Foot and Ankle Care by Podiatrists and Amputations in Patients With Diabetes and Kidney Failure.

Importance: Patients with kidney failure have an increased risk of diabetes-related foot complications. The benefit of regular foot and ankle care in this at-risk population is unknown. Objective: To investigate foot and ankle care by podiatrists and the outcomes of diabetic foot ulcers (DFUs) in patients with kidney failure. Design, Setting, and Participants: This retrospective cohort study included Medicare beneficiaries with type 2 diabetes receiving dialysis who had a new DFU diagnosis. The analysis of the calendar year 2016 to 2019 data from the United States Renal Data System was performed on June 15, 2023, with subsequent updates on December 11, 2023. Exposures: Foot and ankle care by podiatrists during 3 months prior to DFU diagnosis. Main Outcomes and Measures: The outcomes were a composite of death and/or major amputation, as well as major amputation alone. Kaplan-Meier analysis was used to estimate 2 to 3 years of amputation-free survival. Foot and ankle care by podiatrists and the composite outcome was examined using inverse probability-weighted Cox regression, while competing risk regression models were used for the analysis of amputation alone. Results: Among the 14 935 adult patients with kidney failure and a new DFU (mean [SD] age, 59.3 [12.7] years; 35.4% aged ≥65 years; 8284 men [55.4%]; Asian, 2.7%; Black/African American, 35.0%; Hispanic, 17.7%; White, 58.5%), 18.4% (n = 2736) received care by podiatrists in the 3 months before index DFU diagnosis. These patients were older, more likely to be male, and have more comorbidities than those without prior podiatrist visits. Over a mean (SD) 13.5 (12.0)-month follow-up, 70% of those with podiatric care experienced death and/or major amputation, compared with 74% in the nonpodiatric group. Survival probabilities at 36 months were 26.3% vs 22.8% (P < .001, unadjusted Kaplan-Meier survival analysis). In multivariate regression analysis, foot and ankle care was associated with an 11% lower likelihood of death and/or amputation (hazard ratio [HR], 0.89 95% CI, 0.84-0.93) and a 9% lower likelihood of major amputation (above or below knee) (HR, 0.91; 95% CI, 0.84-0.99) than those who did not. Conclusions and Relevance: The findings of this study suggest that patients with kidney failure at risk for DFUs who receive foot and ankle care from podiatrists may be associated with a reduced likelihood of diabetes-related amputations.

Tale of Two Erythropoiesis-Stimulating Agents: Utilization, Dosing, Litigation, and Costs of Darbepoetin and Epoetin Among South Carolina Medicaid-Covered Patients With Cancer and Chemotherapy-Induced Anemia.

PURPOSE: The US Food and Drug Administration (FDA) has approved epoetin and darbepoetin for chemotherapy-induced anemia (CIA). Approved epoetin and darbepoetin dosing schedules were three times per week and weekly, respectively, although off-label, less frequent scheduling was common. In 2004, 2007, and 2008, a US Food and Drug Administration Advisory Committees warned of risks associated with erythropoiesis-stimulating agents. During this period, lawsuits alleging illegal darbepoetin marketing practices have concluded, resulting in $1.1 billion in fines and settlements and one criminal conviction. No prior study, to our knowledge, has reported on the use of darbepoetin versus epoetin for CIA. METHODS: We evaluated the dosing, utilization, and costs of erythropoiesis-stimulating agents among 3,761 South Carolina Medicaid patients with CIA. RESULTS: Epoetin and darbepoetin utilization rates were 22% and 28% in 2003, 10% and 33% in 2007, and 3% and 7% in 2010, respectively. Mean per-patient per-administration epoetin and darbepoetin doses were 40,983 IU and 191 µg, respectively, in 2003 and 47,753 IU and 369 µg, respectively, in 2010. Mean monthly patient costs for epoetin and darbepoetin were $1,030 and $981, respectively, in 2003 and $932 and $1,352, respectively, in 2010. Epoetin use decreased steadily between 2002 and 2010; darbepoetin use increased steadily between 2003 and 2007 and then decreased steadily thereafter. Per-patient dosing of darbepoetin, but not epoetin, increased steadily between 2003 and 2010, and monthly per-patient epoetin costs decreased 3% while the per-patients costs of darbepoetin increased 30% between 2003 and 2010. CONCLUSION: To our knowledge, our findings are the first data reporting on epoetin versus darbepoetin use for CIA and support recently concluded lawsuits involving allegations of illegal marketing practices of the manufacturer of darbepoetin.

