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Comparación de una política de transfusión de plaquetas profiláctica versus sólo terapéutica en pacientes con trastornos congénitos o adquiridos de insuficiencia de la médula ósea

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Antecedentes

Los trastornos de la médula ósea abarcan un grupo de enfermedades caracterizadas por una producción reducida de glóbulos rojos, glóbulos blancos y plaquetas, o defectos en su función, o ambos. El trastorno más común de la médula ósea es el síndrome mielodisplásico. La trombocitopenia, un recuento plaquetario bajo, ocurre con frecuencia en los pacientes con insuficiencia de la médula ósea. Las transfusiones de plaquetas se utilizan de manera sistemática en los pacientes con trombocitopenia secundaria a trastornos de insuficiencia de la médula ósea para tratar o prevenir la hemorragia. El síndrome mielodisplásico es actualmente el motivo más común para recibir una transfusión de plaquetas en algunos países occidentales.

Objetivos

Determinar si una política de transfusión de plaquetas sólo terapéutica (transfusión administrada cuando el paciente presenta hemorragia) tiene la misma efectividad y seguridad que una política de transfusión de plaquetas profiláctica (transfusión administrada para prevenir la hemorragia según un umbral plaquetario predeterminado) en pacientes con trastornos congénitos o adquiridos de insuficiencia de la médula ósea.

Métodos de búsqueda

Se realizaron búsquedas de ensayos controlados aleatorios (ECA), ensayos controlados no aleatorios (ECNA) y estudios controlados de antes y después (CAD) en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) (la Cochrane Library 2017, número 9), Ovid MEDLINE (desde 1946), Ovid Embase (desde 1974), PubMed (sólo e‐publications), la Transfusion Evidence Library (desde 1950), y en bases de datos de ensayos en curso hasta el 12 octubre 2017.

Criterios de selección

Se incluyeron los ECA, los ECNA y los estudios CAD sobre la transfusión de concentrados de plaquetas (preparados a partir de unidades individuales de sangre total o por aféresis a cualquier dosis, frecuencia, o factor desencadenante de la transfusión) administrada para tratar o prevenir la hemorragia en pacientes con trastornos congénitos o adquiridos de insuficiencia de la médula ósea.

Se excluyeron los estudios no controlados, los estudios transversales y los estudios de casos y controles. Se excluyeron los ECA con asignación al azar grupal, los ensayos con asignación al azar grupal no aleatorios, y los estudios CAD con menos de dos sitios de intervención y dos sitios control debido al riesgo de factores de confusión. Se incluyeron todos los pacientes con trastornos de insuficiencia de la médula ósea a largo plazo que requirieron transfusiones de plaquetas, incluidos neonatos. Se excluyeron los estudios de las alternativas a la transfusión de plaquetas, o estudios con pacientes que recibían quimioterapia intensiva o un trasplante de células madre.

Obtención y análisis de los datos

Se utilizaron los procedimientos metodológicos estándar descritos por Cochrane. Debido a la falta de evidencia no fue posible informar sobre ninguno de los resultados de la revisión.

Resultados principales

Se identificó un ECA que cumplió los criterios de inclusión de esta revisión. El estudio incluyó solamente a nueve pacientes adultos con SMD durante un período de estudio de tres años. El ensayo se interrumpió debido a la tasa deficiente de reclutamiento (reclutamiento planificado de 60 participantes en el transcurso de dos años). La evaluación del riesgo de sesgo no fue posible para todos los dominios. El ensayo fue simple ciego y de un único centro. Nunca se revelaron las características clínicas ni demográficas de los participantes. Los resultados del ensayo relevantes para esta revisión fueron las evaluaciones de las hemorragias, la mortalidad, la calidad de vida y la duración de la estancia hospitalaria, aunque no hubo datos disponibles para informar sobre ninguno de estos resultados.

No se identificaron ECNA ni estudios CAD completados.

No se identificaron ECA, ECNA o CAD en curso.

Conclusiones de los autores

No se encontró evidencia para determinar la seguridad ni la eficacia de la transfusión terapéutica de plaquetas en comparación con la transfusión profiláctica de plaquetas en pacientes con trastornos de insuficiencia de la médula ósea a largo plazo. Esta revisión destaca la urgencia de priorizar la investigación en esta área. Los pacientes con insuficiencia de la médula ósea dependen del apoyo de las transfusiones de plaquetas a largo plazo, aunque el único ensayo que evaluó una estrategia terapéutica se interrumpió. Se necesitan estudios de buena calidad que comparen una estrategia terapéutica de transfusión de plaquetas con una estrategia profiláctica de transfusión de plaquetas; dichos ensayos deben incluir resultados que son importantes para los pacientes, como la calidad de vida, la duración de la estancia hospitalaria y el riesgo de hemorragias.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Resumen en términos sencillos

En pacientes con trastornos de la médula ósea, una comparación de la administración de transfusiones de plaquetas sólo cuando se presenta hemorragia versus también administrarlas para prevenir la hemorragia

Objetivo de la revisión

En los pacientes con trastornos de la médula ósea la hemorragia puede ser un problema debido al recuento plaquetario bajo, o debido a que las plaquetas no funcionan de forma adecuada, o ambos. Las transfusiones de plaquetas se pueden administrar cuando ocurre hemorragia para detenerla o antes de que ocurra hemorragia para prevenirla.

En esta revisión se investigó si las transfusiones se deben administrar sólo cuando ocurre hemorragia o con antelación como una medida preventiva. La población de estudio incluyó pacientes de cualquier edad con trastornos de la médula ósea.

Antecedentes

La médula ósea es el sitio en el que se producen muchos tipos de elementos figurados de la sangre. Los eritrocitos se necesitan para transportar oxígeno a todas las partes del cuerpo; los leucocitos luchan contra la infección; y las plaquetas de la sangre ayudan a formar coágulos y prevenir las hemorragias. La insuficiencia de la médula ósea puede tener diferentes causas y puede suceder al nacer o en etapas posteriores de la vida, y puede dar lugar a que haya muy pocos de alguno de los tres tipos de glóbulos en el cuerpo.

