BBTSWho really needs a transfusion?

Simon J StanworthConsultant Haematologist

National Health Service Blood & Transplant/Oxford University Hospitals NHS Trust;

University of Oxford

Conflicts – no financial, investigator on trials

Talk – what are we doing?

Background What does the evidence say to support

‘liberal’ use of red cells, platelets, plasma Putting evidence into practice Pointers moving forward

Population

Group 1

Group 2

Outcomes

Test: policy A

Standard: policy B

Randomised Controlled TrialsAssignment of participants to exposures by play of chance

Patients

Randomised Trials Contrast observational research - examples

Interpretation: “Turn shades of grey into something closer to black and white”

Not all are good: clearer rules for appraising e.g. Cochrane methodology. Examples e.g. Age of Blood

Up to a million in medicine

In patients undergoing cardiac surgery, transfusion of red cells that had been stored for more than 2 weeks was associated with a significantly increased risk of postoperative complications as well as reduced short-term and long-term survival

ABLE, Walsh

Different results: Observational studies

G Murphy

My path into clinical research

• Early exposure to epidemiology in paediatrics• Returned from New Zealand• As for paediatrics, a general dearth of evidence,

contrasted to a plethora of recommendations in guidelines.

• Guidelines on “Use of...”

Dzik

First job plan 2005

1 To update systematic reviews, and to develop new systematic reviews

2 To drive forward a programme of clinical studies, including proposed trials of platelet prophylaxis

3 To develop new studies in conjunction with other NBS medical staff, including FFP and practice change

M Murphy, Williamson

First Systematic reviews: FFP

Stanworth et al, Brit J of Haematology 2004, 126, 139; Update: Yang et al, Transfusion 2011

• Alongside the 2004 FFP guidelines.

• But so little quality data; no substance

• Challenging the role of recommendations in the absence of evidence

McClelland, Murphy, SRI

The structure to this reviewWhat are the important questions?

• Fundamental: prophylaxis vs no-prophylaxis eg TOPPS. May require a higher level of scrutiny.

• Trials of different blood products (PI)

• Trials vs active interventions/ alternatives

Hyde, Brunskill

Developing next steps/ clinical trial

systematic reviews

clinicaltrials/RCT

prospective

guidelines

Review → Need for a trial: prophylactic vs. no-prophylactic platelet transfusions (TOPPS)

Trial question: Is a no-prophylaxis platelet transfusion policy non-inferior to (not worse than) prophylaxis for patients with haematological malignancy?

A no- prophylactic policy in patients with haematological malignancies. 2013. NEJM

NHSBT, funder; Williamson, CTU

Timeline for TOPPS; can we improve?• Idea from SR (2005)• Grant round 1• Grant round 2• Award• Finalise Protocol• Ethics, contracts, sponsorship• Start recruitment (Other competing studies)• End recruitment• Analysis • Write-up (completed 2015)

Murphy, Norfolk, Copplestone, Wood

More RCT’s over last 10 yearsExplosion of red cell trials:• Red cell transfusion review update - primary outcome• Use of red cells for bleeding• Age of Blood - Africa TOTAL• Neonates

Platelets: Haematology, PATCH, PlaNeT studies

But:• Plasma and cryoprecipitate: No RCTs, ISOC studies • Implementation/ Knowledge Translation

Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with

antiplatelet therapy (PATCH)

Unexpected results for RCT’sTransfusions are biological products

Platelet transfusion seems inferior to standard care and cannot be recommended

Multiple red cell trials: Cochrane review

Identify all randomised trialsMeta-analysis

30 trials involving 12498 patients across a diverse range of clinical settings

Carson, 2016

Hebert et al. 1997. Am J Respir Crit Care Med

Hebert et al. 1999. NEJM 340(6)

Mortality 30 days → Guidelines

Limitations (outcomes and interventions)

Clinical diversity and outcomes relevant to some settings may not be adequately defined or trials under-powered

Identified trials evaluated the effect of transfusion in the hospital and not in outpatients - function and fatigue may be more important

Definitions of outcomes (e.g. cardio-vascular) - red cell transfusions have harmful and beneficial effects

Actual mean haemoglobins for transfusion in patients are often different to protocols

Haemoglobin concentration is a surrogate marker of need for transfusion

Carson, Walsh, Docherty

Red blood cell transfusion thresholds in BMF – the need for ‘pilots’ REDDS, REAL

Feasibility RCT to evaluate protocol adherence between a restrictive (Hb 85 - 100g/L) and a liberal (maintain Hb 110-125g/L) transfusion strategy

38 patients (incl drop outs) Follow up: 18 weeks, incl 6 week

run in phase, 12 week period of intervention and follow-up

Killick, Bowen, Karakantza, Callum

Clusters

Group 1

Group 2

Outcomes

Test: liberal strategy

Standard: restrictive strategy

AML (induction): a pilot trial of red blood cell transfusion thresholds and QoL

Morton, Sekhar (New)

A (further) secondary analysis of CRASH2. RBC transfusion may be associated with increase in

all-cause mortality among patients with trauma and with a low predicted risk of death

PLoS Med 11(6): e1001664.

