Real-world treatments and thrombotic events in polycythemia vera patients in the USA.

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with increased risk of thrombotic events (TE) and death. Therapeutic interventions, phlebotomy and cytoreductive medications, are targeted to maintain hematocrit levels < 45% to prevent adverse outcomes. This retrospective observational study examined medical and pharmacy claims of 28,306 PV patients initiating treatment for PV in a data period inclusive of 2011 to 2019. Study inclusion required ≥ 2 PV diagnosis codes in the full data period, at least 1 year of PV treatment history, and ≥ 1 prescription claim and medical claim in both 2018 and 2019. Patients having ≥ 2 hematocrit (HCT) test results in linked outpatient laboratory data (2018-2019) were designated as the HCT subgroup (N = 4246). Patients were characterized as high- or low-risk at treatment initiation based on age and prior thrombotic history. The majority of patients in both risk groups (60% of high-risk and 83% of low-risk) initiated treatment with phlebotomy monotherapy, and during a median follow-up period of 808 days, the vast majority (81% low-risk, 74% high-risk) maintained their original therapy during the follow-up period. Hematocrit control was suboptimal in both risk groups; 54% of high-risk patients initiating with phlebotomy monotherapy sometimes/always had HCT levels > 50%; among low-risk patients, 64% sometimes/always had HCT levels above 50%. Overall, 16% of individuals experienced at least 1 TE subsequent to treatment initiation, 20% (n = 3920) among high-risk and 8% (n = 629) among low-risk patients. This real-world study suggests that currently available PV treatments may not be used to full advantage.

Metabolic acidosis is undertreated and underdiagnosed: a retrospective cohort study.

BACKGROUND: Guidelines recommend treatment of metabolic acidosis (MA) in patients with chronic kidney disease (CKD), but the diagnosis and treatment rates in real-world settings are unknown. We investigated the frequency of MA treatment and diagnosis in patients with CKD. METHODS: In this retrospective cohort study, we examined administrative health data from two US databases [Optum's de-identified Integrated Claims + Clinical Electronic Health Record Database (US EMR cohort; 1 January 2007 to 30 June 2019) and Symphony Health Solutions IDV® (US claims cohort; 1 May 2016 to 30 April 2019)] and population-level databases from Manitoba, Canada (1 April 2006 to 31 March 2018). Patients who met laboratory criteria indicative of CKD and chronic MA were included: two consecutive estimated glomerular filtration results <60 mL/min/1.73 m2 and two serum bicarbonate results 12 to <22 mEq/L over 28-365 days. Outcomes included treatment of MA (defined as a prescription for oral sodium bicarbonate) and a diagnosis of MA (defined using administrative records). Outcomes were assessed over a 3-year period (1 year pre-index, 2 years post-index). RESULTS: A total of 96 184 patients were included: US EMR, 6179; Manitoba, 3223; US Claims, 86 782. Sodium bicarbonate treatment was prescribed for 17.6%, 8.7% and 15.3% of patients, and a diagnosis was found for 44.7%, 20.9% and 20.9% of patients, for the US EMR, Manitoba and US Claims cohorts, respectively. CONCLUSIONS: This analysis of 96 184 patients with laboratory-confirmed MA from three independent cohorts of patients with CKD and MA highlights an important diagnosis and treatment gap for this disease-modifying complication.

Relationship between Metabolic Acidosis and Chronic Kidney Disease Progression across Racial and Ethnic Groups: An Observational, Retrospective Cohort Study.

INTRODUCTION: Metabolic acidosis is associated with chronic kidney disease (CKD) progression and mortality, but the association of race/ethnicity with incident metabolic acidosis and/or its adverse outcomes in patients with CKD is unknown. METHODS: We used deidentified medical records data (2007-2019) to generate a cohort of 136,067 patients with nondialysis-dependent CKD stages 3-5 and ≥2 years' postindex data or death within 2 years. We grouped participants into those with and without metabolic acidosis (serum bicarbonate 12 to <22 mEq/L vs. 22 to <30 mEq/L) as Asian, Black, Hispanic, non-Hispanic White individuals, or unknown. Cox proportional hazards models examined factors associated with (1) incident metabolic acidosis; and (2) time to the composite outcome of death, dialysis, transplant, or ≥40% decline from baseline eGFR (DD40) within each race/ethnic group. RESULTS: Metabolic acidosis incidence was higher for Asian, Black, and Hispanic versus non-Hispanic White individuals (p values for adjusted hazard ratios [HR] all <0.001), but this higher hazard was mitigated in all groups with increasing community education. During the median follow-up of 4.2 years, 47,032 of 136,607 (34.6%) experienced a DD40 event. There was an independent association of metabolic acidosis with DD40 within each race/ethnic group. Adjusted HRs (95% confidence interval) for DD40 were 1.806 (1.312, 2.486), 1.420 (1.313, 1.536), 1.409 (1.211, 1.641), and 1.561 (1.498, 1.626) in Asian, Black, Hispanic, and non-Hispanic White groups, respectively (all p < 0.0001), for metabolic acidosis versus normal serum bicarbonate. DISCUSSION/CONCLUSION: The higher incidence of metabolic acidosis observed in Asian, Black, and Hispanic individuals was mitigated by residing in higher education zip codes. Once established, metabolic acidosis was independently associated with DD40 in patients with CKD in all racial/ethnic groups examined.