Cuando un paciente tiene muy pocas plaquetas puede estar en riesgo de hemorragia grave o potencialmente mortal. Las transfusiones de plaquetas se han utilizado de manera habitual para prevenir o tratar la hemorragia en los pacientes con trastornos de la médula ósea. Sin embargo, hay riesgos involucrados con el uso regular de las transfusiones de plaquetas, como las reacciones a las transfusiones y las infecciones transmitidas por transfusiones.

Actualmente no está claro si la mejor política de transfusión es la administración de transfusiones de plaquetas sólo cuando ocurre hemorragia o la administración para prevenir la hemorragia.

Características de los estudios

Se efectuaron búsquedas en bases de datos científicas para obtener estudios clínicos (ensayos controlados aleatorios y estudios no aleatorios bien diseñados) de pacientes de cualquier edad con trastornos de la médula ósea y un recuento plaquetario bajo. La evidencia está actualizada hasta el 12 de octubre de 2017. Un estudio fue elegible para su inclusión en la revisión. Este estudio se detuvo después de reclutar a sólo nueve participantes debido a que había tomado tres años incluir a los nueve participantes (el estudio había planificado reclutar a 60 participantes en dos años). No se encontraron estudios en curso.

Resultados clave

El único estudio incluido en esta revisión no informó resultados.

Conclusión

No se encontró evidencia que ayude a decidir si la administración de transfusiones de plaquetas para el tratamiento de la hemorragia tiene la misma efectividad que la administración de transfusiones de plaquetas cuando el recuento plaquetario está por debajo de un nivel predeterminado. Hay una necesidad urgente de estudios de buena calidad para responder a las preguntas de esta revisión.

Calidad de la evidencia

No se evaluó la calidad de la evidencia debido a que no se obtuvieron datos del único estudio incluido.

Authors' conclusions

Implications for practice

Evidence related to the efficacy and safety of a therapeutic platelet transfusion strategy in comparison with a prophylactic platelet transfusion strategy is still absent. However, we identified one randomised controlled trial for inclusion with no data. We can make no recommendations to support or refute therapeutic platelet transfusion policies for this patient population. The absence of evidence should stimulate research priorities in this area. Platelet transfusions for people with bone marrow disorders should still be managed according to national transfusion guidelines.

Implications for research

In this review we identified a major gap in the literature, and further research to examine the therapeutic application of platelet transfusions in people with acquired or hereditary bone marrow disorders is justified.

There is an urgent need for good‐quality studies in which therapeutic and prophylactic platelet transfusion strategies are directly compared in this population. A multicentre randomised controlled trial might be the ideal study design in order to enrol a sufficient number of participants as the prevalence of people with bone marrow disorders is low, and also to allow for a longer follow‐up study period. Future studies should determine a standardised set of outcome measures. Patient‐reported outcomes such as quality of life and the length and frequency of hospital admissions should also be considered.

Background

Please see Published notes for a glossary of technical terms.

Description of the condition

The bone marrow is the site of the production of red cells, white cells, and platelets from stem cells (termed collectively as haematopoiesis). Bone marrow failure disorders encompass a wide range of diseases that cause quantitative (reduced numbers (cytopenia)) or qualitative (reduced function) defects of red cells, white cells, and platelets.

Clinical symptoms of people with bone marrow failure disorders are related to the underlying cytopenias (anaemia, neutropenia, and thrombocytopenia) that arise from this ineffective haematopoiesis. People can present with fatigue and shortness of breath due to anaemia (low red cell count), recurrent infections due to neutropenia (low neutrophil count, a type of white cell), and bleeding or bruising due to thrombocytopenia (low platelet count). Although anaemia is the most common cytopenia, at least one‐third of people with conditions like myelodysplastic syndromes (MDS) have moderate or severe thrombocytopenia (Hellstrom‐Lindberg 2003). Symptoms due to thrombocytopenia depend not only on the severity of the thrombocytopenia but also any associated comorbidities (coagulation abnormalities or lesions that are more likely to bleed, e.g. peptic ulcer).

Bone marrow failure syndromes can be broadly classified into congenital and acquired disorders.

The most common causes of acquired bone marrow failure are aplastic anaemia and MDS, with MDS being the most commonly diagnosed acquired bone marrow failure in adults (Sekeres 2010).

Myelodysplastic syndromes encompass a diverse group of clonal stem cell disorders that are characterised by dysplasia in one or more cell lines (blood cells have an abnormal shape or size), ineffective haematopoiesis, development of peripheral cytopenias, and an increased risk of developing acute myeloid leukaemia (AML) (Steensma 2006). Overall, the incidence of MDS is estimated at between 2.3 to 4.5 per 100,000 per year (Dinmohamed 2014; Garcia‐Manero 2012; Ma 2007; Ma 2012; Neukirchen 2011). However, the incidence increases markedly with age, with the highest incidence in those aged over 80 years (> 30 per 100,000 per year) (Dinmohamed 2014; Ma 2007; Ma 2012; Neukirchen 2011; Rollison 2008). It is also estimated that the incidence of secondary myelodysplasia is increasing because there are a larger number of long‐term cancer survivors who have been treated with chemotherapy such as anthracyclines and etoposide, which increase the risk of developing myelodysplasia (Le Deley 2007).

Acquired aplastic anaemia is a rare disorder that is characterised by 'empty bone marrow' replaced by fat cells. The incidence in Europe and North America is about two per million population per year (Issaragrisil 2006; Montané 2008), whereas the incidence in Asia is higher, with estimates ranging from 3.9 to 7.4 cases per million per year (Young 2008). In most cases the cause is unknown, but environmental factors (industrial chemicals, agricultural pesticides) (Issaragrisil 2006; Young 2008), drugs (Issaragrisil 2006; Young 2008), and hepatitis viruses have been reported to cause aplastic anaemia (Rauff 2011). Treatment is tailored to the individual needs of the patient, but involves a combination of supportive care for pancytopenia (reduced numbers of all the cellular elements of blood) (red cell and platelet transfusions, prophylactic antimicrobials), immunosuppressive therapy, and haemopoietic stem cell transplantation. Most patients are not deemed suitable for a haemopoietic stem cell transplant owing to advanced age, comorbidities, or lack of a compatible donor. As a result, supportive management remains the mainstay of treatment.