Platelets & Plasmaand randomised trials

The NeoBolus StudyFluid bolus therapy in neonates: A multi-centre, prospective cross-sectional studyAmy Keir (Australia), Oliver Karam (Switzerland), Cassandra Josephson

(USA), Martha Sola-Visner (US), Helen Liley (Australia), Prakesh Shah(Canada), Simon Stanworth (UK)

Beyond haematology:Evidence-based focused review of platelet transfusions for critically ill patients with thrombocytopenia

Arnold, Heddle

PlaNeT1: Platelet transfusions (n=415) were administered to 116 infants (69%)

Pre-transfusion median 27 x109/L (IQR: 19-36 x109/L)

PlaNeT-1 study group (UK), Pediatrics, 2009

PlaNeT-2 trial

• Define optimal and safe platelet transfusion support for severely thrombocytopenic pre-term neonates

Compare clinical outcomes in neonates randomised to maintain plt counts at or above above either 25x109/L or 50x109/L

Curley, New, PlaNeT-2 study group (UK, Ireland), MATISSE (NL)

Recruitment despite challenges

0

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Aug-11

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n-12

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Actual *Predicted (based on current accrual 11/month to 660)

PlaNeT-2 study group (UK, Ireland), MATISSE (NL)

Use in cancer. TOPPS. Primary Outcome

WHO grade 2-4 bleeding: - no-prophylaxis: 50% (151/300) - prophylaxis: 43% (128/298)

Alternative treatments in thrombocytopeniaPBM

Population

Group 1

Group 2

HaemostaticOutcomes

Test: tranexamic acid

Standard: placebo

TREATT: TRial to EvaluAte Tranexamic acid therapy in Thrombocytopenia

Estcourt, Wood, Others

Should we be revisiting use of desmopressin?(DRIVE trial)

Thrombocytopenic patients undergoing invasive

procedure

Randomised

DDAVP Matching placebo

Laboratory outcomesMicrofluidics, platelet function, thrombin generation

Feasibility and Clinical outcomesBleeding, thromboembolism, serious adverse events

Desborough

Plasma and lack of controlled trials

Which factor is important?

Blood-exchange induced coagulopathy model

Murine model

• Our completed feasibility trial (46 patients, 2 civilian centres UK and military; analysis ongoing)

• Intervention group:Receive cryoprecipitate within 90 minutes of admission

• Comparator group:Receive standard massive haemorrhage protocol

Curry, Brohi, Doughty

ConclusionWhere does the trial evidence

support the need for transfusion?

• Limited data to support effectiveness

• Life threatening bleeding (?coagulopathy – FFP, source of fibrinogen)

• Some groups - Sickle & surgery, neonates, cardiac • Platelets and some treatment plans for haematological

malignancies and thrombocytopenia

CURRENT FEEDBACK PRACTICE

1.Audit standards based on clinical guidelines

2. Hospitals audit consecutive cases over 2-3 months

3. Feedback compared to standards/other hospitals Hospital

Transfusion Team

Grant-Casey, NCA; Lorencatto, Gould

Why use drugs that don’t work?Lipworth et al; BMJ, 2012, 344: d286Why do clinicians prescribe rFVIIa

• Gaps in evidence• Observational association• Compelled to do something• Autonomy• Commercial

How to respond?

GuidelinesEducation

• Group• Individual

Reminders• Computerized• Paper

Audit / FeedbackAudit / Approval

Monitoring Intervention

Tinmouth

Audit & Feedback is an intervention

The effect of audit and feedback on professional behaviour and on patient outcomes ranges from little or no effect to a substantial effect

The quality of the evidence is low/moderate

Future studies of audit and feedback should directly compare different ways of providing feedback, and consider cost implications.

Foy, Ivers

Applying behavioural theories to understand physicians’ transfusing practices

More rigorous methods needed to evaluate uptake of research findings & to develop theory based intervention(s) to promote improvement in transfusion

Transfusion (clinical) practice is a form of behaviourPsychology is the scientific study of behaviourPrevious studies → relevance of psychological / behaviour

change theory in understanding & changing practice

AFFINITIE first step Francis

UK hospitals

Appropriateness of transfusionsRandomisation

Enhanced Enhanced Enhanced Feedbackcontent follow on content & as usual

follow on

Appropriateness of transfusions

Cluster trial

NCA, Foy, Everyone!

Nature of the Interventions:

Content and Follow- up support

Audit & Feedback remains a powerful tool, but considerable scope to improve, as for all areas of implementation

Looking ahead

Diagnostic Strategies & tests Plasma & Pro-haemostatic agents Alternatives Implementation Use of IT

Randomised trials• Transfusion• Other areas of policy and

strategy eg more pilots

• Google: “Carrying out 12,000 RCTs every year” e.g. shades of colour on toolbars

• Capital One credit: soliciting new clients (font & colour letters)

• Casino (Harrah’s): “Don’t harass women, don’t steal and you’ve got to have a control group”

Who? Thanks Funders – NHSBT, NIHR Resources – SRI, CTU, NCA Researchers (TOPPS, TREATT, REDDS, REAL, CRYOSTAT,

PlaNeT, DRiVe, AFFINITIE) Networks of clinicians, local research teams

Summary: red cells

• No benefit to ‘liberal’ thresholds

• Gaps in selected clinical settings

• Lower haemoglobin thresholds?

• Better markers of the need for transfusion

• Anaemia management – use of iron

PBM: Alternative treatments in thrombocytopenia

Desborough et al. Brit J Haem, 2016

Decreased bleeding and transfusion requirements

Increased bleeding with red cell transfusion

No improvement in bleeding or transfusion