So‐Osman 2014.

Study characteristics
Methods	Design: RCT, factorial design, multicentre study Setting: all hospitals participating in the study (1 university hospital and 3 medium‐sized to large general hospitals) were located in the Netherlands Recruitment: May 2004 to October 2008 Maximum follow‐up: 3 months postoperatively
Participants	2579 eligible participants were randomised; however, only 2442 participants were included in the study due to participant withdrawal (104 not operated/operated elsewhere, 23 withdrew consent, 9 still on waiting list at end of study, 1 minor surgery). A total of 683 participants were included in stratum I and 1759 participants included in stratum II. Erythropoietin = EPO; total hip replacement = THR; total knee replacement = TKR Stratum I Group 1(Epo and autologous transfusion (AUTO + EPO)) (cell salvage/intervention group): N = 214. M:F 30:184. Mean (SD) age 70 (13). THR = 150. TKR = 64. Primary THR = 129. Primary TKR = 61. Group 2(Epo only (EPO, no CS) (control/no cell salvage group): N = 125. M:F 12:113. Mean (SD) age 71 (12). THR = 64. TKR = 61. Primary THR = 56. Primary TKR = 56. Group 3 (Autotransfusion only (AUTO only)) (cell salvage/intervention group): N = 206. M:F 29:177. Mean (SD) age 71 (12). THR = 136. TKR = 70. Primary THR = 120. Primary TKR = 64. Group 4(No autotransfusion (no EPO, no CS)) (control/no cell salvage group): N = 138. M:F 16:122. Mean (SD) age 70 (11). THR = 77. TKR = 61. Primary THR = 67. Primary TKR = 60. Stratum II Group 1 (AUTO) (cell salvage/intervention group): intraoperative cell salvage and/or postoperative reinfusion drain (Autotransfusion group). N = 1061. M:F 367:694. Mean (SD) age 69 (10). THR = 695. TKR = 366. Primary THR = 643. Primary TKR = 344. Group 2 (Control/No AUTO) (control/no cell salvage group): no autotransfusion (control group). N = 698. M:F 288:410. Mean (SD) age 68 (10). THR = 342. TKR = 356. Primary THR = 319. Primary TKR = 339. There was no baseline imbalance between groups.
Interventions	Stratum I Group 1(Epo and autologous transfusion (AUTO + EPO)) (cell salvage/intervention group): participants received EPO 40,000 U (Neorecormon or Eprex) for 3 weeks prior to the date of surgery. Epo was given in conjunction with ferrous fumarate 200 mg three times a day (TDS). The OrthoPAT Cell saver was used for both intra‐ and postoperative autotransfusion. Postoperative drain salvage for retransfusion was performed using either the Bellovac‐BT (Astra‐Tech, Zoetermeed, the Netherlands) or DONOR system (Van Straten Medical, Nieuwegein, the Netherlands). The DONOR system uses a continuous suction at a vacuum pressure of 150 mmHg and filters blood prior to re‐transfusion. The Bellovac‐ABT system uses intermittent suction pressure by a manually expandable bag at 90 mmHg and is sequentially filtered three times prior to re‐transfusion. Participants undergoing total knee replacement only received postoperative drain salvage interventions as the operations were performed under tourniquet and so intraoperative blood loss was thought to be negligible and did not warrant cell salvage use. Group 2(Epo only (EPO, noCS) (control/no cell salvage group): epo‐only group received epo in concordance with the schedule described for Group 1. Group 3 (Autotransfusion only (AUTO only)) (cell salvage/intervention group): autotransfusion‐only group (autotransfusion group) received either intraoperative cell salvage or postoperative drain salvage in concordance with the devices described in Group 1. Group 4(No autotransfusion (no EPO, no CS)) (control/no cell salvage group): the no autotransfusion group received neither autotransfusion or epo. Stratum II Group 1 (AUTO) (cell salvage/intervention group): the cell saver and postoperative drain reinfusion group (Autotransfusion group) received either intraoperative and postoperative cell salvage via the OrthoPAT cell saver (Haemonetics, Breda, the Netherlands) or postoperative drain reinfusion via the Belovac‐ABT or DONOR reinfusion systems. Participants undergoing total knee replacement only received postoperative reinfusion drains as the procedure was performed under tourniquet and therefore intraoperative blood loss was deemed negligible and did not warrant use of intraoperative cell saver. The OrthoPAT cell saver collected blood intraoperatively and up to 6 hours postoperatively in participants undergoing total hip replacement. The collected shed blood was washed, centrifuged, and concentrated to a haematocrit of 60% to 80% prior to retransfusion. Group 2 (Control/No AUTO) (control/no cell salvage group): the no autologous transfusion group received standard care with no intra‐ or postoperative cell salvage or autotransfusion.