The inherited bone marrow failure syndromes include Fanconi anaemia, dyskeratosis congenita, Shwachman‐Diamond syndrome, Pearson syndrome, congenital amegakaryocytic thrombocytopenia, familial aplastic anaemia (X‐linked and autosomal forms), and Diamond Blackfan anaemia (Shimamura 2009). Fanconi anaemia is the most common inherited bone marrow failure disorder, with a reported incidence of approximately 1 in 360,000 live births and a carrier frequency of 1 in 300 (Giri 2004). Haematopoietic stem cell transplantation is the definitive treatment in many of these disorders, but supportive therapy in terms of red cell and platelet transfusions is often needed for symptomatic relief, either prior to transplant, or for those people not suitable to undergo transplant.

Description of the intervention

Despite increasing knowledge about the biology of the underlying diseases, supportive management remains the mainstay of treatment for most people with chronic bone marrow failure disorders.

Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in people with thrombocytopenia. Platelet transfusions have an obvious beneficial effect in the management of active bleeding in people with severe thrombocytopenia. However, questions still remain on how this limited resource should be used to prevent severe and life‐threatening bleeding. Prophylactic platelet transfusions have been shown to reduce World Health Organization (WHO) Grade 2 or above bleeding in people with haematological malignancies receiving chemotherapy or an allogeneic haematopoietic stem cell transplant (Crighton 2015; Stanworth 2013; Wandt 2012).

The evidence for the use of platelet transfusions to prevent bleeding in people with other conditions is less clear‐cut (Schiffer 2013; Stanworth 2013; Stanworth 2014; Wandt 2012). International guidelines considering people with long‐term thrombocytopenia recommend either a therapeutic‐only strategy (platelet transfusions are given to treat bleeding) (Kaufman 2015; Killick 2014; Liumbruno 2009), or a prophylactic platelet transfusion strategy (platelet transfusions are given when the platelet count falls below a prespecified platelet count threshold) (German Medical Association 2014; Killick 2016; NBA 2012; Zeller 2016). This threshold is most commonly a platelet count of 5 x 109/L, German Medical Association 2014, or 10 x 109/L (Bosly 2007; Killick 2016). This threshold can also vary if a person has additional risk factors for bleeding such as sepsis (Killick 2016).

People can become refractory to platelet transfusions (Stanworth 2015). In an analysis of the TRAP 1997 study data, there was a progressive decrease in the post‐transfusion platelet count increments and time interval between transfusions as the number of preceding transfusions increased (Slichter 2005). This effect was seen irrespective of whether the patient developed detectable human leukocyte antigen (HLA) antibodies (Slichter 2005). Avoidance of unnecessary prophylactic platelet transfusions is therefore very important in people who are likely to require repeated platelet transfusions over a prolonged period of time because they can become refractory to treatment after repeated transfusions (Hod 2008; Slichter 2005; Stanworth 2015).

Platelet transfusions are associated with adverse events. Mild to moderate reactions to platelet transfusions include rigor, fever, and urticaria (Tinegate 2012). These reactions are not life‐threatening but can be extremely distressing for the recipient. Rarer, but more serious sequelae include anaphylaxis, haemolytic transfusion reactions, transfusion‐transmitted infections, transfusion‐associated circulatory overload (TACO), and transfusion‐related acute lung injury (TRALI) (Blumberg 2010; Kaufman 2015; Raval 2015).

This review does not focus on the absolute need for platelet transfusions in people with chronic bone marrow failure disorders, but instead focuses on whether a prophylactic platelet transfusion policy is required.

How the intervention might work

The morning platelet count is usually used to indicate when a person requires a prophylactic platelet transfusion. In the 1970s it became standard practice to transfuse platelets at platelet counts below 20 x 109/L in an attempt to prevent bleeding (Beutler 1993). This practice was based partly on the findings of non‐randomised studies that showed that gross haemorrhage (haematuria (blood in the urine), haematemesis (vomiting of blood), and melaena (dark‐coloured stools)) was present at platelet counts below 5 x 109/L more frequently than when the platelet count was between 5 x 109/L and 100 x 109/L (Gaydos 1962; Slichter 1978). However, these studies did not show any threshold effect at a platelet count of 20 x 109/L, nor was any threshold effect seen (Gaydos 1962; Slichter 1978). A threshold of 10 x 109/L is now considered the standard platelet count threshold in people with haematological malignancies who have reversible bone marrow failure (Estcourt 2015; Kaufman 2015; NICE 2015), after multiple studies confirmed the threshold of 10 x 109/L as "safe enough" for prophylactic platelet transfusion (Gmur 1991; Rebulla 1997; Schiffer 2001; Wandt 1998).

There is much less evidence for the benefit of prophylactic platelet transfusions for people with chronic bone marrow failure. A small retrospective study considered platelet transfusion in outpatients with stable chronic severe aplastic anaemia (Sagmeister 1999). Prophylactic platelets were given if the count was 5 x 109/L or less. In total, 55,239 patient days were reviewed with 18,706 days when the platelet count was 10 x 109/L or less. Three major bleeding episodes occurred while participants were on the treatment protocol. The authors concluded that this restrictive policy, with a median transfusion interval of seven days, was feasible, safe, and economical.

Only 7.1 x 109/L platelets per day are required to maintain vascular integrity, and hence spontaneous bleeding in clinically stable patients is uncommon unless the platelet count is less than 5 x 109/L (Slichter 2004). A further large study also showed no relationship between the morning platelet count and the risk of clinically significant bleeding (WHO Grade 2 bleeding) the following day except when the platelet count was very low (≤ 5 x 109/L) (Slichter 2010).

