Alternatives to blood transfusion for patients having surgery: Oral iron, IV iron and erythropoietin

National Clinical Guideline Centre (UK)

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National Clinical Guideline Centre (UK). Blood Transfusion. London: National Institute for Health and Care Excellence (NICE); 2015 Nov. (NICE Guideline, No. 24.)

Blood Transfusion.

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5Alternatives to blood transfusion for patients having surgery: Oral iron, IV iron and erythropoietin

Preoperative anaemia is associated with increased postoperative morbidity and mortality as well as increased transfusion requirements. The commonest causes of preoperative anaemia are iron deficiency where body iron stores and the serum ferritin are reduced, and functional iron deficiency which is a state associated with infectious, inflammatory or malignant disease where there is insufficient iron incorporation into erythroid precursors in the face of apparently adequate body iron stores together with a serum ferritin value within normal limits.

Oral iron is used in the treatment of iron deficiency anaemia. Compliance with oral iron may be poor due to side effects including nausea, diarrhoea and constipation. Intravenous iron is an alternative when oral iron is poorly tolerated, or in clinical situations where there is functional iron deficiency. Erythropoietin is the hormone which stimulates erythropoiesis and recombinant erythropoietin is a further option for treating preoperative anaemia.

5.1. Review question: What is the clinical- and cost-effectiveness of oral iron, IV iron and erythropoietin in reducing blood transfusion requirements in surgical patients?

For full details see review protocol in Appendix C.

Table 7PICO characteristics of review question

Population	Adults Children Surgical patients with anaemia or at risk of anaemia. WHO definition of anaemia- Hb level <12 g/dl for females, Hb<13 g/dl for males, Hb<11.0 g/dl for children (0.5–5.0 years). Hb <11.5 g/dl for Hb children (5–12 years), Hb<12.0 g/dl for teens (12–15 years).
Intervention	Oral iron IV iron Erythropoietin (EPO); Erythropoietin (alfa) Erythropoietin (EPO); Erythropoietin (beta) Erythropoietin(EPO); Erythropoietin (zeta) Erythropoietin(EPO); Erythropoietin (theta) Oral iron + IV iron Oral iron + Erythropoietin IV iron +Erythropoietin Oral iron + IV iron + Erythropoietin Placebo
Comparison	All interventions will be compared with each other
Outcomes	Quality of life Number of units transfused Length of hospital stay Mortality (all causes) at 30 days Mortality (transfusion related) at 30 days Infections (includes pneumonia, surgical site infection, UTI and septicaemia/bacteraemia) at Within 30 days of surgery Number of patients needing transfusions Bleeding Serious adverse events (as described in studies) Mortality (all causes) Thrombosis
Study designs	RCTs Systematic reviews

5.2. Clinical evidence

We searched for randomised trials comparing the effectiveness of oral iron, IV iron and erythropoietin (EPO) in reducing blood transfusion requirements in surgical patients or patients at risk of anaemia.

From 39 studies, 41 papers reporting data were included in the review. ¹⁷^,²³^,³¹^,³⁶^,⁵⁷^,⁶⁹^,⁷³^,⁸⁰^,⁸⁴^,⁹⁰^,⁹⁴^,¹⁰¹^,¹⁰⁴^,¹¹²^,¹²⁹^,¹⁵⁵^,¹⁵⁷^,¹⁶⁵^,¹⁶⁸^,¹⁷¹^,¹⁷⁵^,¹⁷⁷^,¹⁸³^,¹⁹⁰^,²⁰⁹^,²³¹^,²⁴²^,²⁴⁹^,²⁵⁰^,²⁷²^,²⁷⁵^,²⁸⁸^,²⁹⁴^,³⁰⁷^,³²⁴^,³³⁵^,³³⁸ Evidence from these is summarised in the clinical evidence summary (Table 9-Table 16). See also the study selection flow chart in Appendix E, forest plots in Appendix K, GRADE tables in in Appendix J, clinical evidence tables in Appendix H and clinical studies exclusion list in Appendix P.
Eight studies reported no outcomes of interest and were not included in the analysis. ¹⁷^,³¹^,⁶⁹^,¹⁶⁸^,²⁴²^,²⁹⁴^,³⁰⁷^,³²⁴
No relevant clinical studies comparing erythropoietin plus IV iron with erythropoietin plus oral iron were identified.
One Cochrane review comparing erythropoietin with placebo/no treatment was included.⁸⁴
The studies evaluated patients undergoing surgery for different reasons (for example, cardiac, orthopaedic or colorectal cancer).
The studies also differed with respect to:
- the baseline haemoglobin levels
- transfusion administered according to a pre-specified protocol/ physician's discretion.
For more details on the study characteristics, see the summary of included studies (Table 8) and clinical evidence tables (Appendix H).

