Risk of venous thromboembolism among women receiving ospemifene: a comparative observational study.

Introduction: The primary aim of this study was to compare the incidence of venous thromboembolism (VTE) among women initiating ospemifene vs other selective estrogen receptor modulator (SERM) therapies for estrogen-deficiency conditions or breast cancer prevention, and vs women with untreated vulvar and vaginal atrophy (VVA). The secondary objective examined numerous additional safety outcomes. Methods: This was a retrospective cohort study using the IBM Watson MarketScan claims database. Women receiving ospemifene, another SERM, or with a new diagnosis of VVA with no treatment from 1 May 2013 to 2 October 2018 were followed through the claims for incident adverse outcomes. The primary outcome was the first occurrence of VTE following cohort entry; secondary outcomes included cerebrovascular events and other adverse events potentially associated with SERM use. Cox models compared the risk of VTE between ospemifene and comparators, using a variety of approaches to control for confounding. Results: The incidence of VTE during the first continuous treatment episode was 3.39 (95% confidence interval [CI]: 1.55-6.43) events per 1,000 person-years (PY) for ospemifene (N = 8977), 11.30 (95% CI: 8.81-14.28) events per 1,000 PY for comparator SERM (N = 12,621), and 10.92 (95% CI: 10.49-11.37) events per 1,000 PY for untreated VVA (N = 242,488). Cox models indicated no increase in risk of VTE for ospemifene vs other SERMs (hazard ratio [HR]: 0.40, 95% CI: 0.19-0.82), and vs untreated VVA (HR: 0.47, 95% CI: 0.24-0.91). Conclusion: This real-world safety analysis found no increase in risk of VTE or other adverse events with use of ospemifene in postmenopausal women. Plain Language Summary: Introduction: This study assessed the risk of venous thromboembolism (VTE) among women treated with ospemifene or another selective estrogen receptor modulator (SERM) therapy and women with untreated vulvar and vaginal atrophy (VVA). Numerous additional safety outcomes were examined.Methods: This study was conducted in the IBM Watson MarketScan claims database. Women receiving ospemifene, another SERM, or with a new diagnosis of VVA with no treatment from 1 May 2013 to 2 October 2018 were followed through the claims for adverse outcomes, including VTE, cerebrovascular events (such as stroke), and other outcomes that might occur with use of a SERM. The analyses compared the risk of VTE between ospemifene and the other two groups, using methods that accounted for differences in patient characteristics between the groups. Because few women over 72 years old used ospemifene, the main analyses examined women aged 54-72 years.Results: The analyses included 8,977 ospemifene users, 12,621 other SERM users, and 242,488 women with untreated VVA. Among women aged 54-72 years, only 9 experienced a VTE during ospemifene treatment, while 55 other SERM users and 1,788 women with untreated VVA had a VTE. The analyses that accounted for differences between the groups confirmed that the risk of VTE was no higher in ospemifene users than in either comparison group.Conclusion: This real-world safety analysis found no increase in risk of VTE or other adverse events with use of ospemifene in postmenopausal women.

Individualized HbA1c target selection and achievement in the Multinational Observational Study Assessing Insulin Use (MOSA1c) type 2 diabetes study.

AIM: To identify which individual-, physician-, and the healthcare system-related factors can predict individualized hemoglobin A1c (HbA1c) targets and the likelihood of reaching those targets after initial insulin therapy over a two-year follow-up period. METHODS: Real-world data, including baseline characteristics of people with type 2 diabetes mellitus (T2DM), psychosocial data, and diabetes medication use, collected from the Multinational Observational Study Assessing Insulin Use (MOSA1c) study in 18 countries were analyzed. RESULTS: Overall, 225 of 1194 people with T2DM (18.8%) who received initial insulin therapy for ≥3 months reached HbA1c targets at two-year follow-up; most were likely to be White (64.9%) and perceptions of their relationship with physicians were less positive than those who did not reach HbA1c targets. Higher baseline HbA1c (>8%) was the strongest predictor of being assigned an HbA1c target >7% (odds ratio [OR] 6.06, 95% confidence interval [CI] 3.97, 9.26). A smaller difference between baseline and target HbA1c levels was the strongest predictor of reaching an HbA1c target at two-year follow-up (large vs small difference, OR 0.28, 95% CI 0.17, 0.47). CONCLUSIONS: Several factors were significantly associated with establishing individualized HbA1c targets and reaching these targets. A small proportion of people with T2DM on insulin therapy reached their HbA1c target. Personalized management of glycemic targets necessitates the adoption of multi-factorial strategies, as several factors could influence an individual's glycemic outcome. CLINICALTRIALS. GOV IDENTIFIER: NCT01400971.

