Iron-deficiency is the most common nutritional deficiency in the world. It affects patients in both developed and developing countries and has been commonly recognized for centuries. In 1831, Blaud’s pills – an iron supplement named for the French physician Pierre Blaud, who is said to have developed them – made it to market.
Despite its prevalence, the treatment of iron-deficiency anemia has remained controversial. Shortly after their introduction, some researchers compared Blaud’s pills to placebos, or even poisons.1
About a century later, in 1932, the first parenteral form of iron became available. Unfortunately, the formulation, ferric oxyhydroxide, caused a variety of serious adverse events (AEs), such as diarrhea and hyperphosphatemia. Today, patients with iron-deficiency anemia have a variety of treatment options, from commonly prescribed oral iron pills taken regularly to five different types of intravenous (IV) iron. Still, the field remains rife with controversy and misunderstanding.
For example, one formulation of IV iron, high-molecular weight iron dextran, was approved by the FDA in 1996; after reports of serious AEs associated with the drug, including anaphylaxis, it was removed from the market in 2009. The damage was done, though, according to experts who spoke with ASH Clinical News. High-molecular weight iron dextran gave IV iron a bad name, and many doctors hold the misconception that other formulations of IV iron lead to similar problems, despite clinical trials demonstrating their safety.
“The formulation that actually caused the problem is no longer on the market,” said Maureen Achebe, MD, MPH, Clinical Director of the Non-Malignant Hematology Clinic at Brigham and Women’s Hospital in Boston. “The iron formulations that are coming on the market today are safe and should be encouraged to be used.”
Using IV iron has become much easier, Dr. Achebe added. “There are a number of IV iron formulations on the market, so it makes it easier for us to use IV iron now than we could before the early 2000s.”
ASH Clinical News spoke with Dr. Achebe and other experts about the safety and efficacy of IV iron products, how they are perceived in the community, and barriers to their use in the clinic.
Most patients with iron-deficiency anemia end up taking oral iron pills, which are inexpensive, safe, and convenient. “As it stands now, oral iron is the standard of care,” said Dr. Achebe, but only for patients who can tolerate it. Unfortunately, a very large proportion – about 70% of patients who take oral iron – experience significant gastrointestinal side effects.
The pills can make patients constipated or nauseous, and these side effects can prevent patients from taking the pills, thus rendering them ineffective. In patients with conditions like inflammatory bowel disease, the pills may cause even more discomfort. Plus, patients usually must take the pills consistently for months to get their iron concentrations back up to healthy levels.
If a patient has a condition that causes loss of iron faster than it can be absorbed through the gastrointestinal tract, oral iron will not be sufficient. These patients may require IV iron or blood transfusions. “It’s important to make sure that you know why the patient needs iron,” Dr. Achebe noted. “Like a fever, iron deficiency is a symptom.”
IV iron is considered frontline treatment for certain scenarios. For example, if a patient has chronic kidney disease or cancer, guidelines currently state that IV iron is likely to be the most effective option.2,3 However, there are many conditions for which experts argue oral iron is often ineffective, yet it is still the standard frontline treatment, while IV iron should be the treatment of choice.
Both Dr. Achebe and Michael Auerbach, MD, a hematologist and oncologist in private practice in Baltimore, cited iron-deficiency anemia in patients with inflammatory bowel disease as an example. Not only are patients often unable to properly absorb iron through the gastrointestinal tract, but oral iron is likely to aggravate an already irritated bowel. Other indications for which IV iron would be preferable include heavy menstrual bleeding or telangiectasia, because the absorption of oral iron cannot keep up with the rate at which a patient is continually losing it.
The American Metabolic and Bariatric Associations still recommend oral iron as the frontline therapy for patients with iron-deficiency anemia before and after bariatric surgery, and a recent study published in The Lancet suggested that preoperative treatment with IV iron was for anemic patients was not superior to placebo in reducing the need for transfusions.4 Dr. Achebe explained, however, that patients who have undergone bariatric surgery are unlikely to benefit from oral iron because they are unable to absorb enough of it after such a dramatic change to the digestive tract.
Dr. Auerbach, who also is Clinical Professor of Medicine at Georgetown University School of Medicine in Washington, D.C., agreed, saying, “My hair stands up when bariatric patients get oral iron. These people so desperately need to be iron sufficient to maintain the energy that they need for ongoing exercise.” Dr. Auerbach noted that the Lancet study was not sufficiently powered to determine whether preoperative iron-deficient patients benefit from IV iron.
In an editorial published in The Lancet Haematology, Dr. Auerbach and colleagues argued that IV iron should be positioned as the frontline treatment for iron deficiency in several patient populations, including heart failure, chronic kidney disease, inflammatory bowel disease, pregnancy, abnormal uterine bleeding, and after bariatric surgery.5 “Meta-analyses and prospective comparisons of different formulations support equivalent safety to placebo with less toxicity than oral iron,” the authors wrote. “Of the available formulations, the preponderance of published evidence supports equal safety and efficacy.”
IV Iron Options and Indications
There are currently five formulations of IV iron on the market. They vary in dose and the speed at which they can be administered. Some can be taken all at once over the course of several hours, others require multiple shorter visits.
The least expensive of the formulations is low-molecular weight (LMW) iron dextran, which can be given all in one dose. But one of the factors limiting its use in the clinic is confusion among doctors. “It got a bad reputation because, prior to 2009, it was confused with high-molecular weight iron dextran, which was associated with the highest number of serious AEs of any IV iron formulation ever,” Dr. Auerbach explained. “Most doctors didn’t understand there was a difference between the two.”
