3 expression was generally categorized as high using cutoffs of ≥ 50% (prevalence range: 45.8-79.5%; N = 6) or ≥ 75% (prevalence range: 47.3-75.6%; N = 5) of cells with positivity. Two studies used an H-score of ≥ 150 to define high DLL3 expression with prevalence ranging from 33.3-53.1%. No consistent associations were seen between DLL3 expression level and patient age, sex, smoking history, or disease stage. Two studies reported change in DLL3 expression category (high versus low) before and after chemotherapy. No statistically significant differences were reported between DLL3 expression groups and survival (overall, progression-free, or disease-free) or treatment response. CONCLUSIONS: There is a high prevalence of DLL3 expression in SCLC. Further research and analytical methods may help to characterize different populations of patients with SCLC based on DLL3 expression. While no significant prognostic factor in the included studies was identified, additional cohort studies using standardized methodology, with longer follow-up, are needed to better characterize any potential differences in patient survival or response by DLL3 expression level in SCLC.

Diversity and Representation Among United States Participants in Amgen Clinical Trials.

OBJECTIVE: Describe the demographic profile of US participants in Amgen clinical trials over a 10-year period and variations across therapeutic areas, indications, and geographies. METHODS: Cross-sectional retrospective study including participants enrolled (2005-2020) in phase 1-3 trials completed between January 1, 2012 and June 30, 2021. RESULTS: Among 31,619 participants enrolled across 258 trials, one-fifth represented racial minority populations (Asian, 3%; Black or African American, 17%; American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, multiracial, each < 1%); fewer than one-fifth (16%) represented an ethnic minority population (Hispanic or Latino). Compared with census data, representation of racial and ethnic groups varied across US states. Across most therapeutic areas (bone, cardiovascular, hematology/oncology, inflammation, metabolic disorders, neuroscience) except nephrology, participants were predominantly White (72-81%). A similar proportion of males and females were enrolled between 2005 and 2016; male representation was disproportionately higher than female between 2016 and 2020. Across most medical indications, the majority of participants were 18-65 years of age. CONCLUSIONS AND RELEVANCE: While the clinical research community is striving to achieve diversity and proportional representation across clinical trials, certain populations remain underrepresented. Our data provide a baseline assessment of the diversity and representation of US participants in Amgen-sponsored clinical trials and add to a growing body of evidence on the importance of diversity in clinical research. These data provide a foundation for strategies aimed at supporting more equitable and representative research, and a baseline from which to assess the impact of future strategies to advance health equity.

Controlling for Differential Regression-To-The-Mean via Propensity Scores: A Simulation Study.

Purpose: Regression-to-the-mean (RTM) is a statistical phenomenon that may occur in epidemiologic studies where inclusion in the study cohort is contingent upon experiencing a laboratory/clinical measurement beyond a defined threshold. When differential across treatment groups, RTM could bias the final study estimate. This poses substantial challenges in observational studies that index patients upon experiencing extreme laboratory or clinical values. Our objective was to investigate propensity score-based methods as a tool for mitigating this source of bias via simulation. Methods: We simulated a noninterventional comparative effectiveness study, comparing treatment with romiplostim to standard-of-care therapies for immune thrombocytopenia (ITP), a disease characterized by low platelet counts. Platelet counts were generated from normal distributions according to the underlying ITP severity, a strong confounder of treatment and outcome. Patients were assigned treatment probabilities based upon ITP severity, which created varied levels of differential and non-differential RTM. Treatments were compared via the difference in median platelet counts during 23 weeks of follow-up. We calculated four summary metrics of the platelet counts measured prior to cohort entry and built six propensity score models to adjust for those variables. We adjusted for these summary metrics using inverse probability of treatment weights. Results: Across all simulated scenarios, propensity score adjustment reduced bias and increased precision of the treatment effect estimator. Adjusting for combinations of the summary metrics was most effective at reducing bias. Adjusting for the mean of prior platelet counts or the difference between the cohort-qualifying platelet count and the largest prior count eliminated the most bias when assessed individually. Conclusion: These results suggest that differential RTM could be reasonably addressed by propensity score models with summaries of historical laboratory values. This approach can be easily applied to any comparative effectiveness or safety study, though investigators should carefully consider the best summary metric for their data.

Comparability of Osteoporosis Treatment Groups Among Female Medicare Beneficiaries in the United States.