Table 8

Summary of studies included in the review.

5.2.1. Summary of included studies

5.2.2. Clinical evidence summary (Summary GRADE profiles)

Table 9

Erythropoietin compared with placebo for surgical patients.

Table 10

IV iron compared with placebo/no IV iron for surgical patients.

Table 11

Oral iron compared with placebo/no oral iron for surgical patients.

Table 12

Erythropoietin plus IV iron compared with placebo for surgical patients.

Table 13

Oral iron compared with IV iron for surgical patients.

Table 14

Erythropoietin plus IV iron compared with IV iron for surgical patients.

Table 15

Erythropoietin plus oral iron compared with oral iron for surgical patients.

Table 16

Erythropoietin plus IV iron or oral iron compared with placebo plus IV iron or oral iron for surgical patients.

5.3. Economic evidence

Published literature

One study comparing oral iron with no iron and one comparing IV iron with no IV iron were identified.¹⁸³^,¹⁸⁸ Four studies comparing erythropoietin with placebo or no erythropoietin were identified.⁶⁷^,⁷⁸^,³⁰⁴^,³¹⁹ These are summarised in the economic evidence profiles below (Table 17, Table 18 and Table 19).

Table 17

Economic evidence profile: oral iron versus standard clinical treatment.

Table 18

Economic evidence profile: IV iron versus usual practice.

Table 19

Economic evidence profile: erythropoietin versus no intervention or standard current practice.

See also the study selection flow chart in Appendix E and study evidence tables in Appendix H.

Economic considerations

Craig 2006⁶⁷ reported that the price of erythropoietin alpha would need to decrease by 95% for erythropoietin alpha to be cost effective (below £30,000 per QALY). The cost of erythropoietin alpha (Eprex, Janssen) has decreased from £76.61 for 10,000 units in 2005 (as reported in Craig 2006⁶⁷) to £55.31 for 10,000 units in 2014 (BNF 67¹⁵⁰). This 28% decrease in price is not sufficient for erythropoietin alpha to be cost effective (below £30,000 per QALY).

The GDG wanted to know in terms of red blood cell units how much transfusion would need to be reduced for erythropoietin to be cost neutral. The following approach was taken to calculate the minimum number of units avoided for erythropoietin to be cost neural:

Minimum units avoided for Erythropoeitin to be cost neutral = CostErythropoeitin/CostSubsequentUnits

The cost of erythropoietin and of a subsequent unit of red blood cell transfused are summarised in Table 20 and Table 21, respectively.

Table 20

Cost of erythropoietin (including administration).

Table 21

Cost of transfusion per unit.

Based on these costs, the mean minimum number of units avoided per person for erythropoietin to be cost neural is 5.3 units. The clinical evidence indicates that the mean units avoided was approximately 0.55.

Unit costs

Relevant unit costs are provided in Appendix N to aid consideration of cost-effectiveness.

5.4. Evidence statements

Clinical

EPO versus placebo

Twelve RCTs compared EPO versus placebo. The evidence showed clinically important benefit with EPO for the outcomes number of patients transfused, number of units transfused and length of stay.