Predicting Early Death Among Elderly Dialysis Patients: Development and Validation of a Risk Score to Assist Shared Decision Making for Dialysis Initiation.

BACKGROUND: A shared decision-making tool could help elderly patients with advanced chronic kidney disease decide about initiating dialysis therapy. Because mortality may be high in the first few months after initiating dialysis therapy, incorporating early mortality predictors in such a tool would be important for an informed decision. Our objective is to derive and validate a predictive risk score for early mortality after initiating dialysis therapy. STUDY DESIGN: Retrospective observational cohort, with development and validation cohorts. SETTING & PARTICIPANTS: US Renal Data System and claims data from the Centers for Medicare & Medicaid Services for 69,441 (aged ≥67 years) patients with end-stage renal disease with a previous 2-year Medicare history who initiated dialysis therapy from January 1, 2009, to December 31, 2010. CANDIDATE PREDICTORS: Demographics, predialysis care, laboratory data, functional limitations, and medical history. OUTCOMES: All-cause mortality in the first 3 and 6 months. ANALYTICAL APPROACH: Predicted mortality by logistic regression. RESULTS: The simple risk score (total score, 0-9) included age (0-3 points), low albumin level, assistance with daily living, nursing home residence, cancer, heart failure, and hospitalization (1 point each), and showed area under the receiver operating characteristic curve (AUROC)=0.69 in the validation sample. A comprehensive risk score with additional predictors was also developed (with AUROC=0.72, high concordance between predicted vs observed risk). Mortality probabilities were estimated from these models, with the median score of 3 indicating 12% risk in 3 months and 20% in 6 months, and the highest scores (≥8) indicating 39% risk in 3 months and 55% in 6 months. LIMITATIONS: Patients who did not choose dialysis therapy and did not have a 2-year Medicare history were excluded. CONCLUSIONS: Routinely available information can be used by patients with chronic kidney disease, families, and their nephrologists to estimate the risk of early mortality after dialysis therapy initiation, which may facilitate informed decision making regarding treatment options.

Erythropoiesis-stimulating agent use among non-dialysis-dependent CKD patients before and after the trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) using a large US health plan database.

BACKGROUND: In a landmark study, TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) examined the use of erythropoiesis-stimulating agent (ESA) therapy to treat anemia among patients with chronic kidney disease (CKD) and found no benefit compared to placebo. STUDY DESIGN: A retrospective observational design was used to determine the impact of TREAT on clinical practice. SETTING & PARTICIPANTS: A large US health plan database with more than 1.2 million claims for patients with non-dialysis-dependent CKD stages 3 and 4. FACTOR: ESA prescribing 2 years before and after publication of TREAT. OUTCOMES: Rate of ESA prescribing for ESA-naive and -prevalent cohorts. MEASUREMENTS: (1) Monthly ESA prescribing in the 2 years before and after publication of TREAT (ordinary least squares regression), (2) adjusted likelihood of prescribing ESA after TREAT (clustered logistic regression), and (3) probability of receiving ESA therapy based on anemia status (χ(2) test). RESULTS: For patients with CKD stage 3, the proportion prescribed ESA therapy declined from 17% pre-TREAT to 11% post-TREAT (a 38% decline), and for those with CKD stage 4, from 34% to 27% (a 22% decline). Prescribing of ESA therapy was declining even before TREAT, but the decline accelerated in the post-TREAT period (stage 3: change of slope, -0.08 [P<0.001]; stage 4: change of slope, -0.16 [P<0.001]). ESA prescribing declined after TREAT regardless of anemia status; among patients with hemoglobin levels <10g/dL, only 25% of patients with CKD stage 3 and 33% of patients with stage 4 were prescribed ESAs 2 years after TREAT, a notable 50% decline. After adjusting for all covariates, the probability of prescribing ESAs was 35% lower during the 2-year period after versus before publication of TREAT (OR, 0.65; 95% CI, 0.63-0.67). LIMITATIONS: The cumulative effect of adverse safety concerns in the period before TREAT also influenced physician prescribing of ESA therapy and could not be separated from the influence of TREAT. CONCLUSIONS: TREAT appears to be a watershed study that was followed by a marked decline in ESA prescribing for patients with CKD.