A large retrospective review of almost 3000 adults with thrombocytopenia showed no relationship between the morning platelet count or the lowest platelet count of the day and the risk of severe or life‐threatening bleeding (WHO Grade 3 to 4 bleeding) (Friedmann 2002). This raised the question as to whether a threshold‐defined prophylactic platelet transfusion approach is appropriate.

Most recent clinical trials of platelet transfusions have used bleeding as an outcome. An assessment of bleeding is a more clinically relevant measure of the effect of platelet transfusions than surrogate markers such as the platelet count increment. The definition of what constitutes clinically significant bleeding has varied between studies. Although the majority of more recent platelet transfusion studies now classify it as WHO Grade 2 or above, there has been greater heterogeneity in the past (Estcourt 2013; WHO 1979). One limitation of all the scoring systems that have been based on the WHO system is that the categories are relatively broad and subjective. This means that a small change in a patient's bleeding risk may not be detected. Another limitation is that the modified WHO categories are partially defined by whether a bleeding patient requires a blood transfusion. The threshold for intervention may vary between clinicians and institutions, and so the same level of bleeding could be graded differently in different institutions. The difficulties with assessing and grading bleeding may limit the ability to compare results between studies, which should be kept in mind when interpreting the evidence for the effectiveness of prophylactic platelet transfusions in this review.

Why it is important to do this review

Blood products including platelet components are a valuable and finite resource, and their availability depends on the goodwill of voluntary donations. Also, platelet components have a limited shelf life of five to seven days, which makes management of platelet inventories difficult and resource intensive (Fuller 2011; Riley 2012).

As discussed above, the recommended platelet count threshold varies significantly from country to country (German Medical Association 2014; Kaufman 2015; Killick 2014; Killick 2016; Liumbruno 2009). This indicates significant uncertainty among clinicians regarding the correct management of people with chronic bone marrow disorders.

This review aimed to provide evidence of whether a therapeutic‐only platelet transfusion strategy is as effective and safe as a prophylactic platelet transfusion strategy for the prevention of clinically significant or life‐threatening bleeding in people with primary bone marrow failure disorders who are thrombocytopenic.

Overall, avoiding the need for unnecessary prophylactic platelet transfusions in people with bone marrow failure disorders will have significant logistical and financial implications for national health services as well as decreasing patients’ exposure to the risks of transfusion. It will also have implications on the quality of life of patients, as it is challenging for patients and caregivers to visit hospital on a regular basis to receive platelet transfusions. The outcomes of this review are perhaps even more important in the development of platelet transfusion strategies in the developing world, where access to blood components is much more limited (Verma 2009).

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

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs), non‐RCTs, and controlled before‐after studies (CBAs) irrespective of language or publication status. 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.

Types of participants

We included all people with long‐term bone marrow failure disorders that require platelet transfusions who were not being actively treated with a haematopoietic stem cell transplant or intensive chemotherapy. These disorders include myelodysplastic syndromes (MDS), acquired aplastic anaemia, and congenital bone marrow failure disorders. Due to the inherited nature of a number of bone marrow failure disorders, we included people of all ages, including neonates.

We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant, as these were the subjects of separate reviews (Crighton 2015; Desborough 2016).

Types of interventions

Intervention

Participants received transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis to treat bleeding (therapeutic platelet transfusions).

Control

Participants received prophylactic platelet transfusions and therapeutic platelet transfusions. Prophylactic platelet transfusions are typically given when the platelet count falls below a given trigger level.

There was no restriction on the dose, frequency, type of platelet component, or transfusion trigger of the platelet transfusions, but we also took this information into account in the analysis, where available.

We included the following comparisons.

  • Therapeutic‐only platelet transfusions (on‐demand triggered by bleeding) versus prophylactic platelet transfusions.

  • Placebo and therapeutic‐only platelet transfusions (on‐demand triggered by bleeding) versus prophylactic platelet transfusions.

Types of outcome measures

The primary and secondary outcomes of this review were outcomes of interest and were not used as inclusion criteria for the assessment of studies.

We planned to categorise all outcomes according to short‐, medium‐, and long‐term outcomes. However, we included only one RCT in the review that did not report any outcomes (NCT01615146).

Primary outcomes

  • The number of participants with at least one bleeding episode (WHO Grade 1 to 4, or WHO Grade 2 to 4)

  • The total number of days on which bleeding occurred or the total number of bleeding episodes per participant (WHO Grade 1 to 4, or WHO Grade 2 to 4)

  • The number of participants with at least one episode of severe or life‐threatening bleeding

  • Time to first bleeding episode from the start of the study (WHO Grade 1 to 4, or WHO Grade 2 to 4)

Secondary outcomes

  • Mortality (all‐cause, secondary to bleeding, and secondary to infection)

  • Number of platelet transfusions per participant and number of platelet components per participant

  • Number of red cell transfusions per participant and number of red cell components per participant

  • Platelet transfusion interval

  • Proportion of participants requiring additional interventions to stop bleeding (surgical, medical (e.g. tranexamic acid), other blood products (e.g. fresh frozen plasma, cryoprecipitate, fibrinogen)) within 30 days from the start of the study

  • Number of hospital admissions and length of hospital stay

  • Quality of life assessment using validated tools

  • Transfusion‐related adverse events (transfusion reactions, transfusion‐associated infections, development of platelet antibodies or platelet refractoriness, thromboembolic events)

Search methods for identification of studies

The Systematic Review Initiative’s Information Specialist (CD) formulated the search strategies in collaboration with the Cochrane Haematological Malignancies Group.

Electronic searches

We searched the following databases.

  • Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2017, Issue 9) (Appendix 1).

  • MEDLINE (OvidSP, 1946 to 12 October 2017) (Appendix 2).

  • Embase (OvidSP, 1974 to 12 October 2017) (Appendix 3).

  • CINAHL (Cumulative Index to Nursing and Allied Health Literature) (EBSCOhost, 1937 to 12 October 2017) (Appendix 4).

  • PubMed (e‐publications only) (www.ncbi.nlm.nih.gov/pubmed) (Appendix 5).

