Rebulla 1997.

Methods	Parallel RCT (enrolled from March 1994 to March 1996). Multicentre study (21 centres). Italy
Participants	Inclusion criteria: People with AML; adolescents and adults (aged 16 to 70 yrs); admitted to hospital for 1st course of induction chemotherapy Exclusion criteria: People diagnosed with promyelocytic leukaemia or secondary AML; people who had received a blood transfusion prior to diagnosis of AML N = 329 people screened for trial. 276 randomised. (37 secondary leukaemia; 10 blood transfusion prior to diagnosis; 4 did not meet age criteria; 2 declined to give consent) Arm 1: N = 144; 9 not included in analysis: 8 alive at discharge (no study records received); 1 death on day 5 (cerebral haemorrhage) (no study records received) Arm 2: N = 132; 12 not included in analysis: 8 alive at discharge (no study records received); 2 died within 24 hours of admission (1 cerebral haemorrhage, 1 cardiac arrest); 2 received non‐myeloablative course of chemotherapy
Interventions	Comparison between prophylactic platelets with different transfusion triggers Arm 1: (Low transfusion trigger). If platelet count < 10 x 109/L AND temperature < 38°C If platelet count 10 to 20 x 109/L AND temperature > 38°C OR in presence of major or minor bleeding OR if invasive procedures were necessary Arm 2: (High transfusion trigger). If platelet count < 20 x 109/L Platelet dose: 1 unit of platelet rich plasma or buffy coat concentrate per 10 kg body weight or 1 apheresis concentrate given. Number of platelets per transfusion (apheresis) median 280 x 109 (range 110 to 588), pooled concentrate median 217 x 109 (range 140 to 555) Platelet type: Apheresis platelets given to 50% of participants in Arm 1 and 42% of participants in Arm 2
Outcomes	Primary outcome: Frequency and severity of haemorrhage Secondary outcomes: Mortality rates Rates of complete remission Number of red cell transfusions Number of platelet transfusions All outcomes measured to end of study Number of days participants on study (mean) Arm 1 = 29.7 days Arm 2 = 27.8 days
Bleeding scale	Severity of haemorrhage marked on an 8 ‐point scale 0 = no bleeding 1 = petechiae or mucosal or retinal bleeding 2 = melaena, haematemesis, haematuria, or haemoptysis 3 = any bleeding requiring a red cell transfusion 4 = retinal bleeding accompanied by visual impairment 5 = non‐fatal cerebral bleeding 6 = fatal cerebral bleeding 7 = fatal non‐cerebral bleeding Definition of significant haemorrhage: score > 1 Definition of life‐threatening haemorrhage: not stated
Bleeding assessment	The physician in charge of the participant collected data on the occurrence and type of bleeding
Red cell transfusion policy	Red cells were given when haemoglobin < 80 g/L
Notes	Participants randomised at: diagnosis Follow‐up of participants: until platelet count > 100 x 109/L OR discharge from hospital OR occurrence of complete remission OR resistance to chemotherapy OR death Stopping guidelines: The trial was scheduled to be stopped if the rate of outcome events reached statistical significance (P < 0.01 by the Chi2 test) Acetaminophen was used as an antipyretic agent Source(s) of funding: not reported Conflicts‐of‐interest statement: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants underwent randomisation as soon as the diagnosis and other inclusion criteria were communicated by telephone to the central randomisation centre at the GIMEMA secretariat in Rome. A random permutated block design was used in the individual centres
Allocation concealment (selection bias)	Low risk	The people who handled randomisation, data management, and statistical analysis were not involved in the treatment of the participants
Blinding of participants and personnel (performance bias) Participant	Unclear risk	It was unclear whether participants were blinded to the intervention, this was not reported in the published study
Blinding of participants and personnel (performance bias) Physician/Medical Staff	High risk	Medical staff routinely involved in the care of the participant were the bleeding assessors and were not blinded to the intervention (additional data supplied by the author and reported in Estcourt 2013)
Blinding of outcome assessment (detection bias) All outcomes	High risk	Bleeding assessors were not blinded to the intervention (additional data supplied by the author and reported in Estcourt 2013)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. 21 of the randomised participants were excluded from analysis (16 no study records received. 2 received non‐myeloablative chemotherapy. 3 died (2 within 24 hours of enrolment into the study); 2 of the three deaths were due to an intracerebral haemorrhage. 9 participants were excluded in the standard‐trigger arm: 8 alive at discharge (no study records received); 1 death on day 5 (cerebral haemorrhage) (no study records received). 12 participants were excluded in the higher‐trigger arm: 8 alive at discharge (no study records received); 2 died within 24 hours of admission (1 cerebral haemorrhage, 1 cardiac arrest); 2 received non‐myeloablative course of chemotherapy
Selective reporting (reporting bias)	Unclear risk	Study protocol not available to allow judgement
Other bias	Low risk	The study appears to be free of other sources of bias
Protocol Deviation balanced?	High risk	Pre‐transfusion platelet count higher than indicated in the protocol in 5.4% of platelet transfusions in Arm 1 and 2% of platelet transfusions in Arm 2

ALL = acute lymphocytic leukaemia

AML = acute myeloid leukaemia

APL = acute promyelocytic leukaemia

DIC = disseminated intravascular coagulation

GvHD = graft versus host disease

ITU = intensive treatment unit

MDS = myelodysplastic syndrome

RBC = red blood cell

RCT = randomised controlled trial

SD = standard deviation