Dennis J. Cotter

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.

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.

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.

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%.

The effect of insurance status on use of recombinant erythropoietin therapy among end-stage renal disease patients in three states

Recombinant human erythropoietin (rHuEPO) has been demonstrated to be effective in ameliorating anemia among persons with chronic renal failure, and is associated with improved functional status and quality of life. Access to rHuEPO has been examined by a variety of clinical, demographic, geographic, and facility characteristics. However, rHuEPO utilization based on insurance status has not been previously examined. All Medicare and Medicaid prevalent end-stage renal disease (ESRD) patients receiving dialysis services in California, Georgia, and Michigan in December 1991 were identified using state and federal administrative program data. The population in each state was stratified by insurance status as follows: Medicare-entitled, Medicare/Medicaid dually entitled, and Medicaid-only entitled. Insurance coverage of the ESRD population by Medicaid, as either a primary or secondary payer, differed greatly by state. In December 1991, the proportion of Medicaid-only and Medicaid/Medicare dually eligible dialysis patients ranged, respectively, from 8% and 43% in California, to 3% and 26% in Michigan, and to 3% and 18% in Georgia. Compared with the Medicare-entitled population, the Medicaid/Medicare dually eligible and Medicaid-only populations disproportionately comprised women, black patients, and individuals younger than 20 years. Using Lees two-stage binary logit model, dual-eligibility was found to be associated with an increased access to rHuEPO. Compared with their state-specific, dually eligible counterparts, the odds of receiving rHuEPO was lower for Medicare-entitled patients in California (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.76,0.93) and Georgia (OR, 0.65; 95% CI, 0.53,0.80), and lower for Medicaid-only patients in Georgia (OR, 0.02; 95% CI, 0.01,0.05) and Michigan (OR, 0.34; 95% CI, 0.23,0.52). We hypothesize that the absence of substantial copayments associated with rHuEPO, approximately

Improved survival with higher hematocrits: where is the evidence?

1,000 per year for a portion of Medicare-entitled patients, resulted in increased access among the dually eligible ESRD population. Dosing of rHuEPO was associated primarily with patient hematocrit level (P < 0.0001) and was unrelated to insurance status. Regardless of insurance status, an unexpectedly large number of Medicare prevalent dialysis patients receiving rHuEPO in each state (31%, 42%, and 41% in California, Georgia, and Michigan, respectively) had hematocrit values lower than 0.28, indicating inadequate treatment of anemia. Eleven percent of all patients receiving rHuEPO in California and nearly 20% in Georgia and Michigan were deemed to be severely anemic (hematocrit < 0.25). The wide variability in access to rHuEPO among the Medicaid-only populations may be indicative of state-specific differences in Medicaid prior approval, copayments, and other drug restrictions. We conclude that the Medicaid-only ESRD population excluded from Medicare coverage is particularly vulnerable to cost-containment measures that focus on expensive technologies such as rHuEPO.

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

The Centers for Medicare and Medicaid Services (CMS) is reviewing Medicare coverage policy for recombinant human erythropoietin (epoetin) therapy. CMS officials are concerned that “Medicare spending on EPO may be higher than necessary without resulting in optimal patient benefit.” Approximately 190 end‐stage renal disease (ESRD) patients die each day—a mortality rate that has remained essentially unchanged since 1994—despite improvements in the “adequacy of dialysis, vascular access, and anemia management”. To date, the evidence cited in support of a survival benefit of epoetin confuses the relationship between treatment response and outcomes with a causal effect of epoetin. A variety of mechanisms may account for a non‐causal association between hematocrit and mortality can occur. We conclude that there is no basis for inferring the survival benefits (or detriments) of increasing a patients hematocrit by adjusting the dosing of epoetin. Furthermore, we note that caution is required in administering large doses of epoetin to unresponsive patients in order to achieve the target hematocrit. A better understanding of the epoetin/survival relationship, well‐grounded in science, is needed to provide a basis for CMS to improve its current epoetin policies, and may help to improve patient mortality.

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

BackgroundIn 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.MethodsESA 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.ResultsThe 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.ConclusionsESA 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.

Major Declines in Epoetin Dosing after Prospective Payment System Based on Dialysis Facility Organizational Status

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.

Organizational Status of Dialysis Facilities and Patient Outcome: Does Higher Injectable Medication Use Mediate Increased Mortality?

Background: Epoetin therapy used to treat anemia among ESRD patients has cost Medicare ∼