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Katherine E Mues,1 Alexander Liede,1 Jiannong Liu,2 James B Wetmore,2 Rebecca Zaha,1 Brian D Bradbury,1 Allan J Collins,2 David T Gilbertson2 1Center for Observational Research, Amgen Inc., Thousand Oaks and San Francisco, CA, 2Chronic Disease Research Group, Minneapolis, MN, USA Abstract: Medicare is the federal health insurance program for individuals in the US who are aged ≥65 years, select individuals with disabilities aged

BACKGROUND: Limited data exist describing vascular access conversions during the first year on dialysis therapy or the effect of converting to and from a catheter on subsequent mortality risk. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We studied a random sample of incident US hemodialysis patients (initiated long-term dialysis < 30 days before study entry) in the Dialysis Outcomes and Practice Patterns Study (DOPPS; 1996-2004). PREDICTORS: At dialysis therapy initiation, we assessed vascular access type in use (arteriovenous fistula [AVF], arteriovenous graft [AVG], or catheter) and other patient characteristics. We characterized changes in vascular access type (conversions) by using regularly collected functional status information. OUTCOME & MEASUREMENTS: We assessed time to all-cause mortality. We first described conversions, then used time-dependent Cox regression to estimate mortality hazard ratios (HRs) for conversions from a catheter to a permanent vascular access (versus no conversion) and conversions from a permanent vascular access to a catheter (versus no conversion). RESULTS: The study included 4,532 patients; 69.2% were dialyzing with a catheter; 17.6%, with an AVG; and 13.1%, with an AVF. In patients initiating therapy with an AVF or AVG, 22% experienced a conversion (failure), and median times to first failure were 62 and 84 days, respectively. In catheter patients, 59% converted to an AVF/AVG (predominantly AVG [57%]); median times to first conversion were 92 and 66 days, respectively. Conversion to a permanent access was associated with an adjusted mortality HR of 0.69 (95% confidence interval, 0.55 to 0.85). The effect was similar for conversion to an AVF or AVG, and these persisted across demographic groups and facilities with different conversion practices. Conversion from a permanent vascular access to a catheter was associated with an adjusted mortality HR of 1.81 (95% confidence interval, 1.22 to 2.68). LIMITATIONS: Potential for residual confounding because of unmeasured factors influencing decision to convert. CONCLUSION: Vascular access conversions are common in incident patients. Continued efforts to increase early nephrologist referral and permanent vascular access placement may help decrease mortality risk in incident dialysis patients. Copyright © 2009 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND: Confounding-by-indication is a bias in nonexperimental studies that occurs when outcomes are compared for treated and untreated patients and the treatment or medication dose is related to predictors of the outcome. Two recent publications reported that greater epoetin alfa (EPO) doses were associated with increased mortality rates. We assessed whether confounding-by-indication might account for these results. STUDY DESIGN: We used a retrospective cohort study design. SETTING & PARTICIPANTS: Hemodialysis patients were randomly selected from a large dialysis organization from July 2000 to June 2002 and were required to have completed a 9-month baseline period. PREDICTOR: EPO dose assessed during months 7 to 9 of the baseline period and monthly throughout the follow-up period. Hemoglobin (Hb) was assessed as average value during months 4 to 6 of the baseline period and monthly throughout the follow-up period. All other covariates were assessed during months 1 to 6 of the baseline period. OUTCOME: All-cause mortality during the 1 year of follow-up. Baseline Cox models were fitted with log EPO and Hb with and without adjustment for baseline patient characteristics. Time-dependent models were fitted with time-varying log EPO and Hb and, separately, lagged log EPO and Hb, with adjustment for baseline patient characteristics. RESULTS: 22,955 patients met our inclusion criteria. In the unadjusted model, we observed increased mortality risk with increasing EPO dose (hazard ratio [HR], 1.31 per log unit increase; 95% confidence interval [CI], 1.26 to 1.36). Adjustment for baseline patient characteristics resulted in an appreciably decreased HR (HR, 1.21; 95% CI, 1.15 to 1.28). In the lagged time-dependent analyses, estimates ranged from HR of 0.93 (95% CI, 0.92 to 0.95) to HR of 1.01 (95% CI, 0.99 to 1.03) for the 1- and 2-month lagged models, respectively. LIMITATIONS: This analysis was limited to prevalent hemodialysis patients, and inhospital EPO dosing information was unavailable. CONCLUSIONS: The observed mortality risk estimates associated with EPO dose in nonexperimental studies in dialysis patients may be highly sensitive to the analytic method used. This highlights the complexity of evaluating the association between EPO dose, Hb level, and mortality in these studies. Copyright © 2008 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND: Information on use of colorectal cancer tests, particularly for the purpose of population surveillance, is often obtained through self-report. The Behavioral Risk Factor Surveillance System (BRFSS) is a major source for population-based estimates and is used by health professionals, public health organizations, and researchers to identify and quantify self-reported utilization of screening procedures. METHODS: We provide estimates of the reliability of responses among persons age > or = 50 to questions on the 1999 BRFSS questionnaire addressing two colorectal cancer testing procedures, fecal occult blood test (FOBT), and sigmoidoscopy or colonoscopy (endoscopy), based on responses of 868 persons who responded to a callback survey. RESULTS: We found moderate reliability for questions addressing ever having an FOBT exam, (Kappa [K] = 0.55, 95% confidence interval [95% CI]: 0.49-0.61) and good reliability for questions addressing ever having an endoscopy exam (K = 0.69, 95% CI: 0.65-0.74). Questions addressing the timing of the most recent exam were only slightly less reliable (K = 0.49, 95% CI: 0.43-0.55 and K = 0.62, 95% CI: 0.57-0.67, respectively). We observed comparable reliability across levels of most demographic and risk factor characteristics for both ever having and recency of exam. CONCLUSION: Our results suggest that colorectal cancer testing questions on the BRFSS display a reasonable level of test-retest reliability. Copyright © 2005 by Elsevier Science (USA). [ABSTRACT FROM AUTHOR]

Administrative claims databases often do not capture date or fact of death, so studies using these data may inappropriately treat death as a censoring event-equivalent to other withdrawal reasons-rather than a competing event. We examined 1-, 3-, and 5-year inverse-probability-of-treatment weighted cumulative risks of a composite cardiovascular outcome among 34 527 initiators of telmisartan (exposure) and ramipril (referent), who were aged ≥55 years, in Optum (United States) claims data from 2003 to 2020. Differences in cumulative risks of the cardiovascular endpoint due to censoring of death (cause-specific), as compared with treating death as a competing event (subdistribution), increased with greater follow-up time and older age, where event and mortality risks were higher. Among ramipril users, 5-year cause-specific and subdistribution cumulative risk estimates per 100, respectively, were 16.4 (95% CI, 15.3-17.5) and 16.2 (95% CI, 15.1-17.3) among ages 55-64 (difference = 0.2) and were 43.2 (95% CI, 41.3-45.2) and 39.7 (95% CI, 37.9-41.4) among ages ≥75 (difference = 3.6). Plasmode simulation results demonstrated the differences in cause-specific versus subdistribution cumulative risks to increase with increasing mortality rate. We suggest researchers consider the cohort's baseline mortality risk when deciding whether real-world data with incomplete death information can be used without concern. This article is part of a Special Collection on Pharmacoepidemiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although clinical trials have shown that denosumab significantly increases bone mineral density at key skeletal sites more than oral bisphosphonates, evidence is lacking from head-to-head randomized trials evaluating fracture outcomes. This retrospective cohort study uses administrative claims data from Medicare fee-for service beneficiaries to evaluate the comparative effectiveness of denosumab vs alendronate in reducing fracture risk among women with PMO in the US. Women with PMO ≥ 66 yr of age with no prior history of osteoporosis treatment, who initiated denosumab (n = 89 115) or alendronate (n = 389 536) from 2012 to 2018, were followed from treatment initiation until the first of a specific fracture outcome, treatment discontinuation or switch, end of study (December 31, 2019), or other censoring criteria. A doubly robust inverse-probability of treatment and censoring weighted function was used to estimate the risk ratio associated with the use of denosumab compared with alendronate for hip, nonvertebral (NV; includes hip, humerus, pelvis, radius/ulna, other femur), non-hip nonvertebral (NHNV), hospitalized vertebral (HV), and major osteoporotic (MOP; consisting of NV and HV) fractures. Overall, denosumab reduced the risk of MOP by 39%, hip by 36%, NV by 43%, NHNV by 50%, and HV fractures by 30% compared with alendronate. Denosumab reduced the risk of MOP fractures by 9% at year 1, 12% at year 2, 18% at year 3, and 31% at year 5. An increase in the magnitude of fracture risk reduction with increasing duration of exposure was also observed for other NV fracture outcomes. In this cohort of almost half-a-million treatment-naive women with PMO, we observed clinically significant reductions in the risk of MOP, hip, NV, NHNV, and HV fractures for patients on denosumab compared with alendronate. Patients who remained on denosumab for longer periods of time experienced greater reductions in fracture risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Purpose: We describe constructs designed to protect the integrity of the results from comparative analyses using real-world data (RWD): staging and clean room., Methods: Staging involves performing sequential preliminary analyses and evaluating the population size available and potential bias before conducting comparative analyses. A clean room involves restricted access to data and preliminary results, policies governing exploratory analyses and protocol deviations, and audit trail. These constructs are intended to allow decisions about protocol deviations, such as changes to design or model specification, to be made without knowledge of how they might affect subsequent analyses. We describe an example for implementing staging with a clean room., Results: Stage 1 may involve selecting a data source, developing and registering a protocol, establishing a clean room, and applying inclusion/exclusion criteria. Stage 2 may involve attempting to achieve covariate balance, often through propensity score models. Stage 3 may involve evaluating the presence of residual confounding using negative control outcomes. After each stage, check points may be implemented when a team of statisticians, epidemiologists and clinicians masked to how their decisions may affect study outcomes, reviews the results. This review team may be tasked with making recommendations for protocol deviations to address study precision or bias. They may recommend proceeding to the next stage, conducting additional analyses to address bias, or terminating the study. Stage 4 may involve conducting the comparative analyses., Conclusions: The staging and clean room constructs are intended to protect the integrity and enhance confidence in the results of analyses of RWD., (© 2024 John Wiley & Sons Ltd.)

