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Meta-Analysis
. 2016 Oct 31;10(10):CD012055.
doi: 10.1002/14651858.CD012055.pub2.

Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: a meta-analysis and systematic review

Michael Desborough  1 , Andreas V Hadjinicolaou, Anna Chaimani, Marialena Trivella, Paresh Vyas, Carolyn Doree, Sally Hopewell, Simon J Stanworth, Lise J Estcourt
Affiliations
Meta-Analysis

Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: a meta-analysis and systematic review

Michael Desborough et al. Cochrane Database Syst Rev. .

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 methods: 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).

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.

PubMed Disclaimer

Conflict of interest statement

Michael Desborough: none known.

Andreas Hadjinicolaou: none known.

Anna Chaimani: none known.

Marialena Trivella: none known.

Paresh Vyas: none known.

Carolyn Doree: none known.

Sally Hopewell: none known.

Simon Stanworth: none known.

Lise Estcourt: none known.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
Thrombopoietin mimetic versus placebo. Number of participants with at least one bleeding episode
4
4
Thrombopoietin mimetic versus placebo. All‐cause mortality.
5
5
Proportion of participants receiving a platelet transfusion.
6
6
Thrombopoietin mimetic versus placebo. Thromboembolism.
1.1
1.1. Analysis
Comparison 1: Thrombopoietin mimetic versus placebo, Outcome 1: Number of participants with at least one bleeding episode
1.2
1.2. Analysis
Comparison 1: Thrombopoietin mimetic versus placebo, Outcome 2: Number of participants with at least one severe or life‐threatening bleeding episode
1.3
1.3. Analysis
Comparison 1: Thrombopoietin mimetic versus placebo, Outcome 3: All‐cause mortality
1.4
1.4. Analysis
Comparison 1: Thrombopoietin mimetic versus placebo, Outcome 4: Mortality due to bleeding
1.5
1.5. Analysis
Comparison 1: Thrombopoietin mimetic versus placebo, Outcome 5: Mortality due to infection
1.6
1.6. Analysis
Comparison 1: Thrombopoietin mimetic versus placebo, Outcome 6: Proportion of participants receiving a platelet transfusion
1.7
1.7. Analysis
Comparison 1: Thrombopoietin mimetic versus placebo, Outcome 7: Transfusion reactions
1.8
1.8. Analysis
Comparison 1: Thrombopoietin mimetic versus placebo, Outcome 8: Thromboembolism
1.9
1.9. Analysis
Comparison 1: Thrombopoietin mimetic versus placebo, Outcome 9: Drug reactions
See this image and copyright information in PMC

Update of

References

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References to ongoing studies

EudraCT 2010‐022890‐33 {published data only}
    1. EudraCT 2010-022890-33. Eltrombopag for the treatment of thrombocytopenia due to low- and intermediate risk myelodysplastic syndromes. EudraCT Number: 2010-022890-33.
    1. Oliva E, Latagliata R, Santini V, Palumbo G, Poloni A, Cortelezzi A, et al. Efficacy and safety of eltrombopag for the treatment of thrombocytopenia of low and INT-1 risk MDS: Preliminary results of a prospective, randomized, single-blind placebo-controlled trial. Blood 2012;120(21):Abstract 923.
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EudraCT 2014‐000174‐19 {published data only}
    1. EudraCT 2014-000174-19. Efficacy and safety of Eltrombopag in patients with acquired moderate aplastic anemia (EMAA) who are treated with Ciclosporin A. EudraCT number: 2014-000174-19.
NCT02099747 {published data only}
    1. NCT02099747. A prospective randomized multicenter study comparing horse antithymocyte globuline (hATG) + cyclosporine A (CsA) with or without Eltrombopag as front-line therapy for severe aplastic anemia patients. ClinicalTrials.gov Identifier: NCT02099747.
    1. Risitano AM, Peffault, De Latour R, Dufour C, Marsh J. The race study: A SAAWP prospective randomized multicenter study comparing horse antithymocyte globulin (HATG) + cyclosporine a (CSA) with or without eltrombopag as front-line therapy for severe aplastic anaemia patients. Bone Marrow Transplantation 2014;49(Suppl 1):Abstract WP-O005.
NCT02158936 {published data only}
    1. EudraCT 2013-000918-37. A study of Eltrombopag in combination with azacitidine for subjects with low platelet counts due to intermediate 1, intermediate 2 or high risk myelodysplastic syndromes (MDS). EudraCT number: 2013-000918-37.
    1. NCT02158936. A study of Eltrombopag or placebo in combination with azacitidine in subjects with international prognostic scoring system (IPSS) intermediate-1, intermediate-2 or high-risk myelodysplastic syndromes (MDS). ClinicalTrials.gov Identifier: NCT02158936.
    1. RBR-4m42nq. TRC112121 a phase III, randomized, double-blind, placebo-controlled, multi-center Eltrombopague or placebo in combination with azacitidine in patients with Myelodysplastic Syndrome with IPSS intermediate-1 classification, intermediate-2 and high-risk [TRC112121 um estudo fase III,randomizado, duplo-cego, controlado porplacebo, multicêntrico de eltrombopague ouplacebo em combinação com azacitidina emindivíduos com síndrome mielodisplásicacom classificação IPSS intermediário-1,intermediário-2 e alto risco]. Registro Brasileiro de Ensaios Clínicos identifier: RBR-4m42nq.

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References to other published versions of this review

Desborough 2016c
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