Alternative or additional agents to platelet transfusions to prevent bleeding in people with blood cancers receiving intensive treatment

Review question

What is the best way to prevent bleeding for people being treated with intensive chemotherapy or stem cell transplantation for blood, or bone marrow cancers? Should we use platelet transfusions (the current standard treatment), or use other agents instead of (or as well as) platelet transfusions.

Background

Approximately one in eight cancers arise from the blood, bone marrow, or lymph nodes. These cancers are divided into many different types that are treated differently. Examples include acute myeloid leukaemia and lymphoma. Some of these cancers can be cured with high-dose (intensive) chemotherapy or stem cell transplantation. These treatments destroy the cancer but can also damage the normal blood-producing cells. One consequence of this is a reduction in the number of platelets in the blood. Platelets are essential to make the blood clot normally. Consequently, people receiving these treatments are vulnerable to bleeding until their platelets increase in number.

Platelet transfusions (taken from a blood donor) are often given to try to prevent people with blood cancer from bleeding. We do not know how well these transfused platelets work. We know that there are risks from platelet transfusion, such as transmission of infections. It is possible that there are better ways to prevent bleeding in this setting. In this review, we examined whether other agents could be used instead of (or as well as) platelet transfusion to prevent bleeding. We also assessed the risk of serious side effects, such as forming abnormal blood clots (thromboembolic events). Potential agents include artificial platelets, platelet-poor plasma, fibrinogen concentrate, recombinant activated factor VII, desmopressin and thrombopoietin mimetics. Terms and treatments are described in the glossary in the 'Published notes' section of this review).

Study characteristics

The evidence is current to May 2016. We identified 16 clinical trials: 10 completed trials and six ongoing trials. We included the 10 completed trials in this review. Six trials included adults with acute myeloid leukaemia undergoing intensive chemotherapy, two trials included adults with lymphoma undergoing intensive chemotherapy and two trials included adults undergoing allogeneic stem cell transplantation. The age range of participants was between 16 and 81 years. Men and women were equally well represented. All trials took place in high-income countries. The manufacturer of the agent that was under investigation sponsored eight trials, and two trials did not report their source of funding. We identified nine trials (536 participants) assessing thrombopoietin mimetics and one trial (18 participants) assessing platelet-poor plasma. These trials were conducted between 1974 and 2015. No trial assessed artificial platelets, fibrinogen concentrate, recombinant activated factor VII or desmopressin).

Key results

For adults treated with thrombopoietin mimetics, we are very uncertain whether there is a difference in the number of participants with: any bleeding, risk of life-threatening bleeding, number of platelet transfusions, overall risk of death or thromboembolic events because the quality of the evidence was very low. We found no trials of thrombopoietin mimetics that looked at: the number of days on which bleeding occurred, time from start of trial to first bleed or quality of life.

For adults treated with platelet-poor plasma, we are very uncertain whether there is a difference in the number of participants with: any bleeding or risk of life-threatening bleeding. We found no trials that looked at: the number of days on which bleeding occurred, time from start of trial to first bleeding episode, number of platelet transfusions, overall risk of death, thromboembolic events or quality of life.

Quality of the evidence

The quality of the evidence was very low, making it difficult to draw conclusions or make recommendations regarding the usefulness and safety of thrombopoietin mimetics or platelet-poor plasma. There was no trial evidence for artificial platelets, fibrinogen concentrate, recombinant activated factor VII or desmopressin.

Authors' conclusions: 

There is insufficient evidence to determine if platelet-poor plasma or TPO mimetics reduce bleeding for participants with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation. To detect a decrease in the proportion of participants with clinically significant bleeding from 12 in 100 to 6 in 100 would require a trial containing at least 708 participants (80% power, 5% significance). The six ongoing trials will provide additional information about the TPO mimetic comparison (424 participants) but this will still be underpowered to demonstrate this level of reduction in bleeding. None of the included or ongoing trials include children. There are no completed or ongoing trials assessing artificial platelet substitutes, fibrinogen concentrate, recombinant activated factor VII or desmopressin in people undergoing intensive chemotherapy or stem cell transplantation for haematological malignancies.

