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Background: The incidence of oropharyngeal cancer (OPC) due to tobacco and alcohol, respectively, has been declining, while that linked to human papilloma virus (HPV) has been rising. Epidemiologic, biologic, and prognostic characteristics of OPC differ by HPV-status. This study compared overall survival (OS) among HPV-positive and -negative patients with OPC in a real-world setting. Methods: This retrospective observational study used electronic medical records data from the Geisinger Health System to select patients diagnosed with OPC between January 1, 2010 and September 30, 2015. Patients were designated as HPV-positive if the HPV or P16 test closest to the diagnosis date was positive. All other patients were deemed HPV-negative. Descriptive statistics and relevant statistical tests were used to compare baseline characteristics by HPV status; survival by HPV status was examined using Kaplan–Meier methods and multivariable Cox models. Results: In this study, 152 patients met all selection criteria; 110 (72.4%) were HPV-positive. HPV-positive patients were more likely to be men (89.1% vs 73.8%; P=.019) and to have lymph node involvement (88.2% vs 59.5%; P=.0008); they were less likely to have cerebrovascular disease (6.9% vs. 23.5%; P=.01), or distant metastases (1.8% vs 9.5%; P=.029) vs HPV-negative patients. Among HPV-positive patients, 75.5%, 12.7%, and 10.9% had squamous cell carcinoma NOS, basaloid squamous cell carcinoma, and squamous cell carcinoma large cell non-keratinizing, respectively; corresponding values for HPV-negative patients were 85.7%, 0.0%, and 2.4%, respectively (P=.0013). HPV-positive patients were nominally younger than HPV-negative patients (median: 58 vs 61 years; P=.085). Log-rank test showed OS of HPV-positive patients (median OS from treatment initiation: not reached) is higher than of HPV-negative patients (median OS: 3.7 years; P=.002). In multivariable analyses, HPV-negative status was associated with increased mortality risk (P=.0035); other significant risk factors included alcohol use, diabetes, and distant metastases. Conclusions: HPV-positive status was associated with a decreased risk of mortality among OPC patients in this study. Despite the small sample size and potential violation of assumption of proportional hazard rate, this study underscores the prognostic implication of HPV status in OPC, which may have important ramifications in optimizing treatment decisions among this patient population.

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.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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.

Clinical trials impose exclusion criteria that may limit the generalizability of results.To (a) determine the percentage of real-world patients who would qualify for psoriasis randomized controlled trials; (b) ascertain differences between moderate-to-severe psoriasis patients who would be eligible, ineligible, or potentially eligible for clinical trials; and (c) compare their biologic treatment patterns.Moderate-to-severe psoriasis patients were identified from the U.S. Department of Defense health care database from January 1, 2008, to October 31, 2013. Eligibility classification for psoriasis trials was based on common trial exclusion criteria involving medical conditions and recent treatment history. Patient characteristics and treatment patterns of 4 biologics (adalimumab, etanercept, infliximab, and ustekinumab) were compared between groups. Adherence was measured by medication possession ratio and persistence as continuous time on drug with ≤ 90-day gap between supply times.Among 16,284 qualifying psoriasis patients, 4,677 (28.7%) were medically ineligible, and 8,466 (52.0%) had ineligibility-related treatments that could be stopped prior to trial entry; the latter patients were considered potentially eligible for psoriasis trials. Common reasons for medical ineligibility included malignancies and hematologic disorders; treatment ineligibilities included use of topical corticosteroids and phototherapy. Medically ineligible patients were older and had more comorbidities, while potentially eligible patients were younger and healthier than trial-eligible patients. Most treatment patterns were similar across groups, except that, compared with the trial-eligible group, medically ineligible patients had greater adherence to infliximab and potentially trial-eligible patients had greater adherence and persistence to adalimumab.This large real-world study found that patients who may be ineligible for psoriasis trials differ in important respects (e.g., comorbidities, prior treatments) from their trial-eligible counterparts. Regardless of their differences at baseline, adherence, persistence, and switching of biologic medications are largely similar, with few differences noted among groups.Financial support for this study was provided by Lilly USA. Wu has received research funding from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Coherus Biosciences, Dermira, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, Sandoz, and Sun Pharmaceutical Industries, and he is a consultant for AbbVie, Amgen, Celgene, Dermira, Eli Lilly, Pfizer, Regeneron, and Sun Pharmaceutical Industries. Malatestinic, Goldblum, Solotkin, Lin, Johnston, and Araujo are employees and/or stock owners of Lilly. Nordstrom, Kistler, and Fraeman are employees of Evidera, which received funding from Lilly to conduct this study. LCDR Hawley is a military service member. This work was prepared as part of her official duties. Title 17 U.S.C. 105 provides that "copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a U.S. government work as a work prepared by a military service member or employee of the U.S. government as part of that person's official duties. Research data were derived from an approved Naval Medical Center, Portsmouth, Virginia, institutional review board protocol. The views expressed in this work are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. government. Study concept and design were contributed by Malatestinic and Araujo, along with the other authors. Nordstrom, Kistler, Fraeman, and Sicignano collected the data, and data interpretation was performed by Wu, Lin, and Hawley, along with Malatestinic, Nordstrom, Solotkin, and Araujo. The manuscript was written by Johnston, Malatestinic, Kistler, Wu, and Araujo, along with Nordstrom, Goldblum, Solotkin, Hawley, and Sicignano, and revised by Goldblum, Solotkin, Malatestinic, and Araujo, along with Nordstrom, Wu, Fraeman, Johnston, Hawley, and Sicignano.