Dialysis chains and placement on the waiting list for a cadaveric kidney transplant.

BACKGROUND: The proliferation of multi-unit for-profit dialysis chains in the ESRD industry has raised concerns for patient quality of care including access to renal transplantation therapy (RTT). The effect of dialysis facility chain status on RTT is unknown. METHODS: Data from the United States Renal Data System were used to identify 4,465 dialysis facilities and 56,714 dialysis patients who started hemodialysis in 2006. Patients were followed from initiation of hemodialysis in 2006 to placement on the renal transplant waiting list or to December 31, 2009. The role of dialysis facility chain status (affiliation, size, and ownership) on placement on the renal transplant waiting list was evaluated by multi-level mixed-effect regression models that account for clustering within facilities. RESULTS: Patients from for-profit chain facilities, compared to nonprofit chain facilities, were 13% (95% CI 0.77-0.98) less likely to be waitlisted. In contrast, among nonchains, facility ownership did not influence likelihood of being waitlisted. There was also a marginally significant difference in waiting list placement by chain size: large chains compared with mid or small chains were 8% (95% CI 0.84-1.00) less likely to place patients on the waiting list. After adjustment for patient and facility characteristics, dialysis facility chain affiliation (chain-affiliated or not) was not found to be independently associated with the likelihood of placement on the transplant waitlist. CONCLUSION: Dialysis chain affiliation expands previously observed ownership-related differences in placement on the waiting list. For-profit ownership of dialysis chain facilities appears to be a significant impediment to access to renal transplants.

Comparative effectiveness of two anemia management strategies for complex elderly dialysis patients.

BACKGROUND: Randomized trials found that use of erythropoiesis-stimulating agents to target normal hematocrit (Hct) levels (>39%) compared with 27%-34.5% increases cardiovascular risk and mortality among chronic kidney disease patients. However, the effects of the most widely used Hct target in the past 2 decades, 34.5%-39%, have never been examined. OBJECTIVE: To compare the effects of 2 Hct target strategies-30.0%-34.5% (low) and 34.5%-39.0% (mid) in a high-risk population: elderly dialysis patients with significant comorbidities. RESEARCH DESIGN: Observational data from the US Renal Data System were used to emulate a randomized trial in which patients were assigned to either Hct strategy. Follow-up started after completing 3 months of hemodialysis and ended 6 months later. We conducted the observational analogs of intention-to-treat and per-protocol analyses. Inverse-probability weighting was used to adjust for measured time-dependent confounding by indication. SUBJECTS: A total of 22,474 elderly patients with both diabetes and cardiovascular disease who initiated hemodialysis in 2006-2008. MEASURES: Hazard ratios (HRs) and survival probabilities for all-cause mortality and a composite cardiovascular and mortality endpoint. RESULTS: The intention-to-treat HR (95% confidence interval) for mid versus low Hct strategy was 1.05 (0.99-1.11) for all-cause mortality and 1.03 (0.98-1.08) for the composite endpoint. The per-protocol HR (95% confidence interval) for mid versus low Hct strategy was 0.98 (0.78-1.24) for all-cause mortality and 1.00 (0.81-1.24) for the composite outcome. CONCLUSIONS: Among hemodialysis patients, we did not find differences in 6-month survival or cardiovascular risk between clinical strategies that target Hct at 30.0%-34.5% versus 34.5%-39.0%.

Major declines in epoetin dosing after prospective payment system based on dialysis facility organizational status.