It is often difficult to obtain valid estimates of comparative treatment effectiveness and safety owing to differences across patient populations taking different medications in the real world. One approach for assessing comparability between treatment groups in effectiveness studies is to use negative control outcomes (NCOs). NCOs share similar sources of bias with the primary outcomes but have no plausible causal relationship to the treatment of interest. Observing differences in the risk of NCOs thus provides evidence for residual confounding between groups. This retrospective study assessed the comparability of postmenopausal women, treated with osteoporosis medications with various mechanisms of action such as denosumab (receptor activator of nuclear factor κB ligand [RANKL] inhibitor), zoledronic acid (bisphosphonate derivative), or oral bisphosphonates including alendronate. Administrative claims data were extracted from the US Centers for Medicare and Medicaid Services' Chronic Condition Warehouse database (May 2010-December 2016). Propensity scores were used to match denosumab patients 1:1 to comparators. Four nonfracture NCOs and three early fracture NCOs (before substantial biologic effects of treatment would be expected) were assessed over 1-year and 3-month follow-up periods, respectively. According to comparability decision rules established a priori, patients initiating denosumab were comparable to those initiating zoledronic acid or alendronate, irrespective of prior osteoporosis treatment experience. Among new users, new switchers, and in the historical fracture subgroup, no meaningful differences were observed in the cumulative incidence of the seven NCOs comparing denosumab to zoledronic acid. This empirical examination can assist in the selection of appropriate comparator groups for future comparability research using real-world data. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Association Between Granulocyte Colony-Stimulating Factor (G-CSF) Use and Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) Among Elderly Patients with Breast, Lung, or Prostate Cancer.

INTRODUCTION: Patients diagnosed with cancer have an increased risk both for myelodysplastic syndromes (MDS) and for acute myeloid leukemia (AML) following treatment. METHODS: Using SEER-Medicare data, we selected patients aged 66 years and older who completed systemic therapy between 2002 and 2014 for breast (stage I-III), lung (stage I-III), or prostate (stage I-IV) cancer. For each cancer, we estimated the risk of a composite endpoint of MDS or AML in patients receiving granulocyte colony-stimulating factor (G-CSF) vs. not. RESULTS: The 10-year cumulative risk difference (granulocyte colony-stimulating factor [G-CSF] - no G-CSF) for MDS-AML was 0.45% (95% CI 0.13-0.77%) in breast cancer and 0.39% (95% CI 0.15-0.62%) in lung cancer. G-CSF use was associated with a hazard ratio of 1.60 (95% CI 1.07-2.40) in breast cancer and 1.50 (95% CI 0.99-2.29) in lung cancer. Filgrastim use was associated with a hazard ratio of 1.01 (95% CI 1.00-1.03) per administration in breast cancer and 1.02 (95% CI 0.99-1.05) per administration in lung cancer. Pegfilgrastim was associated with a hazard ratio of 1.08 (95% CI 1.01-1.15) per administration in breast cancer and 1.12 (95% CI 1.00-1.25) per administration in lung cancer. Analyses in prostate cancer were limited because of the low number of events. CONCLUSIONS: The use of G-CSF in patients diagnosed with breast and lung cancer is associated with an increased risk of MDS-AML. However, the MDS-AML absolute risk difference is very low.

The Design and Validation of a New Algorithm to Identify Incident Fractures in Administrative Claims Data.

Our study validated a claims-based algorithm for the identification of incident and recurrent fractures in administrative data. We used Centers for Medicare and Medicaid (CMS) claims from 2005 to 2014 linked to the Reasons for Geographic and Racial Differences in Stroke (REGARDS) database. Case qualifying (CQ) fractures were identified among participants with ≥12 months of fee-for-service coverage before first fracture claim and ≥6 months after. Recurrent fractures were defined as the first CQ fracture that occurred following a clean period of at least 90 days from the last claim associated with the preceding incident fracture. We used medical records (discharge summary, imaging, and surgical report) to adjudicate fractures. We calculated positive predictive values (PPVs) for incident and recurrent fractures. Our study was not designed to assess the algorithm sensitivity or negative predictive value. We identified 2049 potential incident fractures from claims among 1650 participants. Record retrieval was attempted for 728 (35.5%) suspected incident fractures (prioritizing more recent CQ fractures associated with osteoporosis, but without explicitly requiring any osteoporosis ICD-9 diagnosis code). Our final sample included 520 claims-identified fractures with medical records, of which 502 (96.5%) were confirmed. The PPVs (95% CI) of the hip, wrist, humerus, and clinical vertebra-all exceeded 95%. We identified 117 beneficiaries with 292 ≥2 CQ fracture episodes at the same site, and attempted retrieval on 105 (36.0%) episodes. Our analytic sample included 72 (68.5%) CQ episodes from 33 participants. The PPVs for identifying recurrent clinical vertebral, hip/femur, and nonvertebral fractures with a 90-day clean period exceeded 95%. Although we could not ascertain sensitivity, our updated fracture identification algorithms had high PPV for the identification of incident and recurrent fractures of the same site. Although medical record review and clinical adjudication remain a gold standard, our claims-based algorithm provides an alternative approach to fracture ascertainment when high PPV is desired. © 2019 American Society for Bone and Mineral Research.

