Abstract: We identified seven completed trials (472 participants), and four ongoing trials (recruiting 837 participants) which are due to be completed by December 2020. Of the seven completed trials, five trials (456 participants) compared a TPO mimetic versus placebo (four romiplostim trials, and one eltrombopag trial), one trial (eight participants) compared DDAVP with placebo and one trial (eight participants) compared tranexamic acid with placebo. In the DDAVP trial, the only outcome reported was the bleeding time. In the tranexamic acid trial there were methodological flaws and bleeding definitions were subject to significant bias. Consequently, these trials could not be incorporated into the quantitative synthesis. No randomised trial of artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, rFVIIa, rFXIII, rIL6 or rIL11 was identified. We assessed all five trials of TPO mimetics included in this review to be at high risk of bias because the trials were funded by the manufacturers of the TPO mimetics and the authors had financial stakes in the sponsoring companies. The GRADE quality of the evidence was very low to moderate across the different outcomes. There was insufficient evidence to detect a difference in the number of participants with at least one bleeding episode between TPO mimetics and placebo (RR 0.86, 95% CI 0.56 to 1.31, four trials, 206 participants, low-quality evidence). There was insufficient evidence to detect a difference in the risk of a life-threatening bleed between those treated with a TPO mimetic and placebo (RR 0.31, 95% CI 0.04 to 2.26, one trial, 39 participants, low-quality evidence). There was insufficient evidence to detect a difference in the risk of all-cause mortality between those treated with a TPO mimetic and placebo (RR 0.74, 95%CI 0.52 to 1.05, five trials, 456 participants, very low-quality evidence). There was a significant reduction in the number of participants receiving any platelet transfusion between those treated with TPO mimetics and placebo (RR 0.76, 95% CI 0.61 to 0.95, four trials, 206 participants, moderate-quality evidence). There was no evidence for a difference in the incidence of transfusion reactions between those treated with TPO mimetics and placebo (pOR 0.06, 95% CI 0.00 to 3.44, one trial, 98 participants, very low-quality evidence). There was no evidence for a difference in thromboembolic events between TPO mimetics and placebo (RR 1.41, 95%CI 0.39 to 5.01, five trials, 456 participants, very-low quality evidence). There was no evidence for a difference in drug reactions between TPO mimetics and placebo (RR 1.12, 95% CI 0.83 to 1.51, five trials, 455 participants, low-quality evidence). No trial reported the number of days of bleeding per participant, platelet transfusion episodes, mean red cell transfusions per participant, red cell transfusion episodes, transfusion-transmitted infections, formation of antiplatelet antibodies or platelet refractoriness. In order to demonstrate a reduction in bleeding events from 26 in 100 to 16 in 100 participants, a study would need to recruit 514 participants (80% power, 5% significance). There is insufficient evidence at present for thrombopoietin (TPO) mimetics for the prevention of bleeding for people with thrombocytopenia due to chronic bone marrow failure. There is no randomised controlled trial evidence for artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, rFVIIa, rFXIII or rIL6 or rIL11, antifibrinolytics or DDAVP in this setting.

Plain-language summary: The evidence is current to April 2016. We identified 11 randomised controlled trials, of which seven had been completed. Of the seven completed trials, five trials (456 participants) assessed TPO mimetics, one trial (eight participants) assessed tranexamic acid and one trial (eight participants) assessed DDAVP. The trial of DDAVP only assessed the bleeding time: the time taken for bleeding to stop after a small cut is made in the participant's forearm. It did not assess any of the outcomes of interest to this review. The trial of tranexamic acid had significant methodological flaws in the way bleeding was reported. No randomised trial of artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, rFVIIa, rFXIII, rIL6 or rIL11 was identified. Consequently, quantitative analysis was only performed on the five trials assessing TPO mimetics. Four of these trials included adults with myelodysplastic syndrome (MDS) and one trial assessed adults with MDS or acute myeloid leukaemia (AML). We assessed all five trials of TPO mimetics included in this review to be at high risk as the manufacturers if the TPO mimetics were directly involved in the design and publication of the trials. Differences in severity of disease and number of participants undergoing chemotherapy between trials meant that network meta-analysis could not be performed. A requirement of network meta-analysis is that participants in each trial should meet the eligibility criteria for each trial that is included. The four ongoing trials are all comparing TPO mimetics versus placebo; they are expected to recruit 837 participants in total and are due to be completed by December 2020. TPO mimetics may make little or no difference to the number of participants with any bleeding or severe/life-threatening bleeding. We are very uncertain whether TPO mimetics reduce the risk of mortality. TPO mimetics probably reduce the number of participants who need a platelet transfusion. We are very uncertain whether TPO mimetics reduce the risk of transfusion reactions or risk of thromboembolism. TPO mimetics may have little or no effect on the risk of drug reactions. No trial reported the number of days bleeding per participant, platelet transfusion episodes, mean red cell transfusions per participant, red cell transfusion episodes, transfusion-transmitted infections, formation of antiplatelet antibodies or platelet refractoriness. The quality of the evidence was low or very low for all outcomes except the number of participants receiving a platelet transfusion which was moderate-quality evidence.