In this international study, we examined the incidence of hip fractures, postfracture treatment, and all-cause mortality following hip fractures, based on demographics, geography, and calendar year. We used patient-level healthcare data from 19 countries and regions to identify patients aged 50 years and older hospitalized with a hip fracture from 2005 to 2018. The age- and sex-standardized incidence rates of hip fractures, post-hip fracture treatment (defined as the proportion of patients receiving anti-osteoporosis medication with various mechanisms of action [bisphosphonates, denosumab, raloxifene, strontium ranelate, or teriparatide] following a hip fracture), and the all-cause mortality rates after hip fractures were estimated using a standardized protocol and common data model. The number of hip fractures in 2050 was projected based on trends in the incidence and estimated future population demographics. In total, 4,115,046 hip fractures were identified from 20 databases. The reported age- and sex-standardized incidence rates of hip fractures ranged from 95.1 (95% confidence interval [CI] 94.8-95.4) in Brazil to 315.9 (95% CI 314.0-317.7) in Denmark per 100,000 population. Incidence rates decreased over the study period in most countries; however, the estimated total annual number of hip fractures nearly doubled from 2018 to 2050. Within 1 year following a hip fracture, post-hip fracture treatment ranged from 11.5% (95% CI 11.1% to 11.9%) in Germany to 50.3% (95% CI 50.0% to 50.7%) in the United Kingdom, and all-cause mortality rates ranged from 14.4% (95% CI 14.0% to 14.8%) in Singapore to 28.3% (95% CI 28.0% to 28.6%) in the United Kingdom. Males had lower use of anti-osteoporosis medication than females, higher rates of all-cause mortality, and a larger increase in the projected number of hip fractures by 2050. Substantial variations exist in the global epidemiology of hip fractures and postfracture outcomes. Our findings inform possible actions to reduce the projected public health burden of osteoporotic fractures among the aging population. © 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)., (© 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).)

Purpose: This narrative review describes the application of negative control outcome (NCO) methods to assess potential bias due to unmeasured or mismeasured confounders in non-randomized comparisons of drug effectiveness and safety. An NCO is assumed to have no causal relationship with a treatment under study while subject to the same confounding structure as the treatment and outcome of interest; an association between treatment and NCO then reflects the potential for uncontrolled confounding between treatment and outcome., Methods: We focus on two recently completed NCO studies that assessed the comparability of outcome risk for patients initiating different osteoporosis medications and lipid-lowering therapies, illustrating several ways in which confounding may result. In these studies, NCO methods were implemented in claims-based data sources, with the results used to guide the decision to proceed with comparative effectiveness or safety analyses., Results: Based on this research, we provide recommendations for future NCO studies, including considerations for the identification of confounding mechanisms in the target patient population, the selection of NCOs expected to satisfy required assumptions, the interpretation of NCO effect estimates, and the mitigation of uncontrolled confounding detected in NCO analyses. We propose the use of NCO studies prior to initiating comparative effectiveness or safety research, providing information on the potential presence of uncontrolled confounding in those comparative analyses., Conclusions: Given the increasing use of non-randomized designs for regulatory decision-making, the application of NCO methods will strengthen study design, analysis, and interpretation of real-world data and the credibility of the resulting real-world evidence., (© 2023 John Wiley & Sons Ltd.)

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)., (© 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).)

Purpose: Evaluation of drug safety during pregnancy is dependent on the number of exposed women during routine clinical practice with data available for analysis. We examined medication fills in pregnant and nonpregnant women within select disease cohorts: general population, migraine, diabetes, and hyperlipidemia to explore the potential use of claims data to assess medication use and safety during pregnancy., Methods: This cohort study, using IBM MarketScan® Research Databases claims data, included women 10-54 years of age with pregnancy resulting in a liveborn infant between January 2010 and September 2015 and matched nonpregnant women. Medication use (antidepressants, antihypertensives, sedatives, glucose-lowering medications, antiepileptics, antipsychotics, lipid-lowering medications) was abstracted from pharmacy claims 180 days before last menstrual period through 180 days postdelivery., Results: Among 753,760 women in the general pregnancy population (including 73,268 migraine, 50,155 hyperlipidemia, and 8361 diabetes; non-exclusive cohorts), antidepressants, antihypertensives, and sedatives were the most commonly used medications during pregnancy. Medications of interest were less commonly used in the pregnancy cohort than in the matched nonpregnant cohort within each time period (e.g., 3.7% vs 13.1% antidepressant use in 1st trimester). Most prescription fills were less common during pregnancy then pre-pregnancy. Post-pregnancy, prescription fills increased to or exceeded pre-pregnancy levels, except antihypertensive and glucose-lowering medications, which increased during pregnancy., Conclusions: Medication use among pregnant women was low and different from that among matched nonpregnant women. The underlying size of large commercial claims databases offer opportunities for efficient evaluation of potential safety concerns, particularly for rare drug exposures, compared to traditional pregnancy registries., (© 2022. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Purpose: Guidelines recommend primary prophylactic (PP) granulocyte colony stimulating factor (G-CSF) for prevention of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy with high risk (HR: > 20%), or intermediate risk (IR:10-20%) of FN and ≥ 1 patient risk factor (e.g., age ≥ 65y). The current retrospective cohort study describes patterns of PP-G-CSF in older Medicare patients undergoing myelosuppressive chemotherapy with HR/IR of FN., Methods: Patients aged ≥ 66y initiating chemotherapy regimens with HR/IR of FN to treat breast, colorectal, lung, or ovarian cancer, or Non-Hodgkin's Lymphoma were selected using Medicare 20% sample (2013-2015) and 100% cancer patient (2014-2017) data. PP-G-CSF use was identified in the first cycle. Timing of pegfilgrastim pre-filled syringe (PFS) administration, proportion of patients completing all cycles (adherence) with pegfilgrastim PFS or on-body injector (OBI), and duration of short-acting G-CSF (sG-CSF) was described across all cycles., Results: Of 64,893 patients receiving HR/IR for FN, 71% received HR and 29% IR regimens. Overall, PP-G-CSF use in the first cycle was 53% (HR: 74%; IR: 44%) and varied across cancers. Adherence with pegfilgrastim was slightly higher among OBI initiators (78%) than PFS (74%). Number of PP-sG-CSF administrations (mean [SD]) per cycle was 5.1 (SD: 2.7) overall, 5.4 (2.6) for HR, and 4.9 (2.7) for IR., Conclusion: Despite cancer treatment guidelines recommending PP-G-CSF use to reduce risk of FN associated with HR and IR (with ≥ 1 patient risk-factor) regimens, PP-G-CSF remains underutilized in older patients, across cancer types and regimens. Opportunities exist for improvement in use of PP-G-CSF., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To examine the temporal patterns of patient characteristics, treatments used and outcomes associated with COVID-19 in patients who were hospitalised for the disease between January and 15 November 2020., Design: Observational cohort study., Setting: COVID-19 subset of the Optum deidentified electronic health records, including more than 1.8 million patients from across the USA., Participants: There were 51 510 hospitalised patients who met the COVID-19 definition, with 37 617 in the laboratory positive cohort and 13 893 in the clinical cohort., Primary and Secondary Outcome Measures: Incident acute clinical outcomes, including in-hospital all-cause mortality., Results: Respectively, 48% and 49% of the laboratory positive and clinical cohorts were women. The 50- 65 age group was the median age group for both cohorts. The use of antivirals and dexamethasone increased over time, fivefold and twofold, respectively, while the use of hydroxychloroquine declined by 98%. Among adult patients in the laboratory positive cohort, absolute age/sex standardised incidence proportion for in-hospital death changed by -0.036 per month (95% CI -0.042 to -0.031) from March to June 2020, but remained fairly flat from June to November, 2020 (0.001 (95% CI -0.001 to 0.003), 17.5% (660 deaths /3986 persons) in March and 10.2% (580/5137) in October); in the clinical cohort, the corresponding changes were -0.024 (95% CI -0.032 to -0.015) and 0.011 (95% CI 0.007 0.014), respectively (14.8% (175/1252) in March, 15.3% (189/1203) in October). Declines in the cumulative incidence of most acute clinical outcomes were observed in the laboratory positive cohort, but not for the clinical cohort., Conclusion: The incidence of adverse clinical outcomes remains high among COVID-19 patients with clinical diagnosis only. Patients with COVID-19 entering the hospital are at elevated risk of adverse outcomes., Competing Interests: Competing interests: JHP, AAL, CBrooks, JZ, CBennett, BDB, MB, CAB, PC, AC, CWC, KG, FH, JM, JP and KAR are employees and stockholders of Amgen. JMS reports consulting for Amgen and owns stock in Amgen. OA, S-CC, GD, KG, HK, KR, LS, LW, PY and LZ are employees and stockholders in Takeda, Pharmaceutical Company Limited. YB, JJ, QX, ZW and JZ are employees and stockholders in Bristol-Myers Squibb. KBC, an employee of Moderna, was formerly an employee of Amgen and owns stock in Amgen. GlaxoSmithKline (GSK), Takeda, AbbVie, Boehringer Ingelheim and UCB Bioscience (UCB) have collaborative agreements with the Center for Pharmacoepidemiology, Department of Epidemiology, University of North Carolina at Chapel Hill which provides salary support to MJ-F and MJ-F is a member of the Scientific Steering Committee (SSC) for a postapproval safety study funded by GSK. All compensation for services provided on the SSC is invoiced by and paid to UNC Chapel Hill., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Secondary hyperparathyroidism (SHPT) is common among dialysis patients, and calcimimetics are a mainstay of treatment. This study assessed whether cinacalcet use is associated with gastrointestinal bleeding in a large hemodialysis cohort., Methods: A linked database of clinical records and medical claims for patients receiving hemodialysis in a large dialysis organization, 2007-2010, was used. A nested case-control study was performed among patients aged ≥18 years who had received hemodialysis for ≥90 days, had Medicare Parts A, B, and D coverage for ≥1 year, and had clinical evidence of SHPT (parathyroid hormone >300 pg/mL). Cases were those who experienced death or hospitalization caused by gastrointestinal bleeding. Each case was matched to up to four controls. Exposure was measured by any cinacalcet use, current use, past use, cumulative exposure days, and cumulative dosage. Conditional logistic models were used to assess the association., Results: Of 48 437 patients included, 2570 experienced gastrointestinal bleeding events (2498 non-fatal, 72 fatal), and 2465 (2397 non-fatal, 68 fatal) were matched to 9500 controls; 17.2% of cases and 15.8% of controls had cinacalcet exposure and 11.1% of both cases and controls had current use. The adjusted odds ratios (95% CI) of gastrointestinal bleeding for any use, current use, and past use of cinacalcet were 1.04 (0.91-1.19), 0.97 (0.83-1.13), and 1.22 (0.99-1.50), respectively, with no use as the reference., Conclusion: The results do not suggest an elevated risk of gastrointestinal bleeding resulting in hospitalization or death for hemodialysis patients exposed to cinacalcet., (© 2021 John Wiley & Sons Ltd.)