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world.

BACKGROUND: Mutations in STK11 (STK11m) and frequently co-occurring KRAS mutations (KRASm/STK11m) are associated with poor survival in metastatic NSCLC (mNSCLC) immuno-oncology trials. There are limited data regarding the prognostic significance of these mutations in a real-world setting. METHODS: This retrospective cohort study analyzed de-identified electronic medical records from the Flatiron Clinico-Genomic database to identify patients with mNSCLC who had initiated first-line immunotherapy (IO; alone or in combination) or chemotherapy under routine care between January 1, 2013 and June 30, 2017. The primary objectives were to assess the prevalence of STK11m and KRASm/STK11m and to determine associations of these mutations with overall and progression-free survival (OS, PFS). RESULTS: Of 2407 patients with mNSCLC, STK11m and KRASm/STK11m were present in 13.6% and 6.5% of patients, respectively. Worse OS outcomes were observed in patients with STK11m versus STK11wt mNSCLC receiving IO (first-line, HR [95% CI], 1.4 [0.9-2.3; p = 0.1]; second-line [subset of first-line cohort], HR, 1.6 [1.3-2.0; p = 0.0002]) or chemotherapy (first-line, HR, 1.4 [1.2-1.6; p < 0.0001]); PFS outcomes showed similar trends. KRASm/STK11m double mutations were associated with worse OS and PFS outcomes versus KRASwt/STK11wt with IO and chemotherapy, similar to the single mutation (STK11m vs STK11wt) findings. CONCLUSIONS: This large observational genomic study among patients receiving routine care highlights the negative prognostic impact of STK11m in patients with mNSCLC treated with IO or chemotherapy. These results complement previous clinical trial data and provide further evidence in the real world of a patient population that would benefit from new treatment options.

Incidence of venous thromboembolism among postmenopausal women prescribed ospemifene, selective estrogen receptor modulators for noncancer indications, or untreated vulvar and vaginal atrophy.

OBJECTIVE: Ospemifene is a nonsteroidal selective estrogen receptor modulator (SERM) for the treatment of moderate symptomatic vulvar and vaginal atrophy (VVA) due to menopause. A postauthorization safety study is currently examining the incidence of venous thromboembolism (VTE) among postmenopausal women receiving ospemifene or other SERM (raloxifene, bazedoxifene, or tamoxifen, for noncancer indications), or with untreated VVA. METHODS: This interim analysis used the US MarketScan Commercial and Medicare Supplemental claims database from 2013 to 2017 to identify incident VTE. The incidence rate and 95% confidence interval of VTE during the first continuous course of treatment (or continuous untreated time for the untreated cohort) were calculated for each cohort overall and by age group, with sensitivity analyses examining incidence in the short term (up to 90 days) and long term (all available follow-up, regardless of treatment changes). RESULTS: Analyses included 8,188 ospemifene users, 11,777 other SERM users, and 220,242 women with untreated VVA. The incidence per 1,000 person-years and 95% confidence interval of VTE were 3.7 (1.7-7.1) for ospemifene, 11.5 (8.9-14.6) for other SERM, and 11.3 (10.8-11.7) for untreated VVA. Stratification by age and altering the time frame for analysis produced results with similar patterns to the primary analysis. CONCLUSIONS: This interim analysis of an ongoing study suggests a favorable safety profile for ospemifene with respect to VTE. Comparative analyses with covariate adjustment will be performed when data accrual is complete.

Prescriber Compliance With Liver Monitoring Guidelines for Pazopanib in the Postapproval Setting: Results From a Distributed Research Network.

OBJECTIVES: Pazopanib received US Food and Drug Administration approval in 2009 for advanced renal cell carcinoma. During clinical development, liver chemistry abnormalities and adverse hepatic events were observed, leading to a boxed warning for hepatotoxicity and detailed label prescriber guidelines for liver monitoring. As part of postapproval regulatory commitments, a cohort study was conducted to assess prescriber compliance with liver monitoring guidelines. METHODS: Over a 4-year period, a distributed network approach was used across 3 databases: US Veterans Affairs Healthcare System, a US outpatient oncology community practice database, and the Dutch PHARMO Database Network. Measures of prescriber compliance were designed using the original pazopanib label guidelines for liver monitoring. RESULTS: Results from the VA (n = 288) and oncology databases (n = 283) indicate that prescriber liver chemistry monitoring was less than 100%: 73% to 74% compliance with baseline testing and 37% to 39% compliance with testing every 4 weeks. Compliance was highest near drug initiation and decreased over time. Among patients who should have had weekly testing, the compliance was 56% in both databases. The more serious elevations examined, including combinations of liver enzyme elevations meeting the laboratory definition of Hy's law were infrequent but always led to appropriate discontinuation of pazopanib. Only 4 patients were identified for analysis in the Dutch database; none had recorded baseline testing. CONCLUSIONS: In this population-based study, prescriber compliance was reasonable near pazopanib initiation but low during subsequent weeks of treatment. This study provides information from real-world community practice settings and offers feedback to regulators on the effectiveness of label monitoring guidelines.