ERR1 and PGC1α associated mitochondrial alterations correlate with pan-cancer disparity in African Americans.

BACKGROUND: African American (AA) patients have higher cancer mortality rates and shorter survival times compared to European American (EA) patients. Despite a significant focus on socioeconomic factors, recent findings strongly argue the existence of biological factors driving this disparity. Most of these factors have been described in a cancer-type specific context rather than a pan-cancer setting. METHODS: A novel in silico approach based on Gene Set Enrichment Analysis (GSEA) coupled to Transcription Factor enrichment was carried out to identify common biological drivers of pan-cancer racial disparity using The Cancer Genome Atlas (TCGA) dataset. Mitochondrial content in patient tissues was examined using a multi-cancer tissue microarray approach (TMA). RESULTS: Mitochondrial oxidative phosphorylation was uniquely enriched in AA tumors compared to EA tumors across various cancer types. AA tumors also showed strong enrichment for the ERR1-PGC1α-mediated transcriptional program, which has been implicated in mitochondrial biogenesis. TMA analysis revealed that AA cancers harbor significantly more mitochondria compared to their EA counterparts. CONCLUSIONS: These findings highlight changes in mitochondria as a common distinguishing feature between AA and EA tumors in a pan-cancer setting, and provide the rationale for the repurposing of mitochondrial inhibitors to treat AA cancers.

Glucocorticoid Exposure and Fracture Risk in a Cohort of US Patients With Selected Conditions.

The purpose of this work was to evaluate systemic glucocorticoid exposure and fracture among patients with newly-diagnosed inflammatory and immune-modulated conditions. Using administrative data, inception cohorts of rheumatoid arthritis (RA), asthma/chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), multiple sclerosis (MS), lupus, and sarcoidosis patients age 18 to 64 years with benefits coverage ≥12 months before diagnosis (January 1, 2005 to December 31, 2012) were followed to clinical fracture, cancer diagnosis, or December 31, 2012. Glucocorticoid users were new to therapy. Fracture incidence rates (IRs) per 1000 person-years were stratified by prednisone equivalent doses. Cox's proportional hazards models assessed risk by daily and cumulative dose, and by time since discontinuation, adjusted for baseline characteristics. Most patients (72% of 403,337) had glucocorticoid exposure; 52% were under age 50. IR (95% confidence interval [CI]) of any osteoporotic fracture was elevated at doses <5 mg/day (IR 9.33; 95% CI, 7.29 to 11.77) versus 0 mg/day (IR 4.87 (95% CI, 4.72 to 5.02). Fracture rates were elevated at doses <5 mg/day in patients <50 years and those ≥50 years. In both age groups, fracture risk increased with increasing cumulative exposure, being approximately 2.5-fold higher at cumulative dose ≥5400 mg compared to <675 mg. At ≥5400 mg, IR values were 5.69 (95% CI, 4.32 to 7.35) in patients <50 years and 17.10 (95% CI, 14.97 to 19.46) in older patients. Fracture risk decreased significantly within months following glucocorticoid discontinuation. In patients with a variety of inflammatory conditions, fracture risk increased at doses as low as <5 mg/day. Risk increased with increasing cumulative exposure and decreased soon following glucocorticoid discontinuation. Trends were similar between patients older and younger than 50 years. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Curcumin induces apoptosis and cell cycle arrest via the activation of reactive oxygen species-independent mitochondrial apoptotic pathway in Smad4 and p53 mutated colon adenocarcinoma HT29 cells.