Objective: To examine age, gender, and temporal differences in baseline characteristics and clinical outcomes of adult patients hospitalised with COVID-19., Design: A cohort study using deidentified electronic medical records from a Global Research Network., Setting/participants: 67 456 adult patients hospitalised with COVID-19 from the USA; 7306 from Europe, Latin America and Asia-Pacific between February 2020 and January 2021., Results: In the US cohort, compared with patients 18-34 years old, patients ≥65 had a greater risk of intensive care unit (ICU) admission (adjusted HR (aHR) 1.73, 95% CI 1.58 to 1.90), acute respiratory distress syndrome(ARDS)/respiratory failure (aHR 1.86, 95% CI 1.76 to 1.96), invasive mechanical ventilation (IMV, aHR 1.93, 95% CI, 1.73 to 2.15), and all-cause mortality (aHR 5.6, 95% CI 4.36 to 7.18). Men appeared to be at a greater risk for ICU admission (aHR 1.34, 95% CI 1.29 to 1.39), ARDS/respiratory failure (aHR 1.24, 95% CI1.21 to 1.27), IMV (aHR 1.38, 95% CI 1.32 to 1.45), and all-cause mortality (aHR 1.16, 95% CI 1.08 to 1.24) compared with women. Moreover, we observed a greater risk of adverse outcomes during the early pandemic (ie, February-April 2020) compared with later periods. In the ex-US cohort, the age and gender trends were similar; for the temporal trend, the highest proportion of patients with all-cause mortality were also in February-April 2020; however, the highest percentages of patients with IMV and ARDS/respiratory failure were in August-October 2020 followed by February-April 2020., Conclusions: This study provided valuable information on the temporal trends of characteristics and outcomes of hospitalised adult COVID-19 patients in both USA and ex-USA. It also described the population at a potentially greater risk for worse clinical outcomes by identifying the age and gender differences. Together, the information could inform the prevention and treatment strategies of COVID-19. Furthermore, it can be used to raise public awareness of COVID-19's impact on vulnerable populations., Competing Interests: Competing interests: YB, XC, JJ, QX, MS, ZW and JZ are employees of Bristol Myers Squibb and hold stock or stock options at Bristol Myers Squibb. BDB, CB, CAB, AC, CWC, AAL, JM, JZ are employees and stockholders of Amgen. OA, GD, VG, KG, HAK, SM, KR, LS, PY and LZ are employees and stockholders in Takeda, Pharmaceutical Company Limited. GlaxoSmithKline (GSK), Takeda, AbbVie, Boehringer Ingelheim and UCB Bioscience (UCB) have collaborative agreements with the Center for Pharmacoepidemiology, Department of Epidemiology and University of North Carolina at Chapel Hill which provides salary support to MJ-F as Director. MJ-F is a member of the Scientific Steering Committee (SSC) for a postapproval safety study funded by GSK. All compensation for services provided on the SSC is invoiced by and paid to UNC Chapel Hill., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Evaluate the relationship between duration of primary prophylactic short-acting granulocyte colony-stimulating factor (PP-sG-CSF) and risk of neutropenia-related hospitalization (NRH) in older patients receiving myelosuppressive chemotherapy., Methods: Using the Medicare claims database, we conducted a nested case-control study in a cohort of patients aged ≥66 years with breast, colorectal, lung, ovarian, or prostate cancer, or non-Hodgkin lymphoma who initiated a first cycle of any myelosuppressive chemotherapy January 1, 2008-September 30, 2016, and received PP-sG-CSF. We matched up to four controls to each NRH case by age, cancer type, regimen febrile neutropenia (FN) risk category, and year using incidence density sampling. We used conditional logistic regression adjusted for race, sex, and modified Charlson comorbidity index (CCI) to estimate relative risk of NRH related to duration of PP-sG-CSF categorized as <5 and ≥ 5 days., Results: Of 2148 patients receiving PP-sG-CSF, 108 (5%) experienced NRH in the first cycle. We matched 333 controls to 96 cases. Cases were similar to controls in mean age, tumor type, and intermediate/high-risk regimen, but were more likely to have CCI ≥5 and less likely to use PP-sG-CSF ≥5 days (31% vs. 39%). Adjusted ORs (95% CI) for NRH were 0.69 (0.40-1.19) for ≥5 vs. <5 days of PP-sG-CSF among patients receiving any myelosuppressive chemotherapy, 0.43 (0.21-0.89) for intermediate/high-risk regimen, and 0.42 (0.19-0.89) for any myelosuppressive chemotherapy with all agents given on cycle day one only., Conclusions: Among older patients with cancer who are receiving PP-sG-CSF, ≥5 days of use was associated with substantial reduction in NRH risk., Competing Interests: Declaration of Competing Interest Shuling Li, Jiannong Liu, Tingting Gong, and Haifeng Guo are employees of Chronic Disease Research Group, Hennepin Healthcare Research Institute, which has received project funding from Amgen, Inc. Prasad L. Gawade, Michael A. Kelsh, Brian D. Bradbury, and Rajesh Belani are employees of and own stock in Amgen Inc. Gary Lyman has worked as a consultant for Amgen, Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To evaluate patterns of primary prophylactic (PP) granulocyte colony-stimulating factor (G-CSF) use following chemotherapy by cancer type and febrile neutropenia (FN) risk., Methods: Using a commercial administrative database, we identified adult patients diagnosed with breast, colorectal, lung, ovarian cancer, or non-Hodgkin lymphoma (NHL) who initiated chemotherapy with high risk (HR) or intermediate risk (IR) for FN between January 1, 2013, and August 31, 2017. We describe use of PP-G-CSF, proportion completing all their cycles with pegfilgrastim, timing of pegfilgrastim, and duration of short-acting G-CSF., Results: Among 22,868 patients (breast 11,513; colorectal 3765; lung 4273; ovarian 1287; and NHL 2030), 36.8% received HR and 63.2% received IR (64.4% of whom had ≥ 1 risk factor [RF] for FN). Proportions of patients receiving PP-G-CSF in the first cycle were 76.1%, 28.2%, and 26.4% among patients receiving HR, IR, and IR plus ≥ 1 RF, respectively. Among breast cancer patients receiving HR regimens and initiating PP-pegfilgrastim, 60.4% (95% confidence interval [CI] 57.2-63.6%) initiating via on-body injector (OBI) and 51.9% (95% CI 48.0-55.8%) initiating via prefilled syringe (PFS) completed all their cycles with OBI and PFS, respectively. Among all cycles with PP-PFS, 8.5% received PFS on the same day as chemotherapy completion. Mean administrations/cycle were 3.2 (standard deviation [SD] 2.3) for filgrastim, 3.0 (SD 1.6) for filgrastim-sndz, and 4.3 (SD 2.5) for tbo-filgrastim., Conclusions: There is under- and mistimed use of PP-G-CSF among patients at HR for FN. Novel pegfilgrastim delivery devices could help breast cancer patients at HR for FN complete all their cycles with timely prophylaxis.

Purpose: In contrast to randomized clinical trials, comparative safety and effectiveness assessments of osteoporosis medications in clinical practice may be subject to confounding by indication. We used negative control outcomes to detect residual confounding when comparing osteoporosis medications., Methods: Using MarketScan Commercial and Supplemental claims, we identified women aged ≥55 years who initiated an oral bisphosphonate (BP) (risedronate, alendronate, or ibandronate), denosumab (an injected biologic), or intravenous zoledronic acid (ZA) from October 1, 2010 to September 30, 2015. Women with Paget's disease or cancer were excluded. We compared individual oral BPs to each other, denosumab to ZA, denosumab to oral BPs, and ZA to oral BPs, with respect to 11 negative control outcomes identified by subject matter experts. We estimated the 12-month cumulative risk difference (RD) using inverse probability of treatment and censoring weights., Results: Among 148 587 women, most initiated alendronate (57%), followed by ibandronate (12%), ZA (11%), risedronate (10%), and denosumab (10%). Compared with denosumab, patients initiating ZA had similar risks of all negative control outcomes. Compared with oral BPs, patients initiating denosumab had a higher risk of a wellness visit (RD = 1.2%, 95% CI: 0.4, 1.9) and a lower risk of receiving herpes zoster vaccine (RD = -0.6%, 95% CI: -1.1, -0.2). Comparing ZA with oral BP initiators resulted in two outcomes with positive associations., Conclusions: Caution is warranted when comparing injectable vs oral osteoporosis medications, given the potential for unmeasured confounding. Evaluating negative control outcomes could be a standard validity check prior to conducting comparative studies., (© 2020 John Wiley & Sons Ltd.)

