Trial To Reduce Cardiovascular Events With Aranesp Therapy Research Articles

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

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. Post hoc analysis of a randomized controlled trial. 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). Randomized treatment assignment (darbepoetin vs placebo). All-cause mortality, CV mortality, nonfatal myocardial infarction, heart failure, and stroke within the first 180 days of dialysis therapy initiation. Proportional hazards regression. 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). Post hoc analyses of a subgroup of study participants. 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.

Change in Hemoglobin Trajectory and Darbepoetin Dose Approaching End-Stage Renal Disease: Data from the Trial to Reduce Cardiovascular Events with Aranesp Therapy Trial

Background: The pathogenesis of chronic kidney disease associated anemia is multifactorial and includes decreased production of erythropoietin (EPO), iron deficiency, inflammation, and EPO resistance. To better understand the trajectory of these parameters, we described temporal trends in hemoglobin (Hb), ferritin, transferrin saturation, C-reactive protein (CRP), and darbepoetin dosing in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT). Methods: We performed a post hoc analysis of 4,038 participants in TREAT. Mixed effects linear regression models were used to determine the trajectory of parameters of interest prior to end-stage renal disease (ESRD). Likelihood ratio tests were used to determine the overall differences in biomarker values and differences in trajectories between those who did and did not develop ESRD. Results: Hb declined precipitously in the year prior to the development of ESRD (irrespective of treatment assignment), and was on average 1.15 g/dL (95% CI –1.26 to –1.04) lower in those who developed ESRD versus those who did not, at the time of ESRD/end of follow-up. Simultaneously, the mean darbepoetin dose and CRP concentration increased, while serum ferritin and transferrin saturations were >140 μg/L and 20%, respectively. Conclusions: Our analyses provide descriptive insights regarding the temporal changes of Hb, darbepoetin dose, and related parameters as ESRD approaches in participants of TREAT. Hb declined as much as 1–2 years prior to the development of ESRD, without biochemical evidence of iron deficiency. The most precipitous decline occurred in the months immediately prior to ESRD, despite administration of escalating doses of darbepoetin and in parallel with an increase in CRP.

ESRD After Heart Failure, Myocardial Infarction, or Stroke in Type 2 Diabetic Patients With CKD

How cardiovascular (CV) events affect progression to end-stage renal disease (ESRD), particularly in the setting of type 2 diabetes, remains uncertain. Observational study. 4,022 patients with type 2 diabetes, anemia, and chronic kidney disease from the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). Postrandomization CV events. ESRD (defined as initiation of dialysis for >30 days, kidney transplantation, or refusal or nonavailability of renal replacement therapy) and post-ESRD mortality within 30 days and during overall follow-up after an intercurrent CV event. Population limited to clinical trial participants with diabetes and anemia. 155 of 652 (23.8%) ESRD cases occurred after an intercurrent CV event; 110 (16.9%) cases followed heart failure, 28 (4.3%) followed myocardial infarction, 12 (1.84%) followed stroke, and 5 (0.77%) followed multiple CV events. ESRD rate was higher within 30 days in individuals with an intercurrent CV event compared with those without an intercurrent event (HR, 22.2; 95% CI, 17.0-29.0). Compared to no intercurrent CV events, relative risks for ESRD were higher after the occurrence of heart failure overall (HR, 3.4; 95% CI, 2.7-4.2) and at 30 days (HR, 20.1; 95% CI, 14.5-27.9) than after myocardial infarction or stroke (P<0.001). Compared withindividuals without pre-ESRD events, those with ESRD following intercurrent CV events were older, were more likely to have prior CV disease, and had higher (24.4 vs 23.1mL/min/1.73m2; P=0.01) baseline estimated glomerular filtration rates (eGFRs) and higher eGFRs at last measurement before ESRD (18.6 vs 15.2mL/min/1.73m2; P<0.001), whereas race, sex, and medication use were similar. Post-ESRD mortality was similar (P=0.3) with and without preceding CV events. Most ESRD cases occurred in individuals without intercurrent CV events who had lower eGFRs than individuals with intercurrent CV events, but similar post-ESRD mortality. Nevertheless, intercurrent CV events, particularly heart failure, are strongly associated with risk for ESRD. These findings underscore the need for kidney-specific therapies in addition to treatment of CV risk factors to lower ESRD incidence in diabetes.