The evidence suggested that that there was higher mortality and thrombosis in patients receiving EPO, but there was considerable uncertainty. The evidence suggested no difference of effect between patients receiving EPO and placebo with respect to serious adverse events and infection, but there was some uncertainty. The quality of evidence ranged from low to very low.

No evidence was identified for quality of life.

IV iron versus placebo

Five RCTs compared IV iron with placebo. The evidence suggested that fewer numbers of patients were transfused when they received IV iron but there was some uncertainty. The evidence suggested that there was higher length of hospital stay and more infections in patients receiving IV iron, but there was considerable uncertainty. The evidence showed that there was no important difference between the groups for the outcomes mortality and serious adverse events, but there was some uncertainty. The quality of evidence ranged from low to very low.

No evidence was identified for quality of life.

Oral iron versus placebo

Two RCTs compared oral iron with placebo. The evidence suggested that fewer numbers of patients were transfused in patients receiving oral iron, but there was considerable uncertainty. The evidence was of very low quality.

No evidence was identified for critical outcomes such as number of units transfused, thrombosis and mortality at 30 days; and important outcomes such as length of stay in hospital, serious adverse events, infections and quality of life.

EPO plus IV iron versus placebo

Four RCTs compared EPO plus IV iron with placebo. The evidence showed clinically important benefit for EPO plus IV iron for the outcomes numbers of patients transfused and numbers of units transfused. The evidence suggested lower mortality and length of hospital stay with EPO plus IV iron, but there was considerable uncertainty. There was no difference between the groups for the outcome on serious adverse events. The evidence was of low and very low quality.

No evidence was identified for thrombosis (critical outcome) and quality of life (important outcome).

Oral iron versus IV iron

Two RCTs compared oral iron with IV iron. The evidence suggested that there were fewer numbers of patients transfused with IV iron but there was considerable uncertainty. The evidence suggested that length of hospital stay may be lower and fewer patients may have deep vein thrombosis in patients receiving oral iron, but there was considerable uncertainty. There was no difference between the groups for the outcome on quality of life. The quality of evidence ranged from high to low.

No evidence was identified for critical outcomes such as number of units transfused, and mortality at 30 days and important outcomes such as serious adverse events and infections.

EPO plus IV iron versus IV iron alone

Two RCTs compared EPO plus IV iron with IV iron. The evidence suggested that fewer numbers of patients were transfused when receiving EPO plus IV iron but there was considerable uncertainty. There was no difference between the groups for the outcomes of mortality (all cause at 30 days) and serious adverse events.

The evidence was of moderate to very low quality.

No evidence was identified for critical outcomes such as number of units transfused and thrombosis, and important outcomes such as length of stay in hospital, infections and quality of life.

EPO plus oral iron versus oral iron

Four RCTs compared EPO plus oral iron with oral iron. The evidence showed clinically important benefit for EPO plus oral iron for the outcome numbers of patients transfused. The evidence suggested that there was lower mortality (all cause at 30 days), infections, and length of hospital stay in patients receiving EPO plus oral iron; however, there was considerable uncertainty. The evidence suggested deep vein thrombosis and other thrombovascular events were higher in patients receiving EPO plus oral iron but there was considerable uncertainty. The evidence quality ranged from moderate to very low quality.

No evidence was identified for the important outcomes such as serious adverse events and quality of life.

EPO plus IV iron or oral iron versus oral iron or IV iron

One RCT compared EPO plus IV iron or oral iron with oral iron or IV iron. The evidence suggested that there were fewer serious adverse events with EPO plus oral iron or IV iron, but there was considerable uncertainty. There was no important difference between the groups for the outcomes mortality (all cause at 30 days) and thrombosis. The evidence ranged from moderate to very low quality.