Purpose: As more biosimilars become available in the United States, postapproval noninterventional studies describing biosimilar switching and comparing effectiveness and/or safety between switchers and nonswitchers will play a key role in generating real-world evidence to inform clinical practices and policy decisions. Ensuring sound methodology is critical for making valid inferences from these studies., Methods: The Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) convened a workgroup consisting of academic researchers, industry scientists, and practicing clinicians to establish best practice recommendations for the conduct of noninterventional studies of biosimilar and reference biologic switching. The workgroup members participated in eight teleconferences between August 2017 and February 2018 to discuss specific topics and build consensus., Results: This report provides workgroup recommendations covering five main considerations relating to noninterventional studies describing reference biologic to biosimilar switching and comparing reference biologic to biosimilars for safety and effectiveness in the presence of switching at treatment initiation and during follow-up: (a) selecting appropriate data sources from a range of available options including insurance claims, electronic health records, and registries; (b) study designs; (c) outcomes of interest including health care utilization and clinical endpoints; (d) analytic approaches including propensity scores, disease risk scores, and instrumental variables; and (e) special considerations including avoiding designs that ignore history of biologic use, avoiding immortal time bias, exposure misclassification, and accounting for postindex switching., Conclusion: Recommendations provided in this report provide a framework that may be helpful in designing and critically evaluating postapproval noninterventional studies involving reference biologic to biosimilar switching., (© 2019 John Wiley & Sons, Ltd.)

Introduction: Red blood cell transfusions have been associated with infection risk. We investigated whether hospital transfusions are associated with infections in maintenance hemodialysis patients requiring transfusions for chronic anemia., Methods: In this retrospective cohort study, hemodialysis patients who experienced an incident hospitalization during 2012-2013 were identified from the Medicare end-stage renal disease database. Hospital transfusions were first categorized into one of five groups based on adjusted likelihood of administering red blood cell transfusions during inpatient hospital stays that occurred over the previous year (2011) among the general Medicare cohort. Next, in a patient-level analysis, patients were categorized according to transfusion use at the incident hospitalization hospital. Outcomes were infection-related rehospitalization and a composite of infection-related hospitalization and all-cause mortality during the 60 days following hospital discharge. We estimated adjusted rate ratios for the association between hospital transfusion use and risk of rehospitalization or the composite endpoint using Poisson regression models., Findings: The study included 1578 hospitals and 61,455 hemodialysis patients. Patient characteristics were balanced across hospital transfusion use groups. The overall transfusion rate was 16.0%. The overall 30-day infection-related hospitalization rate (95% confidence interval) per 100 patient-months was 8.8 (8.6-9.1); rates did not differ by transfusion use group. Rate ratios for infection-related rehospitalization were 1.00 (0.91-1.10) over 30 days and 0.98 (0.91-1.05) over 60 days comparing the lowest and highest transfusion use groups., Discussion: We found no differences in risk of infection-related rehospitalization for patients receiving maintenance hemodialysis across the varying blood transfusion rates of US hospitals., (© 2019 International Society for Hemodialysis.)

Background: Prior studies have developed a chronic kidney disease-mineral and bone disorder (CKD-MBD) composite score based on combinations of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) that have been shown to be associated with an increased risk of clinical outcomes in the USA. We examined this association in a contemporary, international cohort of hemodialysis patients., Methods: We studied 19 313 patients surviving ≥12 months in the Dialysis Outcomes and Practice Patterns Study Phases 3-5 (2005-15) from Europe, Canada and the USA. The CKD-MBD composite score was defined as the number of markers above target levels (P, 3.5-5.5 mg/dL; Ca, 8.4-10.2 mg/dL; PTH, 150-600 pg/mL). Using Cox models, we estimated hazard ratios (HRs) for death and a composite event (death or hospitalization), contrasting MBD 2/3 (2-3 parameters above target) with MBD 0 (all in target), adjusted for a disease risk score (DRS)., Results: MBD 2/3 above target was observed in 10-14% of patients across regions and was associated with greater DRS-adjusted mortality {HR 1.41 [95% confidence interval (CI) 1.10-1.82]} and composite events [HR 1.23 (95% CI 1.10-1.38)] in the USA compared with MBD 0; the mortality association was stronger for patients ≥ 65 years of age [HR 1.82 (95% CI 1.28-2.58)] compared with patients <65 years of age [HR 1.11 (95% CI 0.80-1.55)]. HRs observed in Canada and Europe were generally consistent but weaker. Estimates for MBD 2/3 outside target (above or below) were slightly lower in all regions., Conclusions: Simultaneous consideration of Ca, P and PTH may help in identifying patients on dialysis with a higher risk of major clinical outcomes related to CKD-MBD., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Morbidity and mortality vary seasonally. Timing and severity of influenza seasons contribute to those patterns, especially among vulnerable populations such as patients with ESRD. However, the extent to which influenza-like illness (ILI), a syndrome comprising a range of potentially serious respiratory tract infections, contributes to mortality in patients with ESRD has not been quantified., Methods: We used data from the Centers for Disease Control and Prevention (CDC) Outpatient Influenza-like Illness Surveillance Network and Centers for Medicare and Medicaid Services ESRD death data from 2000 to 2013. After addressing the increasing trend in deaths due to the growing prevalent ESRD population, we calculated quarterly relative mortality compared with average third-quarter (summer) death counts. We used linear regression models to assess the relationship between ILI data and mortality, separately for quarters 4 and 1 for each influenza season, and model parameter estimates to predict seasonal mortality counts and calculate excess ILI-associated deaths., Results: An estimated 1% absolute increase in quarterly ILI was associated with a 1.5% increase in relative mortality for quarter 4 and a 2.0% increase for quarter 1. The average number of annual deaths potentially attributable to ILI was substantial, about 1100 deaths per year., Conclusions: We found an association between community ILI activity and seasonal variation in all-cause mortality in patients with ESRD, with ILI likely contributing to >1000 deaths annually. Surveillance efforts, such as timely reporting to the CDC of ILI activity within dialysis units during influenza season, may help focus attention on high-risk periods for this vulnerable population., (Copyright © 2019 by the American Society of Nephrology.)

Purpose: Evaluate changes in use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in cancer patients receiving myelosuppressive chemotherapy following regulatory and reimbursement actions., Methods: Calendar year patient cohorts (2005-2013) with breast, colorectal, lung, multiple myeloma, non-Hodgkin lymphoma, ovarian, or prostate cancer and receiving myelosuppressive chemotherapy were identified within the Marketscan database. Incidence of ESA treatment and transfusion were estimated in each year, as was median number of ESA administrations. Clinical characteristics associated with ESA administration and transfusions were evaluated by using multivariable logistic regression. Additionally, annual new ESA user cohorts within the Oncology Services Comprehensive Electronic Records database (2011-2014) were examined to assess hemoglobin levels at ESA initiation., Results: Across all tumor types, ESA use decreased substantially (breast cancer: 53.7 to 3.2%; lung cancer: 66.0 to 13.3%, non-Hodgkin lymphoma: 39.8 to 3.8%), transfusion use increased (2 to 5.5%, 5.5 to 18.2%, and 4.5 to 9.1%, respectively), and median number of ESA administrations declined. Across all tumor types, proportion of patients initiating an ESA with hemoglobin >10 g/dL was <10% from 2011 onward. In recent years, cancer patients who are older, female, and have chronic kidney disease or moderate or severe liver disease were most likely to receive ESAs., Conclusion: Subsequent to important regulatory and reimbursement ESA-related actions, total ESA exposure among cancer patients receiving myelosuppressive chemotherapy declined substantially. Today, fewer patients receive ESA therapy, and among those treated, more are initiated at hemoglobin levels <10 g/dL and are exposed for a shorter duration, consistent with current product labeling., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Patients receiving hemodialysis with values outside of target levels for parathyroid hormone (PTH: 150-600 pg/mL), calcium (Ca: 8.4-10.2 mg/dL), and phosphate (P: 3.5-5.5 mg/dL) are at elevated morbidity and mortality risk. We examined whether patients receiving care in dialysis facilities where greater proportions of patients have at least two values out of target have a higher risk of adverse clinical outcomes., Methods: The study cohort consisted of 39,085 prevalent hemodialysis patients in 1298 DaVita dialysis facilities as of September 1, 2009, followed from January 1, 2010, until an outcome, a censoring event, or December 31, 2010. We determined the quintile of the distribution across facilities of the proportion of patients with at least two of three parameters out of, or above, target over a 4-month baseline period. The primary composite outcome was cardiovascular hospitalization or death. Secondary outcomes included death, cardiovascular hospitalization, and parathyroidectomy. Poisson regression models were used to estimate the association of facility quintile with outcomes., Results: Facility quintile was associated with a 7 % increased risk of cardiovascular hospitalization or death (quintile 5 versus 1, RR 1.07, 95 % CI 1.01-1.13) using the out-of-target measure of exposure and a 12 % increased risk (RR 1.12, 95 % CI 1.06-1.19) using the above-target measure. No association was seen for death using either measure. Patients in facility quintiles 3-5 (versus 1) were at increased parathyroidectomy risk (RR ranged from 2.05, 95 % CI 1.10-3.82, for quintile 3 to 2.73, 95 % CI 1.50-4.98, for quintile 5)., Conclusions: Facility level analysis of a large prevalent sample of US patients on hemodialysis demonstrates that patients in facilities with the least control of PTH, Ca, and P had the greatest risk of parathyroidectomy or the combination of cardiovascular hospitalization or death.

