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1.
N Engl J Med ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33631065

RESUMO

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

2.
Blood ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33202419

RESUMO

Convalescent plasma (CP) from blood donors with anti-SARS-CoV-2 antibodies may benefit patients with COVID-19 by providing immediate passive immunity via transfusion, or when used to manufacture hyperimmune immunoglobulin preparations. Optimal product characteristics (including neutralizing antibody titers), volume of transfusion, and timing of administration remain to be determined. Preliminary safety data for COVID-19 CP are encouraging, but establishing the clinical efficacy of CP requires recruitment of patients to high-quality randomized trials and an ongoing international collaborative effort.

3.
Cochrane Database Syst Rev ; 10: CD013600, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33044747

RESUMO

BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required.  OBJECTIVES: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 19 August 2020. SELECTION CRITERIA: We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' 2.0 tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, mortality (time to event), improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events (AEs), and serious adverse events (SAEs). MAIN RESULTS: This is the second living update of our review. We included 19 studies (2 RCTs, 8 controlled NRSIs, 9 non-controlled NRSIs) with 38,160 participants, of whom 36,081 received convalescent plasma. Two completed RCTs are awaiting assessment (published after 19 August 2020). We identified a further 138 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 73 are randomised (3 reported in a study registry as already being completed, but without results). We did not identify any completed studies evaluating hyperimmune immunoglobulin. We did not include data from controlled NRSIs in data synthesis because of critical risk of bias. The overall certainty of evidence was low to very low, due to study limitations and results including both potential benefits and harms.  Effectiveness of convalescent plasma for people with COVID-19  We included results from two RCTs (both stopped early) with 189 participants, of whom 95 received convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. We are uncertain whether convalescent plasma decreases all-cause mortality at hospital discharge (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.22 to 1.34; 1 RCT, 86 participants; low-certainty evidence).  We are uncertain whether convalescent plasma decreases mortality (time to event) (hazard ratio (HR) 0.64, 95% CI 0.33 to 1.25; 2 RCTs, 189 participants; low-certainty evidence). Convalescent plasma may result in little to no difference in improvement of clinical symptoms (i.e. need for respiratory support) at seven days (RR 0.98, 95% CI 0.30 to 3.19; 1 RCT, 103 participants; low-certainty evidence). Convalescent plasma may increase improvement of clinical symptoms at up to 15 days (RR 1.34, 95% CI 0.85 to 2.11; 2 RCTs, 189 participants; low-certainty evidence), and at up to 30 days (RR 1.13, 95% CI 0.88 to 1.43; 2 studies, 188 participants; low-certainty evidence).  No studies reported on quality of life.  Safety of convalescent plasma for people with COVID-19 We included results from two RCTs, eight controlled NRSIs and nine non-controlled NRSIs assessing safety of convalescent plasma. Reporting of safety data and duration of follow-up was variable. The controlled studies reported on AEs and SAEs only in participants receiving convalescent plasma. Some, but not all, studies included death as a SAE.  The studies did not report the grade of AEs. Fourteen studies (566 participants) reported on AEs of possible grade 3 or 4 severity. The majority of these AEs were allergic or respiratory events. We are very uncertain whether convalescent plasma therapy affects the risk of moderate to severe AEs (very low-certainty evidence).  17 studies (35,944 participants) assessed SAEs for 20,622 of its participants. The majority of participants were from one non-controlled NRSI (20,000 participants), which reported on SAEs within the first four hours and within an additional seven days after transfusion. There were 63 deaths, 12 were possibly and one was probably related to transfusion. There were 146 SAEs within four hours and 1136 SAEs within seven days post-transfusion. These were predominantly allergic or respiratory, thrombotic or thromboembolic and cardiac events. We are uncertain whether convalescent plasma therapy results in a clinically relevant increased risk of SAEs (low-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. There was limited information regarding grade 3 and 4 AEs to determine the effect of convalescent plasma therapy on clinically relevant SAEs. In the absence of a control group, we are unable to assess the relative safety of convalescent plasma therapy.  While major efforts to conduct research on COVID-19 are being made, recruiting the anticipated number of participants into these studies is problematic. The early termination of the first two RCTs investigating convalescent plasma, and the lack of data from 20 studies that have completed or were due to complete at the time of this update illustrate these challenges. Well-designed studies should be prioritised. Moreover, studies should report outcomes in the same way, and should consider the importance of maintaining comparability in terms of co-interventions administered in all study arms.  There are 138 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 73 are RCTs (three already completed). This is the second living update of the review, and we will continue to update this review periodically. Future updates may show different results to those reported here.


Assuntos
Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Viés , Causas de Morte , Infecções por Coronavirus/mortalidade , Humanos , Imunização Passiva/efeitos adversos , Imunização Passiva/métodos , Imunização Passiva/estatística & dados numéricos , Ensaios Clínicos Controlados não Aleatórios como Assunto/estatística & dados numéricos , Pandemias , Pneumonia Viral/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Resultado do Tratamento
4.
Blood Transfus ; 18(6): 423-433, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32955419

RESUMO

BACKGROUND: Management of patients with major haemorrhage often requires urgent administration of multiple blood products, commonly termed a massive transfusion (MT). Clinical practice in these scenarios is supported in part by evidence-based MT guidelines, which typically recommend use of an MT protocol (MTP). MTPs aim to provide practical and specific interpretation of MT guidelines for local institutional use, outlining tasks and pre-configuration of blood product packs to be transfused to provide efficient and evidence-based transfusion management. Institutions can support this aim by the measurement of MTP performance and patient outcomes through collection of quality indicators (QI). Many international guidelines now recommend the routine collection of a range of QIs relating to MT/MTP; however, there is significant variation in procedures and no benchmarks or minimal evidence to guide practice. MATERIALS AND METHODS: We conducted a scoping review to document and evaluate reported QIs for MTP. We conducted a search of CENTRAL, MEDLINE and EMBASE for published studies from inception until May 14, 2020, that reported at least one MTP QI and use of an MTP or equivalent protocol. Included studies were evaluated using a QI classification system based on current MT QI guidelines and the Donabedian QI framework. RESULTS: We identified 107 eligible studies. Trauma patients were the most commonly evaluated group, and total blood products transfused and in-hospital mortality were the most commonly reported QIs. Reflecting the lack of international consensus and benchmarks, we found significant variability in the reporting of QIs, which often did not reflect guideline recommendations. DISCUSSION: Our review highlights the importance of establishing international consensus on prioritised QIs with quantifiable targets that are important to the process of MT.

6.
Semin Hematol ; 57(2): 92-99, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32892848

RESUMO

The transfusion of platelets for both prophylaxis and treatment of bleeding is relevant to all areas of medicine and surgery. Historically, guidance regarding platelet transfusion has been limited by a lack of good quality clinical trials and so has been based largely on expert opinion. In recent years however there has been renewed interest in methods to prevent and treat hemorrhage, and the field has benefited from a number of large clinical trials. Some studies, such as platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH) and platelets for neonatal transfusion Study 2 (PLANET-2), have reported an increased risk of harm with platelet transfusion in specific patient groups. These studies suggest a wider role of platelets beyond hemostasis, and highlight the need for further clinical trials to better understand the risks and benefits of platelet transfusions. This review evaluates the indications for platelet transfusion, both prophylactic and therapeutic, in the light of recent studies and clinical trials. It highlights new developments in the fields of platelet storage and platelet substitutes, and novel ways to avoid complications associated with platelet transfusions. Lastly, it reviews initiatives designed to reduce inappropriate use of platelet transfusions and to preserve this valuable resource for situations where there is evidence for their beneficial effect.

