Clinical Criteria for Transitioning from Oral to IV Iron Replacement Therapy in Patients with Iron Deficiency Anemia

Introduction: Oral iron supplementation is an effective means of iron replacement. Nevertheless, there is a frequent need to transition patients with iron deficiency anemia (IDA) from oral to intravenous (IV) iron therapy for inadequate response. No definitive guidance on the optimal timing for this change in therapy exists. Serum hepcidin may be a marker in predicting response to oral iron therapy, but currently, hepcidin assays are not commercially available. We evaluated the ability of various early response characteristics to accurately predict for an overall hemoglobin (Hb) response to oral iron. Our objective was to identify an early predictor of overall Hb response in patients on oral iron treatment as a guide to the decision to switch from oral to IV iron in patients unlikely to benefit from continued oral iron.

Methods: Proprietary datasets from 6 published randomized studies in which oral iron (325 mg of ferrous sulfate containing 65 mg of elemental iron, t.i.d.[4 studies], 304.3 mg capsules containing 100 mg bivalent iron b.i.d [1 study] and as prescribed by the investigator [1 study]) was used as a comparator to ferric carboxymaltose were analyzed. Five studies were pooled into one primary analysis dataset and one study was analyzed separately due to differences in study design that precluded pooling. Patients were grouped by the underlying etiology of their IDA (postpartum, heavy uterine bleeding, gastrointestinal, and others) and stratified by those who had ≥ 1 g/dL Hb change after 14 days of oral iron therapy (responders) and those who did not (non-responders). Further analyses evaluated Hb response at various time points based on initial 14 day Hb response (≥ 1 g/dL change vs < 1 g/dL). We systemically evaluated changes in hemoglobin, absolute reticulocyte count, % reticulocyte count, ferritin, and transferrin saturation at specific time points to determine their ability to predict overall Hb response.

Results: A total of 738 patients who were randomized to oral iron were included in the pooled study analysis. In the separate study, a total of 253 patients, all non-responders, were included. The mean baseline values for the 6 studies were Hb 9.9 g/dL, ferritin 19.9 ng/mL, and TSAT 16.9%. The vast majority of patients (96%) were females with a mean age of 36 years. In the pooled analysis, by day 14 of oral iron treatment, 27.2% (201/738) of patients had a Hb increase of < 1 g/dL (non-responders). Of these 201 patients, less than half (46.8%, 94/201) achieved an increase in Hb ≥ 1 g/dL from baseline after 2 additional weeks of oral iron (by day 28) and only 63.2% (127/201) had an increase in Hb ≥ 1g/dL from baseline after 6 to 8 weeks of oral iron (42 to 56 days). Furthermore, only 27.4% (55/201) and 5.5% (11/201) had an increase in Hb of 2 or 3 g/dL respectively at the Day 42 or 56 measurement. In comparison, responders (those who had a Hb increase ≥ 1 g/dL by 14 days of treatment) sustained a robust Hb response with continued dosing of oral iron. After 4 weeks of oral iron (28 days), 84.9% of the responders had a ≥ 2 g/dL increase in Hb from baseline. After 6 to 8 weeks of oral iron (42 or 56 days), 92.9% of the patients had ≥ 2 g/dL Hb increase from baseline, significantly different from non-responders (p < 0.0001). Patients with etiology of postpartum anemia had the most robust Hb response to oral iron. Results observed in the sixth study were similar to the pooled analysis. Only 10.2% (17/167) of non-responders who continued oral iron after day 14 achieved a Hb ≥ 2g/dL by Day 35, whereas 38.8% (57/147) who were switched to IV ferric carboxymaltose achieved a Hb > 2/dL by Day 35 (p =0.0001). Hb response after 14 days of oral iron was a strong predictor of overall response (sensitivity = 90.1%, specificity = 79.3%, positive predictive value = 92.9%, negative predictive value= 72.7%), surpassing other parameters evaluated in this study.

Conclusion: In the absence of significant continuous blood loss, Hb measurements taken 14 days after initiation of oral iron therapy can reliably predict overall response in Hb to oral iron therapy. Accordingly, day 14 Hb may be a useful tool for clinicians in determining when to switch patients from oral to IV iron.