No evidence was identified for the critical outcomes, such as number of patients transfused and number of units transfused, and important outcomes such as length of stay in hospital, infections and quality of life.

Economic

One cost–consequence analysis found that oral iron (ferrous sulphate) was less costly and more effective than no intervention in reducing blood transfusion requirements in anaemic surgical patients (£147 less per patient, 1.4 fewer units of blood transfused per patient). This analysis was assessed as partially applicable with potential serious limitations.

One cost–consequence analysis found that IV iron (ferrous carboxymaltose) was less costly and more effective than no intervention in reducing blood transfusion requirements in anaemic surgical patients (£166 less per patient, 59% reduction in proportion receiving blood transfusion). This analysis was assessed as partially applicable with potential serious limitations.

One cost-utility analysis found that EPO alpha was not cost-effective compared to no intervention in reducing blood transfusion requirements in anaemic surgical patients (ICER: £21,193,000 per QALY gained). This analysis was assessed as directly applicable with potentially serious limitations.

One cost-utility analysis found that EPO was dominant (less costly, no difference in effectiveness) compared to no intervention in reducing blood transfusion requirements in surgical patients. This analysis was assessed as directly applicable with potentially serious limitations.

One cost-utility analysis found that EPO was not cost-effective compared to no intervention in reducing blood transfusion requirements in adolescent female idiopathic surgical patients (ICER: £1,020,000 per QALY gained). This analysis was assessed as partially applicable with potentially serious limitations.

One cost consequence analysis found that EPO was dominant (less costly, more effective) compared to no intervention in reducing blood transfusion requirements in knee and hip arthroplasty surgical patients. This analysis was assessed as partially applicable with potentially serious limitations.

