• Mr Toby Richards • Vascular & Endovascular Surgeon • Senior Lecturer in Surgery • University College London

Preoperative Anaemia – A reversible Risk?

Thank You / Disclosures Grants: NIHR - HTA Covidien / UCL Vifor Pharma / UCL UCH vascular charity SHINE award for Innovation Vifor Pharma Rosetree Foundation Associations: BBTS NHSBT NATA BioIron LSHTM UCL

Industry: Covidien Gore Baxter KCI Starbucks Costa coffee Etc..!

• Introduction

• Pre Op anaemia & transfusion » The problem

» Audit results

» Iron therapy

» PREVENTT

• Post Op Anaemia » Hb

» Transfusion

» Outcomes

» Trials

Presentation Outline

Surgery: - What Problem?

• LA

• Keyhole

Surgery: - The Problem

• Blood Loss

• Transfusion

Anaemia

• Anaemia NSQIP – Infection James R. Dunne et al: JSR 2002; 102, 237

– Cardiac Events Wen-Chich Wu et al: JAMA 2007; 22, 2481

– LOS & composite Stefan W Leichtle et al: Jamcollsurg 2010; 212, 187

• Transfusion – Morbidity & Mortality Laurent G. Glance et al: Anaesthesiology 2011; 114: 283

Problem of Anaemia / Transfusion

US Veterans Database (NSQIP) (n=227,425) Anaemia (n=69,229; 30.4%) 30day mortality 30day composite morbidities (9 defined areas) Multivariate regression (9 defined subgroups) (56 cofactors)

Univariate analysis

Effect of Anaemia on Outcome

Transfusion

Proportion of CABG patients receiving RBCs

0 10 20 30 40 50 60 70 80

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HGFEDCBA

%

National audit of blood use in cardiac surgery, 2011

• 941,406 patients • 173 Hospitals • 2005-2009

• 48,291 transfused

Where to start?

Gynaecology surgery

• 12,836 females – Myomectomy 464 (3.6%) – Simple hysterectomy 11,193 (87.2%) – Complex hysterectomy 1,179 (9.2%) – 48.6 ± 12.1 years

• Anaemia 3,071 (23.9%)

• Transfusion 9.2% vs. 1.5%, p<0.001

Morbidity & Mortality

Morbidity & Mortality

Study on Preop Anaemia

• Anaemia in Surgical practice

• The problem

• Diagnosis Treatment

UCH – Diagnosis of Anaemia

1535 Patients Investigated

1511 Patients Operated

718 Patients > 48 hrs

154 Anaemic 190 Units 64 Transfused

564 Non- Anaemic 58 Transfused 121 Units

UCH – PREVENTT audit

Diagnosis AID v FID v IID?

• MCV < 80 5% • MCH < 27 48% • Ferritin < 30 31% • Ferritin < 100 64% • Fe < 10.6 54% • T sats < 20% 58%

• Effect of Inflammation CrP

Iron Therapy

FAIR-HF Study

Functional iron deficiency

• Inadequate iron supply to meet demand despite normal or abundant iron stores

– Normal or high ferritin levels – TSAT <20%

Absolute iron deficiency

• Depleted body iron stores – Low serum ferritin (<100ng/ml) or – TSAT <20%

Toby Richards - PREVENTT

What is Iron Deficiency? A. Inflammation / Cancer B. Failure Absorption C. Iron not recycled D. Reduced EPO E. BM failure

FAIR-HF Study

• Natural History of Disease

• Morbidity & Mortality

Iron Therapy Surgery

Intravenous Iron in Surgery Spanish Anaemia Working Group

Treatment of ID anaemias

All Colon cancer

Hysterectomy Arthroplasty

Iron to treat Anaemia

• N = 7966 • 77 RCT

• Hb higher IV iron v oral (MD 0.59 gm/dl; 95% CI 0.29 to 0.89) IV iron v control (MD 1.06 gm/dl; 95% CI 0.52 to 1.61)

Iron to treat Anaemia

• BT IV iron v oral (MD -0.54 units; 95% CI -0.96 to -0.12) IV iron v control (MD -1.71 units; 95% CI -3.20 to -0.22) • Oral Iron reduced transfusion (RR 0.71; 95% CI 0.54 to 0.94) HARD ENDPOINTS: - • No difference in QALY • No clinical benefit noted in terms of mortality (RR 1.08; 95% CI 0.50 to 2.32)

Lost to Follow up / Discontinued (n=15)

Analyse (n=235)

Lost to Follow up / Discontinued (n=15)

Analyse (n=235)

Assess for Eligibility : Patients undergoing elective major surgery

Anaemia (Hb: <12 g/dl) 14 - 42 days before operation

Informed consent

Randomisation 1:1 (n=500 planned)

Exclusion: Iron therapy or blood transfusion in 90 days

B12 or Folate deficiency Unstable cardiac disease

Renal dialysis or creatinine > 180 ALT or AST > 3 x upper limit of normal

Ferric Carboxymaltose (n= 250) Dose by weight (1000mg max)

Placebo (n=250) N/Saline infusion 100

PREVENTT RCT 2

Co - Primary Outcome: event - unit of blood or death

Secondary Outcomes: POMS

Complications of Tx & transfusion

Surgical Complications + LOS

wound healing + infection

Readmission to hospital

Mortality during follow up (cancer)

Who to treat ??