Metabolic acidosis is associated with increased risk of adverse kidney outcomes and mortality in patients with non-dialysis dependent chronic kidney disease: an observational cohort study.

BACKGROUND: Management of chronic kidney disease (CKD) requires the management of risk factors, such as hypertension and albuminuria, that affect CKD progression. Identification of additional modifiable risk factors is necessary to develop new treatment strategies for CKD. We sought to quantify the association of metabolic acidosis with CKD progression and mortality in a large U.S. community-based cohort. METHODS: In this longitudinal, retrospective cohort study we identified non-dialysis-dependent patients with stage 3‒5 CKD from Optum's de-identified integrated electronic health records. We selected cohorts of patients with confirmed metabolic acidosis or normal serum bicarbonate levels based on 2 consecutive serum bicarbonate values: 12 to < 22 mEq/L or 22-29 mEq/L, respectively, 28‒365 days apart. The primary composite outcome was ≥ 40 % decline in estimated glomerular filtration rate (eGFR), renal replacement therapy (chronic dialysis or kidney transplant), or all-cause mortality (DD40). Secondary outcomes included each component of the composite outcome. Cox proportional hazards models were used for the DD40 outcome and secondary outcomes, while logistic regression models were used for the DD40 outcome at 2 years. RESULTS: A total of 51,558 patients qualified for the study. The unadjusted 2-year incidence of adverse renal and fatal outcomes was significantly worse among patients in the metabolic acidosis group vs. those who had normal serum bicarbonate levels: 48 % vs. 17 % for DD40, 10 % vs. 4 % for ≥ 40 % decline in eGFR, 20 % vs. 6 % for renal replacement therapy, and 31 % vs. 10 % for all-cause mortality (all P < 0.001). Over a ≤ 10-year period, for each 1-mEq/L increase in serum bicarbonate, the adjusted hazard ratio for DD40 was 0.926 (95 % confidence interval [CI], 0.922-0.930; P < 0.001); over a ≤ 2-year period, the adjusted odds ratio for DD40 was 0.873 (95 % CI, 0.866-0.879; P < 0.001). CONCLUSIONS: In this large community cohort of patients with stage 3‒5 CKD, the presence of metabolic acidosis was a significant, independent risk factor for the composite adverse outcome of CKD progression, renal replacement therapy, and all-cause mortality (DD40).

The direct cost of seizure events in severe childhood-onset epilepsies: A retrospective claims-based analysis.

OBJECTIVE: The objective of the study was to assess the direct cost of medically treated seizure events in severe childhood-onset epilepsies. Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC) are representative conditions associated with frequent intractable seizures. METHODS: Commercial and Medicaid insurance claims from 2010 to 2015 were queried to identify patients with possible LGS, possible DS, or TSC, having ≥2 years of continuous insurance from the date of first epilepsy/seizure diagnosis or antiepileptic drug (AED) fill (index date). Utilization and cost data in patients with and without seizure events requiring acute treatment were evaluated for two years postindex. Medically treated seizure events resulting in minor, moderate, severe, and no injury were included. Average costs were normalized to 2017 dollars at 3% per annum and reported for each cohort, by insurance type and degree of injury. RESULTS: Among 9754 patients, 55.4-58.8% of LGS, 47.7-55.8% of DS, and 13.7-28.0% of TSC cohorts had ≥1 medically treated seizure event, depending on insurance type. Events during two-year postindex averaged 2.8-3.3 in LGS, 3.1-3.3 in DS, and 1.9-2.2 in TSC; cost per event averaged $8147-$14,759 in LGS, $4637-$8751 in DS, and $5335-$9672 in TSC. In patients with events, average all-cause costs per-patient-per-year (PPPY) were $71,512-$84,939 in LGS; $31,278-$43,758 in DS; and $42,997-$48,330 in TSC. CONCLUSIONS: Patients with intractable seizures having at least one medically treated seizure event incur substantial all-cause costs. Our results can be used to inform cost effectiveness and budget impact models to estimate the value of existing and future treatments for these and similar conditions.