Recommendations and link to evidence

Oral Iron, IV Iron, erythropoietin

Recommendation	Do not offer erythropoietin to reduce the need for blood transfusion in patients having surgery, unless: the patient has anaemia and meets the criteria for blood transfusion, but declines it because of religious beliefs or other reasons or the appropriate blood type is not available because of the patient's red cell antibodies.
Relative values of different outcomes	The GDG agreed that the number of patients transfused, number of units transfused, mortality at 30 days and quality of life were critical outcomes for decision making. Length of stay in hospital, serious adverse events, thrombosis, and infections and were considered to be important outcomes.
Trade off between clinical benefits and harms	Evidence from 14RCTs comparing EPO with placebo/no EPO showed that there was evidence of clinically important benefit with the use of EPO for the outcomes number of patients transfused, number of units transfused and length of hospital stay. However, there was also evidence of an increase in mortality and the number of patients with thrombotic complications in the EPO group compared to the placebo group, but there was considerable uncertainty in the effect estimates. The evidence suggested no difference of effect between patients receiving EPO and placebo with respect to serious adverse events and infection, but there was some uncertainty in the effect estimates. No evidence was identified for the outcome quality of life. The GDG considered that the benefit from a reduction in the numbers of patients transfused, units transfused and length of hospital stay was offset by a potential increase in mortality and thrombotic complications. There was no evidence available for the outcomes new cardiac events and quality of life.
Economic considerations	Four economic analyses were identified. Two cost-utility analyses found that EPO was not cost-effective compared with no intervention in reducing blood transfusion requirements in surgical patients. Both of these analyses reported very high ICERs (£1,020,000 per QALY and £21,193,000 per QALY). A sensitivity analysis in one of these papers suggested that the cost of EPO would need to reduce by 95% in order for its use to be considered cost-effective. The GDG considered UK relevant unit costs and noted that the required 95% reduction in cost is not reflected in current prices. Of note, in both these analyses, a small QALY gain was observed for those receiving erythropoietin. However, the GDG noted that these analyses were based on single studies that were not included in the clinical review. Furthermore, neither analysis captured adverse events associated with erythropoietin. Two further studies (one cost-utility and one cost-consequence analysis) found that EPO was dominant compared with no intervention in reducing blood transfusion requirements in surgical patients. In both studies, the GDG agreed that the cost of EPO was lower than current prices. Furthermore, sensitivity analyses in one of these papers indicated that EPO was no longer cost-saving when a restrictive transfusion trigger of 8g/dl was used; the baseline blood loss was reduced; the dose of EPO was increased; the cost of EPO was increased (to closer reflect list prices). Based on the unit cost of EPO (£887) and the unit cost of transfusing one unit of red blood cells (£167), a threshold analysis was conducted indicating that the mean units of blood that would need to be avoided to offset the cost of EPO was approximately 5.3. The clinical evidence identified in this review indicated that the mean units avoided with EPO was approximately 0.55. Given the high additional expense of EPO, and mixed clinical evidence of both benefit and harm, in particular the evidence of increased mortality and thrombotic complications compared to placebo, the GDG agreed that the use of EPO is not cost-effective for reducing blood transfusion requirements in surgical patients.
Quality of evidence	The quality of evidence for all the critical outcomes was of very low quality, except for mortality where the evidence was of low quality. Key issues with this review were in relation to the variability between the studies. There were differences with respect to baseline haemoglobin levels across the studies and it was not always possible to determine if patients were anaemic at baseline as most of the studies did not report baseline haemoglobin values by gender. Also in studies where patients were reported to be anaemic at baseline, it was not clear from the studies if the haemoglobin level was corrected before surgery. There was a lack of evidence for the paediatric population. The GDG felt it reasonable that the same recommendations should apply for children as for adults. Studies also differed with respect to the use of transfusion protocols and differences within the protocols themselves. Two of the economic evaluations were assessed as directly applicable with potentially serious limitations and two were assessed as partially applicable with potentially serious limitations.
Other considerations	The GDG discussed the applicability of the recommendation with respect to patients in whom transfusion is not an option based upon: Refusal of blood transfusion -Refusal of blood components may or may not be based upon religious beliefs, for example Jehovah's Witnesses Lack of availability of blood of the appropriate blood type(s) due to red cell antibodies. The GDG noted that EPO may be considered as an option in anaemic patients who refuse blood transfusion or if there is a lack of availability of blood of the appropriate blood type(s). The GDG noted that EPO is recommended for use in some non-surgical patients where it had been prescribed for other causes, for example, chronic renal disease and in people with anaemia having chemotherapy to treat cancer Please refer NICE guidance on Chronic Kidney Disease²¹¹and Anaemia Management in Chronic Kidney Disease²¹² and NICE technology appraisal 323.²¹⁴ Although the GDG decided that EPO should not be recommended, other interventions are available to reduce transfusion in surgical patients (please see the recommendations related to Cell Salvage, Tranexamic Acid, and Oral and IV Iron).