Purpose: Missed in-center hemodialysis treatments (MHT) are a general indicator of health status in hemodialysis patients. This analysis was conducted to estimate the association between cinacalcet use and MHT rate., Methods: We studied patients receiving hemodialysis and prescription benefits services from a large dialysis organization. Incident cinacalcet users were propensity score matched to controls on 31 demographic, clinical, and laboratory variables. We applied inverse probability (IP) of censoring and crossover weights to account for informative censoring. Weighted negative binomial modeling was used to estimate MHT rates and pooled logistics models were used to estimate the association between cinacalcet use and MHT., Results: Baseline demographic and clinical variables included serum calcium, phosphorus, parathyroid hormone, and vitamin D use, and were balanced between 15,474 new cinacalcet users and 15,474 matched controls. In an analysis based on intention-to-treat principles, 40.8% of cinacalcet users and 46.5% of nonusers were censored. MHT rate was 13% lower among cinacalcet initiators versus controls: IP of censoring weighted incidence rate ratio was 0.87 (95% confidence interval [CI]: 0.84-0.90 p < 0.001). In analyses based on as-treated principles, 72.8% and 61.5% of cinacalcet users and nonusers, respectively, crossed over or were censored. MHT rate was 15% lower among cinacalcet initiators versus controls: IP of censoring/crossover weighted incidence rate ratio was 0.85 (95%CI: 0.82-0.87 p < 0.001)., Conclusions: After controlling for indication and differential censoring, cinacalcet treatment was associated with lower MHT rates, which may reflect better health status. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia in patients with CKD, including those receiving dialysis, although clinical trials have identified risks associated with ESA use. We evaluated the effects of changes in dialysis payment policies and product labeling instituted in 2011 on mortality and major cardiovascular events across the United States dialysis population in an open cohort study of patients on dialysis from January 1, 2005, through December 31, 2012, with Medicare as primary payer. We compared observed rates of death and major cardiovascular events in 2011 and 2012 with expected rates calculated on the basis of rates in 2005-2010, accounting for differences in patient characteristics and influenza virulence. An abrupt decline in erythropoietin dosing and hemoglobin concentration began in late 2010. Observed rates of all-cause mortality, cardiovascular mortality, and myocardial infarction in 2011 and 2012 were consistent with expected rates. During 2012, observed rates of stroke, venous thromboembolic disease (VTE), and heart failure were lower than expected (absolute deviation from trend per 100 patient-years [95% confidence interval]: -0.24 [-0.08 to -0.37] for stroke, -2.43 [-1.35 to -3.70] for VTE, and -0.77 [-0.28 to -1.27] for heart failure), although non-ESA-related changes in practice and Medicare payment penalties for rehospitalization may have confounded the results. This initial evidence suggests that action taken to mitigate risks associated with ESA use and changes in payment policy did not result in a relative increase in death or major cardiovascular events and may reflect improvements in stroke, VTE, and heart failure., (Copyright © 2016 by the American Society of Nephrology.)

Background and Objectives: Fractures are a major source of morbidity and mortality in patients receiving dialysis. We sought to determine whether rates of fractures and tendon ruptures vary geographically., Design, Setting, Participants, & Measurements: Data from the US Renal Data System were used to create four yearly cohorts, 2007-2010, including all eligible prevalent patients on hemodialysis in the United States on January 1 of each year. A secondary analysis comprising patients in a large dialysis organization conducted over the same period permitted inclusion of patient-level markers of mineral metabolism. Patients were grouped into 10 regions designated by the Centers for Medicare and Medicaid Services and divided by latitude into one of three bands: south, <35°; middle, 35° to <40°; and north, ≥40°. Poisson regression was used to calculate unadjusted and adjusted region-level rate ratios for events., Results: Overall, 327,615 patients on hemodialysis were included. Mean (SD) age was 61.8 (15.0) years old, 52.7% were white, and 55.0% were men. During 716,962 person-years of follow-up, 44,014 fractures and tendon ruptures occurred, the latter being only 0.3% of overall events. Event rates ranged from 5.36 to 7.83 per 100 person-years, a 1.5-fold rate difference across regions. Unadjusted region-level rate ratios varied from 0.83 (95% confidence interval, 0.81 to 0.85) to 1.20 (95% confidence interval, 1.18 to 1.23), a 1.45-fold rate difference. After adjustment for a wide range of case mix variables, a 1.33-fold variation in rates remained. Rates were higher in north and middle bands than the south (north rate ratio, 1.18; 95% confidence interval, 1.13 to 1.23; middle rate ratio, 1.13; 95% confidence interval, 1.10 to 1.17). Latitude explained 11% of variation, independent of region. A complementary analysis of 87,013 patients from a large dialysis organization further adjusted for circulating mineral metabolic parameters and protein energy wasting yielded similar results., Conclusions: Rates of fractures vary geographically in the United States dialysis population, even after adjustment for known patient characteristics. Latitude seems to contribute to this phenomenon, but additional analyses exploring whether other factors might influence variation are warranted., (Copyright © 2016 by the American Society of Nephrology.)

Background: Little is known about epoetin alfa (EPO) dosing at dialysis centers after implementation of the US Medicare prospective payment system and revision of the EPO label in 2011., Study Design: Retrospective cohort study., Setting & Participants: Approximately 412,000 adult hemodialysis patients with Medicare Parts A and B as primary payer in 2009 to 2012 to describe EPO dosing and hemoglobin patterns; of these, about 70,000 patients clustered in about 1,300 dialysis facilities to evaluate facility-level EPO titration practices and patient-level outcomes in 2012., Predictor: Facility EPO titration practices when hemoglobin levels were <10 and >11g/dL (grouped treatment variable) determined from monthly EPO dosing and hemoglobin level patterns., Outcomes: Patient mean hemoglobin levels, red blood cell transfusion rates, and all-cause and cause-specific hospitalization rates using a facility-based analysis., Measurements: Monthly EPO dose and hemoglobin level, red blood cell transfusion rates, and all-cause and cause-specific hospitalization rates., Results: Monthly EPO doses declined across all hemoglobin levels, with the greatest decline in patients with hemoglobin levels < 10g/dL (July-October 2011). In 2012, nine distinct facility titration practices were identified. Across groups, mean hemoglobin levels differed slightly (10.5-10.8g/dL) but within-patient hemoglobin standard deviations were similar (∼0.68g/dL). Patients at facilities implementing greater dose reductions and smaller dose escalations had lower hemoglobin levels and higher transfusion rates. In contrast, patients at facilities that implemented greater dose escalations (and large or small dose reductions) had higher hemoglobin levels and lower transfusion rates. There were no clinically meaningful differences in all-cause or cause-specific hospitalization events across groups., Limitations: Possibly incomplete claims data; excluded small facilities and those without consistent titration patterns; hemoglobin levels reported monthly; inferred facility practice from observed dosing., Conclusions: Following prospective payment system implementation and labeling revisions, EPO doses declined significantly. Under the new label, facility EPO titration practices were associated with mean hemoglobin levels (but not standard deviations) and transfusion use, but not hospitalization rates., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Confounding, a concern in nonexperimental research using administrative claims, is nearly ubiquitous in claims-based pharmacoepidemiology studies. A fixed-length look-back window for assessing comorbidity from claims is common, but it may be advantageous to use all historical claims. We assessed how the strength of association between a baseline-identified condition and subsequent mortality varied by when the condition was measured and investigated methods to control for confounding., Methods: For Medicare beneficiaries undergoing maintenance hemodialysis on 1 January 2008 (n = 222 343), we searched all Medicare claims, 1 January 2001 to 31 December 2007, for four conditions representing chronic and acute diseases, and classified claims by number of months preceding the index date. We used proportional hazard models to estimate the association between time of condition and subsequent mortality. We simulated a confounded comorbidity-exposure relationship and investigated an alternative method of adjustment when the association between the condition and mortality varied by proximity to follow-up start., Results: The magnitude of the mortality hazard ratio estimates for each condition investigated decreased toward unity as time increased between index date and most recent manifestation of the condition. Simulation showed more biased estimates of exposure-outcome associations if proximity to follow-up start was not considered., Conclusions: Using all-available claims information during a baseline period, we found that for all conditions investigated, the association between a comorbid condition and subsequent mortality varied considerably depending on when the condition was measured. Improved confounding control may be achieved by considering the timing of claims relative to follow-up start., (Copyright © 2015 John Wiley & Sons, Ltd.)

Aim: The objective of this study was to examine the time-varying relationship of chronic kidney disease-mineral bone disorder (CKD-MBD) related biochemical parameters (parathyroid hormone (PTH), calcium, phosphate) over a 12-month period., Material and Methods: Using data from a large US provider of dialysis services from 2010 through 2012, we constructed a cohort of adult patients receiving in-center hemodialysis who had biochemical parameters measured at both baseline and 12 months of follow-up. We used descriptive statistics to assess the overall distributions of the biochemical parameters at both measurements, to examine how patients transitioned between categories for each biochemical parameter, and to evaluate how the biochemical parameters changed with respect to each other., Results: Among the 132,087 patients included in our analyses, the cross-sectional distributions for the combined categories of 150 - < 300 and 300 - < 600 pg/mL for PTH between the two measurements remained unchanged (67% of patients). For calcium and phosphate, the distributions across all categories also remained largely unchanged. Considering within-patient changes over time. however, a majority (74%) of patients who initially had a PTH < 150 pg/mL transitioned to a higher category, while a majority (56%) of patients who initially had a PTH > 600 pg/mL transitioned to a lower category. We observed that phosphate values on average directly trended with PTH values over the follow-up period., Conclusion: We found that while calcium showed relatively little variation, parallel bidirectional variation in PTH and phosphate over time was quite common among adult patients receiving hemodialysis. Optimal control of phosphate is likely to be dependent not only on consistent adherence to dietary restrictions and phosphate binders, but may additionally rely on adequate and sustained control of PTH.

