By Zheng Cheng Zhu
Key reference:
Richards, T., Baikady, R. R., Clevenger, B., Butcher, A., Abeysiri, S., Chau, M., Macdougall, I. C., Murphy, G., Swinson, R., Collier, T., Van Dyck, L., Browne, J., Bradbury, A., Dodd, M., Evans, R., Brealey, D., Anker, S. D., & Klein, A. (2020). Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial. Lancet (London, England), 396(10259), 1353–1361. https://doi.org/10.1016/S0140-6736(20)31539-7
Quick Summary
- Anaemia (haemoglobin <130g/L male, <120g/L female) is associated with post-operative complications and is an independent risk factor for peri-/post-operative mortality
- Pre-operative intravenous iron infusion is routinely used to correct anaemia and iron deficiency, however its efficacy in improving post-operative outcomes remains unclear
- PREVENTT is a multicentre, randomised, double blinded, controlled trial investigating if intravenous iron infusion before major elective abdominal surgery reduces blood transfusion and mortality
- PREVENTT found pre-operative iron infusion was NON-SUPERIOR to placebo in reducing blood transfusions, mortality rate, length of ICU/hospital stay, and quality of life
- The outcome of PREVENTT means the correction of anaemia / iron deficiency with intravenous iron infusion alone cannot be recommended, and that a multidisciplinary approach to pre-operative anaemia management may be required to reduce post-operative morbidity/mortality
Preamble
In your pre-admission clinic, you meet Darren, a 67yo gentleman with PMHx of peptic ulcer disease, stage III chronic kidney disease and ischaemic heart disease on aspirin, awaiting his Cat 1 left hemicolectomy 2 weeks from now for colon cancer. He is feeling washed out and breathless, but is keen to get his operation done and dusted for good this time.
You note on his bloods that his haemoglobin (Hb) is 98g/L, and an iron study showing ferritin of 25ng/L. You tell Darren that he has iron deficiency anaemia, which needs to be optimised prior to his surgery. Darren is highly anxious, as he does not want his operation to be delayed. He tells you he has had multiple iron infusions before, which usually corrects his haemoglobin count.
Do you allow Darren to proceed with his operation with an iron infusion beforehand?
What is Iron deficiency and anaemia? What are the peri-operative implications?
Anaemia:
- Hb <130g/L in male,
- <120g/L in non-pregnant females, and
- <110g/L in pregnant females
- Iron deficiency is the most common cause
Iron deficiency (with or without anaemia):
- Serum ferritin <30ng/L, or
- Serum ferritin 30-100ng/L with CRP >5mg/L and transferrin saturation <20% in context of inflammatory process
Iron deficiency anaemia (IDA):
- Decreased erythropoiesis due to inadequate iron stores
- Biochemical Hb and iron studies reflecting anaemia and iron deficiency
- Most common cause include
- Nutritional deficiency (reduced intake or malabsorption)
- Chronic blood loss (gastrointestinal, gynaecological, iatrogenic (pharmacologically-impaired haemostasis, phlebotomy, haemodialysis) etc.
Anaemia of chronic disease with iron deficiency
- Inflammatory cytokines elicit production of hepcidin, which produces a net functional low iron state by:
- Reducing mobilisation of intracellular iron stores,
- Reducing gastrointestinal absorption of dietary iron, and
- promoting sequestration of iron into macrophages
- Inflammatory cytokines further inhibit erythropoiesis by suppressing renal production of erythropoietin and direct inhibition of marrow erythroid cell proliferation
Darren’s case is not unique. Anaemia is present in approximately 30-60% of pre-operative population, with IDA and anaemia of chronic disease being two most common causes. Darren’s PMHx certainly puts him at higher risk for chronic GI bleeding and impaired erythropoiesis.