Recommendations	2. Offer oral iron before and after surgery to patients with iron-deficiency anaemia.
Relative values of different outcomes	The GDG considered the mortality (all-causes at 30 days), transfusion related mortality number of patients transfused and quality of life as the critical outcomes for decision making. Other outcomes including, number of units transfused, thrombotic complications, length of stay, serious adverse events ,and infections were considered to be important outcomes.
Trade-off between clinical benefits and harms	Evidence from 2 RCTs comparing oral iron with placebo/no oral iron showed that fewer patients were transfused in the oral iron group compared to placebo; but there was considerable uncertainty in the effect estimates. The GDG noted the potential for side effects of oral iron, for example, nausea and gastric discomfort, and the risk of accidental overdose in children. There was no evidence available for the following outcomes: mortality, number of units transfused, thrombotic complications, quality of life, infections, serious adverse events, infections and length of hospital stay. Evidence from 2 RCTs comparing oral iron with IV iron suggested that fewer numbers of patients were found to be transfused in the IV iron group compared to oral iron, but there was considerable uncertainty in the effect estimates. The evidence showed clinically important benefit for oral iron for the outcome length of hospital stay. The evidence suggested that there were fewer patients with deep vein thrombosis in the oral iron group, but there was considerable uncertainty in the effect estimates. . There was no important difference between oral iron and IV iron for the outcome of quality of life. There was no evidence available for the following outcomes: number of units transfused, quality of life, thrombotic complications and serious adverse events. There was no specific evidence available for use of oral iron in paediatrics; the GDG agreed that the same recommendations should apply for children as for adults, as children may be iron deficient and would be likely to benefit from iron replacement prior to surgery in the same way as adults.
Economic considerations	A cost–consequence analysis was identified which found that oral iron was both less costly and more effective than no intervention in reducing blood transfusion requirements in anaemic surgical patients. The GDG considered the unit costs of oral iron and discussed the related administrative costs. They concluded that use of oral iron was likely to be cost effective. No relevant economic evaluation was identified comparing oral iron and iv iron. The unit costs of both oral and IV iron were calculated and presented to the GDG. The unit cost of oral iron therapy was £2.90 per month and IV iron therapy (including drug cost, staff time, clinic space, administrator time and transport) was £230.09 per high dose low frequency regimen. The clinical evidence found that there may be a lower rate of transfusion with IV iron which could potentially offset this cost, however this evidence was low quality and as such the GDG had low confidence in this effect. Given the higher cost of IV iron and as the clinical evidence indicated that there was no clinically important difference in quality of life between those receiving oral versus IV iron the GDG concluded it was unlikely that IV iron would be a cost effective alternative when both were appropriate options. Therefore, the GDG recommended oral iron unless patients cannot tolerate or absorb oral iron; are diagnosed with anaemia less than 14 days before surgery, or may not be able to adhere to oral iron treatment, in which case IV iron should be considered.
Quality of evidence	The quality of evidence for all the critical outcomes in this review was of very low quality, except for number of patients transfused when comparing oral iron and IV iron. In this case, the evidence was of low quality. Key issues with this review were in relation to the variability between the studies. There were differences with respect to baseline haemoglobin levels across the studies and it was not always possible to determine if patients were anaemic at baseline as most of the studies did not report baseline haemoglobin values by gender. Also in studies where patients were reported to be anaemic at baseline, it was not clear from the studies if the haemoglobin level was corrected before surgery. Studies also differed with respect to the use of transfusion protocols and differences within the protocols themselves. There was a lack of evidence for the paediatric population. The GDG felt it reasonable that the same recommendations should apply for children as for adults. The economic evaluation was assessed as partially applicable with potentially serious limitations.
Other considerations	The GDG considered the issue of patient preference, noting that patients may prefer to be prescribed oral iron instead of having IV iron administered. However, the GDG agreed that the success of oral iron therapy is also largely dependent on compliance of the patient (see Medicines Adherence guideline). The GDG noted the importance of iron therapy with particular reference to patients with iron deficiency in whom blood transfusion is not an option, as this may be the only source of treating anaemia. The GDG also discussed the relevance of the duration of iron therapy prior to surgery. The GDG agreed that oral iron would be useful in raising haemoglobin levels if prescribed for a period of approximately 2 weeks. This was considered to be particularly important in light of the current pressures on waiting times for surgery and cancer treatment. It was also noted that this introduces logistic challenges of identifying patients with iron deficiency at sufficient time pre-surgery for the intervention to be given. The GDG also discussed the importance of diagnosis of the type of anaemia before considering the use of oral iron. The GDG noted that in patients with iron deficiency anaemia, postponing the surgery may also be an option till the iron deficiency anaemia has resolved. The evidence review did not differentiate between patients based on the time of administration of oral iron therapy. The majority of the studies included in the evidence review included patients treated with both preoperative and post-operative iron and so these were not evaluated separately. The GDG discussed the available evidence and agreed that for all patients with pre-operative iron deficiency anaemia, treatment with oral iron should continue after surgery as this is likely to be effective. The GDG noted on the basis of their clinical experience that post-surgical patients may be more likely to be truly responsive to iron therapy as the mechanism of developing anaemia is usually blood loss. The GDG also discussed an alternate perspective in this regard which notes that oral iron may not be absorbed in the post-surgical period due to the presence of acute inflammation and therefore oral iron therapy may be of limited effectiveness at this time. The GDG also considered practical issues such as dosing regimens of oral iron and thresholds below which oral iron therapy should be administered. Although these were not explicitly evaluated in the context of this review, the GDG felt that these were practical issues for consideration in clinical practice and related guidance on these topics should be followed by the prescribing clinician. For related guidance please refer the NICE guideline on Anaemia management in chronic kidney disease.