Occurrence of hepatotoxicity with pazopanib and other anti-VEGF treatments for renal cell carcinoma: an observational study utilizing a distributed database network.

PURPOSE: To quantify the hepatic safety of pazopanib and comparator anti-vascular endothelial growth factor (VEGF) therapies in clinical practice among renal cell carcinoma (RCC) patients. METHODS: A population-based cohort study of new anti-VEGF users was conducted in two US healthcare databases, Department of Veterans Affairs (VA) and an oncology practice network (Altos), and the PHARMO Database Network in The Netherlands. A common protocol was used to collect liver chemistry (LC) data from anti-VEGF initiation through 4 years of follow-up. In the VA population, suspected drug-induced liver injury (DILI) outcomes were investigated via chart review, with adjudication by hepatologists. RESULTS: In Altos and VA, respectively, the total RCC patients were: pazopanib (156, 243), bevacizumab (122, 99), sorafenib (82, 249) and sunitinib (285, 751). PHARMO contained too few patients to be included. Few cases of alanine aminotransferase (ALT) ≥8× the upper limit of normal were seen across the anti-VEGF cohorts; incidence rates (per 100 person-years) ranged from 0 (sunitinib) to 8.2 (pazopanib) in Altos and from 0 (bevacizumab and sorafenib) to 2.1 (pazopanib) among VA patients. No cases of Hy's law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; one case was observed in those treated with sorafenib, and two cases were found among sunitinib users. One case of adjudicated DILI was observed in a sunitinib-treated patient; none were found among patients treated with pazopanib, bevacizumab or sorafenib. CONCLUSIONS: Severe liver injury occurred infrequently during exposure to pazopanib and other anti-VEGF therapies in a population-based setting.

Validation of Claims Algorithms for Progression to Metastatic Cancer in Patients with Breast, Non-small Cell Lung, and Colorectal Cancer.

BACKGROUND: Validated algorithms for identifying progression to metastatic cancer could permit the use of administrative claims databases for research in this area. OBJECTIVE: To identify simple algorithms that could accurately detect cancer progression to metastatic breast, non-small cell lung, and colorectal cancer (CRC) using medical and pharmacy claims data. METHODS: Adults with stage I-III breast, non-small cell lung cancer (NSCLC), or CRC in the Geisinger Health System from 2004 to 2011 were selected. Evidence of progression was extracted via manual chart review as the reference standard. In addition to secondary malignancy diagnosis (ICD-9 code for metastases), diagnoses, procedures, and treatments were selected with clinician input as indicators of cancer progression. Random forests models provided variable importance scores. In addition to codes for secondary malignancy, several more complex algorithms were constructed and performance measures calculated. RESULTS: Among those with breast cancer [17/502 (3.4%) progressed], the performance of a secondary malignancy code was suboptimal [sensitivity: 64.7%; specificity: 86.0%; positive predictive value (PPV): 13.9; negative predictive value (NPV): 98.6%]; requiring malignancy at another site or initiation of immunotherapy increased PPV and specificity but decreased sensitivity. For NSCLC [61/236 (25.8%) progressed], codes for secondary malignancy alone (PPV: 47.4%; NPV: 84.8%; sensitivity: 60.7%; specificity: 76.6%) performed similarly or better than more complex algorithms. For CRC [33/276 (12.0%) progressed], secondary malignancy codes had good specificity (92.7%) and NPV (92.3%) but low sensitivity (42.4%) and PPV (43.8%); an algorithm with change in chemotherapy increased sensitivity but decreased other metrics. CONCLUSION: Selected algorithms performed similarly to the presence of a secondary tumor diagnosis code, with low sensitivity/PPV and higher specificity/NPV. Accurate identification of cancer progression likely requires verification through chart review.

Disruptions in Liver Function among Cancer Patients and Patients Treated with Tyrosine Kinase Inhibiting Drugs: Comparisons of Two Population-Based Databases.