BACKGROUND: Epoetin therapy used to treat anemia among ESRD patients has cost Medicare ∼$40 billion. Since January 2011, epoetin has been reimbursed via a new bundled prospective payment system (PPS). Our aim was to determine changes in epoetin dosing and hematocrit levels in response to PPS by different types of dialysis providers. METHODS: Data from the USRDS were used to identify 187,591 and 206,163 Medicare-eligible ESRD patients receiving hemodialysis during January 2010 (pre-PPS) and December 2011 (post-PPS). Standardized weekly mean epoetin dose administered pre- and post-PPS and adjustment in dose (titration) based on previous hematocrit level in each facility was disaggregated by profit status, chain membership and size. RESULTS: Major declines in epoetin use, dosing and achieved hematocrit levels were observed after PPS. Among the three largest dialysis chains, the decline in standardized epoetin dose was 29% at Fresenius, 47% at DaVita, and 52% at DCI. The standardized weekly epoetin dose among profit and nonprofit facilities declined by 38 and 42%, respectively. Changes in titration patterns suggest that a new hematocrit target of 30-33% was in place after PPS, replacing the erstwhile 33-36% hematocrit target used before PPS. CONCLUSION: Historically, important differences in anemia management were evident by dialysis organizational status. However, the confluence of financial incentives bundling epoetin payments and mounting scientific evidence linking higher hematocrit targets and higher epoetin doses to adverse outcomes have culminated in lower access to epoetin and lower doses across all dialysis providers in the first year after PPS.

Influence of safety warnings on ESA prescribing among dialysis patients using an interrupted time series.

BACKGROUND: In March, 2007, a black box warning was issued by the Food and Drug Administration (FDA) to use the lowest possible erythropoiesis-stimulating agents (ESA) doses for treatment of anemia associated with renal disease. The goal is to determine if a change in ESA use was observed following the warning among US dialysis patients. METHODS: ESA therapy was examined from September 2004 through August 2009 (thirty months before and after the FDA black box warning) among adult Medicare hemodialysis patients. An interrupted time series model assessed the impact of the warnings. RESULTS: The FDA black box warning did not appear to influence ESA prescribing among the overall dialysis population. However, significant declines in ESA therapy after the FDA warnings were observed for selected populations. Patients with a hematocrit≥36% had a declining month-to-month trend before (-164 units/week, p=<0.0001) and after the warnings (-80 units/week, p=.001), and a large drop in ESA level immediately after the black box (-4,744 units/week, p=<.0001). Not-for-profit facilities had a declining month-to-month trend before the warnings (-90 units/week, p=.009) and a large drop in ESA dose immediately afterwards (-2,487 units/week, p=0.015). In contrast, for-profit facilities did not have a significant change in ESA prescribing. CONCLUSIONS: ESA therapy had been both profitable for providers and controversial regarding benefits for nearly two decades. The extent to which a FDA black box warning highlighting important safety concerns influenced use of ESA therapy among nephrologists and dialysis providers was unknown. Our study found no evidence of changes in ESA prescribing for the overall dialysis population resulting from a FDA black box warning.

Organizational status of dialysis facilities and patient outcome: does higher injectable medication use mediate increased mortality?

OBJECTIVE: Examine the mediating effect of injectable drugs in the relationship between dialysis facility organizational status and patient mortality. STUDY SETTING: Medicare dialysis population. STUDY DESIGN: Data from the U.S. Renal Data System (USRDS) were used to identify 3,884 freestanding dialysis facilities and 37,942 Medicare patients incident to end-stage renal disease (ESRD) in 2006. The role of injectable medications was evaluated during a 2-year follow-up period by mediational analyses using mixed-effect regression models. DATA COLLECTION: USRDS data were matched with Dialysis Facility Report data from Centers for Medicare and Medicaid Services (CMS) and census data. PRINCIPAL FINDINGS: There was a strong association found between organizational status and use of injectable drugs. Large for-profit chains used significantly higher injectable medications compared with nonprofit chains and independent facilities. However, the relationship between facility organizational status and patient mortality was not found to be mediated through the higher use of injectable drugs. CONCLUSIONS: Large for-profit chain facilities administered higher IV epoetin, iron, and vitamin D dosages, but this did not result in improved survival. Given the associated costs and lack of a survival benefit, the overuse of injectable medications among the U.S. dialysis patients will likely end under the recent bundling of injectable medications without jeopardizing patient outcomes.

High doses of epoetin do not lower mortality and cardiovascular risk among elderly hemodialysis patients with diabetes.