7.
Cochrane Database Syst Rev ; 7: CD012022, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32735048

RESUMO

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the most common cancer of the lymphatic system in Western countries. Several clinical and biological factors for CLL have been identified. However, it remains unclear which of the available prognostic models combining those factors can be used in clinical practice to predict long-term outcome in people newly-diagnosed with CLL. OBJECTIVES: To identify, describe and appraise all prognostic models developed to predict overall survival (OS), progression-free survival (PFS) or treatment-free survival (TFS) in newly-diagnosed (previously untreated) adults with CLL, and meta-analyse their predictive performances. SEARCH METHODS: We searched MEDLINE (from January 1950 to June 2019 via Ovid), Embase (from 1974 to June 2019) and registries of ongoing trials (to 5 March 2020) for development and validation studies of prognostic models for untreated adults with CLL. In addition, we screened the reference lists and citation indices of included studies. SELECTION CRITERIA: We included all prognostic models developed for CLL which predict OS, PFS, or TFS, provided they combined prognostic factors known before treatment initiation, and any studies that tested the performance of these models in individuals other than the ones included in model development (i.e. 'external model validation studies'). We included studies of adults with confirmed B-cell CLL who had not received treatment prior to the start of the study. We did not restrict the search based on study design. DATA COLLECTION AND ANALYSIS: We developed a data extraction form to collect information based on the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). Independent pairs of review authors screened references, extracted data and assessed risk of bias according to the Prediction model Risk Of Bias ASsessment Tool (PROBAST). For models that were externally validated at least three times, we aimed to perform a quantitative meta-analysis of their predictive performance, notably their calibration (proportion of people predicted to experience the outcome who do so) and discrimination (ability to differentiate between people with and without the event) using a random-effects model. When a model categorised individuals into risk categories, we pooled outcome frequencies per risk group (low, intermediate, high and very high). We did not apply GRADE as guidance is not yet available for reviews of prognostic models. MAIN RESULTS: From 52 eligible studies, we identified 12 externally validated models: six were developed for OS, one for PFS and five for TFS. In general, reporting of the studies was poor, especially predictive performance measures for calibration and discrimination; but also basic information, such as eligibility criteria and the recruitment period of participants was often missing. We rated almost all studies at high or unclear risk of bias according to PROBAST. Overall, the applicability of the models and their validation studies was low or unclear; the most common reasons were inappropriate handling of missing data and serious reporting deficiencies concerning eligibility criteria, recruitment period, observation time and prediction performance measures. We report the results for three models predicting OS, which had available data from more than three external validation studies: CLL International Prognostic Index (CLL-IPI) This score includes five prognostic factors: age, clinical stage, IgHV mutational status, B2-microglobulin and TP53 status. Calibration: for the low-, intermediate- and high-risk groups, the pooled five-year survival per risk group from validation studies corresponded to the frequencies observed in the model development study. In the very high-risk group, predicted survival from CLL-IPI was lower than observed from external validation studies. Discrimination: the pooled c-statistic of seven external validation studies (3307 participants, 917 events) was 0.72 (95% confidence interval (CI) 0.67 to 0.77). The 95% prediction interval (PI) of this model for the c-statistic, which describes the expected interval for the model's discriminative ability in a new external validation study, ranged from 0.59 to 0.83. Barcelona-Brno score Aimed at simplifying the CLL-IPI, this score includes three prognostic factors: IgHV mutational status, del(17p) and del(11q). Calibration: for the low- and intermediate-risk group, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high-risk group. Discrimination: the pooled c-statistic of four external validation studies (1755 participants, 416 events) was 0.64 (95% CI 0.60 to 0.67); 95% PI 0.59 to 0.68. MDACC 2007 index score The authors presented two versions of this model including six prognostic factors to predict OS: age, B2-microglobulin, absolute lymphocyte count, gender, clinical stage and number of nodal groups. Only one validation study was available for the more comprehensive version of the model, a formula with a nomogram, while seven studies (5127 participants, 994 events) validated the simplified version of the model, the index score. Calibration: for the low- and intermediate-risk groups, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high-risk group. Discrimination: the pooled c-statistic of the seven external validation studies for the index score was 0.65 (95% CI 0.60 to 0.70); 95% PI 0.51 to 0.77. AUTHORS' CONCLUSIONS: Despite the large number of published studies of prognostic models for OS, PFS or TFS for newly-diagnosed, untreated adults with CLL, only a minority of these (N = 12) have been externally validated for their respective primary outcome. Three models have undergone sufficient external validation to enable meta-analysis of the model's ability to predict survival outcomes. Lack of reporting prevented us from summarising calibration as recommended. Of the three models, the CLL-IPI shows the best discrimination, despite overestimation. However, performance of the models may change for individuals with CLL who receive improved treatment options, as the models included in this review were tested mostly on retrospective cohorts receiving a traditional treatment regimen. In conclusion, this review shows a clear need to improve the conducting and reporting of both prognostic model development and external validation studies. For prognostic models to be used as tools in clinical practice, the development of the models (and their subsequent validation studies) should adapt to include the latest therapy options to accurately predict performance. Adaptations should be timely.


Assuntos
Leucemia Linfocítica Crônica de Células B/mortalidade , Modelos Teóricos , Adulto , Fatores Etários , Viés , Biomarcadores Tumorais , Calibragem , Intervalos de Confiança , Análise Discriminante , Intervalo Livre de Doença , Feminino , Genes p53/genética , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Estadiamento de Neoplasias , Prognóstico , Intervalo Livre de Progressão , Receptores de Antígenos de Linfócitos B/genética , Reprodutibilidade dos Testes , Proteína Supressora de Tumor p53/genética
8.
Cochrane Database Syst Rev ; 7: CD003146, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32716555

RESUMO

BACKGROUND: Sickle cell disease is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. Sickle cell disease can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Stroke affects around 10% of children with sickle cell anaemia (HbSS). Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation. This is an update of a Cochrane Review first published in 2002, and last updated in 2017. OBJECTIVES: To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention (excluding silent cerebral infarcts). SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 8 October 2019. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 19 September 2019. SELECTION CRITERIA: Randomised controlled trials comparing red blood cell transfusions as prophylaxis for stroke in people with sickle cell disease to alternative or standard treatment. There were no restrictions by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and the risk of bias and extracted data. MAIN RESULTS: We included five trials (660 participants) published between 1998 and 2016. Four of these trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of sickle cell disease. Three trials compared regular red cell transfusions to standard care in primary prevention of stroke: two in children with no previous long-term transfusions; and one in children and adolescents on long-term transfusion. Two trials compared the drug hydroxyurea (hydroxycarbamide) and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children); and one in secondary prevention (children and adolescents). The quality of the evidence was very low to moderate across different outcomes according to GRADE methodology. This was due to the trials being at a high risk of bias due to lack of blinding, indirectness and imprecise outcome estimates. Red cell transfusions versus standard care Children with no previous long-term transfusions Long-term transfusions probably reduce the incidence of clinical stroke in children with a higher risk of stroke (abnormal transcranial doppler velocities or previous history of silent cerebral infarct), risk ratio 0.12 (95% confidence interval 0.03 to 0.49) (two trials, 326 participants), moderate quality evidence. Long-term transfusions may: reduce the incidence of other sickle cell disease-related complications (acute chest syndrome, risk ratio 0.24 (95% confidence interval 0.12 to 0.48)) (two trials, 326 participants); increase quality of life (difference estimate -0.54, 95% confidence interval -0.92 to -0.17) (one trial, 166 participants); but make little or no difference to IQ scores (least square mean: 1.7, standard error 95% confidence interval -1.1 to 4.4) (one trial, 166 participants), low quality evidence. We are very uncertain whether long-term transfusions: reduce the risk of transient ischaemic attacks, Peto odds ratio 0.13 (95% confidence interval 0.01 to 2.11) (two trials, 323 participants); have any effect on all-cause mortality, no deaths reported (two trials, 326 participants); or increase the risk of alloimmunisation, risk ratio 3.16 (95% confidence interval 0.18 to 57.17) (one trial, 121 participants), very low quality evidence. Children and adolescents with previous long-term transfusions (one trial, 79 participants) We are very uncertain whether continuing long-term transfusions reduces the incidence of: stroke, risk ratio 0.22 (95% confidence interval 0.01 to 4.35); or all-cause mortality, Peto odds ratio 8.00 (95% confidence interval 0.16 to 404.12), very low quality evidence. Several review outcomes were only reported in one trial arm (sickle cell disease-related complications, alloimmunisation, transient ischaemic attacks). The trial did not report neurological impairment, or quality of life. Hydroxyurea and phlebotomy versus red cell transfusions and chelation Neither trial reported on neurological impairment, alloimmunisation, or quality of life. Primary prevention, children (one trial, 121 participants) Switching to hydroxyurea and phlebotomy may have little or no effect on liver iron concentrations, mean difference -1.80 mg Fe/g dry-weight liver (95% confidence interval -5.16 to 1.56), low quality evidence. We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: risk of stroke (no strokes); all-cause mortality (no deaths); transient ischaemic attacks, risk ratio 1.02 (95% confidence interval 0.21 to 4.84); or other sickle cell disease-related complications (acute chest syndrome, risk ratio 2.03 (95% confidence interval 0.39 to 10.69)), very low quality evidence. Secondary prevention, children and adolescents (one trial, 133 participants) Switching to hydroxyurea and phlebotomy may: increase the risk of sickle cell disease-related serious adverse events, risk ratio 3.10 (95% confidence interval 1.42 to 6.75); but have little or no effect on median liver iron concentrations (hydroxyurea, 17.3 mg Fe/g dry-weight liver (interquartile range 10.0 to 30.6)); transfusion 17.3 mg Fe/g dry-weight liver (interquartile range 8.8 to 30.7), low quality evidence. We are very uncertain whether switching to hydroxyurea and phlebotomy: increases the risk of stroke, risk ratio 14.78 (95% confidence interval 0.86 to 253.66); or has any effect on all-cause mortality, Peto odds ratio 0.98 (95% confidence interval 0.06 to 15.92); or transient ischaemic attacks, risk ratio 0.66 (95% confidence interval 0.25 to 1.74), very low quality evidence. AUTHORS' CONCLUSIONS: There is no evidence for managing adults, or children who do not have HbSS sickle cell disease. In children who are at higher risk of stroke and have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke, and low quality evidence they also reduce the risk of other sickle cell disease-related complications. In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration. In secondary prevention of stroke there is low-quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events. All other evidence in this review is of very low quality.