Background: Little is known about changes in parathyroid hormone (PTH), calcium and phosphorous levels after parathyroidectomy in hemodialysis patients. We studied the effects of parathyroidectomy on these biochemical values in a large cohort of patients receiving maintenance hemodialysis., Methods: This retrospective cohort study included patients identified in both the United States Renal Data System and the database of a large dialysis organization who underwent parathyroidectomy in 2007-09, were aged ≥ 18 years, had Medicare Parts A and B as primary payer and had received hemodialysis for ≥ 1 year pre-parathyroidectomy. Descriptive statistics were calculated for continuous variables; categorical variables were used to characterize the population and evaluate monthly laboratory and medication use; median values were calculated for laboratory measures., Results: Among 1402 parathyroidectomy patients, mean age was 48.9 years, 52.4% were males, 58.8% were African American and mean dialysis duration was 7.5 years. Median PTH levels increased over the year before parathyroidectomy from 1039 to 1661 pg/mL and decreased afterward to 98 pg/mL at 1 month; levels remained ≥ 897 pg/mL for 10% of patients. Median calcium levels fell from 9.6 mg/dL before to 7.9 mg/dL 1 month after parathyroidectomy; levels were ≤ 7.1 mg/dL for 25% and remained ≤ 7.2 mg/dL for the lowest 25% at 3 months. Median phosphorous level was 6.8 mg/dL immediately before parathyroidectomy, decreased to 3.8 mg/dL immediately after and reached 5.8 mg/dL at 1 year., Conclusions: While PTH levels dropped after parathyroidectomy for most patients, surgery was sometimes ineffective in reducing levels and sometimes led to over-suppression. Hypocalcemia could be profound and long lasting, suggesting the need for prolonged vigilance., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Cinacalcet is used to treat secondary hyperparathyroidism among hemodialysis patients. Large-scale epidemiologic studies describing patterns of cinacalcet use, effects on parathyroid hormone (PTH), calcium, and phosphorous levels, and predictors of discontinuation have not been previously reported., Methods: This retrospective cohort study used a clinical database of a large U.S. dialysis provider (2007-2010) merged with administrative data from the United States Renal Data System. Among new users of cinacalcet with Medicare coverage, trends in PTH, calcium, and phosphorus were measured in 30-day intervals following cinacalcet initiation., Results: Seventeen thousand seven hundred sixty-three eligible initiators contributed 111,047 30-day follow-up intervals. Of these, 56 % discontinued cinacalcet by month 4. Of those discontinuing, 76.3 % reinitiated. Mean values of PTH, calcium, and phosphorus decreased to recommended levels within 4 months following initiation. Proximal PTH levels < 150 pg/mL were associated with discontinuation: HR = 1.23 (95 % CI: 1.12, 1.36), whereas low calcium (< 7.5 mg/dL) was suggestive of an association, HR = 1.09 (95 % CI 0.91, 1.32). Being in the Part D gap period increased discontinuation risk: HR = 1.09 (95 % CI: 1.03, 1.16). Low-income subsidy status decreased discontinuation risk: HR = 0.77 (95 % CI 0.69, 0.86). Predictors of reinitiation included low-income subsidy, HR = 1.32 (95 % CI 1.22, 1.43); higher albumin level, HR = 1.23 (95 % CI 1.10, 1.36) and higher calcium level, HR = 1.26 (95 % CI 1.19, 1.33)., Conclusions: Substantial and expected declines in laboratory values occurred following cinacalcet initiation. Early discontinuation and reinitiation of cinacalcet were common and may have occurred for clinical and economic reasons.

Purpose: Cinacalcet is indicated for treatment of secondary hyperparathyroidism in patients receiving hemodialysis. Cinacalcet reduces serum calcium concentrations by decreasing parathyroid hormone secretion, but the frequency and degree of calcium reduction following cinacalcet initiation, subsequent physician response, and ultimate calcium recovery in clinical practice are not well described., Methods: Patients receiving hemodialysis at a large dialysis organization who enrolled in the organization's prescription benefits service and initiated cinacalcet at serum calcium ≥8.4 mg/dL were studied (N = 13 723). Patients were categorized by whether they experienced a reduction in calcium to <8.4 mg/dL and to what level (<7.5, 7.5-7.9, and 8.0-8.3 mg/dL). Baseline characteristics, frequency of subsequent intervention, and calcium recovery were compared., Results: Of those who experienced a reduction in calcium to <8.4 mg/dL (n = 6437 [46.9%]), 6.6% had calcium <7.5 mg/dL and 24.5% had calcium 7.5-7.9 mg/dL, while the majority (68.9%) had a level of 8-8.3 mg/dL. Higher baseline parathyroid hormone and alkaline phosphatase were associated with lower resultant calcium. Among patients with calcium reductions, 45.6-63.5% received one or more directed clinical therapeutic responses, including 15.6-28.4% for whom cinacalcet was discontinued; the majority of patients recovered to calcium ≥8.4 mg/dL within 90 days of first detection. Only modest differences in recovery were noted between patients who did and did not receive any therapeutic response and patients who did and did not discontinue cinacalcet., Conclusion: Serum calcium reductions following cinacalcet initiation were common; declines <7.5 mg/dL were infrequent. Calcium recovery occurred in the majority of patients, with or without therapeutic intervention., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Some US dialysis facilities have reduced default dialysate calcium concentrations from 2.5 mEq/L to lower levels. There has been no rigorous systematic examination of the effects of such a reduction on clinical and biochemical outcomes., Study Design: Retrospective cohort study., Setting & Participants: Medicare-eligible patients who received in-center hemodialysis at a large dialysis organization in January 2008 to December 2010., Predictor: Facility conversion from predominant use (≥75% patients) of 2.50-mEq/L dialysate calcium to predominant use of lower dialysate calcium concentrations versus maintenance of predominant use of 2.50-mEq/L dialysate calcium., Outcomes: All-cause and cause-specific mortality and hospitalization, laboratory markers of metabolic bone disease, and drug utilization., Measurements: Hierarchical mixed linear and Poisson models were fit to compare pre- to postconversion differences in outcomes between converter and matched control facilities. Results, expressed as relative rate ratios (RRRs) and delta-delta (change in mean values), were estimated for early (months 0-2) and late (months 3-12) postconversion to allow for possible latent effects., Results: Facility conversion was associated with greater rates of hospitalization for heart failure exacerbation (late RRR, 1.27 [95% CI, 1.06-1.51]), hypocalcemia (early RRR, 1.19 [95% CI, 1.05-1.35]; late RRR, 1.39 [95% CI, 1.20-1.60]), and intradialytic hypotension (early RRR, 1.07 [95% CI, 1.02-1.11]; late RRR, 1.05 [95% CI, 1.01-1.10]), but no differences were observed for all-cause mortality or hospitalization rates. Facility conversion was also associated with comparative temporal decreases in serum calcium level, increases in serum phosphate and parathyroid hormone levels, and increases in use of phosphate binders, vitamin D, and calcimimetics., Limitations: Possible residual confounding, generalizability beyond Medicare patients uncertain., Conclusions: There are potential safety concerns associated with the default use of dialysate calcium concentrations < 2.50 mEq/L, as well as biochemical evidence of poorer disease control despite associated greater medication use. Individualization of dialysate calcium concentration rather than predominant use of dialysate calcium concentrations < 2.50 mEq/L should be considered., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: It is important to identify an easily defined subset of patients at increased risk of adverse clinical outcomes associated with mineral and bone disorder (MBD) biomarkers (parathyroid hormone, calcium and phosphate)., Methods: Observational cohort study of 26 221 prevalent hemodialysis patients in Davita clinics as of 31 August 2005 and followed up until 31 December 2006 (16 months). Predictors were 12 possible definitions of 'clinically important' MBD based on all 3 biomarkers, and 18 alternative definitions based on only 1 or 2 biomarkers. Events were death alone and a composite of cardiovascular hospitalization or death. Excess events were calculated based on a multivariate Cox model using 5224 patients in target for all MBD biomarkers and applied to 20 997 patients out of target for at least one biomarker. Excess events attributable to MBD were estimated by subtracting the multivariate model-derived predicted number from the actual number. Outcomes were the proportion of excess events attributable to MBD captured by each definition (threshold ≥70%) and the reduction in the population size considered to have clinically important MBD (threshold ≥30%). The excess fraction was excess events divided by actual events., Results: Patients with more biochemical markers out of target tended to be younger, black and have longer times since starting dialysis. The excess fraction associated with MBD ranged from ∼10 to 26% depending on the clinical endpoint and definition. The only definition to meet the thresholds required at least two of the three MBD biomarkers to be out of target (high or low). It captured 82% of excess composite endpoints and 74% of excess deaths and reduced the at-risk population by 46%., Conclusions: Patients with at least two of three MBD biomarkers out of target represent a subgroup of patients at elevated risk of adverse clinical events., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.)