Outcomes	Primary outcomes: intra‐ and postoperative mean erythrocyte use, proportion of transfused participants up to 3 months after surgery Secondary outcomes: cost and cost‐effectiveness at 3 months after surgery, serious adverse events up to 3 months after surgery (death, life‐threatening events, prolonged hospitalisation, dislocation, wound infection, deep prosthetic infection, fractures, limitation in movement, thromboembolic events, cardiovascular events, allergy, infection, malignancy, and other)
Notes	Transfusion protocol: the Dutch national transfusion protocol was applied for the use of allogeneic erythrocyte transfusions. A single unit transfusion policy was used. Autologous blood was reinfused independent of haemoglobin value. Prospective registration status: the study was retrospectively registered with a trials registry (ISRCTN 96327523; Dutch Trials registry No. NTR305). Study start date was one year before registration. Ethical approval: the study was approved by the local ethics committees at each participating site. Language of publication: English Study groups: two strata have been combined into a single comparison of Autotransfusion (Stratum I: Group 1(AUTO+EPO) and Group 3(AUTO only); Stratum II: Group 1(AUTO)) versus no autotransfusion (Stratum 1: Group 2(EPO, no AUTO) and Group 4(no EPO, no AUTO); Stratum II: Group 2(Control/No AUTO)). Trial funding: Sanquin Blood Supply (PPOC‐03‐002), ZonMW (06‐601), Roche and Haemonetics Conflicts of interest: none reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation took place in one run for all possible combinations using a computer‐generated allocation table
Allocation concealment (selection bias)	Low risk	Randomisation and group allocation were performed prior to recruitment using a computer‐generated randomisation sequence and the results placed into a sealed, opaque envelope opened after participant recruitment and informed consent.
Blinding of participants and personnel (performance bias) Objective outcome: mortality	Low risk	No objective outcomes reported (mortality unlikely to be affected by blinding if reported in future publications)
Blinding of participants and personnel (performance bias) Subjective: transfusion protocol	Low risk	Transfusion protocol in place: all participants were transfused according to a restrictive transfusion policy as advised in the Dutch transfusion guidelines.
Blinding of participants and personnel (performance bias) Subjective: all other outcomes	High risk	Clinical site staff, clinicians, research nurses, and participants were not blinded to treatment allocation, and a number of outcomes are lacking clear diagnostic/decision‐making guidelines
Blinding of outcome assessment (detection bias) Objective outcomes: mortality and transfusions	Low risk	No objective outcomes reported (mortality unlikely to be affected by blinding if reported in future publications)
Blinding of outcome assessment (detection bias) Subjective outcomes	Unclear risk	Study investigators were blinded to treatment allocation, but multiple outcome data were collected by unblinded clinicians
Incomplete outcome data (attrition bias) All outcomes	Low risk	Analyses performed as ITT
Selective reporting (reporting bias)	Low risk	A study protocol was published and the trial registered prior to participant recruitment. All outcomes specified in the study protocol are described in the paper.
Other bias	Low risk	No baseline imbalance. Funding (mixed pharmaceutical and non‐pharmaceutical) and conflicts (none) reported. Authors state that the "sponsors of the study had no input in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the article for publication".