Why PLANET-2 needs to succeed?

Simon Stanworth

Anna Curley

1. The trial question is still relevant?

• (Still) no evidence base• No recent informative literature/studies• US study not funded

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

Neonatal studies

Recommendation: For critically ill children with severe thrombocytopenia and no evidence of bleeding, there is insufficient evidence to recommend for or against platelet transfusion.

2. Common clinical problem

• Thrombocytopenia common, platelet transfusions still only main therapy

• Thrombopoietin analogues

3.

4. We should be learning lessons from other clinical groups/ settings?

1. The leukaemia population – no prophylaxis

2. TOPPS trial.

TOPPS

Prophylactic platelet transfusion used as standard practice but no supporting evidence base

Randomised clinical trial of no prophylaxis vs. prophylaxis: Prophylactic platelet transfusions reduce bleeding (50% to 43%)

May not be effective in all patient subgroups e.g. autologous stem cell transplants.

Other strategies e.g. TXA review and proposals new trial

PP

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Group 1

Group 2

HaemostaticOutcomes

Test: no-prophylaxis

Standard: prophylactic platelets at < 10x109/L

TOPPs: design

Recording bleeding

Grading bleeding (WHO) in adult trials

Grade 1 - mild Grade 2 - moderate (red cell transfusion not

needed acutely) Grade 3 - severe (requiring red cell

transfusion within 24 hours) Grade 4 - debilitating/ life-threatening

Subgroups – TOPPS Results: Primary Outcome

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

Predominant bleeding was grade 2

Learning about outcomes - bleeding

Next steps• Individualising use of platelet transfusions - subgroups• Risk factors

Rates of WHO grade 2-4 bleeding

Prophylaxis No Prophylaxis

AutologousHSCT

95/210(45%)

99/210(47%)

‘Other’: chemotherapy/ allogeneic HSCT

33/90(38%)

52/90(58%)

Protocol adherence & Data completeness

Most transfusions in both arms were given according to protocol: no-prophylaxis [89%; 450/504] vs. prophylaxis [91%; 810/894]

Assessments completed on 93% (8405/9030) and 97% (8733/8970) of days in the no-prophylaxis group & prophylaxis groups

5.Platelet count poor predictor of bleeding risk

Morning platelet count and bleeding risk

Dose of prophylactic platelet transfusions and prevention of hemorrhage. Slichter et al. NEJM 2010;362:600-613

Bleeding the Following DayUnadjusted Odds Ratios (OR)

Odds Ratios and 95% Confidence Intervals

10.20 20.80.60.4 1.81.61.41.2

Total Platelet Count

Absolute Immature Platelet Number

Immature Platelet Fraction

P = 0.030

P = 0.008

P = 0.346

OR 0.60, 95% CI 0.41 to 0.88

OR 0.97, 95% CI 0.90 to 1.03

OR 0.98, 95% CI 0.97 to 1.00

6.The risks of platelet transfusion

• Uncertainty in neonatal transfusion practice. • Biological product • Risks of blood transfusion. • Potential for important benefits to reduce bleeding

in neonates, and long term developmental consequences.

• Prioritisation – the need for studies in children

Risks of platelet transfusions

Haemovigilance data (UK) Compared findings for adults vs children/infants:

extrapolated data from ‘Where does blood go?’, 2008

Incidence of adverse outcomes of blood transfusion (per 100,000 red cells issued)

Adults 13 Children <18 yrs 18 Infants <12 mths 37

Stainsby et al, Br J Haematol 2008; 141:73-79

Haemovigilance: errors and clinical events

Reasons for increase in errors Under-reporting in neonatal population:

immunological immaturity, masked by symptoms, or simply not recognised

e.g. necrotising enterocolitis other complications, such as line-associated

infections, problems with multiple cannulations or extravasations rarely reported

7. Other potential side effects Necrotising enterocolitis

Retrospective analysis of neonates with NEC Results suggested platelet transfusions in

thrombocytopenic infants with NEC associated with greater morbidity

Kenton et al, J Perinatol. 2005;25:173-7

8. Addressing other clinical uncertainties

• Use of non-steroidal anti-inflammatory drugs

• The baby with rapidly falling platelet counts

• Use of blood components, platelets (or plasma) as a volume expander.

9. Strengthening haematology research

• The benefits of collaboration

• The importance of supportive care & transfusion for sick neonates – colloids/albumin

• Baseline for new targeted research e.g. individualise use of platelet and other blood components, thrombopoietin.

Because the public want research

The Planet-2 babies

The Planet two team

• TSC

• TMG

• CTU

• PIs

• Research nurses

• IDMC