We have designed a pragmatic randomized controlled trial comparing daily and alternate day oral iron therapy in patients with IDA. A pilot study has shown that both regimens lead to clinically meaningful increases in hemoglobin and serum ferritin.
At equal total doses, alternate day dosing was found to produce less gastrointestinal side effects than consecutive day dosing, while simultaneously mitigating any increase in serum hepcidin following iron supplementation.
Dosing
The DEODO Study was a pilot randomized controlled trial that compared administering daily or every other day oral iron (ferrous sulfate) for those living with IDA in Toronto, Canada (Sunnybrook Health Sciences Centre and St Michael’s Hospital). The trial took place as an outpatient at two academic hospitals (Sunnybrook Health Sciences Centre and St Michael’s Hospital), with participants being referred by primary care providers, blood centers or community health workers for referral. They were randomly allocated one of two treatment groups before being administered oral iron for 12 weeks; four study visits included as bloodwork examination, review of medical histories or new health concerns as well as questionnaires about fatigue or potential side effects from taking oral iron treatment.
Oral iron supplements cause an increase in hepcidin levels that inhibit subsequent doses from being absorbed, lasting 24 h after the last dose and subsiding within 48 h – this results in wide fluctuations in iron absorption rates; its exact cause remains unknown, however; potential mechanisms could include changes to iron markers and intra-enterocyte functions as potential contributors to this variance.
Moretti et al. (2017) demonstrated that providing non-anemic iron deficient women with iron supplements on consecutive days leads to an increase in hepcidin that reduces absorption. Furthermore, they demonstrated that dosing iron in alternate day doses optimised fractional iron absorption resulting in optimal fractional absorption – perhaps an ideal dosing regime.
This pilot study confirms the hypothesis that giving iron in alternate day rather than daily doses may overcome hepcidin-mediated blockades to absorption. A larger investigation must now take place to validate these findings.
The results from this pilot study demonstrate that switching between weekly and biweekly dosing does not increase serum ferritin levels; rather, it reduces pill burden; saving 18 tablets of iron per week while having fewer gastrointestinal side effects than consecutive-day dosing groups. Furthermore, such changes might improve patient tolerability and compliance with oral iron therapy, making this factor important in future trials’ design and conduct.
Side effects
Iron deficiency anemia (IDA) can be treated effectively with oral iron supplementation; it’s generally well tolerated but may cause adverse gastrointestinal side effects; its optimal dose and timing remains unknown, however. To determine what dose and timing would best achieve hemoglobin repletion in those living with IDA, this randomized controlled trial compared alternate day with daily dosing regimens using cross over design in a randomized controlled trial; its primary outcomes included total and fractional iron absorption measured using isotopic labelling of erythrocytes along with serum Hepcidin levels; hemoglobin repletion as secondary outcomes.
120 patients with IDA were randomly assigned either consecutive-day or alternate day iron supplementation. One group received one dose of 60 mg iron every morning for three consecutive days while the other group received it once every alternate day; following a wash out period, groups switched dosing arms. Hemoglobin, serum ferritin and reticulocyte count measurements were made at prespecified follow up points and serum hepcidin was assessed before and after this study.
Both groups saw increases in hemoglobin levels while hepcidin decreased over the four month study. At four months post-treatment, however, alternate day group had significantly higher hepcidin, serum ferritin, and transferrin saturation (%TS) levels than consecutive-day group; there was significant time-group interaction for these parameters but not for primary outcomes such as Hb and serum ferritin levels.
Provide iron supplements on alternate days in single morning doses has proven to enhance iron absorption and might be an easier regimen to adhere to. However, more research needs to be conducted in order to compare the effect of different iron dosing schedules on hepcidin and other biomarkers of iron status as well as any associated GI side-effects. A randomized clinical trial that compares continuous with alternate day dosing could provide answers. As part of this endeavor, it would also be necessary to determine whether lower doses could still result in comparable increases in hemoglobin, and determine the maximal safe dose of iron. If this were possible, daily dosing with lower doses might become an attractive alternative for some IDA patients. It might even prove cheaper than alternate-day dosing in low income countries where most of these patients reside.