  • Transfusion Evidence Library (www.transfusionevidencelibrary.com) (1950 to 12 October 2017) (Appendix 6).

  • LILACS (Latin American and Caribbean Health Sciences Literature database) (BIREME, 1980 to 12 October 2017) (Appendix 7).

  • IndMED (1986 to 12 October 2017) (Appendix 8).

  • PakMediNet (1995 to 12 October 2017) (Appendix 9).

  • KoreaMed (1958 to 12 October 2017) (Appendix 9).

  • Web of Science Conference Proceedings Citation Index‐Science (CPCI‐S) (Thomson Reuters, 1990 to 12 October 2017) (Appendix 10).

We searched for ongoing trials to 12 October 2017 in the following clinical trial registers.

We applied the sensitivity‐maximising Cochrane RCT search filter to the MEDLINE search and the SIGN RCT studies filter (www.sign.ac.uk/methodology/filters.html) to Embase and CINAHL (Lefebvre 2011). We did not apply any restrictions on date, language, or publication status.

Once we identified studies for inclusion we searched MEDLINE (Ovid) for errata or retraction statements for the reports of these studies.

Searching other resources

We conducted handsearching of the reference lists of included studies and any relevant systematic reviews to identify further relevant studies. We contacted lead authors of included studies to identify any unpublished material, missing data, or information regarding ongoing studies where possible.

Data collection and analysis

We planned to summarise data in accordance with standard Cochrane methodologies. However, this was not possible due to lack of data.

Selection of studies

We selected studies according to the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). The Systematic Review Initiative’s Information Specialist (CD) initially screened all search hits for relevance against the eligibility criteria, discarding all those that were clearly irrelevant. Two review authors (AA, AH) thereafter independently screened all the remaining references for relevance against the full eligibility criteria.

Full‐text papers were retrieved for all references for which a decision on eligibility could not be made from title and abstract alone. We requested additional information from study authors as necessary to assess the eligibility for inclusion of individual studies. Any disagreements regarding study selection were resolved by discussion, or by consulting a third review author (LJE) when necessary.

We reported the results of study selection using a PRISMA flow diagram (Moher 2009). We also recorded the reasons for excluding studies based on full‐text assessment, which we included in the 'Characteristics of excluded studies' table.

We collated multiple reports of one study so that the study, and not the report, was the unit of analysis.

Data extraction and management

As recommended in the Cochrane Handbook for Systematic Reviews of Interventions, two review authors (AA, AH) independently extracted data onto standardised forms and performed a cross‐check (Higgins 2011a). We planned to pilot two different data extraction forms for the included RCTs and non‐randomised studies. However, this was not possible because we found one eligible RCT that was halted after recruiting nine participants. The review authors reached consensus on the required changes with the assistance of a third review author (LJE). The review authors were not blinded to the names of authors, institutions, or journals, or to the study outcomes. We reported the characteristics of the one included study in the 'Characteristics of included studies' table.

We planned to extract the following information for each study.

  • Source: study ID, report ID, review author ID, date of extraction, ID of author checking extracted data, citation of paper, contact authors' details.

  • General study information: publication type, study objectives, funding source, conflict of interest declared, other relevant study publication reviewed.

  • Study details and methods: location, country, setting, number of centres, total study duration, recruitment dates, length of follow‐up, power calculation, primary analysis (and definition), stopping rules, method of sequence generation, allocation concealment, blinding (of clinicians, participants, and outcome assessors), any other concerns regarding bias, inclusion and exclusion criteria.

  • Characteristics of interventions: number of study arms, description of experimental arm, description of control arm, and other relevant information.

  • Characteristics of participants: age; gender; primary diagnosis; subgroup classification of primary disease type where appropriate, severity of primary disease, where appropriate, prognostic classification of primary disease where appropriate; additional therapy received; risk of alloimmunisation; baseline haematology laboratory parameters; confounders reported.

  • Participant flow: total number screened for inclusion, total number recruited, total number excluded, total number allocated to each study arm, total number analysed (for review outcomes), number of allocated participants who received planned treatment, number of dropouts with reasons (percentage in each arm), protocol violations, missing data.

  • Outcomes: number of participants with at least one bleeding episode; total number of days on which bleeding occurred or the total number of bleeding episodes per participant; number of participants with at least one episode of severe or life‐threatening bleeding; time to first bleeding episode; mortality (all‐cause, secondary to bleeding, and secondary to infection); number of platelet transfusions per participant and number of platelet components per participant; number of red cell transfusions per participant and number of red cell components per participant; platelet transfusion interval; proportion of participants requiring additional interventions to stop bleeding (surgical, medical (e.g. tranexamic acid), other blood products (e.g. fresh frozen plasma, cryoprecipitate, fibrinogen)); quality of life assessment.

  • For interventional cohort and pre‐post single‐arm or multiple‐arm studies, we collected data on: confounding factors, the comparability of groups on confounding factors; methods used to control for confounding and on multiple effect estimates (both unadjusted and adjusted estimates) as recommended in Chapter 13 of the Cochrane Handbook for Systematic Reviews of Interventions (Reeves 2011).

Assessment of risk of bias in included studies

Randomised controlled trials

Only one RCT was eligible for inclusion in this review. The information related to methodology of this trial was limited to the trial registration document.

In future updates of this review we will assess the risk of bias for all included RCTs using the Cochrane 'Risk of bias' tool according to Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). Two review authors will independently assess each element of potential bias listed below as 'high', 'low', or 'unclear' risk of bias. We will also briefly describe the support for our judgement of risk of bias in the 'Characteristics of included studies’ table. In addition, we will ensure that consensus on the degree of risk of bias is achieved through comparison of the review authors’ statements or by consulting with a third review author when necessary. We used Cochrane's tool for assessing risk of bias, which includes the following domains.

Selection bias

We will describe for each included study if and how the allocation sequence was generated and if allocation was adequately concealed prior to assignment. We will also describe the method used to conceal the allocation sequence in detail and determine if intervention allocation was foreseen in advance of, or during recruitment, or changed after assignment.