Burden of illness in patients with possible Lennox-Gastaut syndrome: A retrospective claims-based study.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe and treatment-resistant epilepsy syndrome characterized by multiple subtypes of intractable seizures, moderate to severe cognitive impairment, and slow spike-wave complexes on electroencephalographic (EEG) recordings. Lennox-Gastaut syndrome is also associated with increased risk for injury, reduced quality of life, long-term disability, and early mortality. By evaluating private and public US medical insurance claims, we quantified healthcare utilization and direct costs in patients with possible LGS. METHODS: Commercial and Medicaid insurance claims (Truven Health Analytics) from October 2010 to September 2015 were queried to identify patients with intractable epilepsy, intellectual disability, ≥1 prescription for selected antiepileptic drugs (AEDs), and ≥2 years of continuous enrollment. To identify patients with LGS in the absence of a specific International Classification of Diseases ICD-9 diagnosis code, current or prior rufinamide use was selected as a disease indicator of LGS per previously published methodology. Characteristics significantly predictive of rufinamide use were identified with multivariate regression by comparing groups with and without LGS, then assessed in non-rufinamide users fulfilling all other inclusion criteria. Controls without epilepsy, seizures, or prescriptions for selected AEDs were matched to patients with possible LGS by age, gender, US region, and dates of insurance coverage. Average healthcare utilization and costs per patient per year (PPPY) were evaluated for a 2-year postindex period and compared between the cohort with LGS and controls by insurance type. Costs were normalized to 2017 dollars at 3% per annum. RESULTS: In the study, 6019 patients with possible LGS (53% male, mean age of 13 years, in both insurance groups) were identified: 2270 with commercial insurance and 3749 with Medicaid. The cohort with LGS used >8 times more services and >7 times more drugs than controls (all p < 0.001) in both insurance groups. The biggest contributors to service use PPPY were outpatient physician visits and home health services in the commercial-insured cohort with LGS and other outpatient visits and home health services in the Medicaid-insured cohort with LGS. Average total costs PPPY (services + drugs) were significantly higher for the cohort with LGS vs. controls: $65,026 (SD $34,324) vs. $2442 (SD $10,670) for commercial-insured and $63,930 (SD $45,761) vs. $3849 (SD $13849) for Medicaid-insured patients. The biggest cost contributors PPPY were inpatient care in the commercial-insured cohort with LGS and home health services in the Medicaid-insured cohort with LGS. CONCLUSIONS: Patients with possible LGS have significantly higher healthcare utilization and costs than patients without epilepsy or seizures. Our results suggest that direct costs associated with LGS are substantial and highlight the need for new and effective treatments.

Cost comparison of immediate one-stage and tissue-expander breast reconstructions after mastectomy in commercially insured patients.

OBJECTIVE: Growing acceptance of nipple-sparing mastectomy and rising rates of prophylactic mastectomy due to genetic findings make immediate one-stage implant breast reconstruction an attractive option for many American women facing post-mastectomy breast reconstruction. We compared medical services utilization and cost of immediate one-stage reconstruction with that of the more common tissue-expander (TE) breast reconstruction. DESIGN: Retrospective administrative claims database analysis. METHODS: We obtained commercial insurance claims on patients in the U.S. who had undergone one-stage or TE post-mastectomy implant breast reconstructions in 2008, and we compared 18-month results in terms of the frequency and cost of return visits for additional procedures and/or for the treatment of complications. Return visits were categorized as planned, planned with revision, or unplanned. RESULTS: Among 1,316 immediate implant breast reconstructions, 95 (7%) were one-stage procedures and 1,221 (93%) were TE reconstructions. The data showed a modest, nonsignificant trend toward fewer return visits after one-stage reconstruction versus TE reconstruction (191 vs. 242 visits per 100 patients, respectively; relative risk [RR]: 0.95). Patients with TE reconstructions returned more often for planned returns and planned returns with revisions. Patients with one-stage reconstructions returned more often for unplanned events. The total costs over 18 months were $34,839 and $39,062 for one-stage and TE reconstructions, respectively, for a difference of -$4,223 (P = 0.38). The initial reconstruction, including the mastectomy, accounted for 64% of the 18-month costs with one-stage reconstructions and for 54% of the 18-month costs for TE reconstructions. CONCLUSION: Costs and utilization trended lower over 18 months for one-stage versus TE reconstructions following post-mastectomy breast reconstructions but did not achieve statistical significance.

Serum Bicarbonate and Graft and Patient Outcomes Among Kidney Transplant Recipients: A Retrospective Cohort Study Evaluating Changes in Serum Bicarbonate Over Time.

