Beth L. Nordstrom

Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: Meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data

Uncertain short‐ and long‐term cancer risks with anti‐TNF therapies is a concern, and led to a recent black box warning. This meta‐analysis, requested by the European Medicines Agency, aimed at better assessing short‐term risks by using meta‐analytic techniques based on individual patient data from all corporate‐sponsored randomized controlled trials (RCTs) of adalimumab, etanercept, and infliximab.

The impact of wording in “Dear doctor” letters and in black box labels

The Food and Drug Administration and pharmaceutical manufacturers use “Dear doctor” letters to alert physicians about drug safety. To determine how such warnings may be improved, we retrospectively examined how variations in the wording of one series of “Dear doctor” letters affected their impact on concomitant dispensing of cisapride (Propulsid; Janssen Pharmaceutica, Titusville, NJ) and several medications contraindicated for concomitant use.

Anemia as a Predictor of Cardiovascular Events in Patients with Elevated Serum Creatinine

Patients with anemia and patients with chronic kidney disease have elevated risks for cardiovascular disease. Available studies have been too small to provide details about the relationship or to provide for extensive covariate control. In a large insurance database with linked laboratory values, records of women with serum creatinine >1.2 mg/dl and men with serum creatinine >1.4 mg/dl, identified from July 2000 through June 2003, were sought, and the insurance claims searches for hospitalizations that were associated with myocardial infarction, coronary revascularization, unstable angina, stroke, or congestive heart failure. New onset of dialysis also was sought. Multivariate Poisson regression was used to estimate rate ratios for these events at various hemoglobin (Hb) levels, with adjustment for patient characteristics and previous event history. Among 88,657 patients with high serum creatinine, the risk for hospitalization with myocardial infarction was two to five times higher in anemic (Hb <12 g/dl) patients than in people with Hb from 12.0 to 12.9 g/dl. A similar but less dramatic pattern of higher incidence of coronary revascularization was observed with lower Hb levels. Risks for hospitalization with congestive heart failure declined regularly with increasing Hb levels from a doubling of risk at Hb <10 g/dl to a 61% decrease at 15 g/dl, both relative to 12.0 to 12.9 g/dl. The risk for progression to dialysis was only slightly elevated (7 to 34%) in anemic patients. Anemia raises the risk for cardiovascular disease in patients with elevated serum creatinine.

Risk of malignancy in children with juvenile idiopathic arthritis not treated with biologic agents.

To estimate the relative risk of incident cancer diagnosis among patients with juvenile idiopathic arthritis (JIA) compared to patients without JIA.

Identification of metastatic cancer in claims data

To develop algorithms to identify metastatic cancer in claims data, using tumor stage from an oncology electronic medical record (EMR) data warehouse as the gold standard.

Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US Department of Defense administrative claims database

BACKGROUND Data are limited for mortality and comorbidities in patients with multiple sclerosis (MS). OBJECTIVES Compare mortality rates and event rates for comorbidities in MS (n=15,684) and non-MS (n=78,420) cohorts from the US Department of Defense (DoD) database. METHODS Comorbidities and all-cause mortality were assessed using the database. Causes of death (CoDs) were assessed through linkage with the National Death Index. Cohorts were compared using mortality (MRR) and event (ERR) rate ratios. RESULTS All-cause mortality was 2.9-fold higher in the MS versus non-MS cohort (MRR, 95% confidence interval [CI]: 2.9, 2.7-3.2). Frequent CoDs in the MS versus non-MS cohort were infectious diseases (6.2, 4.2-9.4), diseases of the nervous (5.8, 3.7-9.0), respiratory (5.0, 3.9-6.4) and circulatory (2.1, 1.7-2.7) systems and suicide (2.6, 1.3-5.2). Comorbidities including sepsis (ERR, 95% CI: 5.7, 5.1-6.3), ischemic stroke (3.8, 3.5-4.2), attempted suicide (2.4, 1.3-4.5) and ulcerative colitis (2.0, 1.7-2.3), were higher in the MS versus non-MS cohort. The rate of cancers was also higher in the MS versus the non-MS cohort, including lymphoproliferative disorders (2.2, 1.9-2.6) and melanoma (1.7, 1.4-2.0). CONCLUSIONS Rates of mortality and several comorbidities are higher in the MS versus non-MS cohort. Early recognition and management of comorbidities may reduce premature mortality and improve quality of life in patients with MS.

Expanding the use of administrative claims databases in conducting clinical real-world evidence studies in multiple sclerosis.