Curcumin is a natural dietary polyphenol compound that has various pharmacological activities such as antiproliferative and cancer-preventive activities on tumor cells. Indeed, the role reactive oxygen species (ROS) generated by curcumin on cell death and cell proliferation inhibition in colon cancer is poorly understood. In the present study, we hypothesized that curcumin-induced ROS may promote apoptosis and cell cycle arrest in colon cancer. To test this hypothesis, the apoptosis-inducing potential and cell cycle inhibition effect of ROS induced by curcumin was investigated in Smd4 and p53 mutated HT-29 colon adenocarcinoma cells. We found that curcumin treatment significantly increased the level of ROS in HT-29 cells in a dose- and time-dependent manner. Furthermore, curcumin treatment markedly decreased the cell viability and proliferation potential of HT-29 cells in a dose- and time-dependent manner. Conversely, generation of ROS and inhibitory effect of curcumin on HT-29 cells were abrogated by N-acetylcysteine treatment. In addition, curcumin treatment did not show any cytotoxic effects on HT-29 cells. Furthermore, curcumin-induced ROS generation caused the DNA fragmentation, chromatin condensation, and cell nuclear shrinkage and significantly increased apoptotic cells in a dose- and time-dependent manner in HT-29 cells. However, pretreatment of N-acetylcysteine inhibited the apoptosis-triggering effect of curcumin-induced ROS in HT-29 cells. In addition, curcumin-induced ROS effectively mediated cell cycle inhibition in HT-29 cells. In conclusion, our data provide the first evidence that curcumin induces ROS independent apoptosis and cell cycle arrest in colon cancer cells that carry mutation on Smad4 and p53.

Real-world effectiveness of osteoporosis therapies for fracture reduction in post-menopausal women.

Studies examining real-world effectiveness of osteoporosis therapies are beset by limitations due to confounding by indication. By evaluating longitudinal changes in fracture incidence, we demonstrated that osteoporosis therapies are effective in reducing fracture risk in real-world practice settings. INTRODUCTION: Osteoporosis therapies have been shown to reduce incidence of vertebral and non-vertebral fractures in placebo-controlled randomized clinical trials. However, information on the real-world effectiveness of these therapies is limited. METHODS: We examined fracture risk reduction in older, post-menopausal women treated with osteoporosis therapies. Using Medicare claims, we identified 1,278,296 women age ≥ 65 years treated with zoledronic acid, oral bisphosphonates, denosumab, teriparatide, or raloxifene. Fracture incidence rates before and after treatment initiation were described to understand patients' fracture risk profile, and fracture reduction effectiveness of each therapy was evaluated as a longitudinal change in incidence rates. RESULTS: Fracture incidence rates increased during the period leading up to treatment initiation and were highest in the 3-month period most proximal to treatment initiation. Fracture incidence rates following treatment initiation were significantly lower than before treatment initiation. Compared with the 12-month pre-index period, there were reductions in clinical vertebral fractures for denosumab (45%; 95% confidence interval [CI] 39-51%), zoledronic acid (50%; 95% CI 47-52%), oral bisphosphonates (24%; 95% CI 22-26%), and teriparatide (72%; 95% CI 69-75%) during the subsequent 12 months. Relative to the first 3 months after initiation, clinical vertebral fractures were reduced for denosumab (51%; 95% CI 42-59%), zoledronic acid (25%; 95% CI 17-32%), oral bisphosphonates (23%; 95% CI 20-26%), and teriparatide (64%; 95% CI 58-69%) during the subsequent 12 months. CONCLUSION: In summary, reductions in fracture incidence over time were observed in cohorts of patients treated with osteoporosis therapies.

Occurrence of Serious Infection in Patients with Rheumatoid Arthritis Treated with Biologics and Denosumab Observed in a Clinical Setting.

