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Treatment of Anemia With Darbepoetin Prior to Dialysis Initiation and Clinical Outcomes: Analyses From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

ABSTRACT: RATIONALE & OBJECTIVE:Evidence from clinical trials to guide patient preparation for maintenance dialysis therapy is limited. Although anemia is associated with mortality and cardiovascular (CV) disease in individuals initiating maintenance dialysis therapy, it is not known if treatment of anemia before dialysis therapy initiation with erythropoiesis-stimulating agents alters outcomes. STUDY DESIGN:Post hoc analysis of a randomized controlled trial. SETTING & PARTICIPANTS:Participants with type 2 diabetes and chronic kidney disease who progressed to dialysis therapy (n=590) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). EXPOSURE:Randomized treatment assignment (darbepoetin vs placebo). OUTCOMES:All-cause mortality, CV mortality, nonfatal myocardial infarction, heart failure, and stroke within the first 180 days of dialysis therapy initiation. ANALYTICAL APPROACH:Proportional hazards regression. RESULTS:Overall, 590 of 4,038 (14.6%) participants initiated dialysis therapy during the trial (n=298 and 292 in the darbepoetin and placebo groups, respectively). Corresponding hemoglobin levels were 11.3±1.6 and 9.5±1.5g/dL (P<0.001). Death from any cause occurred in 31 (10.4%) participants assigned to darbepoetin and 28 (9.6%) assigned to placebo (HR, 1.16; 95% CI, 0.69-1.93), while death from CV causes occurred in 15 (5.0%) and 13 (4.5%) participants, respectively (HR, 1.21; 95% CI, 0.58-1.93). There were no differences in risk for nonfatal myocardial infarction or heart failure. Stroke occurred in 8 (2.8%) participants assigned to darbepoetin and 1 (0.3%) assigned to placebo (HR, 8.6; 95% CI, 1.1-68.7). LIMITATIONS:Post hoc analyses of a subgroup of study participants. CONCLUSIONS:Despite initiating dialysis therapy with a higher hemoglobin level, prior treatment with darbepoetin was not associated with a reduction in mortality, myocardial infarction, or heart failure in the first 180 days, but a higher frequency of stroke was observed. In the absence of more definitive data, this may inform decisions regarding the use of erythropoiesis-stimulating agents to treat mild to moderate anemia in patients with type 2 diabetes and chronic kidney disease nearing dialysis therapy initiation.

SUBMITTER: Mc Causland FR

PROVIDER: S-EPMC6420804 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Treatment of Anemia With Darbepoetin Prior to Dialysis Initiation and Clinical Outcomes: Analyses From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

Mc Causland Finnian R FR Claggett Brian B Burdmann Emmanuel A EA Chertow Glenn M GM Cooper Mark E ME Eckardt Kai-Uwe KU Ivanovich Peter P Levey Andrew S AS Lewis Eldrin F EF McGill Janet B JB McMurray John J V JJV Parfrey Patrick P Parving Hans-Henrik HH Remuzzi Giuseppe G Singh Ajay K AK Solomon Scott D SD Toto Robert D RD Pfeffer Marc A MA

American journal of kidney diseases : the official journal of the National Kidney Foundation 20181219 3

<h4>Rationale & objective</h4>Evidence from clinical trials to guide patient preparation for maintenance dialysis therapy is limited. Although anemia is associated with mortality and cardiovascular (CV) disease in individuals initiating maintenance dialysis therapy, it is not known if treatment of anemia before dialysis therapy initiation with erythropoiesis-stimulating agents alters outcomes.<h4>Study design</h4>Post hoc analysis of a randomized controlled trial.<h4>Setting & participants</h4>P ...[more]

PMID: 30578152

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Project description: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.A retrospective observational design was used to determine the impact of TREAT on clinical practice.A large US health plan database with more than 1.2 million claims for patients with non-dialysis-dependent CKD stages 3 and 4.ESA prescribing 2 years before and after publication of TREAT.Rate of ESA prescribing for ESA-naive and -prevalent cohorts.(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 (?(2) test).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).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.TREAT appears to be a watershed study that was followed by a marked decline in ESA prescribing for patients with CKD.