Background: Recent studies suggest that inflammatory bowel disease (IBD) may share an underlying pathogenesis with other autoimmune diseases. Methods: Two United States data sets with patient-level medical and drug claims were used to explore the occurrence of autoimmune diseases in patients with IBD, particularly Crohn's disease (CD) and ulcerative colitis (UC), with that in controls. From 2001 to 2002 IBD patients were identified using International Classification of Diseases, 9th revision, diagnosis codes in the IMS Health Integrated Administration Claims Database and the Market Scan Commercial Claims and Encounters Database. Controls were selected by matching on sex, age, Census Bureau region, and length of previous medical insurance coverage. Odds ratios (ORs) evaluated the risk relationship between IBD patients and controls within an estimated Mantel-Haenszel 95% confidence interval. Sensitivity analysis tested the case identification method used to select IBD patients. Results: The risk for ankylosing spondylitis (AS) was substantially increased across both data sets: OR (95% confidence interval [CI]) of 7.8 (5.6–10.8) in IMS Health and 5.8 (3.9–8.6) in MarketScan. The risk for rheumatoid arthritis (RA) was 2.7 (2.4–3.0) and 2.1 (1.8–2.3), respectively; for multiple sclerosis (MS); the ORs were 1.5 (1.2–1.9) and 1.6 (1.2–2.1), respectively. There was no increased risk for type 1 diabetes mellitus, and the results for psoriatic arthritis (PsA) were inconsistent. The sensitivity analysis supported these findings. Conclusions: A much higher risk for RA, AS, PsA, and MS was observed in IBD patients compared with controls. Prospective epidemiologic studies are needed to confirm these findings and explore the pathogenic mechanism of this relationship. (Inflamm Bowel Dis 2008)

Large, population-based assessments of systemic sclerosis (SSc) prevalence and comorbidity in the United States (US) are rare. We explored autoimmune disease and other comorbidity patterns among SSc patients in the US from 2001 to 2002 and compared these with controls.Two US datasets with patient-level medical and drug claims were used to assess SSc prevalence and comorbidity: IMS Health Integrated Administrative Claims Database (IMS Health) and the MarketScan Commercial Claims and Encounters Database (MarketScan). SSc patients and comorbidities were identified by International Classification of Diseases (ICD), 9th revision diagnostic codes appearing on medical claims. Patients without SSc diagnostic codes (controls) were selected and matched 4:1 to SSc patients based on sex, age, Census Bureau region, and previous insurance coverage. The prevalence relative risk (RR) statistic compared comorbidity occurrence between SSc patients and controls, with 95% confidence intervals estimated using the Mantel-Haenszel method. Several sensitivity analyses tested methods used for identifying SSc cases and the prevalence of comorbidities.In both databases, SSc prevalence was 0.05% using the standard population model, 0.03% under sensitivity analysis. Among SSc patients the risks for inflammatory bowel disease (IBD) and multiple sclerosis (MS) were notably higher across datasets than for those without SSc: RR 3.2-6.6 for MS, RR 2.1-2.2 for IBD, in MarketScan and IMS Health, respectively (p0.05 for all). The chronic disease burden of SSc patients was much higher than that of controls, as confirmed by two chronicity measures (Chronic Disease Score, Elixhauser Comorbidity Index). The risks for cardiovascular, renal, liver and several neuropsychiatric diseases were higher for SSc patients across both datasets. Sensitivity analyses supported these findings.These data provide a population-based estimate of US prevalence of SSc and document the higher risk for certain other autoimmune diseases among SSc patients when compared to controls. Patients with SSc also had a higher chronic disease burden than those without SSc. These findings are limited by the unknown validity of ICD-9 codes for SSc case identification, unbalanced regional representation, and a likely 'healthy worker' effect in these databases.

