Effect of Predialysis Recombinant Human Erythropoietin on Early Survival After Hemodialysis Initiation in Patients With Chronic Kidney Disease: Co-JET Study.

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.

Postmarketing Benefit-Risk Assessment for Erythropoiesis-Stimulating Agents Using a Health Care Database.

BACKGROUND: While benefit-risk (B-R) assessment in the real-world setting is an important challenge for pharmacovigilance, few studies have explored this approach. To investigate the utility and limitations of B-R assessment using a health care database by applying the Benefit Risk Action Team (BRAT) framework, we have conducted a case study with erythropoietin agents. METHODS: Postmarketing data from the Medical Data Vision health care database were used in a B-R comparison between methoxy polyethylene glycol-epoetin beta (continuous erythropoietin receptor activator; C.E.R.A.) and other erythropoiesis-stimulating agents (ESAs). Data were from patients with chronic kidney disease (CKD) treated with C.E.R.A. (n = 131: nondialysis, 109; hemodialysis, 22) or other ESAs (n = 542: nondialysis, 327; hemodialysis, 215) between July 2011 and March 2014. RESULTS: The B-R profile for C.E.R.A. appeared to be similar to that for other ESAs in both nondialysis and hemodialysis patients with CKD, when benefits and risks were mainly assessed in terms of odds ratios. Despite various point estimates and confidence intervals for each outcome, the results of subgroup analyses showed no notable differences from the overall analysis in B-R assessment. CONCLUSIONS: 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.

Using Clinical Databases to Verify the Impact of Regulatory Agency Alerts in Japan: Hepatitis B Testing Behavior After an Alert Regarding Risk of Viral Reactivation.

BACKGROUND: Measures of the effectiveness of risk minimization activities are necessary for the appropriate use of drugs, and clinical databases are a low-cost method of quickly producing such results. OBJECTIVE: The aim of this study was to explore the secondary application of clinical databases in verifying the impact of risk minimization activities; specifically, whether such databases could be used to identify changes in hepatitis B virus testing behavior after an alert from the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. METHODS: Patient data from December 1, 2010 to November 30, 2012 were extracted from the Medical Data Vision clinical database. The percentages of patients tested for hepatitis B virus DNA (HBV-DNA), hepatitis B surface antigen (HBsAg), and hepatitis B surface antibody (HBsAb)/hepatitis B core antibody (HBcAb) were compared 1 year before (consecutive 6-month periods A and B) and 1 year after (consecutive 6-month periods C and D) a PMDA alert regarding viral reactivation in patients receiving immunosuppressive agents. RESULTS: Data for 9866 patients in the clinical database were analyzed. After the PMDA alert, the percentage of patients tested for HBV-DNA linearly increased in periods A to D: 4.70 % (n = 262/5571), 5.78 % (n = 330/5710), 6.52 % (n = 398/6101), and 7.59 % (n = 479/6315). However, no changes were observed in the rates of HBsAg and HBcAb/HBsAb testing (around 50 and 70 %, respectively). Overall testing rates appeared to differ depending on disease and drug type. CONCLUSION: These findings suggest that the PMDA alert was effective at recommending HBV-DNA testing. This secondary application of clinical databases may be effective for verifying the impact of risk minimization activities.

Impacts of recombinant human erythropoietin treatment during predialysis periods on the progression of chronic kidney disease in a large-scale cohort study (Co-JET study).

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.

Low hemoglobin levels and hypo-responsiveness to erythropoiesis-stimulating agent associated with poor survival in incident Japanese hemodialysis patients.

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.