BBTS Who really needs a transfusion?

Transcription

1 BBTS Who really needs a transfusion? Simon J Stanworth Consultant Haematologist National Health Service Blood & Transplant/ Oxford University Hospitals NHS Trust; University of Oxford Conflicts no financial, investigator on trials

2 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

3 Randomised Controlled Trials Assignment of participants to exposures by play of chance P o p u l a t i o n Test: policy A Group 1 Group 2 Standard: policy B Outcomes Patients

4 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

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6 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

7 Different results: Observational studies G Murphy

8 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

9 First job plan 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

10 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

11 The structure to this review What 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

12 Developing next steps/ clinical trial systematic reviews guidelines clinical trials/rct prospective

13 Review Need for a trial: prophylactic vs. noprophylactic 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 NEJM NHSBT, funder; Williamson, CTU

14 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

15 More RCT s over last 10 years Explosion 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

16 Unexpected results for RCT s Transfusions are biological products Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH) Platelet transfusion seems inferior to standard care and cannot be recommended

17 Multiple red cell trials: Cochrane review Identify all randomised trials Meta-analysis 30 trials involving patients across a diverse range of clinical settings Carson, 2016

18 Hebert et al NEJM 340(6) Hebert et al Am J Respir Crit Care Med

19 Mortality 30 days Guidelines

20 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

21 Red blood cell transfusion thresholds in BMF the need for pilots REDDS, REAL Feasibility RCT to evaluate protocol adherence between a restrictive (Hb g/L) and a liberal (maintain Hb g/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

22 AML (induction): a pilot trial of red blood cell transfusion thresholds and QoL C l u s t e r s Test: liberal strategy Group 1 Group 2 Outcomes Standard: restrictive strategy Morton, Sekhar (New)

23 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): e

24 Platelets & Plasma and randomised trials

25 The NeoBolus Study Fluid bolus therapy in neonates: A multi-centre, prospective cross-sectional study Amy Keir (Australia), Oliver Karam (Switzerland), Cassandra Josephson (USA), Martha Sola-Visner (US), Helen Liley (Australia), Prakesh Shah (Canada), Simon Stanworth (UK)

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

27 PlaNeT1: Platelet transfusions (n=415) were administered to 116 infants (69%) Pre-transfusion median 27 x10 9 /L (IQR: x10 9 /L) PlaNeT-1 study group (UK), Pediatrics, 2009

28 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 25x10 9 /L or 50x10 9 /L Curley, New, PlaNeT-2 study group (UK, Ireland), MATISSE (NL)

29 Recruitment despite challenges Randomisations Jun-11 Aug-11 Oct-11 Dec-11 Feb-12 Apr-12 Jun-12 Aug-12 Oct-12 Dec-12 Feb-13 Apr-13 Jun-13 Aug-13 Oct-13 Dec-13 Feb-14 Apr-14 Jun-14 Aug-14 Oct-14 Dec-14 Feb-15 Apr-15 Jun-15 Aug-15 Oct-15 Dec-15 Feb-16 Apr-16 Jun-16 Actual *Predicted (based on current accrual 11/month to 660) PlaNeT-2 study group (UK, Ireland), MATISSE (NL)

30 Use in cancer. TOPPS. Primary Outcome WHO grade 2-4 bleeding: - no-prophylaxis: 50% (151/300) - prophylaxis: 43% (128/298) Alternative treatments in thrombocytopenia PBM

31 TREATT: TRial to EvaluAte Tranexamic acid therapy in Thrombocytopenia P o p u l a t i o n Test: tranexamic acid Group 1 Group 2 Standard: placebo Haemostatic Outcomes Estcourt, Wood, Others

32 Should we be revisiting use of desmopressin? (DRIVE trial) Thrombocytopenic patients undergoing invasive procedure Randomised DDAVP Matching placebo Laboratory outcomes Microfluidics, platelet function, thrombin generation Feasibility and Clinical outcomes Bleeding, thromboembolism, serious adverse events Desborough

33 Plasma and lack of controlled trials

34 Which factor is important? Blood-exchange induced coagulopathy model

35 Murine model

36 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

37 Conclusion Where 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

38 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

39 Why use drugs that don t work? Lipworth et al; BMJ, 2012, 344: d286 Why do clinicians prescribe rfviia Gaps in evidence Observational association Compelled to do something Autonomy Commercial

40 How to respond? Monitoring Intervention Guidelines Education Group Individual Reminders Computerized Paper Audit / Feedback Audit / Approval Tinmouth

41 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

42 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 behaviour Psychology is the scientific study of behaviour Previous studies relevance of psychological / behaviour change theory in understanding & changing practice AFFINITIE first step Francis

43 Cluster trial UK hospitals Appropriateness of transfusions Randomisation Enhanced Enhanced Enhanced Feedback content follow on content & as usual follow on Appropriateness of transfusions NCA, Foy, Everyone!

44 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

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

46 Transfusion Other areas of policy and strategy eg more pilots Randomised trials 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

47 Who? Thanks Funders NHSBT, NIHR Resources SRI, CTU, NCA Researchers (TOPPS, TREATT, REDDS, REAL, CRYOSTAT, PlaNeT, DRiVe, AFFINITIE) Networks of clinicians, local research teams

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49 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

50 PBM: Alternative treatments in thrombocytopenia Increased bleeding with red cell transfusion Decreased bleeding and transfusion requirements No improvement in bleeding or transfusion Desborough et al. Brit J Haem, 2016