Recommendations	3. Consider intravenous iron before or after surgery for patients who: have iron-deficiency anaemia and cannot tolerate or absorb oral iron, or are unable to adhere to oral iron treatment (see the NICE guideline on medicines adherence) are diagnosed with functional iron deficiency are diagnosed with iron-deficiency anaemia, and the interval between the diagnosis of anaemia and surgery is predicted to be too short for oral iron to be effective. 4. For guidance on managing anaemia in patients with chronic kidney disease, see the NICE guideline on anaemia management in chronic kidney disease. 5. For guidance on managing blood transfusions for people with acute upper gastrointestinal bleeding, see section 1.2 in the NICE guideline on acute upper gastrointestinal bleeding.
Relative values of different outcomes	The GDG considered the mortality (all causes at 30 days), transfusion related mortality number of patients transfused and quality of life as the critical outcomes for decision making. Other outcomes including and number of units transfused thrombotic complications, length of stay, serious adverse events, and infections were considered to be important outcomes.
Trade-off between clinical benefits and harms	Evidence from 5 RCTs comparing IV iron with placebo showed that IV iron was more effective than placebo at reducing the number of patients transfused, but there was some uncertainty. Length of hospital stay and infections appeared to be higher in the IV iron group compared to placebo group; but there was too much uncertainty within the effect estimates to allow confident interpretation of clinical benefit or harm for these two outcomes. There was no important difference of effect between patients receiving IV iron and placebo with respect to mortality at 30 days and serious adverse events, but there was some uncertainty in the effect estimates. Evidence from two RCTs comparing oral iron with IV iron suggested that fewer numbers of patients were found to be transfused in the IV iron group compared to oral iron, but there was considerable uncertainty in the effect estimates. The evidence showed clinically important benefit for oral iron for the outcome length of hospital stay. The evidence suggested that there were fewer patients with deep vein thrombosis in the oral iron group, but there was considerable uncertainty in the effect estimates. . There was no important difference between oral iron and IV iron for the outcome of quality of life. There was no evidence available for the following outcomes: number of units transfused, quality of life, thrombotic complications and serious adverse events. The GDG considered the side effects of IV iron, as all preparations carry a small risk of adverse reactions which can be life threatening if not treated promptly. However, the benefits outweigh the risks for the treatment of iron deficiency when administration of oral iron is ineffective or poorly tolerated. Patients should be closely monitored for signs of hypersensitivity during or for at least 30 minutes after each administration. IV iron is contraindicated in patients with known hypersensitivity to any parenteral iron product, and should not be used to treat pregnant women in the first trimester . Both oral iron and IV iron were considered to be clinically effective for treating anaemia in surgical patients but due to patient preferences oral iron was considered to be the first option for treatment. IV iron was reserved for patients where oral iron may not be suitable ⁹⁹. Based on their knowledge and experience, the GDG noted that oral iron may not be appropriate in people who cannot tolerate or absorb oral iron, are diagnosed with functional iron deficiency, are diagnosed with anaemia, and the interval to surgery is considered short and/or are unable to adhere to oral iron treatment (see the NICE guideline on medicines adherence). Although there was no specific evidence available for the use of IV iron in paediatrics, the GDG agreed that the same recommendations should apply for children as for adults as the accepted clinical indications for IV iron are the same for both groups.