Anaemia is a serious pre-operative condition:
- Independent risk factor for peri- and post-operative morbidity and mortality
- Increase length of hospital stay, requirement for ICU/HDU, as well as rates of readmission
- Need for peri-operative blood transfusions with associated risk of dose-dependent transfusion-related complications
Surgical population are particularly at risk of iatrogenic blood loss and anaemia, with outcomes worsened by:
- Emergency surgery,
- where pre-operative optimisation of anaemia is unlikely to be adequately achieved
- High risk surgeries with likelihood of significant blood loss
- (intra-abdominal, cardiothoracics, obstetrics)
- Co-morbid cardiovascular and neurovascular conditions
- Reduced tolerance to anaemia and anaemia-related complications
- Patient and/or medication related impairment in haemostasis
Current consensus on pre-operative management of Iron deficiency & IDA
As per the International Consensus Statement on the Peri-operative Management of Anaemia and Iron Deficiency:
- Treatment of low iron store (Ferritin <100ng/L with expected operative Hb drop of 30g/L) or iron deficiency anaemia should be initiated as soon as possible, ideally within 6-8 weeks;
- IV iron transfusion should be first line for patients unresponsive or not tolerating oral iron replacement, or if surgery is planned in less than 6 weeks, given at least 2 weeks prior
Gaps in our knowledge
- There is established association between IDA and increased transfusion requirement, duration of stay and mortality,
- However, preoperative treatment of IDA and iron deficiency with IV iron infusion is only weakly supported by low-quality evidence and the theoretical hypothesis that correction of iron deficiencies & IDA will reduce the rates of aforementioned complications
- Hence, there remains uncertainty regarding the actual benefits of routine use of pre-operative IV infusions in these patients
The PREVENTT trial
The PREVENTT trial is an UK-based, multicentre, double-blinded, placebo-controlled trial looking to determine whether pre-operative iron infusion for patients with anaemia undergoing major elective abdominal surgery would:
- Correct anaemia prior to surgery
- Reduce requirement and number of blood transfusions
- Reduce number of deaths
Study design
- Patient selection :
- >18yo adults, identified with anaemia as defined as Hb <130g/L for males, <120g/L for females
- Undergoing elective major abdominal surgery within 10-42 days
- Across 46 UK tertiary centers
- Exclusion criteria:
- Laparoscopic surgery
- Concurrent infection
- Weight <50kg
- Chronic liver disease or known alternate cause for anaemia, acquired iron overload, FHx of haemachromatosis / thalassaemia, transferrin saturation >50%
- Iron studies were used to identify iron deficiency & IDA in pre-defined subgroup analysis
- 487 patients were recruited and randomised to
- Intervention group (n=244): IV 1000mg iron carboxymaltose (Ferrinject) in 100ml saline
- Placebo group (n=243): 100ml saline
- Groups were well matched in terms of baseline characteristics, including age, sex, Hb levels, comorbidities, and surgical factors including American Society of Anesthesiology (ASA) grade, type/duration/timing of surgery
- Of note, known iron deficiency (28% intervention vs 29% placebo group) and predisposing factors for iron deficiency (reflux/gastric ulcer, bleeding disorder, coeliac disease, inflammatory bowel disease, renal/hepatic disease, diabetes, antiplatelet/anticoagulant use) were similar in the two groups
- Patients were blinded through vision shielding, and research participants were blinded to treatment allocation
- Administration of infusions were complete by unblinded personnel with nil further role in the study
- Primary endpoints were:
- Requirement of blood product transfusion AND rate of death
- Number of blood product transfusions <30 days post-op
- Secondary endpoints were:
- Number of blood product transfusions 30 days to 6 months post-op