SummaryDabigatran is approved for stroke risk reduction in patients with nonvalvular atrial fibrillation (NVAF). Data from diverse clinical practice settings will help establish whether the risk:benefit ratio seen in clinical trials is comparable with routine clinical care. This study aimed to compare the safety and effectiveness of dabigatran and warfarin in clinical practice. We undertook a propensity score-matched (PSM) cohort study (N=12,793 per group; mean age 74) comparing treatment with dabigatran or warfarin in the US Department of Defense claims database, October 2009 to July 2013. Treatment-naïve patients with first prescription claim for dabigatran (either FDA-approved dose) or warfarin between October 2010 and July 2012 (index) and a diagnosis of NVAF during the 12 months before index date were included. Primary outcomes were stroke and major bleeding. Secondary outcomes included ischaemic and haemorrhagic stroke, major gastrointestinal (GI), urogenital or other bleeding, myocardial infarction (MI) and death. Time-to-event was investigated using Kaplan-Meier survival analyses. Outcomes comparisons were made utilising Cox-proportional hazards models of PSM groups. Dabigatran users experienced fewer strokes (adjusted hazard ratio [95 % confidence intervals] 0.73 [0.55–0.97]), major intracranial (0.49 [0.30–0.79]), urogenital (0.36 [0.18–0.74]) and other (0.38 [0.22–0.66]) bleeding, MI (0.65 [0.45–0.95]) and deaths (0.64 [0.55–0.74]) than the warfarin group. Major bleeding (0.87 [0.74–1.03]) and major GI bleeding (1.13 [0.94–1.37]) was similar between groups and major lower GI bleeding events were more frequent (1.30 [1.04–1.62]) with dabigatran. In conclusion, compared with warfarin, dabigatran treatment was associated with a lower risk of stroke and most outcomes measured, but increased incidence of major lower GI bleeding.

Objectives: This study evaluated the safety and effectiveness of dabigatran versus warfarin for stroke risk reduction in NVAF patients in routine clinical care using the Department of Defense Military Health System database. Methods: In this retrospective cohort study, patients were included if they had an AF diagnosis within 12 months prior to first OAC treatment, were 18-89 years, and had a first prescription claim for either dabigatran or warfarin between 01-Oct-2010 and 31-Jul-2012 (index date). Patients were excluded if they had heart valve disorders or prosthetic heart valves, transient causes of AF, or any OAC use during the baseline period. Patients were censored when their prescriptions exceeded a 30 day allowable gap, at OAC switch, at disenrollment, at death, or at study end. A total of 14,813 dabigatran and 24,500 warfarin patients were available for propensity score matching (PSM). PSM based on baseline demographics and clinical characteristics was achieved 1:1 with 12,793 matched subjects per group (within a 0.20 caliper of standard deviation). Comparisons of safety and effectiveness outcomes were made based on Cox-proportional hazards models of PSM groups. All FDA-approved dosages were included in this analysis. Results: Results are summarized in Table 1. Conclusions: Hazard ratios in the post-PSM dabigatran cohort suggest that there is a lower likelihood for stroke, hemorrhagic stroke, major intracranial bleeding, major urogenital and other bleeding, MI, and death than in the warfarin cohort. The hazard ratio in the post-PSM dabigatran cohort suggests a higher likelihood for major lower GI bleeding, but a lower likelihood for intracranial, urogenital, and other bleeding than seen with warfarin. These results are generally consistent with findings of the randomized controlled clinical trial, RE-LY, and support that the benefits of dabigatran demonstrated in clinical trials also may be achieved in a broad population receiving routine clinical care.

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.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.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).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.

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.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.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.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.

