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  • Malouf R
  • Ashraf A
  • Hadjinicolaou AV
  • Doree C
  • Hopewell S
  • et al.
Cochrane Database Syst Rev. 2018 May 14;5(5):CD012342 doi: 10.1002/14651858.CD012342.pub2.

Xiangrong He, MD, PhD & Claudia S. Cohn, MD, PhD, both of University of Minnesota, Department of Laboratory Medicine and Pathology.

WHAT IS KNOWN?

Thrombocytopenia represents a common problem for patients withchronic bone marrow failure disorders, the most common of which are myelodysplastic syndrome (MDS) and anaplastic anemia (AA). In addition to thrombocytopenia, both morphologic and functional platelet abnormalities may be seen in these patients as well. Platelet transfusion support is the primary management option for thrombocytopenia and active bleeding in these patients. Platelets are usually transfused prophylactically at counts less than 10 x 109/L and with higher counts in patients with hemorrhage. As compared with no prophylaxis, prophylactic platelet transfusions have been shown to be superior in reducing moderate to severe bleeding, primarily in people with leukemia. However, the evidence of prophylactic use for platelet transfusions in people with chronic bone marrow failure is lacking. Meanwhile, platelets are a precious resource and platelet transfusion carries many risks. Thus, avoiding unnecessary prophylactic platelet transfusions will have significant financial and safety implications for health services.

WHAT DID THIS PAPER SET OUT TO EXAMINE?

The authors set out to to review in thrombocytopenic patients with chronic bone marrow failure, whether prophylactic transfusions are really necessary or whether these patients can be effectively supported with only therapeutic platelet transfusions given with the onset of bleeding. In particular, they wanted to show that a therapeutic-only platelet transfusion strategy is as effective and safe as a prophylactic platelet transfusion strategy for the prevention of clinically significant bleeding in thrombocytopenic patients with primary bone marrow failure disorders.

WHAT DID THEY SHOW?

The review included all patients with MDS, acquired AA, or congenital bone marrow failure disorders that were not being actively treated with a stem cell transplant or intensive chemotherapy. To maximize the number of studies eligible for inclusion, not only randomized controlled trials (RCTs), but good quality non-RCTs, and controlled before-after studies were included. Only one trial met the inclusion criteria for this review. Unfortunately, the trial was incomplete due to an unexpected slow recruiting rate. Therefore, no results were provided by the trial authors. Although the review was unable to make any recommendations on prophylactic platelet transfusion policies for this patient population, it did identify an urgent need for good quality studies in this area.

WHAT ARE THE IMPLICATIONS FOR PRACTICE AND FOR FUTURE WORK?

Thrombocytopenia (platelet counts < 10 x 109/L) is one of the most common complications in patients with chronic bone marrow failure. For example, 40% to 65% of MDS patients have thrombocytopenia. Meanwhile, in some Western countries, bone marrow failure is one of the most common underlying reasons for receiving a prophylactic platelet transfusion. However, guidelines on a therapeutic platelet transfusion strategy versus a prophylactic platelet transfusion strategy in this population are still lacking. Due to the absence of relevant data, the current review was not able to reach any conclusions on the safety and efficacy of prophylactic platelet transfusion compared with therapeutic platelet transfusion for patients with chronic bone marrow failure. Nontheless, this review identified a major gap in the literature and underscored the urgency of prioritizing research in this area. In the meantime, platelet transfusions for people with bone marrow disorders should still be managed according to national transfusion guidelines.

BACKGROUND:

Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both. The most common bone marrow disorder is myelodysplastic syndrome. Thrombocytopenia, a low platelet count, commonly occurs in people with bone marrow failure. Platetet transfusions are routinely used in people with thrombocytopenia secondary to bone marrow failure disorders to treat or prevent bleeding. Myelodysplastic syndrome is currently the most common reason for receiving a platelet transfusion in some Western countries.

OBJECTIVES:

To determine whether a therapeutic-only platelet transfusion policy (transfusion given when patient is bleeding) is as effective and safe as a prophylactic platelet transfusion policy (transfusion given to prevent bleeding according to a prespecified platelet threshold) in people with congenital or acquired bone marrow failure disorders.

SEARCH METHODS:

We searched for randomised controlled trials (RCTs), non-RCTs, and controlled before-after studies (CBAs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2017, Issue 9), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), PubMed (e-publications only), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 12 October 2017.

SELECTION CRITERIA:

We included RCTs, non-RCTs, and CBAs that involved the transfusion of platelet concentrates (prepared either from individual units of whole blood or by apheresis any dose, frequency, or transfusion trigger) and given to treat or prevent bleeding among people with congenital or acquired bone marrow failure disorders.We excluded uncontrolled studies, cross-sectional studies, and case-control studies. We excluded cluster-RCTs, non-randomised cluster trials, and CBAs with fewer than two intervention sites and two control sites due to the risk of confounding. We included all people with long-term bone marrow failure disorders that require platelet transfusions, including neonates. We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant.

DATA COLLECTION AND ANALYSIS:

We used the standard methodological procedures outlined by Cochrane. Due to the absence of evidence we were unable to report on any of the review outcomes.

MAIN RESULTS:

We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes.We identified no completed non-RCTs or CBAs.We identified no ongoing RCTs, non-RCTs, or CBAs.

AUTHORS' CONCLUSIONS:

We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.

  • Desborough M
  • Hadjinicolaou AV
  • Chaimani A
  • Trivella M
  • Vyas P
  • et al.
Cochrane Database Syst Rev. 2016 Oct 31;10(10):CD012055 doi: 10.1002/14651858.CD012055.pub2.
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.