C-Reactive Protein and Risk of ESRD: Results From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)

To better understand a potential association of elevated C-reactive protein (CRP) level with progression of chronic kidney disease (CKD), we examined the relationship of CRP level with the development of end-stage renal disease (ESRD) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). Post hoc analysis of a randomized controlled trial. 4,038 patients with type 2 diabetes, CKD, and anemia in TREAT. Baseline serum CRP concentrations. The primary outcome was development of ESRD; secondary outcomes included doubling of serum creatinine level, a composite of ESRD/serum creatinine doubling, and a composite of death or ESRD. We fit unadjusted and adjusted Cox regression models to test the association of baseline CRP level with time to the development of the outcomes of interest. Mean age of participants was 67 years, 43% were men, and 64% were white. Approximately half (48%) the patients had CRP levels > 3.0mg/L; 668 patients developed ESRD, and 1,270 developed the composite outcome of death or ESRD. Compared with patients with baseline CRP levels≤ 3.0mg/L, those with moderately/markedly elevated CRP levels (≥6.9mg/L; 24% of patients) had a higher adjusted risk for ESRD (HR, 1.32; 95% CI, 1.07-1.63) and the composite outcome of death or ESRD (HR, 1.41; 95% CI, 1.21-1.64). Although nonsignificant, similar trends were noted in competing-risk models. Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Elevated baseline CRP levels are common in type 2 diabetic patients with anemia and CKD and are associated with the future development of ESRD and the composite of death or ESRD.

Coronary Artery Disease Is a Predictor of Progression to Dialysis in Patients With Chronic Kidney Disease, Type 2 Diabetes Mellitus, and Anemia:An Analysis of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

BackgroundAlthough clear evidence shows that chronic kidney disease is a predictor of cardiovascular events, death, and accelerated coronary artery disease (CAD) progression, it remains unknown whether CAD is a predictor of progression of chronic kidney disease to end‐stage renal disease. We sought to assess whether CAD adds prognostic information to established predictors of progression to dialysis in patients with chronic kidney disease, diabetes, and anemia.Methods and ResultsUsing the previously described Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) population, we compared baseline characteristics of patients with and without CAD. Cox proportional hazards models were used to assess the association between CAD and the outcomes of end‐stage renal disease and the composite of death or end‐stage renal disease. Of the 4038 patients, 1791 had a history of known CAD. These patients were older (mean age 70 versus 65 years, P<0.001) and more likely to have other cardiovascular disease. CAD patients were less likely to have marked proteinuria (29% versus 39%, P<0.001), but there was no significant difference in estimated glomerular filtration rate between the 2 groups. After adjusting for age, sex, race, estimated glomerular filtration rate, proteinuria, treatment group, and 14 other renal risk factors, patients with CAD were significantly more likely to progress to end‐stage renal disease (adjusted hazard ratio 1.20 [95% CI 1.01–1.42], P=0.04) and to have the composite of death or end‐stage renal disease (adjusted hazard ratio 1.15 [95% CI 1.01–1.30], P=0.03).ConclusionsIn patients with chronic kidney disease, diabetes, and anemia, a history of CAD is an independent predictor of progression to dialysis. In patients with diabetic nephropathy, a history of CAD contributes important prognostic information to traditional risk factors for worsening renal disease.

Increased risk of stroke with darbepoetin alfa in anaemic heart failure patients with diabetes and chronic kidney disease.