To estimate the incremental cost per life year gained with levosimendan relative to dobutamine in treatment of acute heart failure based on the Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial.SURVIVE enrolled 1,327 patients (levosimendan 664, dobutamine 663) from nine nations with 180-day survival from date of randomisation as the primary endpoint. Hospital resource utilisation was determined via clinical case reports. Unit costs were derived from hospital payment schedules for France, Germany and the UK, and represent a third-party payer perspective. Cost-effectiveness analysis was performed for a subset of the SURVIVE patient population selected in accordance with current levosimendan labeling.Mortality in the levosimendan group was 26 versus 28% for dobutamine (hazard ratio 0.91, 95% confidence interval 0.74-1.13, p=0.40). Initial hospitalisation length of stay was identical (levosimendan 14.4, dobutamine 14.5, p=0.98). Slightly lower rates of readmission were observed for levosimendan relative to dobutamine at 31 (p=0.13) and 180 days (p=0.23). Mean costs excluding study drug were equivalent for the index admission (levosimendan euro5,060, dobutamine euro4,952; p=0.91) and complete episode (levosimendan euro5,396, dobutamine euro5,275; p=0.93).At an acquisition cost of euro600 per vial, there is at least 50% likelihood that levosimendan is cost effective relative to dobutamine if willingness to pay is equal to or greater than euro15,000 per life year gained.

Background Surgical site infections (SSIs) are serious operative complications that occur in approximately 2% of surgical procedures and account for some 20% of health care-associated infections. Methods SSI was identified based on the presence of ICD-9-CM diagnosis code 998.59 in hospital discharge records for 7 categories of surgical procedures: neurological; cardiovascular; colorectal; skin, subcutaneous tissue, and breast; gastrointestinal; orthopedic; and obstetric and gynecologic. Source of data was the 2005 Healthcare Cost and Utilization Project National Inpatient Sample (HCUP NIS). Primary study outcomes were rate of SSI by surgical category and impact of SSI on length of stay and cost. Results were projected to the national level. Results Among 723,490 surgical hospitalizations in the sample, 6891 cases of SSI were identified (1%). On average, SSI extended length of stay by 9.7 days while increasing cost by $20,842 per admission. From the national perspective, these cases of SSI were associated with an additional 406,730 hospital-days and hospital costs exceeding $900 million. An additional 91,613 readmissions for treatment of SSI accounted for a further 521,933 days of care at a cost of nearly $700 million. Conclusion SSI is associated with a significant economic burden in terms of extended length of stay and increased costs of treatment. Our analysis documented nearly 1 million additional inpatient-days and $1.6 billion in excess costs.

Acute heart failure (AHF) is the leading cause of hospital admission among older Americans. The Randomized EValuation of Intravenous Levosimendan Efficacy (REVIVE II) trial compared patients randomly assigned to a single infusion of levosimendan (levo) or placebo (SOC), each in addition to local standard treatments for AHF. We report an economic analysis of REVIVE II from the hospital perspective.REVIVE II enrolled patients (N = 600) hospitalized for treatment of acute decompensated heart failure (ADHF) who remained dyspneic at rest despite treatment with intravenous diuretics. Case report forms documented index hospital treatment (drug administration, procedures, days of treatment by care unit), as well as subsequent hospital and emergency department admissions during follow-up ending 90 days from date of randomization. These data were used to impute cost of admission based on an econometric cost function derived from100,000 ADHF hospital billing records selected per REVIVE II inclusion criteria.Index admission mean length of stay (LOS) was shorter for the levo group compared with standard of care (SOC) (7.03 vs 8.96 days, P = 0.008) although intensive care unit (ICU)/cardiac care unit (CCU) days were similar (levo 2.88, SOC 3.22, P = 0.63). Excluding cost for levo, predicted mean (median) cost for the index admission was levo US $13,590 (9,458), SOC $19,021 (10,692) with a difference of $5,431 (1,234) favoring levo (P = 0.04). During follow-up through end of study day 90, no significant differences were observed in numbers of hospital admissions (P = 0.67), inpatient days (P = 0.81) or emergency department visits (P = 0.41). Cost-effectiveness was performed with a REVIVE-II sub-set conforming to current labeling, which excluded patients with low baseline blood pressure. Assuming an average price for levo in countries where currently approved, there was better than 50% likelihood that levo was both cost-saving and improved survival. Likelihood that levo would be cost-effective for willingness-to-pay below $50,000 per year of life gained was about 65%.In the REVIVE II trial, patients treated with levo had shorter LOS and lower cost for the initial hospital admission relative to patients treated with SOC. Based on sub-group analysis of patients administered per the current label, levo appears cost-effective relative to SOC.

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.