Assuntos
Anemia Falciforme/complicações , Transfusão de Eritrócitos , Prevenção Primária , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controle , Adolescente , Anemia Falciforme/sangue , Antidrepanocíticos/efeitos adversos , Antidrepanocíticos/uso terapêutico , Transfusão de Sangue , Criança , Pré-Escolar , Término Precoce de Ensaios Clínicos , Transfusão de Eritrócitos/efeitos adversos , Hemoglobina Falciforme , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Quelantes de Ferro/uso terapêutico , Flebotomia/efeitos adversos , Acidente Vascular Cerebral/etiologia , Adulto Jovem
9.
Cochrane Database Syst Rev ; 7: CD013600, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32648959

RESUMO

BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required.  OBJECTIVES: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 4 June 2020. SELECTION CRITERIA: We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs.  MAIN RESULTS: This is the first living update of our review. We included 20 studies (1 RCT, 3 controlled NRSIs, 16 non-controlled NRSIs) with 5443 participants, of whom 5211 received convalescent plasma, and identified a further 98 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 50 are randomised. We did not identify any completed studies evaluating hyperimmune immunoglobulin. Overall risk of bias of included studies was high, due to study design, type of participants, and other previous or concurrent treatments. Effectiveness of convalescent plasma for people with COVID-19  We included results from four controlled studies (1 RCT (stopped early) with 103 participants, of whom 52 received convalescent plasma; and 3 controlled NRSIs with 236 participants, of whom 55 received convalescent plasma) to assess effectiveness of convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. All-cause mortality at hospital discharge (1 controlled NRSI, 21 participants) We are very uncertain whether convalescent plasma has any effect on all-cause mortality at hospital discharge (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.61 to 1.31; very low-certainty evidence). Time to death (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma prolongs time to death (RCT: hazard ratio (HR) 0.74, 95% CI 0.30 to 1.82; controlled NRSI: HR 0.46, 95% CI 0.22 to 0.96; very low-certainty evidence). Improvement of clinical symptoms, assessed by need for respiratory support (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma has any effect on improvement of clinical symptoms at seven days (RCT: RR 0.98, 95% CI 0.30 to 3.19), 14 days (RCT: RR 1.85, 95% CI 0.91 to 3.77; controlled NRSI: RR 1.08, 95% CI 0.91 to 1.29), and 28 days (RCT: RR 1.20, 95% CI 0.80 to 1.81; very low-certainty evidence). Quality of life No studies reported this outcome.  Safety of convalescent plasma for people with COVID-19 We included results from 1 RCT, 3 controlled NRSIs and 10 non-controlled NRSIs assessing safety of convalescent plasma. Reporting of adverse events and serious adverse events was variable. The controlled studies reported on adverse events and serious adverse events only in participants receiving convalescent plasma. The duration of follow-up varied. Some, but not all, studies included death as a serious adverse event.  Grade 3 or 4 adverse events (13 studies, 201 participants) The studies did not report the grade of adverse events. Thirteen studies (201 participants) reported on adverse events of possible grade 3 or 4 severity. The majority of these adverse events were allergic or respiratory events. We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence).  Serious adverse events (14 studies, 5201 participants)  Fourteen studies (5201 participants) reported on serious adverse events. The majority of participants were from one non-controlled NRSI (5000 participants), which reported only on serious adverse events limited to the first four hours after convalescent plasma transfusion. This study included death as a serious adverse event; they reported 15 deaths, four of which they classified as potentially, probably or definitely related to transfusion. Other serious adverse events reported in all studies were predominantly allergic or respiratory in nature, including anaphylaxis, transfusion-associated dyspnoea, and transfusion-related acute lung injury (TRALI). We are very uncertain whether or not convalescent plasma affects the number of serious adverse events. AUTHORS' CONCLUSIONS: We are very uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. For safety outcomes we also included non-controlled NRSIs. There was limited information regarding adverse events. Of the controlled studies, none reported on this outcome in the control group. There is only very low-certainty evidence for safety of convalescent plasma for COVID-19.  While major efforts to conduct research on COVID-19 are being made, problems with recruiting the anticipated number of participants into these studies are conceivable. The early termination of the first RCT investigating convalescent plasma, and the multitude of studies registered in the past months illustrate this. It is therefore necessary to critically assess the design of these registered studies, and well-designed studies should be prioritised. Other considerations for these studies are the need to report outcomes for all study arms in the same way, and the importance of maintaining comparability in terms of co-interventions administered in all study arms.  There are 98 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 50 are RCTs. This is the first living update of the review, and we will continue to update this review periodically. These updates may show different results to those reported here.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Causas de Morte , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Término Precoce de Ensaios Clínicos , Humanos , Imunização Passiva/efeitos adversos , Imunização Passiva/métodos , Imunização Passiva/mortalidade , Imunização Passiva/estatística & dados numéricos , Ensaios Clínicos Controlados não Aleatórios como Assunto/mortalidade , Ensaios Clínicos Controlados não Aleatórios como Assunto/estatística & dados numéricos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Respiração Artificial/estatística & dados numéricos , Viés de Seleção , Índice de Gravidade de Doença , Resultado do Tratamento
10.
Cochrane Database Syst Rev ; 7: CD003149, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32614473