The use of an erythropoesis-stimulating agent, darbepoetin alfa (DA), to treat anaemia in patients with diabetes mellitus and chronic kidney disease was associated with a heightened risk of stroke and neutral efficacy in the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), despite epidemiological data suggesting the contrary. However, this association has not been evaluated in another randomized, placebo-controlled trial. Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) was a randomized placebo-controlled trial of DA in 2278 patients with systolic heart failure and anaemia, enrolled from 2006 to 2012 and followed for a median of 28 months. Within RED-HF, 816 patients had diabetes mellitus and chronic kidney disease [estimated glomerular filtration rate (eGFR) 20-60 mL/min/1.73 m(2) ] and met inclusion criteria for TREAT. TREAT-like RED-HF patient data were analysed alone and combined at the patient level with the 4038 TREAT patients. In RED-HF, the annualized event rate of stroke was 2.3 in patients on DA and 1.1 in patients randomized to placebo (P = 0.051). Analysis of the combined group (n = 4854) confirmed a nearly two-fold increase in stroke risk [hazard ratio (HR) 1.94, 95% confidence interval (CI) 1.43-2.63] and an overall neutral effect on mortality (HR 1.00, 95% CI 0.89-1.12) of raising haemoglobin with DA. The placebo-controlled cohort of heart failure patients with anaemia, diabetes mellitus, and chronic kidney disease from RED-HF provides confirmation of the increased stroke risk associated with DA use identified in TREAT.

Cause of Death in Patients With Diabetic CKD Enrolled in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)

The cause of death in patients with chronic kidney disease (CKD) varies with CKD severity, but variation has not been quantified. Retrospective analysis of prospective randomized clinical trial. We analyzed 4,038 individuals with anemia and diabetic CKD from TREAT, a randomized trial comparing darbepoetin alfa and placebo. Baseline estimated glomerular filtration rate (eGFR) and protein-creatinine ratio (PCR). Cause of death as adjudicated by a blinded committee. Median eGFR and PCR ranged from 20.6 mL/min/1.73 m(2) and 4.1 g/g in quartile 1 (Q1) to 47.0 mL/min/1.73 m(2) and 0.1 g/g in Q4 (P<0.01). Of 806 deaths, 441, 298, and 67 were due to cardiovascular (CV), non-CV, and unknown causes, respectively. Cumulative CV mortality at 3 years was higher with lower eGFR (Q1, 15.5%; Q2, 11.1%; Q3, 11.2%; Q4, 10.3%; P<0.001) or higher PCR (Q1, 15.2%; Q2, 12.3%; Q3, 11.7%; Q4, 9.0%; P<0.001). Similarly, non-CV mortality was higher with lower eGFR (Q1, 12.7%; Q2, 8.4%; Q3, 6.7%; Q4, 6.1%; P<0.001) or higher PCR (Q1, 10.3%; Q2, 7.9%; Q3, 9.4%; Q4, 6.4%; P=0.01). Sudden death was 1.7-fold higher with lower eGFR (P=0.04) and 2.1-fold higher with higher PCR (P<0.001). Infection-related mortality was 3.3-fold higher in the lowest eGFR quartile (P<0.001) and 2.8-fold higher in the highest PCR quartile (P<0.02). The overall proportion of CV and non-CV deaths was not significantly different across eGFR or PCR quartiles. Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Measured GFR was not available. In diabetic CKD, both lower baseline GFR and higher PCR are associated with higher CV and non-CV mortality rates, particularly from sudden death and infection. Efforts to improve outcomes should focus on CV disease and early diagnosis and treatment of infection.

Pulse pressure is not an independent predictor of outcome in type 2 diabetes patients with chronic kidney disease and anemia--the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT).

Pulse pressure (PP) remains an elusive cardiovascular risk factor with inconsistent findings. We clarified the prognostic value in patients with type 2 diabetes, chronic kidney disease (CKD) and anemia in the Trial to Reduce cardiovascular Events with Aranesp (darbepoetin alfa) Therapy. In 4038 type 2 diabetes patients, darbepoetin alfa treatment did not affect the primary outcome. Risk related to PP at randomization was evaluated in a multivariable model including age, gender, kidney function, cardiovascular disease (CVD) and other conventional risk factors. End points were myocardial infarction (MI), stroke, end stage renal disease (ESRD) and the composite of cardiovascular death, MI or hospitalization for myocardial ischemia, heart failure or stroke (CVD composite). Median (interquartile range) age, gender, eGFR and PP was 68 (60-75) years, 57.3% women, 33 (27-42) ml min(-1) per 1.73 m2 and 60 (50-74) mm Hg. During 29.1 months (median) follow-up, the number of events for composite CVD, MI, stroke and ESRD was 1010, 253, 154 and 668. In unadjusted analyses, higher quartiles of PP were associated with higher rates per 100 years of follow-up of all end points (P⩽0.04), except stroke (P=0.52). Adjusted hazard ratios (95% confidence interval) per one quartile increase in PP were 1.06 (0.99-1.26) for MI, 0.96 (0.83-1.11) for stroke, 1.01 (0.94-1.09) for ESRD and 1.01 (0.96-1.07) for CVD composite. Results were similar in continuous analyses of PP (per 10 mm Hg). In patients with type 2 diabetes, CKD and anemia, PP did not independently predict cardiovascular events or ESRD. This may reflect confounding by aggressive antihypertensive treatment, or PP may be too rough a risk marker in these high-risk patients.