Performance bias

For each included study, we will describe, where possible, if the study participants and personnel were adequately blinded from knowledge of which intervention a participant received. We will judge studies as low risk of bias if they were blinded, or if we judge that lack of blinding could not have affected the results.

Detection bias

Was blinding of the outcome assessors effective in preventing systematic differences in the way in which the outcomes were determined?

Attrition bias

We will describe for each included study the attrition bias due to the amount, nature, or handling of incomplete outcome data. We will also attempt to evaluate whether intention‐to‐treat analysis was performed or could be performed from published information.

Reporting bias

We will describe for each included study the possibility of selective outcome reporting bias.

Other issues

Was the study apparently free of other problems that could put it at risk of bias?

We will also summarise the risk of bias for each key outcome for each included study. We will judge studies with at least one domain of high risk as at high risk of bias overall.

Non‐randomised studies

No non‐randomised studies were eligible for inclusion in this review.

In the future, when we identify non‐randomised studies meeting our inclusion criteria, we will use the ROBINS‐I tool (formerly known as ACROBAT‐NRSI) to rate the quality of included non‐randomised studies (Sterne 2014). This tool is based on the Cochrane 'Risk of bias' tool for rating the quality of RCTs (Higgins 2011c). The tool covers seven domains, and the quality of evidence is rated as low, moderate, serious, critical, or no information (see Appendix 13 for a copy of the tool), and uses signalling questions for the assessment of the following.

  • Bias due to confounding

  • Bias in the selection of participants

  • Bias in measurement of interventions

  • Bias due to departure from intended interventions

  • Bias due to missing data

  • Bias in measurement of outcomes

  • Bias in the selection of the reported result

In the future, when we identify studies to include in the review, any disagreements on the assessment of the quality of an included study will be resolved by discussion or by consulting a third review author (LJE) when necessary.

We prespecified the main potential confounding factors.

  • Primary diagnosis (aplastic anaemia, MDS, congenital bone marrow disorders)

  • Age: variability in the age of included participants, e.g. infant (nought to one year) versus paediatric (one to 16 years) versus adult (> 16 years) versus older adult (> 60 years)

  • Gender: male‐to‐female ratio

  • Previous severe bleeding (e.g. WHO Grade 3 or 4 or equivalent)

  • Use of anticoagulation during study

  • Performance status (e.g. Eastern Cooperative Oncology Group (ECOG), Karnofsky Performance Score (KPS))

  • Treatment (e.g. azacytidine) versus no treatment (supportive care only)

  • Presence of sepsis or infection

  • Presence of bleeding disorder

We prespecified the possible co‐interventions that could differ between intervention groups and could have an impact on outcomes.

  • Concomittent use of antiplatelet therapy

  • Factor replacements such as fresh frozen plasma, cryoprecipitate, fibrinogen

  • Use of thrombopoietin mimetics (romiplostim, eltrombopag)

  • Whole blood transfusions

  • Use of steroids or danazol

  • Over‐the‐counter or herbal medicines

Measures of treatment effect

Randomised controlled trials

No data available were available for assessment of outcomes and result formulation. In future updates, if RCT data are available, we will measure treatment effect as follows.

For continuous outcomes, we will record the mean, standard deviation (SD), and total number of participants in both the treatment and control groups. For dichotomous outcomes, we will record the number of events and the total number of participants in both the treatment and control groups.

For continuous outcomes using the same scale, we will perform analyses using the mean difference (MD) with 95% confidence intervals (CIs). We will use standardised mean difference (SMD) for continuous outcomes reported using different scales.

If available, we will extract and report hazard ratios (HRs) for mortality data. If HRs are not available, we will make every effort to estimate as accurately as possible the HR using the available data and a purpose‐built method based on the Parmar and Tierney approach (Parmar 1998; Tierney 2007). It sufficient studies provide HRs, we will use HRs in favour of risk ratios (RRs) in a meta‐analysis, but for completeness we will also perform a separate meta‐analysis of data from studies providing only RRs for the same outcome.

For dichotomous outcomes, we will report the pooled RR with a 95% CI (Deeks 2011). Where the number of observed events is small (< 5% of sample per group) and where trials have balanced treatment groups, we will report Peto’s odds ratio (OR) with 95% CIs (Deeks 2011).

For cluster‐RCTs, we will extract and report direct estimates of the effect measure (e.g. RR with a 95% CI) from an analysis that accounts for the clustered design. We will obtain statistical advice to ensure the analysis is appropriate. If appropriate analyses are not available, we will make every effort to approximate the analysis following the recommendations in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011d).

If data allow, we will undertake quantitative assessments using Review Manager 5 (RevMan 2014).

Non‐randomised studies

No non‐randomised studies were eligible for inclusion in this review. In future updates, if data from non‐randomised studies are available, we will measure treatment effect as follows.

For dichotomous outcomes, if available we will extract and report the RR with a 95% CI from statistical analyses adjusting for baseline differences (such as Poisson regressions or logistic regressions) or the ratio of risk ratios (i.e. the risk ratio postintervention/risk ratio pre‐intervention).

For continuous variables, if available we will extract and report the absolute change from a statistical analysis adjusting for baseline differences (such as regression models, mixed models, or hierarchical models) or the relative change adjusted
for baseline differences in the outcome measures (i.e. the absolute postintervention difference between the intervention and control groups, as well as the absolute pre‐intervention difference between the intervention and control groups/the postintervention level in the control group) (EPOC 2015).

If data allow, we will undertake quantitative assessments using Review Manager 5 (RevMan 2014).

All studies

We did not report the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) with CIs as no information was available.

We could not report the available data in any of the formats described above, nor could we perform a narrative report.

Unit of analysis issues

We did not encounter unit of analysis issues due to insufficient studies and reported outcomes. In future updates, if we identify any cluster‐randomised trials, cross‐over studies, or multiple observations for the same outcome, we will treat these in accordance with the recommendations in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c).