RESUMO

BACKGROUND: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Surgical interventions are more common in people with SCD, and occur at much younger ages than in the general population. Blood transfusions are frequently used prior to surgery and several regimens are used but there is no consensus over the best method or the necessity of transfusion in specific surgical cases. This is an update of a Cochrane Review. OBJECTIVES: To determine whether there is evidence that preoperative blood transfusion in people with SCD undergoing elective or emergency surgery reduces mortality and perioperative or sickle cell-related serious adverse events. To compare the effectiveness of different transfusion regimens (aggressive or conservative) if preoperative transfusions are indicated in people with SCD. SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 28 January 2020 We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 19 September 2019. SELECTION CRITERIA: All randomised controlled trials and quasi-randomised controlled trials comparing preoperative blood transfusion regimens to different regimens or no transfusion in people with SCD undergoing elective or emergency surgery. There was no restriction by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and the risk of bias and extracted data. MAIN RESULTS: Three trials with 990 participants were eligible for inclusion in the review. There were no ongoing trials identified. These trials were conducted between 1988 and 2011. The majority of people included had haemoglobin (Hb) SS SCD. The majority of surgical procedures were considered low or intermediate risk for developing sickle cell-related complications. Aggressive versus simple red blood cell transfusions One trial (551 participants) compared an aggressive transfusion regimen (decreasing sickle haemoglobin to less than 30%) to a simple transfusion regimen (increasing haemoglobin to 100 g/L). This trial re-randomised participants and therefore quantitative analysis was only possible on two subsets of data: participants undergoing cholecystectomy (230 participants); and participants undergoing tonsillectomy or adenoidectomy surgeries (107 participants). Data were not combined as we do not know if any participant received both surgeries. Overall, the quality of the evidence was very low across different outcomes according to GRADE methodology. This was due to the trial being at high risk of bias primarily due to lack of blinding, indirectness and the outcome estimates being imprecise. Cholecystectomy subgroup results are reported in the abstract. Results for both subgroups were similar. There was no difference in all-cause mortality between people receiving aggressive transfusions and those receiving conservative transfusions. No deaths occurred in either subgroup. There were no differences between the aggressive transfusion group and conservative transfusion group in the number of people developing: • an acute chest syndrome, risk ratio (RR) 0.84 (95% confidence interval (CI) 0.38 to 1.84) (one trial, 230 participants, very low-quality evidence); • vaso-occlusive crisis, risk ratio 0.30 (95% CI 0.09 to 1.04) (one trial, 230 participants, very low quality evidence); • serious infection, risk ratio 1.75 (95% CI 0.59 to 5.18) (one trial, 230 participants, very low-quality evidence); • any perioperative complications, RR 0.75 (95% CI 0.36 to 1.55) (one trial, 230 participants, very low-quality evidence); • a transfusion-related complication, RR 1.85 (95% CI 0.89 to 3.88) (one trial, 230 participants, very low-quality evidence). Preoperative transfusion versus no preoperative transfusion Two trials (434 participants) compared a preoperative transfusion plus standard care to a group receiving standard care. Overall, the quality of the evidence was low to very low across different outcomes according to GRADE methodology. This was due to the trials being at high risk of bias due to lack of blinding, and outcome estimates being imprecise. One trial was stopped early because more people in the no transfusion arm developed an acute chest syndrome. There was no difference in all-cause mortality between people receiving preoperative transfusions and those receiving no preoperative transfusions (two trials, 434 participants, no deaths occurred). There was significant heterogeneity between the two trials in the number of people developing an acute chest syndrome, a meta-analysis was therefore not performed. One trial showed a reduced number of people developing acute chest syndrome between people receiving preoperative transfusions and those receiving no preoperative transfusions, risk ratio 0.11 (95% confidence interval 0.01 to 0.80) (65 participants), whereas the other trial did not, RR 4.81 (95% CI 0.23 to 99.61) (369 participants). There were no differences between the preoperative transfusion groups and the groups without preoperative transfusion in the number of people developing: • a vaso-occlusive crisis, Peto odds ratio (OR) 1.91 (95% confidence interval 0.61 to 6.04) (two trials, 434 participants, very low-quality evidence). • a serious infection, Peto OR 1.29 (95% CI 0.29 to 5.71) (two trials, 434 participants, very low-quality evidence); • any perioperative complications, RR 0.24 (95% CI 0.03 to 2.05) (one trial, 65 participants, low-quality evidence). There was an increase in the number of people developing circulatory overload in those receiving preoperative transfusions compared to those not receiving preoperative transfusions in one of the two trials, and no events were seen in the other trial (no meta-analysis performed). AUTHORS' CONCLUSIONS: There is insufficient evidence from randomised trials to determine whether conservative preoperative blood transfusion is as effective as aggressive preoperative blood transfusion in preventing sickle-related or surgery-related complications in people with HbSS disease. There is very low quality evidence that preoperative blood transfusion may prevent development of acute chest syndrome. Due to lack of evidence this review cannot comment on management for people with HbSC or HbSß+ disease or for those with high baseline haemoglobin concentrations.


Assuntos
Anemia Falciforme/cirurgia , Transfusão de Sangue/métodos , Hemoglobina Falciforme , Cuidados Pré-Operatórios/métodos , Síndrome Torácica Aguda/etiologia , Adenoidectomia , Anemia Falciforme/sangue , Anemia Falciforme/complicações , Colecistectomia/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tonsilectomia , Reação Transfusional
11.
Vox Sang ; 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32542847

RESUMO

BACKGROUND AND OBJECTIVES: Use of convalescent plasma for coronavirus disease 2019 (COVID-19) treatment has gained interest worldwide. However, there is lack of evidence on its dosing, safety and effectiveness. Until data from clinical studies are available to provide solid evidence for worldwide applicable guidelines, there is a need to provide guidance to the transfusion community and researchers on this emergent therapeutic option. This paper aims to identify existing key gaps in current knowledge in the clinical application of COVID-19 convalescent plasma (CCP). MATERIALS AND METHODS: The International Society of Blood Transfusion (ISBT) initiated a multidisciplinary working group with worldwide representation from all six continents with the aim of reviewing existing practices on CCP use from donor, product and patient perspectives. A subgroup of clinical transfusion professionals was formed to draft a document for CCP clinical application to identify the gaps in knowledge in existing literature. RESULTS: Gaps in knowledge were identified in the following main domains: study design, patient eligibility, CCP dose, frequency and timing of CCP administration, parameters to assess response to CCP treatment and long-term outcome, adverse events and CCP application in less-resourced countries as well as in paediatrics and neonates. CONCLUSION: This paper outlines a framework of gaps in the knowledge of clinical deployment of CPP that were identified as being most relevant. Studies to address the identified gaps are required to provide better evidence on the effectiveness and safety of CCP use.

12.
Cochrane Database Syst Rev ; 5: CD013600, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32406927

RESUMO

BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with respiratory virus diseases, and are currently being investigated in trials as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required.  OBJECTIVES: To assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19. SEARCH METHODS: The protocol was pre-published with the Center for Open Science and can be accessed here: osf.io/dwf53  We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trials registries to identify ongoing studies and results of completed studies on 23 April 2020 for case-series, cohort, prospectively planned, and randomised controlled trials (RCTs). SELECTION CRITERIA: We followed standard Cochrane methodology and performed all steps regarding study selection in duplicate by two independent review authors (in contrast to the recommendations of the Cochrane Rapid Reviews Methods Group). We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulins. DATA COLLECTION AND ANALYSIS: We followed recommendations of the Cochrane Rapid Reviews Methods Group regarding data extraction and assessment. To assess bias in included studies, we used the assessment criteria tool for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events, and serious adverse events.  MAIN RESULTS: We included eight studies (seven case-series, one prospectively planned, single-arm intervention study) with 32 participants, and identified a further 48 ongoing studies evaluating convalescent plasma (47 studies) or hyperimmune immunoglobulin (one study), of which 22 are randomised. Overall risk of bias of the eight included studies was high, due to: study design; small number of participants; poor reporting within studies; and varied type of participants with different severities of disease, comorbidities, and types of previous or concurrent treatments, including antivirals, antifungals or antibiotics, corticosteroids, hydroxychloroquine and respiratory support. We rated all outcomes as very low certainty, and we were unable to summarise numerical data in any meaningful way. As we identified case-series studies only, we reported results narratively. Effectiveness of convalescent plasma for people with COVID-19 The following reported outcomes could all be related to the underlying natural history of the disease or other concomitant treatment, rather than convalescent plasma. All-cause mortality at hospital discharge All studies reported mortality. All participants were alive at the end of the reporting period, but not all participants had been discharged from hospital by the end of the study (15 participants discharged, 6 still hospitalised, 11 unclear). Follow-up ranged from 3 days to 37 days post-transfusion. We do not know whether convalescent plasma therapy affects mortality (very low-certainty evidence).  Improvement of clinical symptoms (assessed by respiratory support) Six studies, including 28 participants, reported the level of respiratory support required; most participants required respiratory support at baseline. All studies reported improvement in clinical symptoms in at least some participants. We do not know whether convalescent plasma improves clinical symptoms (very low-certainty evidence). Time to discharge from hospital Six studies reported time to discharge from hospital for at least some participants, which ranged from four to 35 days after convalescent plasma therapy.  Admission on the intensive care unit (ICU) Six studies included patients who were critically ill. At final follow-up the majority of these patients were no longer on the ICU or no longer required mechanical ventilation. Length of stay on the ICU Only one study (1 participant) reported length of stay on the ICU. The individual was discharged from the ICU 11 days after plasma transfusion. Safety of convalescent plasma for people with COVID-19 Grade 3 or 4 adverse events  The studies did not report the grade of adverse events after convalescent plasma transfusion. Two studies reported data relating to participants who had experienced adverse events, that were presumably grade 3 or 4. One case study reported a participant who had moderate fever (38.9 °C). Another study (3 participants) reported a case of severe anaphylactic shock. Four studies reported the absence of moderate or severe adverse events (19 participants). We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence). Serious adverse events One study (3 participants) reported one serious adverse event. As described above, this individual had severe anaphylactic shock after receiving convalescent plasma. Six studies reported that no serious adverse events occurred. We are very uncertain whether or not convalescent plasma therapy affects the risk of serious adverse events (very low-certainty evidence).  AUTHORS' CONCLUSIONS: We identified eight studies (seven case-series and one prospectively planned single-arm intervention study) with a total of 32 participants (range 1 to 10). Most studies assessed the risks of the intervention; reporting two adverse events (potentially grade 3 or 4), one of which was a serious adverse event. We are very uncertain whether convalescent plasma is effective for people admitted to hospital with COVID-19 as studies reported results inconsistently, making it difficult to compare results and to draw conclusions. We identified very low-certainty evidence on the effectiveness and safety of convalescent plasma therapy for people with COVID-19; all studies were at high risk of bias and reporting quality was low. No RCTs or controlled non-randomised studies evaluating benefits and harms of convalescent plasma have been completed. There are 47 ongoing studies evaluating convalescent plasma, of which 22 are RCTs, and one trial evaluating hyperimmune immunoglobulin. We will update this review as a living systematic review, based on monthly searches in the above mentioned databases and registries. These updates are likely to show different results to those reported here.