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

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 and4. 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 (χ(2) test). For patients with CKD stage 3, the proportion prescribed ESA therapy declined from 17% pre-TREAT to11% post-TREAT (a 38% decline), and for those with CKD stage 4, from 34% to 27% (a 22% decline). Prescribing ofESA therapy was declining even before TREAT, but the decline accelerated in the post-TREAT period (stage3: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 notable50% 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.

Retinopathy and clinical outcomes in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia

ObjectiveRetinopathy is an established microvascular complication of type 2 diabetes mellitus (T2DM), but its independent relationship with macrovascular and other microvascular complications is less well defined across the spectrum of...

CONFIRMATION OF KEY TREAT FINDINGS IN RED-HF, A PLACEBO CONTROLLED HEART FAILURE TRIAL

The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) demonstrated a heightened risk of stroke associated with Darbepoetin alfa (DA) use. Although stroke was not a primary endpoint, this finding raised significant patient safety concerns. The Reduction of Events by Darbepoetin Alfa

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KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD

The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for Anemia in Chronic Kidney Disease provides clinicians with comprehensive evidence-based recommendations to improve patient care. In this commentary, we review these recommendations and the underlying evidence. Most recommendations are well reasoned. For some, the evidence is unclear and recommendations require some qualification. While the KDIGO guideline stresses the potential risks of intravenous iron therapy, withholding iron might have its own risks. The recommendation to avoid hemoglobin levels falling below 9 g/dL sets a lower bound of "acceptability" that may increase blood transfusion. Given the lack of research supporting the optimal transfusion strategy for end-stage renal disease patients, it is difficult to weigh the risks and benefits of red blood cell transfusion. We find a paucity of evidence that hemoglobin concentration targeted between 11 and 11.5 g/dL is associated with a safety risk. Although the evidence that erythropoiesis-stimulating agent use improves patient quality of life is poor, it is possible that the instruments used to measure quality of life may not be well attuned to the needs of chronic kidney disease or dialysis patients. Our last section focuses specifically on the recommendations to treat anemia in children.

Hemoglobin Stability in Patients With Anemia, CKD, and Type 2 Diabetes: An Analysis of the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) Placebo Arm

Sparse data are available about the natural history of hemoglobin (Hb) level trends in contemporary patients with anemia, chronic kidney disease (CKD), and type 2 diabetes mellitus. We intended to describe Hb level trends over time with no or minimal administration of erythropoiesis-stimulating agents. Prospective clinical trial cohort. 2,019 individuals with type 2 diabetes, moderate anemia, and CKD from the placebo arm of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) followed up for 2.3 years with an average of 32 monthly Hb level determinations per patient. Darbepoetin alfa was administered only if Hb level decreased to <9 g/dL. Number of protocol-directed doses of darbepoetin alfa received due to an Hb level decrease to <9 g/dL. 1,106 (55%) placebo patients consistently maintained an Hb level ≥9 g/dL and received no protocol-directed darbepoetin alfa. The other patients received 1 (16%), 2-4 (16%), or 5 or more (13%) doses of darbepoetin alfa. Those who received no darbepoetin alfa doses had higher baseline Hb levels, higher estimated glomerular filtration rates (eGFRs), less proteinuria, and lower ferritin and transferrin saturation values. On average, Hb levels were stable or increased in all groups. Compared with individuals who received no darbepoetin alfa, those who received 5 or more doses were more likely to receive intravenous iron therapy and blood transfusions and progress to renal replacement therapy, but were not at higher risk of death. The strongest predictors of requiring 5 or more doses of darbepoetin alfa were lower baseline Hb level, lower eGFR, and higher proteinuria level. Post hoc analysis of a clinical trial of a specific population with diabetes, anemia, and non-dialysis-dependent CKD. In the TREAT placebo arm, Hb levels were stable with no or minimal protocol-directed darbepoetin alfa during 2.3 years of follow-up. Most patients with moderate anemia, non-dialysis-dependent CKD, and type 2 diabetes are able to maintain a stable Hb level without implementing long-term erythropoiesis-stimulating agent therapy.