A randomized trial had suggested that high doses of erythropoiesis-stimulating agents (ESAs) might increase the risk of cardiovascular outcomes in predialysis diabetic patients. To evaluate this risk in diabetic patients receiving dialysis, we used data from 35,593 elderly Medicare patients on hemodialysis in the US Renal Data System of whom 19,034 were diabetic. A pooled logistic model was used to estimate the monthly probability of mortality and a composite cardiovascular end point. Inverse probability weighting was used to adjust for measured time-dependent confounding by indication, estimated separately for diabetic and non-diabetic cohorts. The adjusted 9-month mortality risk, significantly different between an ESA dose of 45,000 and 15,000 U/week, was 13% among diabetics and 5% among non-diabetics. In diabetic patients, the hazard ratio (HR) for more than 40,000 U/week was 1.32 for all-cause mortality and 1.26 for a composite end point of death and cardiovascular events compared with patients receiving 20,000 to 30,000 U/week. The corresponding HRs in non-diabetic patients were 1.06 and 1.10, respectively. A smaller effect of dose was found in non-diabetic patients. Thus, higher ESA doses, which are often necessary to achieve high hemoglobin levels, are not beneficial, and possibly harmful, to diabetic patients receiving dialysis. Our findings support a Food and Drug Administration advisory recommending that the lowest possible ESA dose be used to treat hemodialysis patients.

The effect of dialysis chains on mortality among patients receiving hemodialysis.

OBJECTIVE: To examine the association between dialysis facility chain affiliation and patient mortality. STUDY SETTING: Medicare dialysis population. STUDY DESIGN: Data from the United States Renal Data System (USRDS) were used to identify 3,601 free-standing dialysis facilities and 34,914 Medicare patients' incidence to end-stage renal disease (ESRD) in 2004. Mixed-effect regression models were used to estimate patient mortality by dialysis facility chain and profit status during the 2-year follow-up. DATA COLLECTION: USRDS data were matched with facility, cost, and census data. PRINCIPAL FINDINGS: Of the five largest dialysis chains, the lowest mortality risk was observed among patients dialyzed at nonprofit (NP) Chain 5 facilities. Compared with Chain 5, hazard ratios were 19 percent higher (95 percent CI 1.06-1.34) and 24 percent higher (95 percent CI 1.10-1.40) for patients dialyzed at for-profit (FP) Chain 1 and Chain 2 facilities, respectively. In addition, patients at FP facilities had a 13 percent higher risk of mortality than those in NP facilities (95 percent CI 1.06-1.22). CONCLUSIONS: Large chain affiliation is an independent risk factor for ESRD mortality in the United States. Given the movement toward further consolidation of large FP chains, reasons behind the increase in mortality require scrutiny.

Estimated effect of epoetin dosage on survival among elderly hemodialysis patients in the United States.

BACKGROUND AND OBJECTIVES: The common finding that low achieved hemoglobin in observational studies and high target hemoglobin in randomized trials each were associated with increased mortality and high epoetin dosage has suggested the possibility that high epoetin dosage might explain the increased mortality risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We considered data from 18,454 patients who were >or=65 yr, were in the US Renal Data System, started hemodialysis in 2003, and survived 3 mo on dialysis. We estimated the association between cumulative average epoetin dosage and survival through the subsequent 9 mo by using inverse probability weighting to adjust for time-dependent confounding by indication. RESULTS: Survival was similar throughout the entire follow-up period for the three hypothetical treatment regimens selected: Low dosage 15,000 U/wk, medium dosage 30,000 U/wk, and high dosage 45,000 U/wk. Compared with a cumulative average dosage of 20,000 to 30,000 U/wk, the estimated hazard ratio (HR; 95% confidence interval [CI]) was 0.90 (0.52 to 1.54) for <10,000, 0.84 (0.67 to 1.05) for 10,000 to <20,000 U/wk, 0.96 (0.76 to 1.21) for 20,000 to <40,000 U/wk, and 0.91 (0.67 to 1.22) for >40,000 U/wk. In contrast, conventional unweighted models, which do not adequately adjust for time-dependent confounding by indication, indicated an association between high cumulative average epoetin dosage and increased mortality. CONCLUSIONS: Our findings suggest that, on average, epoetin dosages >30,000 U/wk do not confer additional harm or benefit in elderly hemodialysis patients.