Assuntos
Infecções por Coronavirus , Imunoglobulinas , Pacientes Internados , Pandemias , Pneumonia Viral , Betacoronavirus , Infecções por Coronavirus/terapia , Cuidados Críticos , Estado Terminal , Humanos , Imunização Passiva/efeitos adversos , Imunização Passiva/métodos , Imunoglobulinas/uso terapêutico , Pneumonia Viral/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , Índice de Gravidade de Doença , Resultado do Tratamento
13.
Semin Thromb Hemost ; 46(3): 245-255, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32259875

RESUMO

This is a review of the evidence for the use of different platelet count thresholds prior to invasive procedures and surgery. This review will focus on three procedures that are common in patients with thrombocytopenia-central venous catheter insertion, liver biopsy, and lumbar punctures and epidural catheters-as well as highlighting the lack of evidence for more major surgery. Tunneled or untunneled central venous catheters are low-risk procedures and can be safely performed without any intervention when the platelet count is 20 × 109/L or above. Evidence for their safety is more limited below this threshold, but as bleeding is easily treated, interventions should focus on treating any bleeding that occurs rather than preventative strategies. The available evidence for neuraxial anesthesia is based on very low-quality evidence from observational studies. Based on this evidence, the risk of an epidural hematoma is less than 0.19% (upper limit of 95% confidence interval) for pregnant women undergoing an epidural anesthetic when the platelet count is between 70 and 99 × 109/L. No randomized trials have been performed in children, nor have any randomized trials been performed in major or emergency surgeries.


Assuntos
Anestesia/efeitos adversos , Cirurgia Geral/métodos , Trombocitopenia/etiologia , Humanos
14.
Cochrane Database Syst Rev ; 4: CD012389, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32250453

RESUMO

BACKGROUND: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient. OBJECTIVES: To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD. SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 14 November 2019. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 07 October 2019. SELECTION CRITERIA: Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention. Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion. Two trials compared the drug hydroxyurea and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children), and one in secondary prevention (children and adolescents). The quality of the evidence was moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence). No deaths were reported in either trial. Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence). Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial) Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence). We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence). The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence). Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence). Neither trial reported on quality of life or cognitive function. AUTHORS' CONCLUSIONS: We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD. Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises). In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions. Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention. All other evidence in this review is of very low-quality.


Assuntos
Anemia Falciforme/complicações , Antidrepanocíticos/uso terapêutico , Infarto Encefálico/prevenção & controle , Transfusão de Eritrócitos , Hidroxiureia/uso terapêutico , Flebotomia , Adolescente , Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/efeitos adversos , Infarto Encefálico/etiologia , Causas de Morte , Criança , Cognição/fisiologia , Humanos , Hidroxiureia/efeitos adversos , Flebotomia/efeitos adversos , Prevenção Primária/métodos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção Secundária/métodos , Acidente Vascular Cerebral/prevenção & controle
15.
Cochrane Database Syst Rev ; 1: CD012643, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31930780

RESUMO

BACKGROUND: Hodgkin lymphoma (HL) is one of the most common haematological malignancies in young adults and, with cure rates of 90%, has become curable for the majority of individuals. Positron emission tomography (PET) is an imaging tool used to monitor a tumour's metabolic activity, stage and progression. Interim PET during chemotherapy has been posited as a prognostic factor in individuals with HL to distinguish between those with a poor prognosis and those with a better prognosis. This distinction is important to inform decision-making on the clinical pathway of individuals with HL. OBJECTIVES: To determine whether in previously untreated adults with HL receiving first-line therapy, interim PET scan results can distinguish between those with a poor prognosis and those with a better prognosis, and thereby predict survival outcomes in each group. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL and conference proceedings up until April 2019. We also searched one trial registry (ClinicalTrials.gov). SELECTION CRITERIA: We included retrospective and prospective studies evaluating interim PET scans in a minimum of 10 individuals with HL (all stages) undergoing first-line therapy. Interim PET was defined as conducted during therapy (after one, two, three or four treatment cycles). The minimum follow-up period was at least 12 months. We excluded studies if the trial design allowed treatment modification based on the interim PET scan results. DATA COLLECTION AND ANALYSIS: We developed a data extraction form according to the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). Two teams of two review authors independently screened the studies, extracted data on overall survival (OS), progression-free survival (PFS) and PET-associated adverse events (AEs), assessed risk of bias (per outcome) according to the Quality in Prognosis Studies (QUIPS) tool, and assessed the certainty of the evidence (GRADE). We contacted investigators to obtain missing information and data. MAIN RESULTS: Our literature search yielded 11,277 results. In total, we included 23 studies (99 references) with 7335 newly-diagnosed individuals with classic HL (all stages). Participants in 16 studies underwent (interim) PET combined with computed tomography (PET-CT), compared to PET only in the remaining seven studies. The standard chemotherapy regimen included ABVD (16) studies, compared to BEACOPP or other regimens (seven studies). Most studies (N = 21) conducted interim PET scans after two cycles (PET2) of chemotherapy, although PET1, PET3 and PET4 were also reported in some studies. In the meta-analyses, we used PET2 data if available as we wanted to ensure homogeneity between studies. In most studies interim PET scan results were evaluated according to the Deauville 5-point scale (N = 12). Eight studies were not included in meta-analyses due to missing information and/or data; results were reported narratively. For the remaining studies, we pooled the unadjusted hazard ratio (HR). The timing of the outcome measurement was after two or three years (the median follow-up time ranged from 22 to 65 months) in the pooled studies. Eight studies explored the independent prognostic ability of interim PET by adjusting for other established prognostic factors (e.g. disease stage, B symptoms). We did not pool the results because the multivariable analyses adjusted for a different set of factors in each study. Overall survival Twelve (out of 23) studies reported OS. Six of these were assessed as low risk of bias in all of the first four domains of QUIPS (study participation, study attrition, prognostic factor measurement and outcome measurement). The other six studies were assessed as unclear, moderate or high risk of bias in at least one of these four domains. Four studies were assessed as low risk, and eight studies as high risk of bias for the domain other prognostic factors (covariates). Nine studies were assessed as low risk, and three studies as high risk of bias for the domain 'statistical analysis and reporting'. We pooled nine studies with 1802 participants. Participants with HL who have a negative interim PET scan result probably have a large advantage in OS compared to those with a positive interim PET scan result (unadjusted HR 5.09, 95% confidence interval (CI) 2.64 to 9.81, I² = 44%, moderate-certainty evidence). In absolute values, this means that 900 out of 1000 participants with a negative interim PET scan result will probably survive longer than three years compared to 585 (95% CI 356 to 757) out of 1000 participants with a positive result. Adjusted results from two studies also indicate an independent prognostic value of interim PET scan results (moderate-certainty evidence). Progression-free survival Twenty-one studies reported PFS. Eleven out of 21 were assessed as low risk of bias in the first four domains. The remaining were assessed as unclear, moderate or high risk of bias in at least one of the four domains. Eleven studies were assessed as low risk, and ten studies as high risk of bias for the domain other prognostic factors (covariates). Eight studies were assessed as high risk, thirteen as low risk of bias for statistical analysis and reporting. We pooled 14 studies with 2079 participants. Participants who have a negative interim PET scan result may have an advantage in PFS compared to those with a positive interim PET scan result, but the evidence is very uncertain (unadjusted HR 4.90, 95% CI 3.47 to 6.90, I² = 45%, very low-certainty evidence). This means that 850 out of 1000 participants with a negative interim PET scan result may be progression-free longer than three years compared to 451 (95% CI 326 to 569) out of 1000 participants with a positive result. Adjusted results (not pooled) from eight studies also indicate that there may be an independent prognostic value of interim PET scan results (low-certainty evidence). PET-associated adverse events No study measured PET-associated AEs. AUTHORS' CONCLUSIONS: This review provides moderate-certainty evidence that interim PET scan results predict OS, and very low-certainty evidence that interim PET scan results predict progression-free survival in treated individuals with HL. This evidence is primarily based on unadjusted data. More studies are needed to test the adjusted prognostic ability of interim PET against established prognostic factors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Quimiorradioterapia , Tomada de Decisões , Progressão da Doença , Intervalo Livre de Doença , Humanos , Prognóstico , Adulto Jovem
16.
Cochrane Database Syst Rev ; 2019(10)2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31684693

