This randomized controlled trial of 200 participants with iron deficiency anemia and hemoglobin of 10 g/dL or less found that there were no differences between alternate day oral iron supplementation compared to daily supplementation in terms of increase in hemoglobin, serum ferritin or reticulocyte count at any of the prespecified follow up points. No major differences were noted between the two arms with regard to adverse effects.
Early reports of potential benefit from intermittent versus consecutive iron supplementation come from a Cochrane systematic review of randomized controlled trials comparing the two strategies on pregnant women (6). This and other studies on menstruating females have demonstrated that intermittent administration of oral iron may be better than daily iron (7). Moretti et al performed a study based on the recognition that iron supplementation causes rise in hepcidin levels that could impede absorption of further doses of iron. Their investigation of 54 non-anemic but iron-depleted women demonstrated that lower dosages ranging between 40 and 80 mg or elemental iron, and avoidance of twice daily doses improved fractional absorption of iron (8). Hence, the authors suggested that alternate day iron supplementation might be advantageous. However, sample size was small; duration of iron supplementation was very short (2 days), and the participants did not have anemia.
In a subsequent study, Stoffel et al determined the iron absorption from oral iron administered on consecutive versus alternate days (5). Participants of this study were iron deficient women who received 60 mg elemental iron for 14 days consecutively or on alternate days for 28 days. As expected, serum hepcidin was higher in the consecutive day group compared to alternate day group. The mean cumulative fractional iron absorption was 16.3% in the consecutive day group compared to 21.8% in alternate day group (p = 0.001). In the same study, the authors assigned ten women to receive once-daily dose and ten women to receive two divided doses. While no differences were observed between these two groups of women in terms of fractional iron absorption or total iron absorption, twice daily administration caused hepcidin to rise more than once daily regimen (5). These studies also did not enroll anemic patients. Further, small sample size and short duration of supplementation limited extrapolation of findings to real world settings. Another limitation of these studies was the lack of clinically relevant outcomes such as change in hemoglobin.
In 2020, Stoffel and colleagues studied the effect of alternate versus daily iron supplementation in iron-deficient and anemic women (9). Doses of 100 mg or 200 mg iron were given in a cross over design to 19 women. Supplementation was only for 3 doses with a wash out period of 16 days. The fractional iron absorption was significantly higher in the alternate day dosing group compared to consecutive day group. Although the inclusion of participants with anemia was a strength, the median hemoglobin was 11.5 g/dL, much higher than values seen in clinical practice in developing countries where iron deficiency anemia is a major problem.
Another study on anemic infants from Kenya reiterated the findings of Stoffel in adults, although the decrease in iron absorption from consecutive day dosing was modest compared to alternate day dosing (10).
While most studies have used iron absorption as the primary outcome, Kaundal et al reported the results of the first randomized controlled trial using improvement in hemoglobin as the primary outcome (11). This trial assigned 62 participants with iron deficiency anemia to receive either 60 mg elemental iron twice daily or 120 mg on alternate days for 6 weeks. In contrast to previous studies, 58% of participants in the twice daily group had a hemoglobin rise of at least 2 g/dL from baseline compared to 35.5% of participants in the alternate day group (p = 0.001). The mean rise of hemoglobin was also higher in the twice daily arm compared to alternate day arm (2.9 vs 2.0 g/dL; p = 0.03). In our study, we compared a single daily dose of 60 mg to alternate day dose of 120 mg in 200 participants, a considerably larger sample size. The duration of supplementation was 2 months, more closely reflecting the real-life practice of rechecking hemoglobin in resource poor settings. The outcomes chosen were clinically meaningful including the mean change in hemoglobin, proportion of participants with a meaningful rise in hemoglobin, reticulocyte response and change in iron stores reflected by serum ferritin. Besides, participants in our study had more severe anemia (mean hemoglobin 6.53 g/dL and 6.68 g/dL in alternate day and consecutive day arms respectively) compared to those in the study by Kaundal et al.
While Kaundal et al demonstrated that consecutive day administration with two doses is superior to alternate day single doses, our study provides new data on similar efficacy of a single daily dose compared to alternate day dosing in improving iron deficiency anemia.
We have no biochemical measurements to explain the disparity between results of our study and those of others that investigated effects on iron absorption. Yet, our results almost parallel the only other randomized controlled trial that used clinically important variables as primary outcomes (11). While Mehta et al reported significant increase in hemoglobin at 21 days among persons taking alternate day iron compared to daily iron, the primary outcome of their randomized controlled trial was hepcidin response (12). Besides, the sample size was small (20 participants in each arm). Such instances of divergent results from studies using surrogate end points and clinical end points are not new and exemplify the need to preform rigorous randomized controlled trials on large number of participants with clinically meaningful endpoints and interventions closely reflecting real world experiences. Although the protocol for a randomized controlled trial comparing alternate day and daily iron has been published recently, it aims to recruit 52 patients and the primary outcome is the feasibility of recruiting the target sample size over 2 years (13).
The major strengths of our study thus include: a large sample size, longer duration of iron supplementation, inclusion of participants with anemia rather than iron deficiency alone, use of commonly employed tolerable doses of iron and measurement of outcomes that are clinically meaningful. Lack of measurement of iron absorption studies or hepcidin levels could be considered limitations.