Cost-Effectiveness of Oral Versus Intravenous First-Line Treatment of Severe Iron Deficiency Anemia in Women with Heavy Menstrual Bleeding

Introduction: Heavy menstrual bleeding (HMB), defined as monthly menstrual losses of sufficient volume to adversely impact a woman’s physical, emotional, social, or material quality of life, impacts 25-33% of all reproductive-age women globally. HMB is an enormous burden on women’s health and is associated with reduced quality-adjusted life expectancy (QALE), predisposing women to the development of iron deficiency (ID) and progression to iron deficiency anemia (IDA). At sufficiently brisk menstrual blood losses, the ability of oral iron to adequately address IDA becomes limited compared to intravenous (IV) repletion. However, in the United States (US), patients are often not afforded an opportunity for upfront IV iron treatment until after displaying intolerance or inadequate response to initial oral iron therapy. Furthermore, IV iron formulations differ greatly in cost, administration, and convenience. We sought to address this pressing issue in women’s health by conducting the first cost-effectiveness analysis of oral versus IV iron supplementation for the first-line treatment of severe IDA in women with HMB.

Methods: We built a Markov simulation of adult women with HMB and severe IDA (hemoglobin < 8 g/dL per the World Health Organization) to examine the cost-effectiveness of 1) first-line IV iron dextran (one-time 1000mg dose) versus 2) first-line IV iron sucrose (five separate 200mg doses) versus 3) first-line oral ferrous sulfate (followed by second-line IV iron as needed). The analysis was conducted across the lifetime menstrual time-horizon (i.e., ages 18 to 51), from the US health system perspective and across all accepted willingness-to-pay (WTP) thresholds in the US. Our base-case assumed monthly HMB losses of 120mL in otherwise healthy women without GI bleeding or iron malabsorption. Patients initially treated with oral iron would progress to second-line IV supplementation in the event of intolerable GI side effects. Iron-related adverse events (i.e., anaphylaxis, hypersensitivity, GI distress) were informed from randomized clinical trials of oral and intravenous iron as well as the World Health Organization Vigibase data (2008-2017). Serial retreatment with iron was time-variant across the lifetime menstrual time-horizon, depending on rate of HMB loss (i.e., occurring faster with increased HMB losses). Effectiveness was calculated in quality-adjusted life years, employing age-, sex-, and disease-specific EQ-5D index values in women with IDA, while the spectrum of anemia severity and its improvement across this spectrum was parameterized via the 2019 Global Burden of Disease Study. The primary outcome was the incremental cost-effectiveness ratio (ICER). We conducted deterministic sensitivity analyses to identify any parameter variations that could change our conclusion (and at what parameter thresholds). We used beta-PERT distributions to inform transition probabilities and utilities, and used gamma distributions for costs, concluding with probabilistic sensitivity analyses to capture uncertainty in all parameters simultaneously over 10,000 Monte Carlo iterations.

Results: In the base case, first-line iron dextran was the cost-effective strategy, costing $89,000 and accruing 14.5 QALYs, versus $92,000 and 14.5 QALYs for first-line iron sucrose, and $87,000 in costs and 13.3 QALYs for oral ferrous sulfate. The ICER of first-line iron dextran versus oral ferrous sulfate (with second-line iron dextran as needed) was $1,300/QALY [95% credible interval $1,100-$1700/QALY], while iron sucrose was absolutely dominated by iron dextran. Deterministic sensitivity analyses revealed no parameter variation that could significantly change the ICER (i.e., the conclusion remains that iron dextran is the cost-effective strategy). In probabilistic sensitivity analyses, first-line iron dextran was favored in 100% of 10,000 Monte Carlo iterations, remaining preferred across the accepted range of WTP thresholds in the US ($50,000-$150,000/QALY).

Conclusion: First-line IV iron dextran is the cost-effective intervention for the treatment of severe IDA in women with HMB, demonstrating increased quality-adjusted-life-expectancy over first-line oral iron with subsequent second-line IV, and reduced costs compared to first-line IV iron sucrose.