RESUMO

BACKGROUND: Sickle cell disease is a genetic haemoglobin disorder, which can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Sickle cell disease is one of the most common severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. The two most common chronic chest complications due to sickle cell disease are pulmonary hypertension and chronic sickle lung disease. These complications can lead to morbidity (such as reduced exercise tolerance) and increased mortality. This is an update of a Cochrane Review first published in 2011 and updated in 2014 and 2016. OBJECTIVES: We wanted to determine whether trials involving people with sickle cell disease that compare regular long-term blood transfusion regimens with standard care, hydroxycarbamide (hydroxyurea) any other drug treatment show differences in the following: mortality associated with chronic chest complications; severity of established chronic chest complications; development and progression of chronic chest complications; serious adverse events. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. Date of the last search: 19 September 2019. We also searched for randomised controlled trials in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 10, 14 November 2018), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 14 November 2018. SELECTION CRITERIA: We included randomised controlled trials of people of any age with one of four common sickle cell disease genotypes, i.e. Hb SS, Sߺ, SC, or Sß+ that compared regular red blood cell transfusion regimens (either simple or exchange transfusions) to hydroxycarbamide, any other drug treatment, or to standard care that were aimed at reducing the development or progression of chronic chest complications (chronic sickle lung and pulmonary hypertension). DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: No studies matching the selection criteria were found. AUTHORS' CONCLUSIONS: There is a need for randomised controlled trials looking at the role of long-term transfusion therapy in pulmonary hypertension and chronic sickle lung disease. Due to the chronic nature of the conditions, such trials should aim to use a combination of objective and subjective measures to assess participants repeatedly before and after the intervention.


Assuntos
Síndrome Torácica Aguda/terapia , Anemia Falciforme/complicações , Transfusão de Eritrócitos/métodos , Hipertensão Pulmonar/terapia , Síndrome Torácica Aguda/etiologia , Antidrepanocíticos/uso terapêutico , Humanos , Hipertensão Pulmonar/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Cochrane Database Syst Rev ; 2019(11)2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31765002

RESUMO

BACKGROUND: Multiple myeloma is a bone marrow-based hematological malignancy accounting for approximately two per cent of cancers. First-line treatment for transplant-ineligible individuals consists of multiple drug combinations of bortezomib (V), lenalidomide (R), or thalidomide (T). However, access to these medicines is restricted in many countries worldwide. OBJECTIVES: To assess and compare the effectiveness and safety of multiple drug combinations of V, R, and T for adults with newly diagnosed transplant-ineligible multiple myeloma and to inform an application for the inclusion of these medicines into the World Health Organization's (WHO) list of essential medicines. SEARCH METHODS: We searched CENTRAL and MEDLINE, conference proceedings and study registries on 14 February 2019 for randomised controlled trials (RCTs) comparing multiple drug combinations of V, R and T for adults with newly diagnosed transplant-ineligible multiple myeloma. SELECTION CRITERIA: We included RCTs comparing combination therapies of V, R, and T, plus melphalan and prednisone (MP) or dexamethasone (D) for first-line treatment of adults with transplant-ineligible multiple myeloma. We excluded trials including adults with relapsed or refractory disease, trials comparing drug therapies to other types of therapy and trials including second-generation novel agents. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias of included trials. As effect measures we used hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for adverse events. An HR or RR < 1 indicates an advantage for the intervention compared to the main comparator MP. Where available, we extracted quality of life (QoL) data (scores of standardised questionnaires). Results quoted are from network meta-analysis (NMA) unless stated. MAIN RESULTS: We included 25 studies (148 references) comprising 11,403 participants and 21 treatment regimens. Treatments were differentiated between restricted treatment duration (treatment with a pre-specified amount of cycles) and continuous therapy (treatment administered until disease progression, the person becomes intolerant to the drug, or treatment given for a prolonged period). Continuous therapies are indicated with a "c". Risk of bias was generally high across studies due to the open-label study design. Overall survival (OS) Evidence suggests that treatment with RD (HR 0.63 (95% confidence interval (CI) 0.40 to 0.99), median OS 55.2 months (35.2 to 87.0)); TMP (HR 0.75 (95% CI 0.58 to 0.97), median OS: 46.4 months (35.9 to 60.0)); and VRDc (HR 0.49 (95% CI 0.26 to 0.92), median OS 71.0 months (37.8 to 133.8)) probably increases survival compared to median reported OS of 34.8 months with MP (moderate certainty). Treatment with VMP may result in a large increase in OS, compared to MP (HR 0.70 (95% CI 0.45 to 1.07), median OS 49.7 months (32.5 to 77.3)), low certainty). Progression-free survival (PFS) Treatment withRD (HR 0.65 (95% CI0.44 to 0.96), median PFS: 24.9 months (16.9 to 36.8)); TMP (HR 0.63 (95% CI 0.50 to 0.78), median PFS:25.7 months (20.8 to 32.4)); VMP (HR 0.56 (95% CI 0.35 to 0.90), median PFS: 28.9 months (18.0 to 46.3)); and VRDc (HR 0.34 (95% CI 0.20 to 0.58), median PFS: 47.6 months (27.9 to 81.0)) may result in a large increase in PFS (low certainty) compared to MP (median reported PFS: 16.2 months). Adverse events The risk of polyneuropathies may be lower with RD compared to treatment with MP (RR 0.57 (95% CI 0.16 to 1.99), risk for RD: 0.5% (0.1 to 1.8), mean reported risk for MP: 0.9% (10 of 1074 patients affected), low certainty). However, the CIs are also compatible with no difference or an increase in neuropathies. Treatment with TMP (RR 4.44 (95% CI1.77 to 11.11), risk: 4.0% (1.6 to 10.0)) and VMP (RR 88.22 (95% CI 5.36 to 1451.11), risk: 79.4% (4.8 to 1306.0)) probably results in a large increase in polyneuropathies compared to MP (moderate certainty). No study reported the amount of participants with grade ≥ 3 polyneuropathies for treatment with VRDc. VMP probably increases the proportion of participants with serious adverse events (SAEs) compared to MP (RR 1.28 (95% CI 1.06 to 1.54), risk for VMP: 46.2% (38.3 to 55.6), mean risk for MP: 36.1% (177 of 490 patients affected), moderate certainty). RD, TMP, and VRDc were not connected to MP in the network and the risk of SAEs could not be compared. Treatment with RD (RR 4.18 (95% CI 2.13 to 8.20), NMA-risk: 38.5% (19.6 to 75.4)); and TMP (RR 4.10 (95% CI 2.40 to 7.01), risk: 37.7% (22.1 to 64.5)) results in a large increase of withdrawals from the trial due to adverse events (high certainty) compared to MP (mean reported risk: 9.2% (77 of 837 patients withdrew)). The risk is probably slightly increased with VMP (RR 1.06 (95% CI 0.63 to 1.81), risk: 9.75% (5.8 to 16.7), moderate certainty), while it is much increased with VRDc (RR 8.92 (95% CI 3.82 to 20.84), risk: 82.1% (35.1 to 191.7), high certainty) compared to MP. Quality of life QoL was reported in four studies for seven different treatment regimens (MP, MPc, RD, RMP, RMPc, TMP, TMPc) and was measured with four different tools. Assessment and reporting differed between studies and could not be meta-analysed. However, all studies reported an improvement of QoL after initiation of anti-myeloma treatment for all assessed treatment regimens. AUTHORS' CONCLUSIONS: Based on our four pre-selected comparisons of interest, continuous treatment with VRD had the largest survival benefit compared with MP, while RD and TMP also probably considerably increase survival. However, treatment combinations of V, R, and T also substantially increase the incidence of AEs, and lead to a higher risk of treatment discontinuation. Their effectiveness and safety profiles may best be analysed in further randomised head-to-head trials. Further trials should focus on consistent reporting of safety outcomes and should use a standardised instrument to evaluate QoL to ensure comparability of treatment-combinations.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Humanos , Lenalidomida/uso terapêutico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Talidomida/uso terapêutico
18.
Cochrane Database Syst Rev ; 11: CD012745, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31778223