There also are two formulations of IV iron that fall into the category of “iron salts”: iron sucrose and ferric gluconate. These formulations are considered as safe and effective as LMW iron dextran but are given in a series of four or five injections. The amount of time a patient needs to sit in the chair at the infusion center is shorter, but they need to return to the office repeatedly. Acknowledging that some patients who are already visiting the office regularly, like those on dialysis or those who are receiving cancer treatment, may prefer these options, Dr. Auerbach, who only treats outpatients said, “I never use either one – not because they are not safe or not good drugs, but because they require four to seven injections to do what LMW iron dextran does in one.”
“There is no difference in safety or efficacy with the multiple visits,” he added, “but it markedly increases the cost and decreases the convenience [of treatment].”
Eleven years ago, the FDA approved ferumoxytol at a dose of 510 mg administered over at least 17 seconds. This much iron delivered this quickly, explained Dr. Auerbach, led to reports of serious AEs, including deaths. In 2015, the FDA added a boxed warning that extended the minimum recommended infusion time, from 17 seconds to 15 minutes, which has greatly minimized the potential for side effects. However, when it was approved at this dose and rate, the drug was not issued a broad approval, but was indicated for the treatment of iron-deficiency anemia in a limited population of individuals with chronic kidney disease. Ferumoxytol is currently approved for treatment of iron deficiency anemia in all populations of individuals.
The last currently available drug is ferric carboxymaltose. Although it has a long safety record, Dr. Auerbach said, “this drug causes hypophosphatemia in more than 50% of the patients who receive it.” Nonetheless, he noted that any cases of hypophosphatemia he has seen in his patients has been transient. A study conducted by Dr. Achebe and colleagues determined that, while ferric carboxymaltose was associated with an increase in hypophosphatemia compared with another IV iron, the clinical significance of this finding was unclear.6
Even so, Dr. Auerbach said that the “absolutely ridiculous vial size” of ferric carboxymaltose is a deterrent to its use. Others echoed his sentiment. The drug comes in vial sizes of 750 mg, meaning that, if a clinician wants to prescribe 1,000 mg, the patient will have to receive two vials, equaling 1,500 mg. The remaining unused 500 mg is discarded. “There’s very little evidence that giving more than 1,000 mg in a single dose is efficacious,” he added.
Although the IV iron formulations are considered similarly safe and effective, there is another powerful factor that determines which formulation patients may get: insurance coverage.
IV iron infusions are expensive products. Ferric carboxymaltose, for example, has a wholesale acquisition cost of $1,140 per vial.
In 2017, a Kaiser Health News analysis of private insurance claims found that private health plans paid an average of $4,316 per visit for an infusion of ferric carboxymaltose.7 Ferumoxytol was the next most expensive infusion drug, at $3,087 per visit. Given the costs, many insurance companies require that patients demonstrate an intolerance to oral iron before trying IV iron.
The Kaiser Health News investigation suggested that there was a good reason for this stipulation: The use of newer and pricier IV iron formulations spiked in recent years, making up more than half of IV iron infusions in 2017, up from fewer than one-third 3 years earlier. Consequently, use of cheaper, older formulations has fallen dramatically.
Experts told ASH Clinical News that insurance companies impose other restrictions on which formulations of IV iron patients can receive and under what circumstances, some of which they do not fully understand.
For example, Dr. Auerbach said that Aetna and United Health Care require providers to use LMW iron dextran, the least expensive formulation. “It’s less convenient for our nurses because it takes an hour to infuse, but I don’t really blame [the insurance companies] for that, so we just use it,” he commented.
But a pharmacist, who requested anonymity because she was not authorized by the pharmacy leaders to speak to the media, said this does not tell the whole story. Iron dextran is the least expensive drug on its own, but, she said, that does not account for the cost of “chair time” at the infusion center. The longer a patient remains at the center, the more expensive the treatment becomes because of facility and labor fees. Patients who receive LMW iron dextran must receive a test dose and be monitored before receiving their full dose, she explained. “After adding in the cost of the time, the cost is probably about the same [compared to some other formulations].”
The pharmacist added that shortly before the start of the pandemic, her group started receiving denials for ferumoxytol and ferric carboxymaltose from both Aetna and United Health Care. “They have stated that patients have to be intolerant to iron dextran, iron gluconate, and iron sucrose, before approving the use of the other two IV iron options.”
This presents “a real inconvenience to patients,” she explained, “because now we either use iron dextran, which means that they literally stay in the infusion clinic for at least 3 hours, or we use ferric gluconate, which means that they have to come back four times. If we use iron sucrose, they have to come back five times.” The COVID-19 pandemic has further complicated the need for multiple trips to the infusion center.
“Since we think [the IV iron formulations] are all safe and they’re all equally efficacious,” Dr. Achebe said, “generally, we choose formulations based on the patients.”
- Neuroth M, Lee C. A history of Blaud’s pills. J Am Pharma Assoc. 1941;30;60-63.
- National Kidney Foundation. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Accessed September 18, 2020, from https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-Anemia-Guideline-English.pdf.
- Aapro M, Beguin Y, BokemeyerC, et al. Management of anaemia and iron deficiency in patients with cancer: ESMO clinical practice guidelines. Ann Oncol. 2018;29:iv96-iv110.
- Richards T, Baikady R, Clevenger B, et al. Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial. Lancet. 2020 September 4. [Epub ahead of print]
- Auerbach M, Gafter-Gvili A, MacDougall I. Intravenous iron: A framework for changing the management of iron deficiency. Lancet Haematol. 2020;7:E342-E3350.
- Wolf M, Rubin J, Achebe M, et al. Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia. JAMA. 2020;323:432-443.
- Kaiser Health News. Infusion Treatments — Needed or Not — Can Deplete Patients’ Wallets. August 2, 2019. Accessed September 17, 2020, from https://khn.org/news/infusion-treatments-for-low-iron-can-deplete-patients-wallets/.