Darbepoetin alfa

Darbepoetin alfa

Systematic review of the impact of erythropoiesis-stimulating agents on fatigue in dialysis patients

One of the cardinal symptoms of anemia in chronic kidney disease (CKD) patients is fatigue. Recently, results from Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) raised questions about the role of erythropoiesis-stimulating agents (ESAs) in improving fatigue and the appropriate hemoglobin (Hb) target in anemic patients with CKD. These discussions should be considered with all available evidence to determine the level of benefits and risks associated with ESA therapy on fatigue among both early-stage CKD patients and end-stage renal disease patients on dialysis. The study was a systematic review of the literature on fatigue in adults on maintenance dialysis therapy. The requirement for inclusion in the review was the measurement of fatigue before and after ESA treatment. Outcomes that were assessed were fatigue as measured by the Kidney Disease Questionnaire, the 36-item Short-Form general health survey, the Nottingham Health Profile, the Profile of Mood States or the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Several different measures of fatigue were used in the studies. Fifteen articles met the criteria for inclusion, including 10 distinct studies and one extension study. There was one placebo-controlled randomized clinical trial (RCT) and one extension, five single-arm, three high versus low, one intravenous versus subcutaneous and one switch from epoetin alfa to darbepoetin alfa. The only placebo-controlled RCT found a 22-26% improvement in fatigue. Single-arm cohort studies demonstrated a reduction in fatigue after a substantial increase in Hb. Studies with a baseline Hb <10 g/dL and partial correction to a minimum Hb ≥ 10 g/dL showed an average improvement in fatigue of 34.6%. Studies with a baseline Hb ≥ 11 g/dL and full correction to a minimum Hb ≥ 12 g/dL showed an average improvement in fatigue of 5.5%, while studies with no change in Hb (either placebo or control group) showed a decline of 0.7% in fatigue outcomes. Partial correction of anemia with ESA results in improvement of fatigue among patients on dialysis, most strikingly in those patients with baseline Hb levels <10 g/dL.

Stroke in Patients With Type 2 Diabetes Mellitus, Chronic Kidney Disease, and Anemia Treated With Darbepoetin Alfa

Background— More strokes were observed in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) among patients assigned to darbepoetin alfa. We sought to identify baseline characteristics and postrandomization factors that might explain this association. Methods and Results— A multivariate logistic regression model was used to identify baseline predictors of stroke in 4038 patients with diabetes mellitus, chronic kidney disease, and anemia randomized to receive darbepoetin alfa or placebo. To determine whether postrandomization blood pressure, hemoglobin level, platelet count, or treatment dose were responsible for the increased risk related to darbepoetin alfa, we performed a nested case-control analysis (1:10 matching) identifying nonstroke controls with propensity matching. The risk of stroke was doubled with darbepoetin alfa. Overall, 154 patients had a stroke, 101/2012 (5.0%) in the darbepoetin alfa arm and 53/2026 (2.6%) in the placebo arm (hazard ratio 1.9; 95% confidence interval, 1.4–2.7). Independent predictors of stroke included assignment to darbepoetin alfa (odds ratio 2.1; 95% confidence interval, 1.5–2.9), history of stroke (odds ratio 2.0; 95% confidence interval, 1.4–2.9), more proteinuria, and known cardiovascular disease. In patients assigned to darbepoetin alfa, postrandomization systolic and diastolic blood pressure, hemoglobin level, platelet count, and darbepoetin alfa dose did not differ between those with and without stroke. Additional sensitivity analyses using maximal values, latest values, or changes over varying periods of exposure yielded similar results. Conclusions— The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa–related stroke. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00093015.

What Caused Excess Strokes in Patients Randomized to Darbepoetin in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)?