RESUMO

BACKGROUND: In the absence of bleeding, plasma is commonly transfused to people prophylactically to prevent bleeding. In this context, it is transfused before operative or invasive procedures (such as liver biopsy or chest drainage tube insertion) in those considered at increased risk of bleeding, typically defined by abnormalities of laboratory tests of coagulation. As plasma contains procoagulant factors, plasma transfusion may reduce perioperative bleeding risk. This outcome has clinical importance given that perioperative bleeding and blood transfusion have been associated with increased morbidity and mortality. Plasma is expensive, and some countries have experienced issues with blood product shortages, donor pool reliability, and incomplete screening for transmissible infections. Thus, although the benefit of prophylactic plasma transfusion has not been well established, plasma transfusion does carry potentially life-threatening risks. OBJECTIVES: To determine the clinical effectiveness and safety of prophylactic plasma transfusion for people with coagulation test abnormalities (in the absence of inherited bleeding disorders or use of anticoagulant medication) requiring non-cardiac surgery or invasive procedures. SEARCH METHODS: We searched for randomised controlled trials (RCTs), without language or publication status restrictions in: Cochrane Central Register of Controlled Trials (CENTRAL; 2017 Issue 7); Ovid MEDLINE (from 1946); Ovid Embase (from 1974); Cumulative Index to Nursing and Allied Health Literature (CINAHL; EBSCOHost) (from 1937); PubMed (e-publications and in-process citations ahead of print only); Transfusion Evidence Library (from 1950); Latin American Caribbean Health Sciences Literature (LILACS) (from 1982); Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (Thomson Reuters, from 1990); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Search Platform (ICTRP) to 28 January 2019. SELECTION CRITERIA: We included RCTs comparing: prophylactic plasma transfusion to placebo, intravenous fluid, or no intervention; prophylactic plasma transfusion to alternative pro-haemostatic agents; or different haemostatic thresholds for prophylactic plasma transfusion. We included participants of any age, and we excluded trials incorporating individuals with previous active bleeding, with inherited bleeding disorders, or taking anticoagulant medication before enrolment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included five trials in this review, all were conducted in high-income countries. Three additional trials are ongoing. One trial compared fresh frozen plasma (FFP) transfusion with no transfusion given. One trial compared FFP or platelet transfusion or both with neither FFP nor platelet transfusion given. One trial compared FFP transfusion with administration of alternative pro-haemostatic agents (factors II, IX, and X followed by VII). One trial compared the use of different transfusion triggers using the international normalised ratio measurement. One trial compared the use of a thromboelastographic-guided transfusion trigger using standard laboratory measurements of coagulation. Four trials enrolled only adults, whereas the fifth trial did not specify participant age. Four trials included only minor procedures that could be performed by the bedside. Only one trial included some participants undergoing major surgical operations. Two trials included only participants in intensive care. Two trials included only participants with liver disease. Three trials did not recruit sufficient participants to meet their pre-calculated sample size. Overall, the quality of evidence was low to very low across different outcomes according to GRADE methodology, due to risk of bias, indirectness, and imprecision. One trial was stopped after recruiting two participants, therefore this review's findings are based on the remaining four trials (234 participants). When plasma transfusion was compared with no transfusion given, we are very uncertain whether there was a difference in 30-day mortality (1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; risk ratio (RR) 0.38, 95% confidence interval (CI) 0.13 to 1.10; very low-quality evidence). We are very uncertain whether there was a difference in major bleeding within 24 hours (1 trial comparing FFP transfusion vs no transfusion, 76 participants; RR 0.33, 95% CI 0.01 to 7.93; very low-quality evidence; 1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; RR 1.59, 95% CI 0.28 to 8.93; very low-quality evidence). We are very uncertain whether there was a difference in the number of blood product transfusions per person (1 trial, 76 participants; study authors reported no difference; very low-quality evidence) or in the number of people requiring transfusion (1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; study authors reported no blood transfusion given; very low-quality evidence) or in the risk of transfusion-related adverse events (acute lung injury) (1 trial, 76 participants; study authors reported no difference; very low-quality evidence). When plasma transfusion was compared with other pro-haemostatic agents, we are very uncertain whether there was a difference in major bleeding (1 trial; 21 participants; no events; very low-quality evidence) or in transfusion-related adverse events (febrile or allergic reactions) (1 trial, 21 participants; RR 9.82, 95% CI 0.59 to 162.24; very low-quality evidence). When different triggers for FFP transfusion were compared, the number of people requiring transfusion may have been reduced (for overall blood products) when a thromboelastographic-guided transfusion trigger was compared with standard laboratory tests (1 trial, 60 participants; RR 0.18, 95% CI 0.08 to 0.39; low-quality evidence). We are very uncertain whether there was a difference in major bleeding (1 trial, 60 participants; RR 0.33, 95% CI 0.01 to 7.87; very low-quality evidence) or in transfusion-related adverse events (allergic reactions) (1 trial; 60 participants; RR 0.33, 95% CI 0.01 to 7.87; very low-quality evidence). Only one trial reported 30-day mortality. No trials reported procedure-related harmful events (excluding bleeding) or quality of life. AUTHORS' CONCLUSIONS: Review findings show uncertainty for the utility and safety of prophylactic FFP use. This is due to predominantly very low-quality evidence that is available for its use over a range of clinically important outcomes, together with lack of confidence in the wider applicability of study findings, given the paucity or absence of study data in settings such as major body cavity surgery, extensive soft tissue surgery, orthopaedic surgery, or neurosurgery. Therefore, from the limited RCT evidence, we can neither support nor oppose the use of prophylactic FFP in clinical practice.