Purpose: In recent years, the use of red blood cell (RBC) transfusion for the treatment of chronic kidney disease (CKD)-related anemia has increased. We used the OptumInsight medical claims database to study the association between receiving a transfusion and hyperkalemia and heart failure events., Methods: Persons 18-64 years of age with diagnosed stage 4 or 5 CKD (not requiring dialysis) between 2006 and 2010 were followed until their first hospitalization or emergency room visit with a diagnosis of hyperkalemia or heart failure, termination of insurance coverage, or death. We used a case-only design and conditional logistic regression to estimate rate ratios (RR) and 95% confidence intervals (CIs) describing associations between RBC transfusion and the risks of hyperkalemia or heart failure. We used single (1:1) and variable (1:m) self-control matching intervals, with adjustment for time-varying confounders., Results: Seven thousand eight hundred twenty-nine individuals met our inclusion criteria; two-thirds were age 50 years or older; 43% were women and 51% had diabetes. Rates of hyperkalemia and heart failure were 7.9/100 person-years (95%CI: 7.3, 8.5) and 16.3/100 person-years (95%CI: 15.5, 17.2), respectively. RBC transfusion was associated with an increased risk of both hyperkalemia (single interval matched RR = 12.0, 95%CI: 1.3, 109; multiple interval matched RR = 6.1, 95%CI: 2.5, 15.1) and heart failure (single interval matched RR = 1.7, 95%CI: 0.3, 9.2; multiple interval matched RR = 3.8, 95%CI: 1.4, 10.3)., Conclusion: In patients with advanced CKD, RBC transfusion appears to be associated with an elevated risk of hyperkalemia and heart failure; further investigation into these risks is warranted., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: The aim of the US dialysis Prospective Payment System bundle, launched in January 2011, was reduction and more accurate prediction of costs of services, whilst maintaining or improving patient care. Dialysis facilities could either adopt the bundle completely (100%) in the first year of launch, or phase-in (25%) over four years. Differences in practice patterns and patient outcomes were hypothesized to occur in facilities that phased-in 25% compared to those that did not., Methods: Data are from STEPPS, a study of 51 small dialysis organization facilities designed to describe trends in dialytic treatment before and after bundle implementation. Baseline was defined as October-December 2010; follow-up as January-December 2011. Facility- and patient-level data were collected at enrollment and regularly thereafter. Cox proportional hazards and linear multi-level models were used to estimate the effect of opting-in 25% (vs. 100%) on practice patterns and clinical outcomes., Results: 12 facilities (patient n = 346) opted-in 25% and 37 facilities (patient n = 1296) opted-in 100% to the dialysis bundle. At baseline, patients at 25% facilities were primarily covered by Medicare, were more likely to be black, and were receiving higher monthly epoetin alfa (EPO) doses. Throughout 2011, patients in 100% facilities received lower monthly EPO doses, and had lower mean hemoglobin concentrations; hospitalization and mortality rates were numerically lower in 25% facilities but not statistically different., Conclusions: The economic pressure for dialysis providers to work within an expanded composite rate bundle whilst maintaining patient care may be a driver of practice indicator outcomes. Additional investigations are warranted to more precisely estimate clinical outcomes in patients attending facilities enrolling into the bundle 100% relative to the previous fee-for-service framework.

Background: Cinacalcet reduces parathyroid hormone (PTH) levels in patients receiving hemodialysis, but no non-experimental studies have evaluated the association between changes in PTH levels following cinacalcet initiation and clinical outcomes. We assessed whether short-term change in PTH levels after first cinacalcet prescription could serve as a surrogate marker for improvements in longer-term clinical outcomes., Methods: United States Renal Data System data were linked with data from a large dialysis organization. We created a point prevalent cohort of adult hemodialysis patients with Medicare as primary payer who initiated cinacalcet November 1, 2004-February 1, 2007, and were on cinacalcet for ≥ 40 days. We grouped patients into quartiles of PTH change after first cinacalcet prescription. We used Cox proportional hazard modeling to evaluate associations between short-term PTH change and time to first composite event (hospitalization for cardiovascular events or mortality) within 1 year. Overall models and models stratified by baseline PTH levels were adjusted for several patient-related factors., Results: For 2485 of 3467 included patients (72%), PTH levels decreased after first cinacalcet prescription; for 982 (28%), levels increased or were unchanged. Several characteristics differed between PTH change groups, including age and mineral-and-bone-disorder laboratory values. In adjusted models, we did not identify an association between greater short-term PTH reduction and lower composite event rates within 1 year, overall or in models stratified by baseline PTH levels., Conclusions: Short-term change in PTH levels after first cinacalcet prescription does not appear to be a useful surrogate for longer-term improvements in cardiovascular or survival risk.

Background and Objectives: Patients receiving dialysis undergo parathyroidectomy to improve laboratory parameters in resistant hyperparathyroidism with the assumption that clinical outcomes will also improve. However, no randomized clinical trial data demonstrate the benefits of parathyroidectomy. This study aimed to evaluate clinical outcomes up to 1 year after parathyroidectomy in a nationwide sample of patients receiving hemodialysis., Design, Setting, Participants, & Measurements: Using data from the US Renal Data System, this study identified prevalent hemodialysis patients aged ≥18 years with Medicare as primary payers who underwent parathyroidectomy from 2007 to 2009. Baseline characteristics and comorbid conditions were assessed in the year preceding parathyroidectomy; clinical events were identified in the year preceding and the year after parathyroidectomy. After parathyroidectomy, patients were censored at death, loss of Medicare coverage, kidney transplant, change in dialysis modality, or 365 days. This study estimated cause-specific event rates for both periods and rate ratios comparing event rates in the postparathyroidectomy versus preparathyroidectomy periods., Results: Of 4435 patients who underwent parathyroidectomy, 2.0% died during the parathyroidectomy hospitalization and the 30 days after discharge. During the 30 days after discharge, 23.8% of patients were rehospitalized; 29.3% of these patients required intensive care. In the year after parathyroidectomy, hospitalizations were higher by 39%, hospital days by 58%, intensive care unit admissions by 69%, and emergency room/observation visits requiring hypocalcemia treatment by 20-fold compared with the preceding year. Cause-specific hospitalizations were higher for acute myocardial infarction (rate ratio, 1.98; 95% confidence interval, 1.60 to 2.46) and dysrhythmia (rate ratio 1.4; 95% confidence interval1.16 to 1.78); fracture rates did not differ (rate ratio 0.82; 95% confidence interval 0.6 to 1.1)., Conclusions: Parathyroidectomy is associated with significant morbidity in the 30 days after hospital discharge and in the year after the procedure. Awareness of clinical events will assist in developing evidence-based risk/benefit determinations for the indication for parathyroidectomy., (Copyright © 2015 by the American Society of Nephrology.)

Background/aims: Recent changes in clinical practice guidelines and reimbursement policies may have affected the use of anemia-related medications and red blood cell (RBC) transfusions in peritoneal dialysis (PD) and hemodialysis (HD) patients. We sought to compare patterns of erythropoiesis-stimulating agents (ESA) and intravenous (IV) iron use, achieved hemoglobin levels, and RBC transfusion use in PD and HD patients., Methods: In quarterly cohorts of prevalent dialysis patients receiving persistent therapy (>3 months), 2007-2011, with Medicare Parts A and B coverage, we assessed ESA and IV iron use and dose, RBC transfusions, and hemoglobin levels. Quarterly transfusion rates were calculated., Results: Observable PD and HD patients numbered 14,958 and 221,866 in Q1/2007 and 17,842 and 256,942 in Q4/2011. Adjusted ESA use was lower in PD (71.4-80.1%) than in HD (86.9-92.0%) patients, decreasing from 80.1% (Q1/2010) to 71.4% (Q4/2011) in PD patients, and from 92.0 to 86.9% in HD patients. The mean adjusted ESA dose decreased by 67.5% in PD and 58.4% in HD patients. IV iron use tended to increase, peaking at 39.3% for PD (Q3/2011) and 80.5% for HD (Q2/2011) patients. Adjusted mean hemoglobin levels fell from 11.7 to 10.6 mg/dl in PD and from 12.0 to 10.7 mg/dl in HD ESA users; adjusted transfusion rates increased from 2.4 to 3.0 per 100 patient-months in PD and from 2.6 to 3.3 in HD patients., Conclusions: In patients receiving persistent dialysis, dose and frequency of ESA administrations decreased during the period 2007-2011. Mean hemoglobin levels decreased by more than 1 g/dl, while transfusion rates increased by approximately 25%., (© 2015 S. Karger AG, Basel.)