OBJECTIVE: Previous studies combining biologic disease-modifying antirheumatic drugs (bDMARD) to treat rheumatoid arthritis (RA) have shown an increased risk of infection. However, the risk of infection with concurrent use of denosumab, a biologic agent for the treatment of osteoporosis, and a bDMARD remains unclear. Here, we evaluated the incidence of serious and opportunistic infections in patients treated concurrently with denosumab and a bDMARD and patients treated with a bDMARD alone. METHODS: A chart review of patients with RA from 2 Canadian rheumatology practices between July 1, 2010, and July 31, 2014, identified 2 groups of patients: those taking denosumab and a bDMARD concurrently (concurrent group) and those taking only a bDMARD (biologic-alone group). Patients were followed from the time of initiation of denosumab, or a matched index date for the biologic-alone group, to the end of the study or loss to followup. Instances of serious or opportunistic infections were recorded. RESULTS: A total of 308 patients (n = 102 for the concurrent group and n = 206 for the biologic-alone group) were evaluated. Within the concurrent group, 3 serious infection events occurred. Within the biologic-alone group, 4 serious infection events and 1 opportunistic infection event occurred. In both groups, all patients with serious or opportunistic infection recovered, and there were no instances of death during the study period. CONCLUSION: This study demonstrated a low occurrence of serious and opportunistic infections in patients with RA taking bDMARD, including patients with concurrent denosumab use.

A Survey of Women's Awareness of and Reasons for Lack of Postfracture Osteoporotic Care.

OBJECTIVES: To identify women's beliefs and other factors associated with lack of osteoporosis (OP) pharmacotherapy (OP-RX) during the 6 months after a fragility fracture, including the woman's perspective on fracture risk, OP, and treatment. DESIGN: Cross-sectional. SETTING: Group Health Cooperative, a mixed-model delivery system. PARTICIPANTS: Female Group Health Cooperative enrollees aged 55 and older with an OP-related fracture according to diagnostic and procedure codes from January 1, 2013, to March 30, 2014 (N = 985). MEASUREMENTS: OP-RX and participant characteristics were ascertained from electronic health records including medications dispensed. A mailed survey was used to obtain data on health behaviors; OP-related history; concern about, knowledge of, and perceived risk of future fracture; beliefs about OP-RX; sources of information on OP; postfracture discussions with providers; and provider recommendations. RESULTS: The response rate was 73%. Of 634 eligible respondents, 84% did not undergo OP-RX during the 6 months after fracture. Fewer than 20% of women thought that OP caused their fracture, 52% did not think they were at risk of future fracture, and 75% did not think or know whether OP-RX reduces risk of fracture. Knowledge about OP and the benefits of treatment was higher in the 16% of women who underwent OP-RX after their fracture. Women reported low levels of engagement with their healthcare providers regarding OP and fracture risk management. CONCLUSION: These findings suggest low awareness about OP and its contribution to fracture risk, lack of understanding about the benefits of pharmacotherapy, and limited discussion about OP with primary care physicians. Information about individual's beliefs and knowledge gaps can help design targeted patient and provider education to improve treatment rates.

Declining rates of osteoporosis management following fragility fractures in the U.S., 2000 through 2009.

BACKGROUND: Clinical practice recommendations state that patients with fragility fractures should be evaluated for osteoporosis and treated for the disease if it is present. The purpose of this study was to assess osteoporosis evaluation and treatment patterns for patients with fragility fractures and assess whether anti-osteoporosis pharmacotherapy initiated immediately following a fragility fracture is associated with improved adherence to the treatment protocol. METHODS: This retrospective cohort study involved data from a large commercially insured population seen in the period from 2001 through 2009. Patients were community-dwelling individuals aged fifty years or older who had a new low-energy fracture at the hip, vertebra, wrist, or humerus with no evidence of a fragility fracture, osteoporosis treatment, malignant disease, or Paget disease for twelve months preceding the fracture. Rates of diagnostic testing and pharmacotherapy for osteoporosis within twelve months post-fracture were evaluated. Patients treated with oral bisphosphonates were evaluated to determine whether twelve-month adherence to the treatment protocol differed between those who had initiated therapy sooner (at zero to ninety days) and those who initiated it later (at ninety-one to 365 days) following the fracture. RESULTS: The 88,571 women and 41,984 men had an average age of 72.3 years and 70.5 years, respectively. Nineteen percent (16,464) of the women and 10% (4014) of the men initiated osteoporosis pharmacotherapy, and 30% (26,481) of the women and 15% (6427) of the men underwent diagnostic testing and/or pharmacotherapy following fracture. Treatment rates were highest following vertebral fracture and lowest following wrist or humeral fracture. Treatment rates significantly decreased over time (from 2001 through 2009). The average twelve-month adherence (medication possession ratio) was 56% and 61% among women and men, respectively. Adherence was similar between patients who had initiated treatment sooner after the fracture and those who had initiated it later after the fracture. CONCLUSIONS: Clinical guidelines for evaluation and treatment following fragility fracture were met for less than one-third of women and less than one-sixth of men. While primary fracture prevention remains the ideal, secondary prevention is critical and there is a need to reverse the downward trend in adherence to post-fracture guidelines.