Prednisone, lupus activity, and permanent organ damage.

OBJECTIVE: To estimate the effect of corticosteroids (prednisone dose) on permanent organ damage among persons with systemic lupus erythematosus (SLE). METHODS: We identified 525 patients with incident SLE in the Hopkins Lupus Cohort. At each visit, clinical activity indices, laboratory data, and treatment were recorded. The study population was followed from the month after the first visit until June 29, 2006, or attainment of irreversible organ damage, death, loss to follow-up, or receipt of pulse methylprednisolone therapy. We estimated the effect of cumulative average dose of prednisone on organ damage using a marginal structural model to adjust for time-dependent confounding by indication due to SLE disease activity. RESULTS: Compared with non-prednisone use, the hazard ratio of organ damage for prednisone was 1.16 (95% CI 0.54, 2.50) for cumulative average doses > 0-180 mg/month, 1.50 (95% CI 0.58, 3.88) for > 180-360 mg/month, 1.64 (95% CI 0.58, 4.69) for > 360-540 mg/month, and 2.51 (95% CI 0.87, 7.27) for > 540 mg/month. In contrast, standard Cox regression models estimated higher hazard ratios at all dose levels. CONCLUSION: Our results suggest that low doses of prednisone do not result in a substantially increased risk of irreversible organ damage.

Dialysis facility ownership and epoetin dosing in patients receiving hemodialysis.

CONTEXT: Epoetin therapy for dialysis-related anemia is the single largest Medicare drug expenditure. The type of facility (profit, chain, and affiliation status) at which a patient receives dialysis might affect epoetin dosing patterns and has implications for future epoetin policies. OBJECTIVE: To examine the association between dialysis facility ownership and the dose of epoetin administered. DESIGN, SETTING, AND PARTICIPANTS: Data from the US Renal Data System were used to identify 159,522 adult Medicare-eligible, end-stage renal disease patients receiving in-center hemodialysis during November and December 2004. Regression models were used to estimate the mean epoetin dose and dose adjustment by profit, chain, and affiliation status. MAIN OUTCOME MEASURES: Weekly mean epoetin dose administered in December 2004 and the adjustment in dose between November and December 2004. RESULTS: Compared with patients in nonprofit dialysis facilities (n = 28,199), patients in large for-profit dialysis chain facilities (n = 106,116) were consistently administered the highest doses of epoetin regardless of anemia status. Compared with nonprofit facilities, for-profit facilities administered, on average, an additional 3306 U/wk of epoetin. Among the 6 large chain facilities with a similar patient case-mix, the average dose of epoetin ranged from 17,832 U/wk at chain 5 (nonprofit facilities with a mean hematocrit level of 34.6%) to 24,986 U/wk at chain 2 (for-profit facilities with a mean hematocrit level of 36.5%). Dosing adjustments also differed by type of facility. On average, compared with nonprofit facilities, for-profit facilities increased epoetin doses 3-fold for patients with hematocrit levels of less 33% and also increased the doses among patients with hematocrit levels in the recommended target of 33% to 36%, especially in the largest for-profit chain facilities. The greatest difference in dosing practice patterns between facilities was found among patients with hematocrit levels of less than 33%. CONCLUSIONS: Dialysis facility organizational status and ownership are associated with variation in epoetin dosing in the United States. Different epoetin dosing patterns suggest that large for-profit chain facilities used larger dose adjustments and targeted higher hematocrit levels.

Translating epoetin research into practice: the role of government and the use of scientific evidence.

Spending for epoetin is Medicare's single largest drug expenditure. We chronicle the evolution of epoetin policy based on a lack of well-designed post-Food and Drug Administration approval studies demonstrating clinical benefit; congressional/federal agency reliance on clinical practice guidelines that might have misinterpreted evidence supporting causality; and the premature translation of research into practice and policy. Were the right choices made? Epoetin showcases the risk and benefit conundrum created when evidentiary standards are relaxed. Our review concludes with broad-based policy recommendations for the newly implemented Medicare Part D program.