Liver toxicity is a recognized adverse event associated with small molecule tyrosine kinase inhibitors (TKIs). Electronic Medical Record (EMR) databases offer the most precise data to investigate the rate of liver function test (LFT) elevations; however, they can be limited in sample size and costly to access and analyze. Health insurance claims databases often contain larger samples sizes but may lack key health information. We evaluated the feasibility of utilizing a large claims database to calculate incidence rates (IRs) of LFT elevations among a general cohort of cancer patients and a cohort of patients treated with TKIs by comparing the results to a "gold standard" oncology-specific EMR database. IRs for the TKI cohorts were very similar between the two databases; however, IRs were higher in the EMR database for the cancer cohorts. Possible explanations for these differences include lack of specificity when defining a cancer case, poor capture of laboratory data, or inaccurate assessment of person-time in the insurance claims database. This study suggests that insurance claims data may provide reliable results when investigating liver toxicities associated with oncology drug exposure; however, there are limitations when assessing laboratory outcomes for cohorts defined solely by disease status.

Incidence of new-onset hypertension in cancer patients: a retrospective cohort study.

This retrospective cohort study was conducted to estimate incidence rates of new-onset hypertension in adult cancer patients identified from the Varian Medical Oncology outpatient database. Incidence rates of increasing levels of hypertension severity were calculated overall and for periods of chemotherapy exposure and nonexposure. Cox models sought predictors of new-onset hypertension severity among baseline and chemotherapy exposure variables. New-onset hypertension was observed in about one-third of 25,090 patients with various cancer types. The incidence rates (IR) of severe and crisis-level hypertension, respectively, were the highest in patients with gastric (18.5 cases per 100 person-years (PY), 5.6 per 100 PY) and ovarian cancer (20.2 per 100 PY, 4.8 per 100 PY). The highest IR of moderate hypertension was observed in patients with renal cancer (46.7 per 100 PY). Across all cancers, chemotherapy exposure was associated with a 2-3.5-fold increase in risk of any degree of hypertension compared to periods of no chemotherapy; higher hypertension levels showed greater variability in relative risks by type and line of therapy but indicated an overall increase associated with chemotherapy exposure. These results help to elucidate the factors influencing HTN among cancer patients and the incidence of HTN relative to chemotherapy exposure.

Warfarin prophylaxis in patients after total knee or hip arthroplasty--international normalized ratio patterns and venous thromboembolism.

OBJECTIVE: Warfarin is frequently used for the prevention of venous thromboembolism (VTE) after total hip or knee arthroplasty (THA/TKA). The current study was conducted to determine the association between international normalized ratio (INR) levels and VTE outcomes. METHODS: Patients who received warfarin following THA/TKA were followed for up to 90 days using an electronic health record database. INR measurements were categorized based on American College of Chest Physicians (ACCP) guidelines. Cox proportional hazards models were used to compare the risk of VTE between patients with INR levels below and within the ACCP-recommended range in patients with ≥2 available INR level measurements. RESULTS: On or after Day 5, 33.3% and 28.6% of INR levels fell within the ACCP-recommended range for THA and TKA, respectively. VTE was diagnosed in 3% of each cohort. INR levels varied over time and were frequently below the ACCP-recommended range. Below-range INR levels were associated with greater risk of VTE in both THA (hazard ratio [HR]: 5.29; 95% CI: 2.64-10.61) and TKA (HR: 4.64; 95% CI: 2.59-8.29). CONCLUSIONS: In the current study, the majority of patients had INR levels below the ACCP-recommended range of 2.0-3.0 during warfarin exposure following orthopedic surgery. INR levels below 2.0 were associated with a four- to five-fold increase in the risk of VTE.

Patient outcomes associated with 2-octyl cyanoacrylate topical skin adhesive in coronary artery bypass graft surgery.