Rationale & Objective: Identification of treatable risk factors for kidney allograft failure is necessary to improve graft longevity. Metabolic acidosis with either low serum bicarbonate or normal serum bicarbonate (eubicarbonatemic metabolic acidosis) is implicated in native kidney disease progression but its effects in kidney transplant recipients are unclear. Study Design: Retrospective cohort study. Setting & Participants: An Integrated Claims-Clinical dataset of US patients with chronic kidney disease (estimated glomerular filtration rates <60 mL/min/1.73 m2) and serum bicarbonate data were used to generate a cohort of kidney transplant recipients with data from ≥1 year before and after transplantation. Primary Predictor: The primary independent variable was a change in serum bicarbonate from baseline. Outcomes: The primary outcomes were graft failure and all-cause mortality. The secondary outcomes were major adverse cardiac events and all-cause hospitalization. Analytical Approach: We used adjusted time-dependent Cox proportional hazards models to assess the risk of graft failure, all-cause mortality, major adverse cardiac events, and time to first hospitalization. Results: In this US community-based cohort of 1,915 kidney transplant recipients with a median follow-up of ∼2.5 years, each 1-mEq/L increase in serum bicarbonate was associated with significantly lower hazard of graft loss, death, major adverse cardiac events, and hospitalization by 10%, 8%, 4%, and 8%, respectively. Limitations: Possible residual confounding. Conclusions: In a US community-based population of kidney transplant recipients, even small incremental increases in serum bicarbonate (1 mEq/L) were significantly associated with reduced hazard of graft loss, all-cause mortality, cardiovascular events, and hospitalization. Interventional trials evaluating the potential benefits of treating metabolic acidosis in kidney transplant recipients are warranted.

Metabolic Acidosis and Adverse Outcomes and Costs in CKD: An Observational Cohort Study.

Rationale & Objective: Metabolic acidosis is a risk factor for progression of chronic kidney disease (CKD), but little is known about its effect on health care costs and resource utilization. We describe the associations between metabolic acidosis, adverse kidney outcomes, and health care costs in patients with CKD stages G3-G5 and not receiving dialysis. Study Design: Retrospective cohort study. Setting & Participants: An integrated claims-clinical data set of US patients with CKD stages G3-G5, with serum bicarbonate values of 12 to <22 mEq/L (metabolic acidosis group) or 22 to 29 mEq/L (normal serum bicarbonate level group). Predictor: The primary exposure variable was the baseline serum bicarbonate level. Outcomes: The primary clinical outcome was the composite of all-cause mortality, maintenance dialysis, kidney transplant, or a decline in the estimated glomerular filtration rate of ≥40% (DD40). The primary cost outcome was all-cause predicted per-patient per-year cost, assessed over a 2-year outcome period. Analytical Approach: Logistic and generalized linear regression models, adjusted for key covariates such as age, sex, race, kidney function, comorbidities, and pharmacy insurance coverage, were used to assess serum bicarbonate levels as a predictor of DD40 and health care costs, respectively. Results: 51,558 patients qualified. The metabolic acidosis group experienced higher rates of DD40 (48.3% vs. 16.7%, P < 0.001) and higher all-cause yearly costs ($65,172 vs. $24,681, P < 0.001). Two-year adjusted odds ratio of DD40 per 1-mEq/L increase in serum bicarbonate levels was 0.873 (95% CI, 0.866-0.879); the parameter estimate (±SE) for costs was -0.070 ± 0.0075 (P < 0.001). Limitations: Possible residual confounding. Conclusions: Patients with CKD and metabolic acidosis had higher costs and rates of adverse kidney outcomes compared with patients with normal serum bicarbonate levels. Each 1-mEq/L increase in serum bicarbonate levels was associated with a 13% decrease in 2-year DD40 events and a 7% decrease in per-patient per-year cost.

Association of the Kidney Failure Risk Equation With High Health Care Costs.

Introduction: The Kidney Failure Risk Equations (KFRE) are accurate and validated to predict the risk of kidney failure in individuals with chronic kidney disease (CKD), but their potential to predict health care costs in the US health care system is unknown. We assessed the association of kidney failure risk from the 4-variable and 8-variable 2-year KFRE models with monthly health care costs in US patients with CKD stages G3 and G4. Methods: This was an ancillary study to a larger observational, retrospective cohort study examining the association between serum bicarbonate and adverse kidney outcomes. Monthly medical costs were calculated from individual health care insurance claims. Generalized linear regression models were used to examine the association of KFRE score with health care costs. Results: A total of 1721 patients qualified for the study (1475 and 246 with CKD stages G3 and G4, respectively). For 8-variable KFRE, each 1% (absolute) increase in risk was associated with 13.5% (P < 0.001) and 4.1% (P < 0.001) higher monthly costs for patients with CKD stage G3 and G4, respectively. For 4-variable KFRE, a 1% increase in risk was associated with 6.7% (P = 0.016) and 2.9% (P= 0.014) increase in monthly costs for patients with CKD stage G3 and G4, respectively. Conclusion: Higher risks of kidney failure as predicted by the 4-variable or 8-variable KFRE were associated with higher 2-year medical costs for patients with CKD stages G3 and G4. The KFRE may be a useful tool to anticipate medical costs and target cost-reducing interventions for patients at risk of kidney failure.

