Although erythropoiesis-stimulating agents (ESAs) are effective at treating anemia, the association between hemoglobin (Hb) levels and survival is still unclear, especially for the incident Japanese hemodialysis (HD) population. The Japan Erythropoietin Treatment (JET) Study is an open multi-center, prospective, observational study designed to evaluate the relationship between the maintenance of Hb levels and new HD patient prognosis after the first administration of epoetin beta. Landmark analyses were performed to examine the relationship between Hb levels at 6 months and survival. Among a total of 10,310 patients, 6631 completed the initial 6 months of epoetin beta treatment (induction phase) and were followed up for a further 2.5 years (maintenance phase). Three-year survival rate of patients with <9 g/dL Hb levels after 6 months was 74.1%, which was significantly lower than 89.3% for patients with Hb levels 10 to 11 g/dL; the adjusted hazard ratio (HR) was 2.08 (95% CI, 1.57-2.77; P < 0.0001). Moreover, the 3-year survival rate for poor responders defined by Hb levels <10 g/dL and weekly epoetin beta doses ≥ 9000 IU during the induction phase was 71.6%, which was significantly lower than 89.4% for the group, which had Hb levels 10 to 11 g/dL excluding poor responders and those with excursion; the HR was 1.71 (95% CI, 1.13-2.60; P = 0.0118). Adverse events related to the treatment were reported in 71 of 10,310 patients (0.69%). These findings suggest that the achieved low Hb levels and poor response to ESA therapy are significantly associated with high mortality.

The effect of recombinant human erythropoietin (rHuEPO) treatment on the progression of chronic kidney disease (CKD) has not been fully evaluated in Japan. We therefore retrospectively evaluated this in a sub-cohort of a prospective multicenter study to investigate optimal hemoglobin (Hb) level of CKD patients on hemodialysis (HD) treated with rHuEPO; Japan Erythropoietin Treatment Study for Target Hb and Survival (JET study). Effect of rHuEPO treatment during predialysis period to delay initiation of HD was retrospectively assessed in 2434 patients from the JET study comparing groups with and without rHuEPO treatment. The assessment was done by Cox proportional hazards regression analysis and inverse probability-weighted (IPW) analysis to adjust for time-dependent confounders. The weights used in the IPW analysis were calculated using a logistic model that included baseline confounders and time-dependent variables. During the predialysis period, 71.7% (1746 patients) were treated with rHuEPO (mean Hb level of 8.7 g/dL at initiation of rHuEPO treatment). Covariates significantly associated with initiation of rHuEPO treatment were Hb level, serum creatinine level, age, diabetes, cardiac insufficiency, and hypertension. The adjusted hazard ratio for time until HD initiation under rHuEPO treatment was 0.272 (95% CI, 0.223-0.331; P < 0.001) in the Cox analysis and 0.63 (95% CI, 0.53-0.76; P < 0.0001) in the IPW analysis. This retrospective study suggests that rHuEPO treatment during the predialysis period has preventive effects on the progression of CKD although further prospective investigation on the efficacy is needed.

Progression of anemia in patients with chronic kidney disease (CKD) is associated with an increased risk of death and hospitalization. It is not sufficiently clear whether treating renal anemia with recombinant human erythropoietin (rHuEPO) has a beneficial effect on early survival after hemodialysis (HD) initiation in patients with CKD. The study was an open-label multicenter retrospective cohort study to evaluate the relationship between rHuEPO treatment and early survival after HD initiation in patients with CKD. Predialysis patients with CKD were divided into two groups: an rHuEPO-treated group (rHuEPO group) and a non-treatment group. The primary endpoint was all-cause mortality in the year after HD initiation. A total of 3261 patients were enrolled (2275 in the rHuEPO group and 986 in the non-treatment group). One-year survival was 95.36% in the rHuEPO group and 90.36% in the non-treatment group. The survival rate was significantly higher in the rHuEPO group (P < 0.0001). The results of multivariate analysis confirmed that predialysis treatment with rHuEPO is a predictor for reduced mortality risk (hazard ratio = 0.61, 95% confidence interval: 0.42-0.87, P = 0.006). Risk for the composite event of death/hospitalization was also lower in the rHuEPO group (hazard ratio = 0.88, 95% confidence interval: 0.78-0.98, P = 0.026). The results of this study suggest that treatment with rHuEPO can decrease early mortality risk after initiation of HD in patients with CKD. A prospective study is needed to further investigate early survival after HD initiation.

Background: This observational study investigated the safety and effectiveness of continuous erythropoietin receptor activator in patients with renal anemia in Japan. Methods: Patients were enrolled between August 2011 and November 2015 and followed for up to 1 year. Outcomes were analyzed according to disease stage (not receiving dialysis, on hemodialysis, on peritoneal dialysis). Results: Three thousand six hundred eighty-four patients were enrolled (1678 not receiving dialysis, 1605 on hemodialysis, 392 on peritoneal dialysis, and 9 other). Study treatment was well tolerated with no new safety concerns; adverse drug reactions were reported in 3.06%, 4.19%, and 4.46% of patients. Study treatment improved or maintained hemoglobin levels in 54.05-77.27% of patients, including erythropoiesis stimulating agent-naïve responders (hemoglobin ≥10.0 g/dL and hemoglobin increase ≥ 1.0 g/dL until week 24) and erythropoiesis-stimulating agent-switched responders (hemoglobin 10.0-12.0 g/dL at week 48). Conclusions: This study shows the safety and effectiveness of long-term continuous erythropoietin receptor activator for renal anemia.

B-R assessment can be performed using the BRAT framework with a health care database, but limitations exist when using a single data source. Care should be taken when selecting data for extraction and defining outcomes of interest. Further research is necessary to facilitate practical application of this approach.