BACKGROUND: Surgical site infection (SSI) is an important cause of morbidity and occasionally death after coronary artery bypass graft (CABG) surgery. These infections also are associated with higher costs and poorer surgical outcomes. We used a retrospective observational database to examine and quantify the effects of the topical skin adhesive 2-octyl cyanoacrylate, used as the final layer of site closure in patients undergoing CABG surgery, on the incidence of post-operative SSI. METHODS: All patients in the Premier Perspective™ Comparative Database of inpatient hospitalizations who underwent CABG surgery in 2005 and 2006 were identified. Qualifying patients were classified into four groups according to the method of surgical site closure on the basis of detailed hospital billing charges: Sutures only; sutures and 2-octyl cyanoacrylate; sutures and staples; and sutures, 2-octyl cyanoacrylate, and staples. Site infections were identified by a combination of International Classification of Diseases (ICD-9-CM) diagnosis codes, patterns of post-operative use of antibiotics, and All Patient Refined Diagnostic Related Group (APR-DRG) and Diagnostic Related Group (DRG) codes indicating post-operative infections at hospital re-admission. RESULTS: A total of 59,006 patients qualified for the study: 38,799 who had sutures only; 10,262 having sutures and 2-octyl cyanoacrylate; 8,180 having sutures and staples; and 1,765 having sutures, 2-octyl cyanoacrylate, and staples. The lowest unadjusted rate of post-CABG SSI was found in the sutures and 2-octyl cyanoacrylate group (4.3%; 95% confidence interval [CI] 3.9-4.7), followed by sutures only (5.3%; 95% CI 5.1-5.5); sutures and staples (6.2%; 95% CI 5.7-6.8); and sutures, staples, and 2-octyl cyanoacrylate (7.1%; 95% CI 6.0%-8.4%). A logistic regression model that controlled for selected baseline patient, hospital, and surgical characteristics showed significantly lower rates of post-CABG SSI (odds ratio 0.76; 95% CI 0.68-0.85) in patients closed with sutures and 2-octyl cyanoacrylate relative to patients who had only sutures. CONCLUSIONS: The observed rates of post-CABG SSI were consistent with the rates observed in the literature. The SSI rate for patients who had sutures and 2-octyl cyanoacrylate used as the final layer of site closure was significantly lower than the rates for patients having other types of closure.

Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

OBJECTIVE: To compare the prevalence of cardiovascular diseases and their risk factors between patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) and control subjects. METHODS: Data for patients continuously enrolled in an integrated outcomes database between January 1, 2001, and December 31, 2002, with International Classification of Diseases, 9th Revision codes of 714.x (RA), 696.0 (PsA), or 720.0 (AS) were evaluated in this cross-sectional comparative study. Control groups were established for each patient group (1:4 ratio) by matching on the basis of age, sex, geographic region, and length of time in plan. Age- and sex-adjusted prevalence of cardiovascular comorbidities and risk factors were calculated; the prevalence ratio of the comorbidities and risk factors for the patient groups compared with the control population were estimated. Use of selected cardiovascular medications was also compared between patient and control groups. RESULTS: The RA, PsA, and AS cohorts comprised 28,208, 3066, and 1843 patients, respectively. The prevalence ratio of ischemic heart disease (1.5, 1.3, 1.2), atherosclerosis (1.9, 1.4, 1.5), peripheral vascular disease (2.4, 1.6, 1.6), congestive heart failure (2.0, 1.5, 1.8), cerebrovascular disease (1.6, 1.3, 1.7), type II diabetes (1.4, 1.5, 1.2), hyperlipidemia (1.2, 1.2, 1.2), and hypertension (1.3, 1.3, 1.3) were higher in patients than controls. For RA, PsA, and AS, use of angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, nitrates/vasodilators, anticoagulants, and antihyperlipidemia agents was significantly higher in patients than controls. CONCLUSION: Cardiovascular diseases and their risk factors were more common in patients with RA, PsA, and AS than in matched controls.

Estimating costs of care for patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: This study examines the resource use patterns and costs of care for patients with incident metastatic colorectal cancer (mCRC) based on analyses of retrospective claims data from selected health plans in the United States. PATIENTS AND METHODS: A case-control analysis was performed using claims from years 1998-2004. Incident mCRC cases were identified based on evidence of a colorectal cancer diagnosis and a metastatic disease diagnosis. Incident mCRC cases could have no other evidence of cancer in the 1-year period before the date of their first mCRC diagnosis. Cases were matched to non-mCRC controls based on age, sex, geographic region, and duration of plan enrollment. Costs were evaluated by phase of disease: diagnosis, treatment, or death phases. Ordinary least squares regressions were performed to evaluate impact of covariates in each phase. RESULTS: Total costs in the follow-up period averaged $97,031 more for mCRC cases than for controls. The main cost drivers for mCRC were hospitalizations ($37,369) and specialist visits ($34,582), which included chemotherapy administration. Approximately 40% of the 672 patients with mCRC who qualified for the phase analysis were identified with a fatal event during follow-up. Monthly costs were similar in the diagnostic phase ($12,205) and death phase ($12,328), but were significantly lower in the treatment phase ($4722). Both mean/median monthly costs increased over time during the study period, regardless of disease phase. CONCLUSION: The economic burden of mCRC is substantial for patients with commercial health plans in the United States, and costs of care have increased substantially in recent years.