Discontinuation and reinitiation patterns of osteoporosis treatment among commercially insured postmenopausal women.

OBJECTIVE: Poor adherence to chronic medications is common and compromises medication effectiveness. We sought to describe longitudinal patterns of osteoporosis medication use. STUDY DESIGN: This was a retrospective observational cohort study using 2005-2009 data from a large, commercially insured population. METHODS: Patients were women aged ≥55 years initiating osteoporosis therapy who had a ≥12-month (baseline) period with no osteoporosis therapy claims preceding initiation, and ≥24 months follow-up after therapy initiation. Discontinuation was defined as a gap >60 days (varied in sensitivity analyses) in prescription claims. Reinitiation was defined as a prescription claim for the same or different osteoporosis therapy following the therapy gap. Discontinuation and reinitiation patterns were described using Kaplan-Meier analysis. Multivariable Cox regression assessed the impact of baseline factors on reinitiation. RESULTS: Of the 92,839 patients, 45%, 58%, and 70% discontinued therapy at 6, 12, and 24 months, respectively, following initiation. Of the discontinuers, 46% reinitiated therapy, with the majority doing so within 6 months of discontinuation. Women were less likely to reinitiate therapy if they were older (P < 0.0001) or were hospitalized during baseline (P = 0.0007). Women who discontinued treatment early (<6 months) following initiation were less likely to reinitiate (P < 0.0001) and remained on therapy for shorter periods following reinitiation. Depending on the available observation time, the median time on therapy following reinitiation was 58-193 days. Study findings did not change appreciably in sensitivity analyses. CONCLUSION: Many patients stop and restart treatment for osteoporosis. A better understanding of determinants of treatment stopping and restarting could inform adherence improvement efforts.

Completeness of prescription information in US commercial claims databases.

PURPOSE: Pharmacy commercial claims databases are widely used for pharmacoepidemiologic research. However, concerns have been raised that these databases may not fully capture claims for generic medications as a result of patients filling outside the context of their insurance. This has implications for many research activities and quality improvement programs. We sought to estimate the percentage of missing prescriptions in US commercial claims data using a novel design. METHODS: Using a large US commercial insurance database, we examined the completeness of warfarin prescription claims among patients with atrial fibrillation receiving regular medical follow-up and testing to manage warfarin dosing. We examined 14 different 6-month cross sections. Each cross section was treated independently to identify patients with at least two outpatient diagnoses of atrial fibrillation, two international normalized ratio tests, and one pharmacy claim. Trends in the percentage of patients with prescription claims for generic and branded warfarin were compared by year and 6-month periods using chi-square tests and generalized linear models adjusting for patient characteristics. RESULTS: Out of 111 170 patients, the percentage of patients with any warfarin drug decreased slightly from 91.7% (95% CI: 91.0, 92.4) in early 2003 to 87.1% (95% CI: 86.7-87.6) in late 2009 (χ(2) = 93.8, p < 0.0001). Over the same interval, the proportion of patients with generic warfarin exposure appearing increased significantly, whereas the proportion of patients with branded warfarin exposure decreased significantly. CONCLUSIONS: Our study supports the possibility that some prescriptions may not be captured in US commercial insurance databases.

Osteoporosis medication adherence: physician perceptions vs. patients' utilization.

Few data are available on physician perceptions of osteoporosis medication adherence. This study compared physician-estimated medication adherence with adherence calculated from their patients' pharmacy claims. Women aged ≥45 years, with an osteoporosis-related pharmacy claim between January 1, 2005 and August 31, 2008, and continuous coverage for ≥12 months before and after first (index) claim, were identified from a commercial health plan population. Prescribing physicians treating ≥5 of these patients were invited to complete a survey on their perception of medication adherence and factors affecting adherence in their patients. Pharmacy claims-based medication possession ratio (MPR) was calculated for the 12-month post-index period for each patient. Physicians who overestimated the percentage of adherent (MPR ≥0.8) patients by ≥10 points were considered "optimistic". Logistic regression assessed physician characteristics associated with optimistic perception of adherence. A total of 376 (17.2%) physicians responded to the survey; 62.0% were male, 58.2% were aged 45 to 60 years, 55.3% had ≥20 years of practice, and 35.4% practiced in an academic setting. Participating physicians prescribed osteoporosis medications for 2748 patients with claims data (mean [SD] age of 62.0 [10.6] years). On average, physicians estimated 67.2% of their patients to be adherent; however, only 40% of patients were actually adherent based on pharmacy data. Optimistic physicians (73.4%) estimated 71.9% of patients to be adherent while only 32.2% of their patients were adherent based on claims data. Physicians in academic settings were more likely to be optimistic than community-based physicians (odds ratio 1.69, 95% CI: 1.01, 2.85). Overestimation of medication adherence may impede physicians' ability to provide high quality care for their osteoporosis patients.