Abstract Objective: Administrative claims databases provide a wealth of data for assessing the effect of treatments in clinical practice. Our aim was to propose methodology for real-world studies in multiple sclerosis (MS) using these databases. Research design and methods: In three large US administrative claims databases: MarketScan, PharMetrics Plus and Department of Defense (DoD), patients with MS were selected using an algorithm identified in the published literature and refined for accuracy. Algorithms for detecting newly diagnosed (‘incident’) MS cases were also refined and tested. Methodology based on resource and treatment use was developed to differentiate between relapses with and without hospitalization. Results: When various patient selection criteria were applied to the MarketScan database, an algorithm requiring two MS diagnoses at least 30 days apart was identified as the preferred method of selecting patient cohorts. Attempts to detect incident MS cases were confounded by the limited continuous enrollment of patients in these databases. Relapse detection algorithms identified similar proportions of patients in the MarketScan and PharMetrics Plus databases experiencing relapses with (2% in both databases) and without (15–20%) hospitalization in the 1 year follow-up period, providing findings in the range of those in the published literature. Limitation: Additional validation of the algorithms proposed here would increase their credibility. Conclusions: The methods suggested in this study offer a good foundation for performing real-world research in MS using administrative claims databases, potentially allowing evidence from different studies to be compared and combined more systematically than in current research practice.

Adherence to guidelines for use of erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia: Results of a retrospective study of an electronic medical-records database in the United States, 2002–2006

BACKGROUND Chemotherapy-induced anemia (CIA) commonly occurs in cancer patients receiving conventional myelosuppressive chemotherapy. Two national guidelines regarding the use of erythropoiesis-stimulating agents (ESAs) in CIA were released in 2002. Because of poorer disease outcomes and increased risk of adverse events associated with ESAs in recent studies, the use of ESAs has been increasingly restricted in practice guidelines in the years 2007 and 2008. OBJECTIVE The aim of this study was to provide a baseline for adherence to national guidelines in the use of ESAs for CIA between 2002 and 2006. METHODS This retrospective study used the Varian Medical Oncology database (Varian Medical Systems, Inc., Palo Alto, California) of electronic medical records, representing 17 outpatient oncology organizations at 71 clinic locations in the United States. Adults diagnosed with any malignant neoplasm who started conventional cytotoxic chemotherapy between January 1, 2002, and September 30, 2006, were included. The proportion of patients receiving an ESA was calculated by hemoglobin (Hb) level during each chemotherapy cycle, stratified by line of chemotherapy and year. Logistic regression modeling identified predictors of ESA use in anemic patients during the first chemotherapy cycle. RESULTS The records of 17,731 cancer patients were evaluated. Median (SD) age was 61 (13) years, and 58.9% were female. Most patients (84.1%) had a solid tumor. Many patients (41.3%) received platinum containing chemotherapy and 74.4% received combination chemotherapy. During the first 5 cycles of first-line chemotherapy among patients with CIA (Hb <11 g/dL), ESAs were used by 55.8% of patients at cycle 1 and 68.9% at cycle 5. ESA use in CIA patients increased across lines of chemotherapy and time. Few patients (2.8%) received an ESA at Hb >13 g/dL. The statistically significant predictors of ESA use included age >65 years, eastern US residence, private health insurance, community-based care, and solid tumors, especially lung cancer. CONCLUSION The patterns we observed were generally consistent with prevailing ESA labels and national guidelines during 2002 through 2006. Although ESA use in patients with CIA increased over chemotherapy cycles, lines of chemotherapy, and time, <70% of CIA episodes were treated with ESAs during the initial 5 chemotherapy cycles.

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.

Risk of recurrent venous thromboembolism among deep vein thrombosis and pulmonary embolism patients treated with warfarin

Abstract Objective: Guidelines for warfarin treatment of venous thromboembolism (VTE) recommend targeting an international normalized ratio (INR) level of 2–3. This study examines the association between INR levels and VTE recurrence among warfarin-treated patients. Methods: A retrospective cohort study in the MedMining electronic health record database included adults treated with warfarin for VTE in 2004–2011. INR levels during warfarin use were categorized as below therapeutic range (<2), in range (2–3), or above range (>3), with time in each category estimated using the Rosendaal method. Recurrent VTE was noted from 30 days after the initial VTE to end of follow-up, which ranged up to 8 years. The incidence of recurrent VTE was calculated, and association with time-varying INR levels estimated using Cox models. Results: Of 1753 qualifying patients, 867 had deep vein thrombosis, and 886 had pulmonary embolism. Mean age was 58 years, and 50.7% were female. Across all follow-up time, VTE recurrences were observed in 134 (7.6%) patients, at a rate of 3.2 (95% confidence interval [CI]: 0.7–9.1) events per 100 person-years. The risk of VTE recurrence was greater during time spent with INR <2 than with INR in the therapeutic range (hazard ratio [HR]: 3.37; 95% CI: 2.16–5.27). Low platelet counts also predicted greater risk of VTE recurrence (HR: 2.13; 95% CI: 1.24–3.67). Limitations: Exposure to warfarin and other anticoagulants was estimated based on prescription data and may be inaccurate. The study data include care within a single health system; thus, care received outside of the health system may be missing, and results may not be generalizable to the broader US population. Conclusions: Approximately 8% of patients experienced a recurrent VTE during follow-up. Subtherapeutic INR levels were associated with a more than three-fold increased risk of VTE recurrence.