Mortality and cardiovascular morbidity associated with haemoglobin levels: a pooled analysis of randomised controlled trials.

BACKGROUND/AIMS: Several randomised controlled trials (RCTs) have raised concerns about potential harm associated with erythropoiesis-stimulating agents (ESAs) in chronic kidney disease patients, especially when haemoglobin (Hb) levels above 13 g/dl were targeted. We report the relationship between Hb levels and outcomes in the methoxy polyethylene glycol-epoetin beta RCT programme. METHODS: We assessed the association between Hb and a composite end point, as well as its components [all-cause mortality, myocardial infarction (MI) or cerebrovascular events (CVE)], in multiple post hoc analyses of 9 prospective RCTs (3,405 chronic kidney disease patients). Mean Hb levels over time and deviation from target were analysed using a Cox regression model. Time-adjusted average Hb, deviation from target, the last Hb, Hb slope and within-patient Hb variability preceding an event were analysed using a time-dependent Cox model. Hazard ratios and 95% confidence intervals were calculated. RESULTS: Average Hb <10 g/dl, decrease from stable baseline Hb >1 g/dl, last Hb <10 g/dl, Hb decline >1.5 g/dl/4 weeks and increased Hb variability were associated with a higher risk of the composite end point and all-cause mortality. An increased risk for CVE and MI was found with a last Hb <10 g/dl and with a decrease from baseline >1 g/dl in the preceding month. CONCLUSION: In multiple analyses from a large programme of prospective clinical trials of ESA treatment, risk of all-cause mortality and cardiovascular morbidity risk was consistently higher at Hb <10 g/dl and in patients whose Hb fell below target.

Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly.

BACKGROUND: C.E.R.A., a continuous erythropoietin receptor activator, is in development to provide anemia correction and stable maintenance of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease (CKD). This study examined its efficacy and safety when administered up to once monthly in patients who have CKD and are on dialysis and randomly convert directly from epoetin alpha or beta one to three times weekly. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: In this three-arm, comparator-controlled, open-label, randomized, parallel-group, Phase III study, 572 dialysis patients (> or =18 yr) who were receiving stable subcutaneous epoetin one to three times weekly were randomly assigned (1:1:1) to continue epoetin or to receive subcutaneous C.E.R.A. once monthly or twice monthly for 52 wk. Dosage was adjusted to maintain Hb +/-1.0 g/dl of baseline level. Primary end point was mean change in Hb level between baseline and the evaluation period (weeks 29 to 36). RESULTS: Mean Hb levels during the evaluation period were similar between groups (once-monthly C.E.R.A. 11.5 g/dl; twice-monthly C.E.R.A. 11.7 g/dl; epoetin 11.5 g/dl). The difference between C.E.R.A. and epoetin in mean change (97.5% confidence interval) in Hb concentration between baseline and evaluation was -0.022 g/dl (-0.262 to 0.217) for once monthly and 0.141 g/dl (-0.098 to 0.380) for twice monthly. Analysis demonstrated that C.E.R.A. was as effective as epoetin in maintaining Hb and was well tolerated. CONCLUSIONS: Subcutaneous C.E.R.A. once or twice monthly successfully maintained tight and stable Hb levels in patients who were on dialysis and randomly converted directly from epoetin one to three times weekly.