1. In patients with CKD, fixed low dose of erythropoietin provides similar efficacy outcomes, such as percentage of patients requiring transfusions, as titration-based dosing based on Hgb levels while decreasing cumulative dose of erythropoietin needed.
Evidence Rating Level: 1 (Excellent)
Chronic kidney disease (CKD) patients have parenchymal loss leading to decreased erythropoietin production and anemia. Historically, anemia due to CKD often required erythropoietin-stimulating agents (ESAs) to increase their hemoglobin (Hgb) and ESAs were titrated to reach certain Hgb levels. ESA exposure can lead to increased cardiovascular events and thus alternative dosing strategies to maximize efficacy (decreased need for transfusions) and safety (decreased cardiovascular events) are needed. In this multicenter, pharmaceutical-sponsored (part of FDA postmarketing requirement), phase 3 randomized controlled trial, 756 patients with non-dialysis CKD were randomized into a 1:1 ratio of receiving either darbepoetin every 4 weeks based on titration Hgb to ≥ 10.0 g/dL (with dose reduction if rapid rate of rise or Hgb ≥ 10.5 g/dL) or darbepoetin fixed dose of 0.45 µg/kg every 4 weeks (with pausing of treatment if Hgb >12.0 g/dL or if systolic BP ≥ 160 mmHg for two consecutive visits). Patients were stratified by RBC transfusions received in the past year and site practice setting. There was no significant difference between the percentage of patients needing transfusions between the titration dose group or fixed dose group (24.4% vs. 24.1%) with similar time to first transfusion. The titration dose group had significantly higher median hemoglobin levels compared to fixed dose group (9.9 g/dL vs 9.4 g/dL) and higher median monthly dose of darbepoetin (53.6 ug vs. 30.9 ug, respectively). Though there were trends of better safety outcomes in the fixed dose group, there was no significant difference in endpoints such as all-cause mortality (HR 0.96), CV mortality (HR 0.89), stroke (HR 4.79), MI (0.75), decompensated HF (HR 0.70), TE events (HR 0.49) and combinations of these. These findings suggest that low fixed dose of ESAs may be a viable alternative to a titration-based strategy for minimizing transfusions and decreasing cumulative dose of ESAs. Limitations in this study include withdrawal of a significant number of patients (756 subjects enrolled, 458 completed the study) but there was equal withdrawal from both groups with similar percentages for each reason. The number one reason was due to developing end-stage renal disease requiring renal replacement therapy (90 subjects from each group). Future studies should be powered for safety endpoints to show improved safety outcomes in addition to non-inferiority efficacy outcomes for low fixed dose of ESAs.
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