Approach

The treatment of choice for anemia of chronic disease (ACD) is first and foremost treatment of the underlying disorder.[17]

Initial treatment of patients with mild to moderate anemia (Hb 8 to 11 g/dL)

If the underlying disorder can be ameliorated or cured, the anemia usually improves or dissipates. This commonly occurs after treatment of infections, after complete resection of tumors, and at complete remission of lymphomas.[29] 

In the case of autoimmune disorders that cause ACD, hemoglobin (Hb) typically rises with effective treatment. For example, treatment with tumor necrosis factor (TNF)-alpha inhibitors can lead to improvements in Hb levels in patients with rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease.​[4][53][54]

Iron supplementation

Intravenous iron is preferred to oral iron because it is associated with a more rapid achievement of target Hb and decreased erythropoiesis-stimulating agent (ESA) requirement compared with oral iron.[55][56][57][58]​​ Currently available intravenous iron formulations appear to be well-tolerated, with low risk of infusion reaction.[59][60][61][62]

One Cochrane review found evidence to suggest that intravenous ferric carboxymaltose may be more effective than intravenous iron sucrose for the treatment of iron deficiency in people with inflammatory bowel disease.[63]

Supplemental iron is not recommended for patients with ACD who have normal or high ferritin levels (except in certain cases of functional iron deficiency).[17]​ Iron supplementation is relatively contraindicated in the setting of active infection.[52]

Symptomatic anemia: underlying disorder not responsive to treatment

Treatment options for patients in whom the underlying disorder is not responsive to treatment (or requires time to respond) and the anemia is persistent despite correction of iron deficiency, include:

  • Observation (for patients with mild to moderate ACD)

  • Red blood cell (RBC) transfusion; or ESA (for patients with symptomatic anemia that significantly impairs their quality of life, or with comorbidities in which a mild to moderate anemia imposes additional risk (e.g., heart failure, significant pulmonary disease, cerebral vascular disease).

RBC transfusion

The benefit of RBC transfusion must always be weighed against its potentially significant risks, which include volume overload, transfusion reaction, acute hemolysis with shock, delayed hemolytic transfusion reaction, transfusion-associated acute lung injury, alloimmunization, and iron overload.[52]

Guidelines for the treatment of anemia in cancer and chronic kidney disease (CKD) do not recommend routine, ongoing RBC transfusion principally because of the risks of iron overload.[52] However, it is reasonable to transfuse in cases of symptomatic anemia.[64]

ESAs

ESAs include recombinant human erythropoietins derived from a cloned human erythropoietin gene (epoetins), such as epoetin alfa or a derivative (e.g., darbepoetin alfa). ESAs may be used in certain patients when the anemia impacts quality of life and/or when repeated RBC transfusion is unwarranted.[65][66][67]

The decision to prescribe an ESA is made in consult with a specialist. RBC transfusion may be required until benefits of ESA therapy manifest.

Transfusion requirement is reduced by ESAs, but there is uncertainty about the risks, and the economic impact is considerable.[66][68]​​ Therefore, a careful evaluation of the risk/benefit ratio before using an ESA is strongly suggested.

ESAs are associated with cardiovascular adverse effects, including increased thrombotic events and hypertension. Risk factors for venous thromboembolism should be evaluated and blood pressure controlled before treatment with an ESA. Pure red cell aplasia due to development of neutralizing antibodies to erythropoietin has been reported rarely, but may be increased with some recombinant formulations.[69]

There have been reports that ESAs reduce overall survival and, in some cancer patients, shorten time to tumor progression. Increased mortality and worsened outcomes have been reported with higher target Hb levels (>11 to 12 g/dL).[70]​ While some subsequent studies found no association between ESA use and increased mortality, uncertainty remains.[66][71][72][73][74]​​

ESA prescribing has declined since safety concerns were raised, and further studies are needed to determine optimal use of ESAs for different patient groups.[75]

Initiating ESA therapy

The appropriate clinical indications for the use of ESAs in the setting of ACD with mild to moderate anemia (Hb 8 to 11 g/dL) should be carefully evaluated. Systematic reviews and meta-analyses have not demonstrated consistent benefits associated with ESA use in patients with anemia associated with chronic or inflammatory disease.[74][76]

ACD may represent a physiologic adaptation (and may not necessarily be harmful); decisions about the treatment of mild and moderate anemia should be carefully considered.[77]

Iron deficiency should be ruled out prior to initiating therapy.