Direct healthcare costs of osteoporosis-related fractures in managed care patients receiving pharmacological osteoporosis therapy.

BACKGROUND: Osteoporosis is a common condition and the economic burden of osteoporosis-related fractures is significant. While studies have reported the incremental or attributable costs of osteoporosis-related fracture, data on the economic impact of osteoporosis-related fractures in commercial health plan populations are limited. OBJECTIVE: To estimate the direct costs of osteoporosis-related fractures among pharmacologically treated patients in a large, commercially insured population between 2005 and 2008. METHODS: In this retrospective cohort study, patients were identified from a large, commercially insured population with integrated pharmacy and medical claims. Inclusion criteria were age 45-64 years; one or more osteoporosis medication claim(s) with first (index) claim between 1 January 2005 and 30 April 2008; and continuous insurance coverage for ≥12 months pre-index and ≥6 months post-index. Patients with pre-index Paget's disease or malignant neoplasm; skilled nursing facility stay; combination therapy at index; or fracture ≤6 months post-index were excluded. A generalized linear model compared differences in 6-month pre-/post-event costs for patients with and without fracture. Propensity score weighting was used to ensure comparability of fracture and non-fracture patients. Generalized estimating equations accounted for repeated measures. RESULTS: The study included 49,680 patients (2613 with fracture) with a mean (SD) age of 56.4 (4.7) years; 95.9% were female. Mean differences between pre- and post-event direct costs were $US14,049 (95% CI 7670, 20,428) for patients with vertebral fractures, $US16,663 (95% CI 11,690, 21,636) for patients with hip fractures, and $US7582 (95% CI 6532, 8632) for patients with other fractures. After adjusting for covariates, osteoporosis-related fractures were associated with an additional $US9996 (95% CI 8838, 11,154; p < 0.0001) in direct costs per patient across all fracture types during the 6 months following fracture. CONCLUSION: Patients with osteoporosis-related fractures were found to incur nearly $US10,000 in estimated additional direct healthcare costs in the 6 months post-fracture, compared with patients with no fracture. Reduced fracture risk may lower associated direct healthcare costs.

Medication adherence and fracture risk among patients on bisphosphonate therapy in a large United States health plan.

The association between bisphosphonate adherence in the first 12 months after therapy initiation and subsequent fracture risk was examined. Patients were identified from a large, commercially-insured population with integrated pharmacy and medical claims. Eligible patients were aged ≥45 years, were new to osteoporosis therapy (no osteoporosis medication claims in prior year) with first (index) bisphosphonate claim between 1/1/2005 and 4/30/2008, and had continuous insurance coverage for ≥12 months pre- and post-index. Patients with fracture claims ≤12-months post-index were excluded. Adherence was assessed using the medication possession ratio (MPR) over 12-months post-index (i.e., sum of days' supply dispensed divided by 365 days). Patients with a MPR>0.8 were considered adherent. The follow-up period to assess incident fracture began at month 13. The analysis included 33,558 new bisphosphonate users with mean age (SD) 59.5 (9.3) years; 94.0% were female. Median MPR at 12 months was 0.61 for alendronate and risedronate; 0.58 for ibandronate. Proportionally more nonfracture patients (39.3%) had a MPR>0.8 compared with fracture patients (34.9%, p<0.001). In multivariate modeling of bisphosphonate users' experience, those with a MPR>0.8 had a 14% lower risk of subsequent fracture than those with MPR<0.5, after controlling for demographics, insurance type, select comorbidities, and other potential confounders (p=0.0459). In a large, commercially-insured population, suboptimal adherence with bisphosphonate treatment was associated with increased fracture risk even after controlling for potential confounders.