Project description:ObjectiveTo identify the optimal estimated glomerular filtration rate (eGFR) at which to initiate dialysis in people with advanced chronic kidney disease.DesignNationwide observational cohort study.SettingNational Swedish Renal Registry of patients referred to nephrologists.ParticipantsPatients had a baseline eGFR between 10 and 20 mL/min/1.73 m2 and were included between 1 January 2007 and 31 December 2016, with follow-up until 1 June 2017.Main outcome measuresThe strict design criteria of a clinical trial were mimicked by using the cloning, censoring, and weighting method to eliminate immortal time bias, lead time bias, and survivor bias. A dynamic marginal structural model was used to estimate adjusted hazard ratios and absolute risks for five year all cause mortality and major adverse cardiovascular events (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) for 15 dialysis initiation strategies with eGFR values between 4 and 19 mL/min/1.73 m2 in increments of 1 mL/min/1.73 m2. An eGFR between 6 and 7 mL/min/1.73 m2 (eGFR6-7) was taken as the reference.ResultsAmong 10 290 incident patients with advanced chronic kidney disease (median age 73 years; 3739 (36%) women; median eGFR 16.8 mL/min/1.73 m2), 3822 started dialysis, 4160 died, and 2446 had a major adverse cardiovascular event. A parabolic relation was observed for mortality, with the lowest risk for eGFR15-16. Compared with dialysis initiation at eGFR6-7, initiation at eGFR15-16 was associated with a 5.1% (95% confidence interval 2.5% to 6.9%) lower absolute five year mortality risk and 2.9% (0.2% to 5.5%) lower risk of a major adverse cardiovascular event, corresponding to hazard ratios of 0.89 (95% confidence interval 0.87 to 0.92) and 0.94 (0.91 to 0.98), respectively. This 5.1% absolute risk difference corresponded to a mean postponement of death of 1.6 months over five years of follow-up. However, dialysis would need to be started four years earlier. When emulating the intended strategies of the Initiating Dialysis Early and Late (IDEAL) trial (eGFR10-14 v eGFR5-7) and the achieved eGFRs in IDEAL (eGFR7-10 v eGFR5-7), hazard ratios for all cause mortality were 0.96 (0.94 to 0.99) and 0.97 (0.94 to 1.00), respectively, which are congruent with the findings of the randomised IDEAL trial.ConclusionsVery early initiation of dialysis was associated with a modest reduction in mortality and cardiovascular events. For most patients, such a reduction may not outweigh the burden of a substantially longer period spent on dialysis.

Project description:Whether and how anemia treatment with erythropoiesis stimulating agents (ESAs) before hemodialysis initiation may be associated with lower mortality after dialysis initiation is unknown. We compared all-cause and cardiovascular mortality in two groups of patients who experienced distinct anemia treatment patterns with ESAs before and after hemodialysis initiation. This retrospective cohort analysis included patients initiating hemodialysis April 1, 2012-June 30, 2013, identified from United States Renal Data System end-stage renal disease (ESRD) and pre-ESRD files. Patients treated with ESAs before and after hemodialysis initiation who maintained Hb ≥ 9.0 g/dL throughout (comparator group, n = 3662) were compared with patients with Hb < 9.0 g/dL before hemodialysis initiation (with or without ESAs) whose levels increased with ESAs after hemodialysis initiation (referent group, n = 4461). Cox proportional hazards models were used to calculate the hazard ratio of all-cause and cardiovascular mortality after hemodialysis initiation. Of 20,454 patients, 4855 (23.7%) had Hb < 9.0 g/dL upon hemodialysis initiation; of these 4855, 26.6% received ESAs before initiation. Comparator group Hb levels increased from 8.2 ± 0.8 mg/dL upon initiation to 10.9 ± 1.2 with ESAs afterward. Comparator patients were more likely than referent patients to be younger (76.3 ± 6.7 versus 77.2 ± 6.9 years), male (51.5% versus 49.8%), and black (24.6% versus 18.6%). Risk of all-cause mortality was lower for the comparator group versus the referent group at 3 (HR 0.83, 95% CI 0.68-1.00, P = 0.052), 6 (0.86, 0.74-1.00, P = 0.047), and 12 (0.88, 0.78-0.99, P = 0.036) months. The pattern was similar for cardiovascular mortality. Hb ≥ 9.0 with ESAs before and after hemodialysis initiation was generally associated with lower post-initiation all-cause and cardiovascular mortality compared with predialysis Hb < 9.0 g/dL in patients whose Hb levels subsequently improved with ESAs after hemodialysis initiation.

Dataset Information

Treatment of Anemia With Darbepoetin Prior to Dialysis Initiation and Clinical Outcomes: Analyses From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

Publications

Treatment of Anemia With Darbepoetin Prior to Dialysis Initiation and Clinical Outcomes: Analyses From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

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