Increasing Serum Bicarbonate is Associated With Reduced Risk of Adverse Kidney Outcomes in Patients with CKD and Metabolic Acidosis.

Introduction: Low serum bicarbonate at a single point in time is associated with accelerated kidney decline in patients with chronic kidney disease (CKD). We modeled how changes in serum bicarbonate over time affect incidence of adverse kidney outcomes. Methods: We analyzed data from Optum's deidentified Integrated Claims-Clinical data set of US patients (2007-2019) with ≥1 year of prior medical record data, CKD stages G3 to G5, and metabolic acidosis (i.e., index serum bicarbonate 12 to <22 mmol/l). The primary predictor of interest was the change in serum bicarbonate, evaluated at each postindex outpatient serum bicarbonate test as a time-dependent continuous variable. The primary outcome was a composite of either a ≥40% decline in estimated glomerular filtration rate (eGFR) from index or evidence of dialysis or transplantation, evaluated using Cox proportional hazards models. Results: A total of 24,384 patients were included in the cohort with median follow-up of 3.7 years. A within-patient increase in serum bicarbonate over time was associated with a lower risk of the composite kidney outcome. The unadjusted hazard ratio (HR) per 1-mmol/l increase in serum bicarbonate was 0.911 (95% confidence interval [CI]: 0.905-0.917; P < 0.001). After adjustment for baseline eGFR and serum bicarbonate, the time-adjusted effect of baseline eGFR and other covariates, the HR per 1-mmol/l increase in serum bicarbonate was largely unchanged (0.916 [95% CI: 0.910-0.922; P < 0.001]). Conclusion: In a real-world population of US patients with CKD and metabolic acidosis, a within-patient increase in serum bicarbonate over time independent of changes in eGFR, was associated with a lower risk of CKD progression.

Association of body mass index with the development of metabolic acidosis in patients with chronic kidney disease.

Aims: Higher body mass index (BMI) is associated with higher bone mass and bone serves as a buffer during the development of metabolic acidosis. The authors sought to examine the relationship between BMI and metabolic acidosis in patients with chronic kidney disease (CKD). Materials and Methods: The study utilized a large US longitudinal data repository including over 103 million patients from healthcare provider organizations to evaluate the relationship between the exposure variable (BMI) and the prevalence and incidence of metabolic acidosis among patients with estimated glomerular filtration rate <60 ml/min/1.73 m2. Incident metabolic acidosis was identified at the first of two consecutive post-index serum bicarbonate values, 10-365 days apart, between 12 and <22 mEq/L in patients with normal index serum bicarbonate. Cox proportional hazard models were adjusted for multiple variables including demographics, comorbidities, income, education, and kidney function. Results: 103,766 patients qualified for this study; 6472 (6.2%) had metabolic acidosis at index. An inverse association between BMI category and metabolic acidosis was observed for both baseline (prevalence) and new-onset (incidence) metabolic acidosis. Compared to BMI category of 18.5 to <25 kg/m2, each category of incrementally higher BMI was associated with a decreasing risk of incident metabolic acidosis; the adjusted hazard ratios (95% confidence interval) were 0.866 (0.824-0.911), 0.770 (0.729-0.813), 0.664 (0.622-0.709), and 0.612 (0.571-0.655) for BMI 25 to <30, 30 to <35, 35 to <40, and 40+ kg/m2, respectively. Conclusions: Among patients with CKD, an incremental increase in BMI was inversely associated with both the prevalence and incidence of metabolic acidosis. These associations suggest that increased body weight may protect against the development of metabolic acidosis, a risk factor for progressive loss of kidney function.

Association of serum bicarbonate with the development of kidney stones in patients with chronic kidney disease: a retrospective cohort study.