Economic considerations	A cost–consequence analysis was identified which found that IV iron was both less costly and more effective than no intervention in reducing blood transfusion requirements in anaemic surgical patients. The GDG considered the variance in unit costs of IV iron and discussed related administrative costs. No relevant economic evaluation was identified comparing oral iron and iv iron. The unit costs of both oral and IV iron were calculated and presented to the GDG. The unit cost of oral iron therapy was £2.90 per month and IV iron therapy (including drug cost, staff time, clinic space, administrator time and transport) was £230.09 per high dose low frequency regimen. The clinical evidence found that there may be a lower rate of transfusion with IV iron which could potentially offset this cost difference, however this evidence was low quality and as such the GDG had low confidence in this effect. Given the higher cost of IV iron and as the clinical evidence indicated that there was no clinically important difference in quality of life between those receiving oral versus IV iron the GDG concluded it was unlikely that IV iron would be a cost effective alternative when both were appropriate options. Therefore, the GDG recommended oral iron unless patients cannot tolerate or absorb oral iron; are diagnosed with anaemia less than 14 days before surgery or may not be able to adhere to oral iron treatment, in which case IV iron should be considered.
Quality of evidence	The quality of evidence for all the critical outcomes in this review was of very low quality, except for number of patients transfused when comparing oral iron and IV iron. In this case, the evidence was of low quality. The identification of specific groups where oral iron may not be suitable and therefore IV iron was appropriate for use was based on the consensus expert opinion of the GDG members. Key issues with this review were in relation to the variability between the studies. There were differences with respect to baseline haemoglobin levels across the studies and it was not always possible to determine if patients were anaemic at baseline as most of the studies did not report baseline haemoglobin values by gender. Also in studies where patients were reported to be anaemic at baseline, it was not clear from the studies if the haemoglobin level was corrected before surgery. Studies also differed with respect to the use of transfusion protocols and differences within the protocols themselves. There was a lack of evidence for the paediatric population. The GDG felt it reasonable that the same recommendations should apply for children as for adults. The economic evaluation was assessed as partially applicable with potentially serious limitations.
Other considerations	The GDG considered the issue of patient preference, noting that patients may prefer to be prescribed oral iron instead of having IV iron administered. However, the GDG agreed that the success of oral iron therapy is also largely dependent on compliance of the patient (see Medicines Adherence guideline). The GDG discussed the importance of iron therapy with particular reference to patients in whom blood transfusion is not an option, as this may be the only source of building up haemoglobin stores. The group also considered patients who may have malabsorption syndrome (for example, people with severe Crohn's disease), in which case IV Iron would be preferred. The GDG agreed that oral iron would be useful in raising haemoglobin levels if prescribed for a period of approximately 2 weeks. The GDG noted, based on their experience, that in cases of emergency surgery, IV iron could be prescribed and would be more effective in improving haemoglobin levels in the limited time available. However, in cases of iron deficiency anaemia, the GDG also noted that postponing the surgery may also be an option. The GDG also discussed the importance of diagnosing the type of anaemia before considering the use of IV iron. The majority of the studies included in the evidence review included patients treated with both preoperative and post-operative iron and so these were not evaluated separately. The GDG discussed the available evidence and agreed that for all patients with pre-operative iron deficiency anaemia, iron therapy should continue after surgery as this is likely to be effective. Although the review did not differentiate between patients based on the time of administration of iron therapy, the GDG noted on the basis of their clinical experience that post-surgical patients may be more likely to be truly responsive to iron therapy as the mechanism of developing anaemia is usually blood loss. The GDG also discussed an alternate perspective in this regard which notes that oral iron may not be absorbed in the post-surgical period due to the presence of acute inflammation and therefore oral iron therapy may be of limited effectiveness at this time.

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