Efficacy
Numerous trials have investigated consecutive day versus alternate-day iron dosing regimens. At equal total iron doses, studies have revealed that consecutive day dosing doesn’t lead to higher serum ferritin, but may cause more gastrointestinal side effects. Alternate-day dosing appears to overcome hepcidin’s block of iron absorption without increasing side effects; and can speed up repletion of iron depots more rapidly while simultaneously decreasing side effects and complaints associated with iron absorption.
Current guidelines to treat IDA recommend daily administration of oral iron supplements; however, iron is only rapidly absorbed from the proximal duodenum and eventually excreted through the distal gut. Hepcidin also reduces iron absorption after an initial oral dose, so regularly administering large quantities of iron will result in decreased fractional absorption and consequently lower blood levels over time. Controlled or slow-release forms of iron tend to be poorly absorbed and don’t offer clinical benefits. Their only real advantage is reduced gastrointestinal side-effects; likely caused by their more gradual passage through the gut and reaching areas with little response from hepcidin.
To determine whether alternate-day dosing of oral iron could overcome hepcidin’s inhibition of its absorption and increase compliance, we conducted a pilot, pragmatic, open-label RCT with outpatients with IDA who had hemoglobin below 12.0 g/dL or ferritin below 30 mcg/L and who met other criteria. Participants were randomly allocated either a daily dose of equal amount, or they received it every other day in equal quantities.
Institutional review boards at each site approved this study and all participants provided written informed consent prior to any study-related procedures using a remote electronic signature software program. All participants were assigned a 12-week treatment group of iron therapy, during which time their hemoglobin, serum ferritin and body iron stores (sTfR, serum transferrin saturation [%TS]) were assessed at the end of this time period. The primary efficacy outcome is change in hemoglobin; those not reaching or maintaining target range levels of hemoglobin will be followed until therapy escalation, an emergency department visit related to anemia or needing intravenous iron infusion or transfusion occur.
Safety
Iron deficiency, which leads to anemia, is a prevalent issue that should be taken seriously. Oral iron supplements are recommended as first line treatment to return hemoglobin (Hb) levels back to normal, but many do not follow through with their iron prescription due to poor compliance, side effects from medications and difficulty managing medications schedule.
This study will compare the efficacy and side effect profile of daily versus alternate-day oral iron administration for improving hemoglobin in patients with IDA. It is a pragmatic, open-label pilot randomized controlled trial enrolling 52 outpatients from two large academic hospitals affiliated with the University of Toronto with IDA who will be randomly allocated either daily 300 mg oral ferrous sulfate (60 mg elemental iron) doses or every other day for 12 weeks for optimal hemoglobin production.
Studies conducted by previous investigators demonstrate that continuous supply of iron increases serum hepcidin levels and diminishes fractional iron absorption, peaking 8 hours after ingestion, remaining elevated 24 hours postdose and returning back to normal by 48 hours. Intermittent administration may provide an effective strategy to bypass this inhibition by increasing iron absorption with each successive dose taken.
Participants will be monitored over four visits (1 week, 4 weeks, 8 weeks and 12 weeks after starting iron) to evaluate Hb levels, bloodwork results, medication compliance issues, fatigue and any possible GI side effects. Their capsule containers will also be returned as evidence of compliance; blood samples will also be collected at these visits.
This will be the only randomized clinical trial to assess Hb as its primary endpoint; previous randomized trials have only assessed iron absorption as their outcome.
Recurrences of iron deficiency anemia (IDA) are an all too familiar problem and require continuous iron therapy in order to restore normal Hb levels. Determining effective oral iron dosing regimens will enable physicians to treat this condition more successfully with fewer complications, as has been demonstrated through various recent randomized trials. Doingle dosing consecutive days instead of alternate day dosing was associated with significantly lower Hb increases than alternate day dosing in women who were iron-depleted.