Background: Epidemiological studies demonstrate an association between kidney stones and risk of chronic kidney disease (CKD) and CKD progression. Metabolic acidosis, as a consequence of CKD, results in a reduced urine pH which promotes the formation of some types of kidney stones and inhibits the formation of others. While metabolic acidosis is a risk factor for CKD progression, the association of serum bicarbonate with risk of incident kidney stones is not well understood. Methods: We used an Integrated Claims-Clinical dataset of US patients to generate a cohort of patients with non-dialysis-dependent CKD with two serum bicarbonate values of 12 to <22 mmol/L (metabolic acidosis) or 22 to <30 mmol/L (normal serum bicarbonate). Primary exposure variables were baseline serum bicarbonate and change in serum bicarbonate over time. Cox proportional hazards models evaluated time to first occurrence of kidney stones during a median 3.2-year follow-up. Results: A total of 142 884 patients qualified for the study cohort. Patients with metabolic acidosis experienced post-index date kidney stones at greater frequency than patients with normal serum bicarbonate at the index date (12.0% vs 9.5%, P < .0001). Both lower baseline serum bicarbonate [hazard ratio (HR) 1.047; 95% confidence interval (CI) 1.036-1.057] and decreasing serum bicarbonate over time (HR 1.034; 95% CI 1.026-1.043) were associated with increased risk of kidney stone development. Conclusions: Metabolic acidosis was associated with a higher incidence of kidney stones and shorter time to incident stone formation in patients with CKD. Future studies may investigate the role of correcting metabolic acidosis to prevent stone formation.

Association of metabolic acidosis with fractures, falls, protein-calorie malnutrition and failure to thrive in patients with chronic kidney disease.

Background: The risk of adverse geriatric outcomes such as falls and fractures is high among patients with chronic kidney disease (CKD). Metabolic acidosis is associated with protein catabolism and bone loss in experimental animal and human studies. We sought to quantify the independent association of metabolic acidosis with adverse muscle, bone and functional outcomes in a large US community-based cohort. Methods: The Optum's de-identified Integrated Claims-Clinical dataset of US patients (2007-2017) was used to generate a cohort of patients with nondialysis-dependent CKD who had estimated glomerular filtration rate >10 to <60 mL/min/1.73 m2 and two serum bicarbonate values 12 to <22 mmol/L or 22-29 mmol/L. The primary outcomes were failure to thrive, protein-calorie malnutrition, and fall or fracture. Cox proportional hazards models were used for the primary outcomes for up to 10 years, while logistic regression models were used at 2 years. Results: A total of 51 558 patients qualified for the study, with a median [Interquartile Range (IQR)] follow-up time of 4.2 (2.5-5.8) years. Over a ≤10-year period, for each 1 mmol/L increase in serum bicarbonate, the hazard ratios (adjusted for age, sex, race, estimated glomerular filtration rate, serum albumin, hemoglobin, diabetes and cardiovascular comorbidities) for failure to thrive, protein-calorie malnutrition and fall or fracture were 0.91 [95% confidence interval (CI): 0.90-0.92], 0.91 (95% CI: 0.90-0.92) and 0.95 (95% CI: 0.95-0.96), all P < 0.001, respectively. Conclusions: The presence and severity of metabolic acidosis was a significant, independent risk factor for failure to thrive, protein-calorie malnutrition and fall or fracture in this large community cohort of patients with stage 3-5 CKD.

Metabolic Acidosis is Associated With Acute Kidney Injury in Patients With CKD.

Introduction: Metabolic acidosis in patients with chronic kidney disease (CKD) results from a loss of kidney function. It has been associated with CKD progression, all-cause mortality, and other adverse outcomes. We aimed to determine whether metabolic acidosis is associated with a higher risk of acute kidney injury (AKI). Methods: This was a retrospective cohort study. Using electronic health records and administrative data, we enrolled 2 North American cohorts of patients with CKD Stages G3-G5 as follows: (i) 136,067 patients in the US electronic medical record (EMR) based cohort; and (ii) 34,957 patients in the Manitoba claims-based cohort. The primary exposure was metabolic acidosis (serum bicarbonate between 12 mEq/l and <22 mEq/l). The primary outcome was the development of AKI (defined using ICD-9 and 10 codes at hospital admission or a laboratory-based definition based on Kidney Disease: Improving Global Outcomes guidelines). We applied Cox proportional hazards regression models adjusting for relevant demographic and clinical characteristics. Results: In both cohorts, metabolic acidosis was associated with AKI: hazard ratio (HR) 1.57 (95% confidence interval [CI] 1.52-1.61) in the US EMR cohort, and HR 1.65 (95% CI 1.58-1.73) in the Manitoba claims cohort. The association was consistent when serum bicarbonate was treated as a continuous variable, and in multiple subgroups, and sensitivity analyses including those adjusting for albuminuria. Conclusion: Metabolic acidosis is associated with a higher risk of AKI in patients with CKD. AKI should be considered as an outcome in studies of treatments for patients with metabolic acidosis.

Metabolic Acidosis and Cardiovascular Disease in CKD.