Erythropoiesis-stimulating agents (ESAs) have been the treatment of choice for patients with renal anemia for >2 decades. Epoetin alfa was first approved in 1989 on the basis of its ability to increase hematocrit swiftly and to reduce the burden of transfusion in patients with chronic kidney disease (CKD) receiving dialysis.1 In addition to transfusion avoidance, recombinant human erythropoietin and its longer-acting cousins were also prescribed on the basis of the common belief that reducing anemia would improve relevant hard clinical end points, including cardiovascular morbidity and mortality. However, an earlier trial of patients receiving chronic hemodialysis who also had significant cardiovascular disease was halted owing to futility and safety considerations, and seemed to signal that a more aggressive anemia treatment target (normalization) would lead to an increased risk of mortality or nonfatal myocardial infarction (hazard ratio, 1.3; 95% confidence interval, 0.9–1.9; the Table).2 The findings of this Normal Hematocrit Trial were readily pushed aside owing to what was perceived as an extremely selected and nonrepresentative study population and a nonsignificant primary result, and did not appear to have a sustained effect on overall prescriber behavior. View this table: Table. Key Features of 4 Landmark Studies of Erythropoesis-Stimulating Agents in Patients With Chronic Kidney Disease Article see p 2903 It was not until relatively recently that large randomized trials in populations with non–dialysis-dependent CKD were conducted to test for that putative cardiovascular benefit from more aggressive anemia correction. In 2006, 2 randomized trials comparing higher and lower hemoglobin treatment targets in patients with CKD were simultaneously published (for pertinent details, see the Table). The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial found no difference between treatment groups in cardiovascular risk using a comprehensive composite end point.3 The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) …

Association Between Cardiac Biomarkers and the Development of ESRD in Patients With Type 2 Diabetes Mellitus, Anemia, and CKD

In patients with chronic kidney disease (CKD), as in other populations, elevations in cardiac biomarker levels predict increased risk of cardiovascular events. We examined the value of troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in assessing the risk of developing end-stage renal disease (ESRD) in diabetic patients with CKD. Prospective cohort study nested within a randomized clinical trial. Patients with type 2 diabetes, CKD (estimated glomerular filtration rate [eGFR], 20-60 mL/min/1.73 m(2)), and anemia enrolled in TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy). Serum levels of the cardiac biomarkers TnT and NT-pro-BNP. Incidence of ESRD and the composite of death or ESRD. We measured TnT and NT-pro-BNP in baseline serum samples from the first 1,000 patients enrolled in TREAT. The relationship of these cardiac biomarker levels to the development of ESRD and death or ESRD was analyzed in multivariable regression models. Detectable TnT (≥0.01 ng/mL) was present in 45% of participants, and median NT-pro-BNP level was elevated at 605 pg/mL. Higher levels of both cardiac biomarkers were associated independently with higher rates of ESRD, as well as death or ESRD, and remained prognostically important after adjustment for eGFR, proteinuria, and other known predictors of CKD progression. The addition of cardiac biomarkers to a multivariable model for prediction of ESRD improved discrimination of those with and without an event by 16.9% (95% CI, 6.3%-27.4%). Observational study in a clinical trial cohort; results require validation. In ambulatory patients with type 2 diabetes, anemia, and CKD, TnT and NT-pro-BNP levels frequently are elevated. These cardiac-derived biomarkers enhance prediction of ESRD beyond established risk factors. Measurement of TnT and NT-pro-BNP may improve the identification of patients with CKD who are likely to require renal replacement therapy, supporting a link between cardiac injury and the development of ESRD.

The future of intravenous iron in nephrology.

Management of anaemia in chronic kidney disease (CKD) patients can be difficult and expensive. The recently completed Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), the largest double-blinded trial of erythropoiesis-stimulating agents (ESA) treatment in CKD to date, provides us with a wealth of new information on the natural history of anaemia in Stage 3 and 4 CKD and the risks and benefits of use of ESAs. This section will discuss some of the TREAT trial results in the context of other recent studies of ESAs and intravenous iron in CKD patients. It will also review applying those results when choosing anaemia goals for an individual, and determining if iron therapy might improve anaemia.