- Hb change at 1) immediately pre-op, 2) 8 weeks and 3) 6 months post-op
- Total length of stay +/- ICU length of stay
- Readmission rate at 8 weeks and 6 months post-op
- Health related quality of life
Findings of PREVENTT
Endpoint 1: Requirement of blood product transfusion AND rate of death <30 days post-op
- There was NO DIFFERENCE in combined transfusion rate and mortality rate
- 69 intervention vs 67 placebo, risk ratio 1.03, 95% CI 0.78-1.37, p=0.84
Endpoint 2: Number of blood product transfusions <30 days post-op
- There was NO DIFFERENCE in number of blood product transfused
- 105 intervention, 111 placebo, rate ratio 0.98, 95 % CI 0.68-1.43, p=0.93
Subgroup analysis:
Subgroup analysis for age (70, <70yo), gender, BMI (30, <30) and type/complexity of surgery did NOT SHOW a difference in primary endpoints
Surprisingly, subgroup analysis for level of anaemia (100g/L, <100g/L) and iron deficiency in ferritin <100ng/ml and TSAT <20% again DID NOT SHOW a difference in primary endpoints
Secondary endpoints:
Hb change:
- Hb levels were similar at randomisation (111.0g/L intervention vs 111.2 placebo)
- IV iron infusion was significantly effective in correcting anaemia pre-operatively
- 21% intervention vs 10% placebo, risk ratio 2.07 95% CI 1.27-3.35
- Hb levels was also significantly higher in the delayed post-operative period for IV transfusion group:
- 8 weeks post-op (mean difference 10.7g/L, 95% CI 7.8-13.7)
- 16 weeks post-op (mean difference 7.3g/L, 95% CI 3.6-11.1)
Readmission rate at 8 weeks and 6 months post-op
- IV transfusion group had significantly reduced rates of readmission at 8 weeks compared to placebo
Total length of stay +/- ICU length of stay, health related quality of life, number of blood product transfusions 30 days to 6 months post-op
- No significant difference was observed for these secondary endpoints
Implications of PREVENTT on future practice
- Pre-operative IV iron infusion improves haemoglobin levels in patients with anaemia (not isolated to IDA) prior to elective major abdominal surgeries,
- However, this does not translate to improved clinical outcomes in blood transfusion requirement, post-op mortality, length of stay and quality of life.
- Detection and treatment of pre-operative anaemia / iron deficiency with IV iron infusion alone appear insufficient in addressing known association between anaemia and operative complications, and therefore cannot be recommended based on this evidence.
- A multidisciplinary approach based on Patient Blood Management guidelines may be required:
- Treat underlying cause of anaemia
- Minimise blood loss
- Improve patient tolerance to anaemia
Based on the PREVENTT trial, you tell Darren that, on top of his iron transfusions, you would ideally get an opinion from his cardiologist regarding his latest stress testing, review his renal function, and consider suspending his aspirin to medically optimise his overall fitness for surgery.
References
Abbott, T. E. F., & Gillies, M. A. (2021). The PREVENNT randomised, double-blind, controlled trial of preoperative intravenous iron to treat anaemia before major abdominal surgery: an independent discussion. British journal of anaesthesia, 126(1), 157–162. https://doi.org/10.1016/j.bja.2020.08.053
Muñoz, M., Acheson, A. G., Auerbach, M., Besser, M., Habler, O., Kehlet, H., Liumbruno, G. M., Lasocki, S., Meybohm, P., Rao Baikady, R., Richards, T., Shander, A., So-Osman, C., Spahn, D. R., & Klein, A. A. (2017). International consensus statement on the peri-operative management of anaemia and iron deficiency. Anaesthesia, 72(2), 233–247. https://doi.org/10.1111/anae.13773
Richards, T., Baikady, R. R., Clevenger, B., Butcher, A., Abeysiri, S., Chau, M., Macdougall, I. C., Murphy, G., Swinson, R., Collier, T., Van Dyck, L., Browne, J., Bradbury, A., Dodd, M., Evans, R., Brealey, D., Anker, S. D., & Klein, A. (2020). Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial. Lancet (London, England), 396(10259), 1353–1361. https://doi.org/10.1016/S0140-6736(20)31539-7