Dealing with missing data

We dealt with missing data according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We had access to further information for one excluded study, Grossman 1980, from previous reviews. We contacted the author of the only included study, NCT01615146, to ask for additional data, but no data were provided.

Assessment of heterogeneity

We did not assess statistical heterogeneity because no analyses were performed. However, in future updates when more studies are included, we will assess statistical heterogeneity using the I2 and Chi2 statistics. We will assess statistical heterogeneity of treatment effects between studies using a Chi2 test with a significance level at P < 0.1. We will use the I2 statistic to quantify the degree of potential heterogeneity and classify it as low if I2 is ≤ 50%, moderate if I2 is 50% to 80%, or considerable if I2 is > 80%. We will use the random‐effects model for low‐to‐moderate heterogeneity. If statistical heterogeneity is considerable, we will not report the overall summary statistic. We will assess potential causes of heterogeneity by sensitivity and subgroup analyses (Deeks 2011).

Assessment of reporting biases

We did not perform a formal assessment of publication bias because no analyses were performed. In future updates of this review when at least 10 studies are identified for inclusion in a meta analysis, we will explore potential publication bias (small‐trial bias) by generating a funnel plot and using a linear regression test. We will consider a P value of less than 0.1 as significant for this test (Sterne 2011).

Data synthesis

We planned to perform analyses according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). However, no available outcome data were reported in the single included study (NCT01615146), and we did not receive any data from the trial authors after we requested unpublished data.

Randomised controlled trials

In future updates of this review where meta‐analysis is feasible, we will use the random‐effects model for pooling data. We will use the Mantel‐Haenszel method for dichotomous outcomes and the inverse‐variance method for continuous outcomes, or outcomes that include data from cluster‐RCTs, or outcomes where HRs are available. If we assess heterogeneity as above 80%, and we identify a cause for the heterogeneity, we will explore this with subgroup analyses. If we cannot find a cause for the heterogeneity, then we will not perform a meta‐analysis, but comment on the results as a narrative with the results from all studies presented in tables.

Non‐randomised studies

In future updates of this review, if meta‐analysis is feasible for non‐RCTs or CBA studies, we will analyse non‐RCTs and CBA studies separately. We will only analyse outcomes with adjusted effect estimates if these are adjusted for the same factors using the inverse‐variance method as recommended in Chapter 13 of the Cochrane Handbook for Systematic Reviews of Interventions (Reeves 2011).

All studies

In future updates of this review, we will use the random‐effects model for all analyses, as we anticipate that true effects will be related, but not the same for included studies. If we cannot perform a meta‐analysis, we will comment on the results narratively with the results from all studies presented in tables.

Summary of findings

In future updates of this review, we will use the GRADE tool (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of evidence for each outcome. We will present a 'Summary of findings' table as suggested in Chapters 11 and 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Schunemann 2011a; Schunemann 2011b). The outcomes included are listed below in order of most relevant endpoints for patients.

  • Number of participants with at least one bleeding episode.

  • Total number of bleeding episodes per participant.

  • Number of participants with at least one severe or life‐threatening bleeding episode.

  • All‐cause mortality.

  • Number of units of platelet transfusion per participant.

  • Quality of life.

  • Transfusion‐related adverse events (transfusion reactions, transfusion‐associated infections, development of platelet antibodies or platelet refractoriness, thromboembolic events).

Subgroup analysis and investigation of heterogeneity

We did not perform subgroup analysis due to lack of data. If adequate data are available in future updates, we will perform subgroup analyses for each of the following outcomes to assess the effect on heterogeneity.

  • Type of bone marrow failure disorder (MDS, aplastic anaemia, congenital bone marrow failure disorder).

  • Age of participants grouped as neonatal (nought to one year), paediatric (one to 16 years), adult (17 years to 60 years), elderly adult (greater than 60 years).

  • Underlying bleeding tendencies (gastric ulcer, angiodysplasia, acquired coagulopathy, etc.).

  • Concomitant treatment for the underlying disorder (azacytidine).

Sensitivity analysis

We did not perform sensitivity analysis. In future updates of this review we will assess the robustness of our findings by performing the following sensitivity analyses where appropriate.

  • Including only those studies with low risk of bias (e.g. RCTs with methods assessed as low risk for random sequence generation and concealment of treatment allocation, and for non‐RCTs if the study is judged to be at low risk of bias for all domains).

  • Including only those studies with less than a 20% dropout rate.

Results

Description of studies

Refer to Characteristics of included studies and Characteristics of excluded studies for more details.

One RCT was eligible for inclusion in the review (NCT01615146). No non‐RCTs were eligible for inclusion in the review.

Results of the search

The search conducted on 12 October 2017 retrieved 9058 potentially relevant records (see PRISMA flow diagram in Figure 1). There were 6975 references after removal of duplicates. We excluded 6957 records based on the abstract. We assessed the eligibility of the remaining 18 references based on full‐text papers checking against the review eligibility criteria. Only one trial met the inclusion criteria for this review (NCT01615146). There were no eligible non‐RCTs.


Study flow diagram.

Study flow diagram.

Included studies

See Characteristics of included studies for full details of the included trial (NCT01615146).

Study design and duration

NCT01615146 was a parallel, single‐centre RCT conducted in Canada. The trial was designed as a single‐blind trial in which the medical and research staff and investigators were blinded to the intervention allocation status. The study started in June 2012 and closed in June 2015. Participants were followed up for six months.

Study participants

Only nine participants were enrolled in the trial over a three‐year trial period; poor participant recruitment rate was the main reason for discontinuation of the trial. The demographic and clinical characteristics of this small number of participants have not been disclosed. However, the following clinical and laboratory data were collected at baseline: participants' demographic data, diagnosis including date and disease stage, history of prior chemotherapy treatment, ECOG performance status, any other comorbidity, previous platelet and red cell transfusions history, red cell transfusion history, prior bleeding events, quality of life questionnaire, routine blood work, and weekly full blood count.

Once the participant's platelet count was greater than 20 x 109/L for at least six weeks, the weekly platelet count test was replaced by clinical monitoring.