Background: Because transfusion avoidance has been the cornerstone of anemia treatment for patients with kidney disease, direct measurement of red blood cell transfusion use to assess dialysis facility anemia management performance is reasonable. We aimed to explore methods for estimating facility-level standardized transfusion ratios (STfRs) to assess provider anemia treatment practices., Study Design: Retrospective cohort study., Setting & Participants: Point prevalent US hemodialysis patients on January 1, 2009, with Medicare as primary payer and dialysis duration of 90 days or longer were included (n = 223,901). All dialysis facilities with eligible patients were included (n = 5,345)., Predictor: Dialysis facility assignment., Outcome: Receiving a red blood cell transfusion in the inpatient or outpatient setting., Measurements: We evaluated 3 approaches for estimating STfR: ratio of observed to expected numbers of transfusions (STfR(obs)), a Bayesian approach (STfR(Bayes)), and a modified version of the Bayesian approach (STfR(modBayes))., Results: The overall national transfusion rate in 2009 was 23.2 per 100 patient-years. Our model for predicting the expected number of transfusions performed well. For large facilities, all 3 STfRs worked well. However, for small facilities, while the STfR(modBayes) worked well, STfR(obs) values demonstrated instability and the STfR(Bayes) may produce more bias., Limitations: Administration of transfusions to dialysis patients reflects medical practice both within and outside the dialysis unit. Some transfusions may be deemed unavoidable and transfusion practices are subject to considerable regional variation., Conclusions: Development of an STfR metric is feasible and reasonable for assessing anemia treatment at dialysis facilities. The STfR(obs) is simple to calculate and works well for larger dialysis facilities. The STfR(modBayes) is more analytically complex, but facilitates comparisons across all dialysis facilities, including small facilities., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Changes in anemia management practices due to concerns about erythropoiesis-stimulating agent safety and Medicare payment changes may increase patient risk of transfusion. We examined anemia management trends in hemodialysis patients and risk of red blood cell (RBC) transfusion according to dialysis facility-level hemoglobin concentration., Study Design: Retrospective follow-up study; 6-month study period (January to June), 3-month exposure/follow-up., Setting & Participants: For each year in 2007-2011, annual cohorts of point-prevalent Medicare primary payer patients receiving hemodialysis on January 1 with one or more hemoglobin measurements during the study period. Annual cohorts averaged 170,000 patients, with 130,000 patients and 3,100 facilities for the risk analysis., Predictor: Percentage of facility patient-months with hemoglobin level<10 g/dL., Outcome: Patient-level RBC transfusion rates., Measurements: Monthly epoetin alfa and intravenous iron doses, mean hemoglobin levels, and RBC transfusion rates; percentage of facility patient-months with hemoglobin levels<10 g/dL (exposure) and patient-level RBC transfusion rates (follow-up)., Results: Percentages of patients with hemoglobin levels<10 g/dL increased every year from 2007 (6%) to 2011 (~11%). Epoetin alfa doses, iron doses, and transfusion rates remained relatively stable through 2010 and changed in 2011. Median monthly epoetin alfa and iron doses decreased 25% and 43.8%, respectively, and monthly transfusion rates increased from 2.8% to 3.2% in 2011, a 14.3% increase. Patients in facilities with the highest prevalence of hemoglobin levels<10 g/dL over 3 months were at ~30% elevated risk of receiving RBC transfusions within the next 3 months (relative risk, 1.28; 95% CI, 1.22-1.34)., Limitations: Possibly incomplete claims data; smaller units excluded; hemoglobin levels reported monthly for patients receiving epoetin alfa; transfusions usually not administered in dialysis units., Conclusions: Dialysis facility treatment practices, as assessed by percentage of patient-months with hemoglobin levels<10 g/dL over 3 months, were associated significantly with risk of transfusions in the next 3 months for all patients in the facility, regardless of patient case-mix., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Most studies of HLA sensitization after red blood cell transfusion in transplant candidates were done before widespread use of leuko reduced blood and based on relatively insensitive, nonspecific antibody assays. We evaluated the effect of transfusion on the breadth and magnitude of HLA antibody formation using current, sensitive, HLA-specific immunoassays., Methods: Serial HLA antibody data were merged with transfusion data from the US Renal Data System for 1324 patients on the kidney transplant wait list (2004-2010). Two study groups were identified: a matched cohort consisting of 89 patients who received transfusion and 251 patients who did not receive transfusion and a crossover cohort consisting of 69 patients. Changes in antibody levels and calculated panel-reactive antibody (CPRA) were compared using χ and Sign tests, respectively. Logistic regression was used to estimate the relative risk of antibody responses., Results: Among the matched cohort, 20% of those who received transfusion compared to 3% of those who did not receive transfusion exhibited an antibody response (P=0.001), whereas in the crossover cohort, 19% exhibited a response in those who received transfusion compared to 1% of those who did not receive transfusion (P=0.0001). Moreover, 26.3% of those who received transfusion had increased CPRA compared to 5.8% of those who did not receive transfusion . These effects were greater in women and blacks compared to men and whites, respectively. Importantly, patients who received transfusion were at an increased risk of a potentially crossmatch positive response (odds ratio=9.6, 95% confidence interval=3.0-30.7)., Conclusions: Sensitization from transfusion can occur in up to 20% of transplant candidates, resulting in higher antibody levels and CPRA values that adversely impact access to transplantation. These results support transfusion avoidance whenever possible.

Altered bone structure and function contribute to the high rates of fractures in dialysis patients compared to the general population. Fracture events may increase the risk of subsequent adverse clinical outcomes. Here we assessed the incidence of post-fracture morbidity and mortality in an international cohort of 34,579 in-center hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). We estimated country-specific rates of fractures requiring a hospital admission and associated length of stay in the hospital. Incidence rates of death and of a composite event of death/rehospitalization were estimated for 1 year after fracture. Overall, 3% of participants experienced a fracture. Fracture incidence varied across countries, from 12 events/1000 patient-years (PY) in Japan to 45/1000 PY in Belgium. In all countries, fracture rates were higher in the hemodialysis group compared to those reported for the general population. Median length of stay ranged from 7 to 37 days in the United States and Japan, respectively. In most countries, postfracture mortality rates exceeded 500/1000 PY and death/rehospitalization rates exceeded 1500/1000 PY. Fracture patients had higher unadjusted rates of death (3.7-fold) and death/rehospitalization (4.0-fold) compared to the overall DOPPS population. Mortality and hospitalization rates were highest in the first month after the fracture and declined thereafter. Thus, the high frequency of fractures and increased adverse outcomes following a fracture pose a significant health burden for dialysis patients. Fracture prevention strategies should be identified and applied broadly in nephrology practices.

Background/aims: Predialysis care has been associated with improved first-year outcomes. We investigated types of predialysis care associated with improved patient outcomes in patients initiating dialysis with a fistula and at least 2 years of predialysis care., Methods: In this retrospective cohort of incident hemodialysis patients with ≥2 years of Medicare coverage before dialysis initiation, care patterns and patients were determined using Medicare claims. Fistula use at initiation was ascertained from the Medical Evidence Report., Results: Patients aged ≥67 years who initiated hemodialysis with a fistula (n = 14,459) differed demographically and clinically from patients who initiated with other vascular access types; however, 55% had diabetes, 28% heart failure, and 40% ischemic heart disease. In the year preceding initiation, 88% of these patients visited a nephrologist, 66% a cardiologist, 9% an endocrinologist, and 3% a dietician; most underwent routine laboratory measurements. In the first year of dialysis, 50% were hospitalized and 1.3% underwent transplant; the mortality rate remained constant (∼20 per 100 patient-years). Of predialysis care factors evaluated, only fistula placement more than 1 month before dialysis initiation was associated with lower hospitalization and mortality risk and greater likelihood of transplant. Other potentially modifiable factors included more contact with cardiologists and endocrinologists., Conclusion: Patients initiating dialysis with a functioning fistula appear to receive substantial predialysis preparation. This selected population does not show the excess mortality risk often observed early in dialysis treatment. Earlier fistula placement and referral to cardiology and endocrinology appear to be important aspects of predialysis care.

Mortality rates for maintenance hemodialysis patients are much higher than the general population and are even greater soon after starting dialysis. Here we analyzed mortality patterns in 86,886 patients in 11 countries focusing on the early dialysis period using data from the Dialysis Outcomes and Practice Patterns Study, a prospective cohort study of in-center hemodialysis. The primary outcome was all-cause mortality, using time-dependent Cox regression, stratified by study phase adjusted for age, sex, race, and diabetes. The main predictor was time since dialysis start as divided into early (up to 120 days), intermediate (121-365 days), and late (over 365 days) periods. Mortality rates (deaths/100 patient-years) were 26.7 (95% confidence intervals 25.6-27.9), 16.9 (16.2-17.6), and 13.7 (13.5-14.0) in the early, intermediate, and late periods, respectively. In each country, mortality was higher in the early compared to the intermediate period, with a range of adjusted mortality ratios from 3.10 (2.22-4.32) in Japan to 1.15 (0.87-1.53) in the United Kingdom. Adjusted mortality rates were similar for intermediate and late periods. The ratio of elevated mortality rates in the early to the intermediate period increased with age. Within each period, mortality was higher in the United States than in most other countries. Thus, internationally, the early hemodialysis period is a high-risk time for all countries studied, with substantial differences in mortality between countries. Efforts to improve outcomes should focus on the transition period and the first few months of dialysis.

Background: Changes in anemia management over the past decade have produced downward shifts in hemoglobin concentrations. We aimed to examine the effect on use of red blood cell (RBC) transfusions., Study Design: Retrospective cohort study., Setting & Participants: We identified point prevalent Medicare hemodialysis patients as of January 1 of each year (1999-2010) and categorized them based on 3-month (April to June) mean hemoglobin levels (<10 or ≥10 g/dL) in each year., Predictors: Hemoglobin patterns over time and clinical profiles based on achieved hemoglobin concentrations., Outcomes: RBC transfusion use., Measurements: We used negative binomial modeling to examine the effect of hemoglobin level <10 g/dL on transfusion use, adjusting for case-mix differences., Results: Proportions of patients with mean hemoglobin levels <10 g/dL decreased from 10% (1999) to ~4% (2005), but began increasing after 2006 and reached 6% by 2010. Accounting for case-mix differences, transfusion rates remained relatively constant at approximately 7.9 per 100 person-months for patients with hemoglobin levels <10 g/dL and 2 per 100 person-months for patients with hemoglobin levels ≥10 g/dL. Patients with average hemoglobin levels <10 g/dL were more likely to receive transfusions (risk ratio, 2.2; 95% CI, 2.1-2.2) even after adjustment; the risk ratio doubled if hemoglobin levels remained <10 g/dL for 6 months (4.4; 95% CI, 3.7-5.2)., Limitations: Limited in generalizability to patients with Medicare as primary payer; residual confounding from factors such as frailty and chronic inflammation cannot be excluded; categorizing patients based on an average of 3 outpatient hemoglobin measurements may introduce some misclassification., Conclusions: Risk of transfusion increases substantially with hemoglobin concentrations <10 g/dL; risk appears to be independent of other clinical factors. If anemia management patterns shift toward lower hemoglobin concentrations, RBC transfusion use likely will increase in dialysis patients., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)