RATIONALE & OBJECTIVE: Metabolic acidosis related to chronic kidney disease (CKD) is associated with an accelerated decline in glomerular filtration rate (GFR) and the development of end-stage kidney disease. Whether metabolic acidosis is associated with cardiovascular (CV) events in patients with CKD is unclear. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: The Optum De-identified Electronic Health Records Dataset, 2007-2017, was used to generate a cohort of patients with non-dialysis-dependent CKD who had at least 3 estimated GFR < 60 mL/min/1.73 m2. Patients with metabolic acidosis (serum bicarbonate 12 to <22 mEq/L) or normal serum bicarbonate (22‒29 mEq/L) at baseline were identified by 2 consecutive measurements 28‒365 days apart. PREDICTOR: Serum bicarbonate as a continuous variable. OUTCOME: Primary outcome was a composite of major adverse cardiovascular events (MACE+). Secondary outcomes included individual components of the composite outcome. ANALYTICAL APPROACH: Cox proportional hazards models to evaluate the association between 1-mEq/L increments in serum bicarbonate and MACE+. RESULTS: A total of 51,558 patients were evaluated, 34% had metabolic acidosis. The median follow-up period was 3.9-4.5 years, depending on the outcome assessed. The adjusted hazard ratio (HR) for MACE+ was 0.964 (95% CI, 0.961-0.968). For the individual components of incident heart failure (HF), stroke, myocardial infarction (MI), and CV death, HRs were 0.98 (95% CI, 0.97-0.98), 0.98 (95% CI, 0.97-0.99), 0.96 (95% CI, 0.96-0.97), and 0.94 (95% CI, 0.93-0.94), respectively, for every 1-mEq/L increase in serum bicarbonate. LIMITATIONS: Possible residual confounding. CONCLUSIONS: Metabolic acidosis in CKD is associated with an increased risk of MACE+ as well as the individual components of incident HF, stroke, MI, and CV death. Randomized controlled trials evaluating treatments for the correction of metabolic acidosis in CKD to prevent CV events are needed.

Impact of fever on outcome in patients with stroke and neurologic injury: a comprehensive meta-analysis.

BACKGROUND AND PURPOSE: Many studies associate fever with poor outcome in patients with neurological injury, but this relationship is blurred by divergence in populations and outcome measures. We sought to incorporate all recent scholarship addressing fever in brain-injured patients into a comprehensive meta-analysis to evaluate disparate clinical findings. METHODS: We conducted a Medline search for articles since January 1, 1995 (in English with abstracts, in humans) and hand searches of references in bibliographies and review articles. Search terms covered stroke, neurological injury, thermoregulation, fever, and cooling. A total of 1139 citations were identified; we retained 39 studies with 67 tested hypotheses contrasting outcomes of fever/higher body temperature and normothermia/lower body temperature in patients with neurological injury covering 14431 subjects. A separate meta-analysis was performed for each of 7 outcome measures. Significance was evaluated with Zc developed from probability values or t values. Correlational effect size, r (es), was calculated for each study and used to derive Cohen's d unbiased combined effect size and relative risk. RESULTS: Fever or higher body temperature was significantly associated with worse outcome in every measure studied. Relative risk of worse outcome with fever was: mortality, 1.5; Glasgow Outcome Scale, 1.3; Barthel Index, 1.9; modified Rankin Scale, 2.2; Canadian Stroke Scale, 1.4; intensive care length of stay, 2.8; and hospital length of stay, 3.2. CONCLUSIONS: In the pooled analyses covering 14431 patients with stroke and other brain injuries, fever is consistently associated with worse outcomes across multiple outcome measures.

Changes in Medical Services and Drug Utilization and Associated Costs After Narcolepsy Diagnosis in the United States.

BACKGROUND: Healthcare utilization and the cost implications associated with undiagnosed and/or misdiagnosed narcolepsy have not been evaluated, and there is scant literature characterizing the newly diagnosed population with narcolepsy with respect to treatment patterns and resource utilization. OBJECTIVE: To analyze the changes in medication use, healthcare utilization, and the associated costs after a new diagnosis of narcolepsy. METHODS: In this retrospective cohort study, we used data from the Truven Health Analytics MarketScan Research Databases, between January 2006 and March 2013, to identify patients who had a probable new diagnosis of narcolepsy-defined as a de novo medical claim for a multiple sleep latency test-which was preceded by ≥6 months of continuous insurance and was followed by a de novo diagnosis of narcolepsy. The utilization and cost of medical services and the percentage of patients filling prescriptions for narcolepsy-related medications were evaluated in 3 consecutive 1-year periods from the date of a positive multiple sleep latency test result (ie, index date), and each year's findings were compared with the annualized results from the 6-month preindex period. RESULTS: A total of 3757 patients who met the definition of a new diagnosis of narcolepsy were identified. The total medical service utilization decreased each year from a preindex average of 28.2 visits per patient per year (PPPY) to 26.9 visits (P <.05), 23.1 visits (P <.0001), and 22.5 visits (P <.0001) PPPY in years 1, 2, and 3 postdiagnosis, respectively. In each outpatient service category, the medical services utilization decreased from preindex to year 3 postdiagnosis, including hospital outpatient and physician visits (P <.0001), and other outpatient and emergency department visits (P <.05). The percentage of patients receiving narcolepsy-related medications increased from 54.0% preindex to 77.4%, 70.0%, and 66.9% for years 1, 2, and 3 postindex (all P <.0001 vs preindex). The total medical service cost PPPY was $12,159 preindex and decreased to $10,708, $8543, and $9136 in years 1, 2, and 3 postindex (all P <.0001 vs preindex). CONCLUSIONS: In this study, the confirmation of a diagnosis of narcolepsy was associated with decreasing utilization and associated costs of medical services in the first 3 years after diagnosis. The total costs encompassing medical services and pharmacy costs were relatively stable during this period.