Study interventions
Theraputic platelet transfusion group

Participants in this group did not receive routine prophylactic platelet transfusions. Platelet transfusion was only given to treat clinically documented bleeding, defined as WHO bleeding of Grade 2 or greater.

Prophylactic platelet transfusion group

Platelet transfusions were given to participants in this group when the platelet count was less than 10 x 109/L. A single dose of random donor platelets (four unit pool or random donor platelets or one apheresis unit) was used.

Off‐protocol transfusion: Any additional platelet transfusions given to participants in either group were recorded.

Study outcomes

The trial's primary outcomes were feasibility outcomes of enrolment, compliance with transfusion protocols, and completion of bleeding evaluations.

The trial's secondary outcomes were bleeding assessments, blood transfusions, frequency of hospital visits, quality of life, and mortality.

Study funding

The trial was publicly sponsored by the following collaborators: the Ottawa Hospital Research Institute, the Canadian Blood Services, and the Canadian Institutes of Health Research.

Excluded studies

We excluded nine studies within 17 full‐text articles for the following the reasons:

Risk of bias in included studies

We assessed the risk of bias of the one included trial based on the information from the trial registry record (NCT01615146). See Figure 2 for a visual representation of the risk of bias in the included study. See the 'Risk of bias’ table within the Characteristics of included studies for further information regarding the risk of bias in this trial.


Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We rated NCT01615146 as at low risk for selection bias.

Random sequence generation

We rated NCT01615146 as at low risk of bias for randomisation sequence generation, as the study used a web‐based randomisation method.

Allocation concealment

We rated NCT01615146 as at low risk of bias for allocation concealment, as the study used a web‐based randomisation method.

Blinding

Blinding of participants and personnel

We assessed NCT01615146 as at high risk of performance bias because participants were aware of the status of the intervention.

Blinding of clinical assessors

We assessed NCT01615146 as at low risk of detection bias because outcome assessors were blinded to the participants' intervention status.

Incomplete outcome data

We assessed NCT01615146 as at unclear risk of attrition bias because the trial was only available as a web page via the clinical trial registry.

Selective reporting

We assessed NCT01615146 as at unclear risk of reporting bias because the trial was only available as a web page via the clinical trial registry.

Other potential sources of bias

We assessed NCT01615146 as at unclear risk of other bias because the trial was only available as a web page via the clinical trial registry.

Effects of interventions

We were unable to report on any of our review's primary or secondary outcomes due to the absence of relevant data.

The one included trial, NCT01615146, was terminated after enrolling a small number of participants. No data were reported on any of the trial outcomes.

Discussion

Summary of main results

We included only one trial in this review (NCT01615146), which closed after recruiting only nine participants. No data were reported and no additional data were provided by the authors.

Overall completeness and applicability of evidence

This review provides an up‐to‐date picture of the lack of evidence regarding the use of therapeutic platelet transfusion strategies compared to prophylactic platelet transfusion strategies for people with bone marrow disorders.

We tried to maximise the number of studies eligible for inclusion in the review by including good‐quality non‐randomised studies (non‐RCTs and CBAs). Despite this, we identified only one trial for inclusion (NCT01615146). This trial was discontinued due to a slow recruitment rate, with only nine participants enrolled over three years. We were unable to report on any of our primary and secondary outcomes because data relevant to this small group of participants were never disclosed. This study was based in a single centre, which might to some extent explain the slow rate of enrolment. We did not identify any ongoing trials eligible for inclusion in the future.

We excluded from this review some studies that had methodologically low‐quality study designs. We consider it important for evidence related to platelet transfusion in this population to be reliable, and drawing conclusions from low‐quality studies such as cross‐sectional or retrospective design studies could be misleading and is not justified.

Quality of the evidence

We found one eligible RCT (NCT01615146), for which the only available information was on the trial registry record. We could not assess the quality of any of the outcomes of our review.

The trial used a web‐based randomisation system (low risk of selection bias). Participants were unblinded to the intervention (high risk of performance bias), but outcome assessors were blinded to the intervention (low risk of detection bias). We could not assess attrition bias, reporting bias, or other bias due to the lack of data.

Potential biases in the review process

To our knowledge, this review is free from bias. We applied a broad and comprehensive search strategy across multiple databases and clinical trial registries to ensure that all relevant studies were retrieved. We did not apply any restriction criteria to our searches. We carefully assessed the relevance of each paper identified and performed all screening and data extractions in duplicate. We prespecified all outcomes and subgroups prior to analysis.

We included only one RCT. We tried to contact the study authors to obtain further information about the trial but have been unsuccessful.

None of the review authors were involved in the included or excluded studies.

Agreements and disagreements with other studies or reviews

Thrombocytopenia (platelet counts < 100 x 109/L) is commonly seen in people with MDS, with a prevalence of 40% to 65% (Kantarjian 2007). Platelet transfusions have been given to people with MDS for decades, and it is currently one of the most common underlying reasons for receiving a prophylactic platelet transfusion (NCABT 2016). Despite this, we identified a major research gap with regard to current platelet transfusion practice for people with bone marrow failure. Guidelines recommend not using a prophylactic platelet transfusion policy in people with chronic bone marrow failure if they are well and not undergoing treatment to cure their bone marrow disorder (Estcourt 2017; Schiffer 2017). Platelet transfusions are known to cause harm in other patient groups (Lee 2016).

One of the studies excluded in this review assessed the use of a restrictive platelet transfusion policy in people with severe aplastic anaemia (Sagmeister 1999). This was a retrospective analysis of 25 adults that included 18,706 patient days with platelet counts less than 10 x 109/L, and 55,239 patient days in total. Only three episodes of major bleeding occurred during the study. The number of platelet transfusions given was 1135; 88% were at platelet counts less than 10 x 109/L and 57% at platelet counts less than 5 x 109/L. Sagmeister and colleagues concluded that a more restrictive policy with low thresholds for platelet transfusions combined with a gradual lengthening of the transfusion intervals was safe and cost‐effective. This study is part of the underlying evidence for the current advice from platelet transfusion guidelines.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.