Read the full abstract...
Background: 

Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in people with thrombocytopenia. Although considerable advances have been made in platelet transfusion therapy since the mid-1970s, some areas continue to provoke debate especially concerning the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding.

Objectives: 

To determine whether agents that can be used as alternatives, or adjuncts, to platelet transfusions for people with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation are safe and effective at preventing bleeding.

Search strategy: 

We searched 11 bibliographic databases and four ongoing trials databases including the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 4), MEDLINE (OvidSP, 1946 to 19 May 2016), Embase (OvidSP, 1974 to 19 May 2016), PubMed (e-publications only: searched 19 May 2016), ClinicalTrials.gov, World Health Organization (WHO) ICTRP and the ISRCTN Register (searched 19 May 2016).

Selection criteria: 

We included randomised controlled trials in people with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation who were allocated to either an alternative to platelet transfusion (artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, recombinant activated factor VII, desmopressin (DDAVP), or thrombopoietin (TPO) mimetics) or a comparator (placebo, standard care or platelet transfusion). We excluded studies of antifibrinolytic drugs, as they were the focus of another review.

Data collection and analysis: 

Two review authors screened all electronically derived citations and abstracts of papers identified by the review search strategy. Two review authors assessed risk of bias in the included studies and extracted data independently.

Main results: 

We identified 16 eligible trials. Four trials are ongoing and two have been completed but the results have not yet been published (trial completion dates: April 2012 to February 2017). Therefore, the review included 10 trials in eight references with 554 participants. Six trials (336 participants) only included participants with acute myeloid leukaemia undergoing intensive chemotherapy, two trials (38 participants) included participants with lymphoma undergoing intensive chemotherapy and two trials (180 participants) reported participants undergoing allogeneic stem cell transplantation. Men and women were equally well represented in the trials. The age range of participants included in the trials was from 16 years to 81 years. All trials took place in high-income countries. The manufacturers of the agent sponsored eight trials that were under investigation, and two trials did not report their source of funding.

No trials assessed artificial platelet substitutes, fibrinogen concentrate, recombinant activated factor VII or desmopressin.

Nine trials compared a TPO mimetic to placebo or standard care; seven of these used pegylated recombinant human megakaryocyte growth and differentiation factor (PEG-rHuMGDF) and two used recombinant human thrombopoietin (rhTPO).

One trial compared platelet-poor plasma to platelet transfusion.

We considered that all the trials included in this review were at high risk of bias and meta-analysis was not possible in seven trials due to problems with the way data were reported.

We are very uncertain whether TPO mimetics reduce the number of participants with any bleeding episode (odds ratio (OR) 0.40, 95% confidence interval (CI) 0.10 to 1.62, one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce the risk of a life-threatening bleed after 30 days (OR 1.46, 95% CI 0.06 to 33.14, three trials, 209 participants, very low quality evidence); or after 90 days (OR 1.00, 95% CI 0.06 to 16.37, one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce platelet transfusion requirements after 30 days (mean difference -3.00 units, 95% CI -5.39 to -0.61, one trial, 120 participants, very low quality evidence). No deaths occurred in either group after 30 days (one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce all-cause mortality at 90 days (OR 1.00, 95% CI 0.24 to 4.20, one trial, 120 participants, very low quality evidence). No thromboembolic events occurred for participants treated with TPO mimetics or control at 30 days (two trials, 209 participants, very low quality evidence). We found no trials that looked at: number of days on which bleeding occurred, time from randomisation to first bleed or quality of life.

One trial with 18 participants compared platelet-poor plasma transfusion with platelet transfusion. We are very uncertain whether platelet-poor plasma reduces the number of participants with any bleeding episode (OR 16.00, 95% CI 1.32 to 194.62, one trial, 18 participants, very low quality evidence). We are very uncertain whether platelet-poor plasma reduces the number of participants with severe or life-threatening bleeding (OR 4.00, 95% CI 0.56 to 28.40, one trial, 18 participants, very low quality evidence). We found no trials that looked at: number of days on which bleeding occurred, time from randomisation to first bleed, number of platelet transfusions, all-cause mortality, thromboembolic events or quality of life.

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