PREoperative intraVENous iron To Treat anaemia in major surgery

Post Operative

• Post Partum

• Orthopaedics

• The need • good multicentre RCTs • Good Endpoints

PPH

• P PP IDA (Hb<90, Ferritin < 15) n=44 • I Iron Sucrose 200md D2 D4 • C Oral Iron 200mg BD 6 weeks • O Hb levels

Multicentre RCT

• P PP IDA (Hb<85, Ferritin < 15) n=128 • I Iron Sucrose 200md D1,2,3 + oral Iron W4 • C Oral Iron 100mg BD 12 weeks • O Hb levels + QALY (of mother)

•

• • P= 0.89 at 4 weeks • • Ferritin significant

QALY SF36: Pain only FATIGUE Physical improved Mental n.s.

Orthopaedics

EVIDENCE and TRIALS • Oral Iron

• Transfusion

• Outcomes

Orthopaedics

• 3 RCT on oral iron ns – Del Campo 1982, Crosby 1994, Aufricht 1994

• No real point in Post Op Iron?

Iron Bru Post - Operation

Draft Evidence Statement: GN3.6 In cardiac and orthopaedic surgery patients the effectiveness of postoperative intravenous iron compared to postoperative oral iron on the incidence of transfusion, postoperative haemoglobin levels and ferritin levels is uncertain14. (Grade D)

SURGERY POST OP HARD EVIDENCE and ENDPOINTS

• Oral Iron not effective

Original Article Liberal or Restrictive Transfusion in High-Risk

Patients after Hip Surgery

Jeffrey L. Carson, M.D., Michael L. Terrin, M.D., M.P.H., Helaine Noveck, M.P.H., David W. Sanders, M.D., Bernard R. Chaitman, M.D., George G. Rhoads, M.D.,

M.P.H., George Nemo, Ph.D., Karen Dragert, R.N., Lauren Beaupre, P.T., Ph.D., Kevin Hildebrand, M.D., William Macaulay, M.D., Courtland Lewis, M.D., Donald Richard

Cook, B.M.Sc., M.D., Gwendolyn Dobbin, C.C.R.P., Khwaja J. Zakriya, M.D., Fred S. Apple, Ph.D., Rebecca A. Horney, B.A., Jay Magaziner, Ph.D., M.S.Hyg., for the

FOCUS Investigators

N Engl J Med Volume 365(26):2453-2462

December 29, 2011

• P Hip #, Hb<100, RF n=2106 • I Hb > 80 • C Hb > 100 • O Alive and able to walk

‘Higher Hb will improve functional outcome’

Lowest Daily Hemoglobin Levels.

Carson JL et al. N Engl J Med 2011;365:2453-2462

Hemoglobin Levels and Transfusions.

Carson JL et al. N Engl J Med 2011;365:2453-2462

Transfusion Restriction

• 1’ endpoint (35.2% vs. 34.7%, P = 0.90)

‘Scores for physical activities of daily living, instrumental activities of daily living, and fatigue were not validated and were not useful for analysis for 45 to 60% of patients’

SURGERY POST OP HARD EVIDENCE and ENDPOINTS

• Oral Iron not effective

• Liberal transfusion not effective – Restrictive transfusion safe

– Mortality – Walk unaided – Post Op Complications

SURGERY POST OP HARD EVIDENCE and ENDPOINTS

• Oral Iron not effective

• Liberal transfusion not effective – Restrictive transfusion safe

– Mortality – Walk unaided – Post Op Complications

– Anaemia and blood not associated with Delirium

SURGERY POST OP HARD EVIDENCE and ENDPOINTS

• Oral Iron not effective

• Liberal transfusion not effective – Restrictive transfusion safe

– Mortality – Walk unaided – Post Op Complications

– Anaemia and blood not associated with Delirium – Infection – QALY?

IV Iron

IV Iron Post Op

• 2004-2011 • Post op IV Iron (PIVI)

• Cost Effective?

IV Iron Post Op

• Cost neutral

• ? NEED

RCT Post op Iron

• P Hip # n=200 • I IV Iron 200mg x 3 • C Standard of Care • O Reticulocyte count

Phase II – pilot for formal phase III RCT

Conclusions • Iron Bru is good stuff

– increase Hb – Other effects of Iron?

• Effective in Observational Studies • Not as effective in RCTs??

• Need for Hard Evidence

• Good Audits • Patient Centred Outcomes • Define Populations where quality effect

• Anaemia / Transfusion / Iron

PBM in the UK – the next big centre National Comparative Audit

of Blood Transfusion

Blood Matters: doing nothing is not an option Sir Bruce Keogh, NHS Medical Director Patient Blood Management: threats and opportunities Lynda Hamlyn, Chief Executive of NHS Blood and Transplant

Patient Blood Management - The Future of Blood Transfusion

Teamwork • TSC • Andrew Bradbury (Birmingham) • Jane Keidan (King’s Lynn) • Stefan Anker (Charite) • Iain MacDougall (King’s College) • Andrew Klein (Papworth) • Toby Richards (UCL) • Shelley van Loen (lay member) • Trevor Burley (lay member)

• DSMC • Chair: Lorna Williamson (Medical and

Research Director, NHS Blood and Transplant) • Angela Crook (Senior Statistician, Medical

Research Council Clinical Trials Unit) • John Pepper (Consultant Cardiac Surgeon,

Royal Brompton)

PREVENTT RCT • Join the Research Collaboration:

– toby.richards@ucl.ac.uk

– 07794439113