Assuntos
Anticoagulantes/uso terapêutico , Transfusão de Componentes Sanguíneos/métodos , Hemorragia/prevenção & controle , Procedimentos Cirúrgicos Operatórios , Anticoagulantes/efeitos adversos , Hemostáticos/uso terapêutico , Humanos , Plasma , Cuidados Pré-Operatórios , Ensaios Clínicos Controlados Aleatórios como Assunto , Tromboelastografia
19.
Trials ; 20(1): 592, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615553

RESUMO

BACKGROUND: Patients with haematological malignancies often develop thrombocytopenia as a consequence of either their disease or its treatment. Platelet transfusions are commonly given to raise a low platelet count and reduce the risk of clinical bleeding (prophylaxis) or stop active bleeding (therapy). Recent studies have shown that many patients continue to experience bleeding despite the use of prophylactic platelet transfusions. Tranexamic acid is an anti-fibrinolytic, which reduces the breakdown of clots formed in response to bleeding. Anti-fibrinolytics have been shown to prevent bleeding, decrease blood loss and use of red cell transfusions in elective and emergency surgery, and are used widely in these settings. The aim of this trial is to test whether giving tranexamic acid to patients receiving treatment for haematological malignancies reduces the risk of bleeding or death and the need for platelet transfusions. METHODS: This is a multinational randomised, double-blind, placebo-controlled, parallel, superiority trial. Patients will be randomly assigned to receive tranexamic acid (given intravenously or orally) or a matching placebo in a 1:1 ratio, stratified by site. Patients with haematological malignancies receiving intensive chemotherapy or stem cell transplantation (or both) who are at least 18 years of age and expected to become severely thrombocytopenic for at least 5 days will be eligible for this trial. The primary outcome of the trial is the proportion of patients who died or had bleeding of World Health Organization grade 2 or above during the first 30 days of the trial. We will measure the rates of bleeding daily by using a short, structured assessment of bleeding, and we will record the number of transfusions given to patients. We will assess the risk of arterial and venous thrombosis for 120 days from the start of trial treatment. DISCUSSION: This trial will assess the safety and efficacy of using prophylactic tranexamic acid during a period of intensive chemotherapy and associated thrombocytopenia in people with haematological disorders. TRIAL REGISTRATION: This study was prospectively registered on Current Controlled Trials on 25 March 2015 (ISRCTN73545489) and is also registered on ClinicalTrials.gov (NCT03136445).


Assuntos
Antifibrinolíticos/administração & dosagem , Fibrinólise/efeitos dos fármacos , Neoplasias Hematológicas/terapia , Hemorragia/prevenção & controle , Trombocitopenia/tratamento farmacológico , Ácido Tranexâmico/administração & dosagem , Administração Intravenosa , Administração Oral , Antifibrinolíticos/efeitos adversos , Austrália , Método Duplo-Cego , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/mortalidade , Hemorragia/sangue , Hemorragia/etiologia , Hemorragia/mortalidade , Humanos , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Trombocitopenia/sangue , Trombocitopenia/etiologia , Trombocitopenia/mortalidade , Ácido Tranexâmico/efeitos adversos , Resultado do Tratamento , Reino Unido
20.
Cochrane Database Syst Rev ; 9: CD012643, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31525824

RESUMO

BACKGROUND: Hodgkin lymphoma (HL) is one of the most common haematological malignancies in young adults and, with cure rates of 90%, has become curable for the majority of individuals. Positron emission tomography (PET) is an imaging tool used to monitor a tumour's metabolic activity, stage and progression. Interim PET during chemotherapy has been posited as a prognostic factor in individuals with HL to distinguish between those with a poor prognosis and those with a better prognosis. This distinction is important to inform decision-making on the clinical pathway of individuals with HL. OBJECTIVES: To determine whether in previously untreated adults with HL receiving first-line therapy, interim PET scan results can distinguish between those with a poor prognosis and those with a better prognosis, and thereby predict survival outcomes in each group. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL and conference proceedings up until April 2019. We also searched one trial registry (ClinicalTrials.gov). SELECTION CRITERIA: We included retrospective and prospective studies evaluating interim PET scans in a minimum of 10 individuals with HL (all stages) undergoing first-line therapy. Interim PET was defined as conducted during therapy (after one, two, three or four treatment cycles). The minimum follow-up period was at least 12 months. We excluded studies if the trial design allowed treatment modification based on the interim PET scan results. DATA COLLECTION AND ANALYSIS: We developed a data extraction form according to the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). Two teams of two review authors independently screened the studies, extracted data on overall survival (OS), progression-free survival (PFS) and PET-associated adverse events (AEs), assessed risk of bias (per outcome) according to the Quality in Prognosis Studies (QUIPS) tool, and assessed the certainty of the evidence (GRADE). We contacted investigators to obtain missing information and data. MAIN RESULTS: Our literature search yielded 11,277 results. In total, we included 23 studies (99 references) with 7335 newly-diagnosed individuals with classic HL (all stages).Participants in 16 studies underwent (interim) PET combined with computed tomography (PET-CT), compared to PET only in the remaining seven studies. The standard chemotherapy regimen included ABVD (16) studies, compared to BEACOPP or other regimens (seven studies). Most studies (N = 21) conducted interim PET scans after two cycles (PET2) of chemotherapy, although PET1, PET3 and PET4 were also reported in some studies. In the meta-analyses, we used PET2 data if available as we wanted to ensure homogeneity between studies. In most studies interim PET scan results were evaluated according to the Deauville 5-point scale (N = 12).Eight studies were not included in meta-analyses due to missing information and/or data; results were reported narratively. For the remaining studies, we pooled the unadjusted hazard ratio (HR). The timing of the outcome measurement was after two or three years (the median follow-up time ranged from 22 to 65 months) in the pooled studies.Eight studies explored the independent prognostic ability of interim PET by adjusting for other established prognostic factors (e.g. disease stage, B symptoms). We did not pool the results because the multivariable analyses adjusted for a different set of factors in each study.Overall survivalTwelve (out of 23) studies reported OS. Six of these were assessed as low risk of bias in all of the first four domains of QUIPS (study participation, study attrition, prognostic factor measurement and outcome measurement). The other six studies were assessed as unclear, moderate or high risk of bias in at least one of these four domains. Nine studies were assessed as high risk, and three studies as moderate risk of bias for the domain study confounding. Eight studies were assessed as low risk, and four studies as high risk of bias for the domain statistical analysis and reporting.We pooled nine studies with 1802 participants. Participants with HL who have a negative interim PET scan result probably have a large advantage in OS compared to those with a positive interim PET scan result (unadjusted HR 5.09, 95% confidence interval (CI) 2.64 to 9.81, I² = 44%, moderate-certainty evidence). In absolute values, this means that 900 out of 1000 participants with a negative interim PET scan result will probably survive longer than three years compared to 585 (95% CI 356 to 757) out of 1000 participants with a positive result.Adjusted results from two studies also indicate an independent prognostic value of interim PET scan results (moderate-certainty evidence).Progression-free survival Twenty-one studies reported PFS. Eleven out of 21 were assessed as low risk of bias in the first four domains. The remaining were assessed as unclear, moderate or high risk of bias in at least one of the four domains. Eleven studies were assessed as high risk, nine studies as moderate risk and one study as low risk of bias for study confounding. Eight studies were assessed as high risk, three as moderate risk and nine as low risk of bias for statistical analysis and reporting.We pooled 14 studies with 2079 participants. Participants who have a negative interim PET scan result may have an advantage in PFS compared to those with a positive interim PET scan result, but the evidence is very uncertain (unadjusted HR 4.90, 95% CI 3.47 to 6.90, I² = 45%, very low-certainty evidence). This means that 850 out of 1000 participants with a negative interim PET scan result may be progression-free longer than three years compared to 451 (95% CI 326 to 569) out of 1000 participants with a positive result.Adjusted results (not pooled) from eight studies also indicate that there may be an independent prognostic value of interim PET scan results (low-certainty evidence).PET-associated adverse eventsNo study measured PET-associated AEs. AUTHORS' CONCLUSIONS: This review provides moderate-certainty evidence that interim PET scan results predict OS, and very low-certainty evidence that interim PET scan results predict progression-free survival in treated individuals with HL. This evidence is primarily based on unadjusted data. More studies are needed to test the adjusted prognostic ability of interim PET against established prognostic factors.


Assuntos
Quimiorradioterapia/métodos , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Humanos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto
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