In patients with congestive cardiac failure or coronary heart disease, and mild to moderate ACD, ESA use has been associated with an increased risk of thromboembolic events and is not recommended.[78][79][80][81][82]

ESA therapy for anemia in CKD

ESAs increase Hb concentration and improve quality of life in predialysis and dialysis patients with anemia.[83][84]​​ However, it is unclear whether ESAs hasten or delay decline in renal function in predialysis patients.[84]

ESAs may be considered for patients with CKD not on dialysis who have Hb levels <10 g/dL. For patients with CKD on dialysis, ESA therapy may be used when Hb levels are between 9 and 10 g/dL, to avoid levels falling below 9 g/dL. Decisions about starting treatment and dosing should be individualized.[52]

Studies have shown increased mortality and adverse cardiovascular outcomes (without additional benefits) with ESA use in patients with CKD with Hb levels >11 g/dL.[69]​ The Food and Drug Administration (FDA) has issued a warning for the use of ESAs (epoetin alfa and darbepoetin alfa) to highlight that these agents should be used at the lowest dose sufficient to reduce the need for RBC transfusions, with treatment being reduced or interrupted in patients with CKD if Hb levels exceed 10 g/dL in those not on dialysis, or if Hb levels approach or exceed 11 g/dL in those on dialysis, or if there is a rapid rise in Hb (>1 g/dL in any 2-week period).[85]

ESA therapy for patients with cancer

Guidelines recommend considering ESAs for patients with chemotherapy-associated anemia who have Hb levels <10 g/dL.[64][69][86]​​ The FDA stipulates that ESAs should not be used in patients receiving treatment with curative intent because of the potential risks of increased tumor progression and reduced survival; this is reflected in the US guidance.[64][69] If there are uncertainties about curative intent, RBC transfusion should be considered before ESA therapy.[64]

In patients with chemotherapy-induced anemia, ESA therapy is effective in increasing Hb concentrations, improving hematologic responses, reducing the need for blood transfusions, and improving health-related quality of life.[68][87] [ Cochrane Clinical Answers logo ] However, uncertainty remains about the risks.

For patients with CKD and cancer, use of ESAs may only be considered with caution and careful evaluation of the risks and benefits.[52]​ Patients receiving palliative chemotherapy may benefit from carefully dosed ESAs in preference to transfusion for the treatment of severe anemia.[69]​ ESAs are not typically recommended for patients with CKD receiving curative cancer treatment, or with a history of cancer or stroke.[52]

ESAs should be used at the lowest dose sufficient to reduce the need for RBC transfusions. Treatment should be discontinued in patients with chemotherapy-induced anemia if there is no response to an ESA after 6 to 8 weeks. There is no benefit in switching to another ESA if the initial ESA has not been effective.[64]

ESA therapy is not recommended for patients with cancer who are not receiving chemotherapy or for those receiving non-myelosuppressive therapy.[64][69]​​​ However, selected patients with myelodysplastic syndrome may be an exception. See  Myelodysplastic syndrome.

Supplemental iron and ESA therapy

Because ESAs often produce functional iron deficiency in iron-replete subjects, supplementary iron therapy may be required to achieve an adequate therapeutic response.[88] [ Cochrane Clinical Answers logo ]

For ESA-treated patients with cancer, the US guidelines recommend consideration of:​[64][69]​​

  • Intravenous iron for chemotherapy-associated anemia, given regardless of the iron status, with baseline and periodic iron studies

  • Intravenous iron in patients with functional iron deficiency (ferritin 30 to 500 ng/mL and transferrin saturation <50%)

A trial of intravenous iron is recommended for patients with CKD who are receiving ESA therapy.[52]

Iron supplementation, alongside ESA treatment, may improve hemoglobin response and reduce RBC transfusion requirements. Baseline and periodic iron studies are recommended.[64]

Monitoring ESA therapy

ESAs should be used cautiously. Close monitoring (particularly during the early phases of treatment) and careful dose titration (every 4 to 6 weeks) are required to maintain correct Hb levels.[69][70][86]​​[89]​​[90][91][92] During initial treatment and dose titration, Hb levels should be monitored weekly until stable and monthly thereafter.

Severe (Hb <8 g/dL) or life-threatening (Hb <6.5 g/dL) anemia

Treatment of the underlying disorder is commenced.

RBC transfusion

May be appropriate in severe anemia or life-threatening anemia, depending on comorbid conditions and rate of anemia development.[17] Likely benefits of transfusion need to be balanced against possible risks (e.g., volume overload, transfusion reaction, acute hemolysis with shock, delayed hemolytic transfusion reaction, transfusion-associated acute lung injury, alloimmunization, iron overload).[52]

The use of a restrictive hemoglobin concentration of 7 to 8 g/dL decreases the proportion of patients exposed to RBC transfusion.[93]​ Transfusion guidelines suggest using a restrictive transfusion strategy, initiating transfusion at Hb levels <7 g/dL.[94]

Decisions about starting treatment should be individualized; some patient subgroups may benefit from RBC transfusion to maintain higher hemoglobin concentrations.[69]

Early ESA therapy for severe anemia

Important pre-emptive therapy in patients who may require transfusions urgently but for whom they may be unacceptable, unavailable, or carry excessive risk (e.g., Jehovah's Witnesses, those with rare blood types, or those with multiple alloantibodies). Concurrent supplemental intravenous iron should also be considered. ESA therapy is not generally beneficial in decreasing transfusion requirement in critical illness.[95][96]

Use of this content is subject to our disclaimer