Alternative agents instead of platelet transfusions to prevent bleeding for people who have bone marrow disorders and low platelet counts

Review question

We evaluated the evidence about whether giving agents that can replace, or reduce platelet transfusion (artificial platelets, platelet-poor plasma, fibrinogen concentrate, recombinant activated factor VII (rFVIIa), recombinant factor XIII (rFXIII), recombinant interleukin (rIL)6 or rIL11, desmopressin (DDAVP), thrombopoietin (TPO) mimetics or antifibrinolytic drugs), to people with a low platelet count prevents bleeding and whether these alternative agents are associated with side effects. Our target population was people with bone marrow disorders which prevent them from producing enough platelets. We excluded people undergoing intensive chemotherapy or stem cell transplantation.

Background

People with low platelet counts due to bone marrow disorders are vulnerable to bleeding which may be severe or life-threatening. In order to treat, or prevent bleeding, they are often given platelet transfusions. However, platelet transfusions are associated with risks such as infection and transfusion reactions. Consequently, there is interest in whether it is possible to use alternative treatments to prevent bleeding. These treatments include: man-made platelets (artificial platelets); stimulating the person's body to produce more platelets (recombinant interleukin (rIL)6, rIL11, TPO mimetics); increasing the levels of proteins in the blood that help the body to form a clot (platelet-poor plasma, fibrinogen concentrate, recombinant activated factor VII (rFVIIa), recombinant factor XIII (rFXIII)); and preventing a blood clot from breaking down (antifibrinolytics) There may be risks associated with agents that prevent bleeding; the most important being an increased risk of forming unwanted blood clots, which could be potentially life-threatening.

Study characteristics

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.

Key results

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.

Quality of the evidence

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.

Authors' conclusions: 

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.

Read the full abstract...
Background: 

People with thrombocytopenia due to bone marrow failure are vulnerable to bleeding. Platelet transfusions have limited efficacy in this setting and alternative agents that could replace, or reduce platelet transfusion, and are effective at reducing bleeding are needed.

Objectives: 

To compare the relative efficacy of different interventions for patients with thrombocytopenia due to chronic bone marrow failure and to derive a hierarchy of potential alternative treatments to platelet transfusions.

Search strategy: 

We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (the Cochrane Library 2016, Issue 3), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1980) and ongoing trial databases to 27 April 2016.

Selection criteria: 

We included randomised controlled trials in people with thrombocytopenia due to chronic bone marrow failure who were allocated to either an alternative to platelet transfusion (artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, recombinant activated factor VII (rFVIIa), desmopressin (DDAVP), recombinant factor XIII (rFXIII), recombinant interleukin (rIL)6 or rIL11, or thrombopoietin (TPO) mimetics) or a comparator (placebo, standard of care or platelet transfusion). We excluded people undergoing intensive chemotherapy or stem cell transfusion.

Data collection and analysis: 

Two review authors independently screened search results, extracted data and assessed trial quality. We estimated summary risk ratios (RR) for dichotomous outcomes. We planned to use summary mean differences (MD) for continuous outcomes. All summary measures are presented with 95% confidence intervals (CI).

We could not perform a network meta-analysis because the included studies had important differences in the baseline severity of disease for the participants and in the number of participants undergoing chemotherapy. This raised important concerns about the plausibility of the transitivity assumption in the final dataset and we could not evaluate transitivity statistically because of the small number of trials per comparison. Therefore, we could only perform direct pairwise meta-analyses of included interventions.

We employed a random-effects model for all analyses. We assessed statistical heterogeneity using the I2 statistic and its 95% CI. The risk of bias of each study included was assessed using the Cochrane 'Risk of bias' tool. The quality of the evidence was assessed using GRADE methods.

Main results: 

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).

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