High Rates of Psychiatric Comorbidity in Narcolepsy: Findings From the Burden of Narcolepsy Disease (BOND) Study of 9,312 Patients in the United States.

OBJECTIVE: To evaluate psychiatric comorbidity patterns in patients with a narcolepsy diagnosis in the United States. METHODS: Truven Health Analytics MarketScan Research Databases were accessed to identify individuals ≥ 18 years of age with ≥ 1 ICD-9 diagnosis code(s) for narcolepsy continuously insured between 2006 and 2010 and non-narcolepsy controls matched 5:1 (age, gender, region, payer). Extensive subanalyses were conducted to confirm the validity of narcolepsy definitions. Narcolepsy subjects and controls were compared for frequency of psychiatric comorbid conditions (based on ICD-9 codes/Clinical Classification Software [CCS] level 2 categories) and psychiatric medication use. RESULTS: The final population included 9,312 narcolepsy subjects and 46,559 controls (each group, mean age = 46.1 years; 59% female). All categories of mental illness were significantly more prevalent in patients with narcolepsy versus controls, with the highest excess prevalence noted for CCS 5.8 Mood disorders (37.9% vs 13.8%; odds ratio [OR] = 4.0; 95% CI, 3.8-4.2), CCS 5.8.2 Depressive disorders (35.8% vs 13.0%; OR = 3.9; 95% CI, 3.7-4.1), and CCS 5.2 Anxiety disorders (25.1% vs 11.9%; OR = 2.5; 95% CI, 2.4-2.7). Excess prevalence of anxiety and mood disorders (narcolepsy vs controls) was higher in younger age groups versus older age groups. Psychiatric medication usage was higher in the narcolepsy group versus controls in the following categories: selective serotonin reuptake inhibitors (36% vs 17%), anxiolytic benzodiazepines (34% vs 19%), hypnotics (29% vs 13%), serotonin-norepinephrine reuptake inhibitors (21% vs 6%), and tricyclic antidepressants (13% vs 4%) (all P values < .0001). CONCLUSIONS: Narcolepsy is associated with significant comorbid psychiatric illness burden and higher psychiatric medication usage compared with the non-narcolepsy population.

All-cause costs increase exponentially with increased chronic kidney disease stage.

OBJECTIVE: To evaluate the economic impact of chronic kidney disease (CKD) on US health plans. STUDY DESIGN: A retrospective analysis identified patients with a renin-angiotensin-aldosterone system inhibitor (RAASi) prescription from an electronic medical record (EMR) database (Humedica); those with =90 days in =1 CKD stage were selected based on estimated glomerular filtration rate or diagnosis code, and a cohort on RAASi medications without CKD was selected. Costs for specific services obtained from OptumInsight were applied to services in EMR data of patients aged <65 years (commercial) and =65 years (Medicare). Dialysis costs were excluded. RESULTS: The study included 106,050 patients with CKD and 56,761 no-CKD controls (90,302 commercial and 72,509 Medicare overall). Mean annualized all-cause costs increased exponentially with advancing stage, from $7537 (no CKD) to $76,969 (CKD stages 4-5) in the commercial group, and $8091 (no CKD) to $46,178 (CKD stages 4-5) in the Medicare group (P <.001; all comparisons with preceding disease stage). Mean costs for end-stage renal disease (ESRD) patients were $121,948 and $87,339 in the commercial and Medicare groups, respectively. Inpatient costs were the largest contributor to total costs, and their relative contribution increased with advancing CKD. CONCLUSIONS: Cost to US health plans increases exponentially with each CKD stage progression. ESRD costs are even higher. Because readmissions lead to higher costs, efforts to reduce readmissions would result in cost reductions. Furthermore, healthcare reengineering paradigms that manage increasing comorbidities with advancing CKD, including heart failure, diabetes, and hyperkalemia, should offer additional potential for cost reductions.