What is the aim of this review?
The aim of this Cochrane Review was to find out whether currently available medications for prevention of blood clots have an appreciable balance between benefits and harms in adults with a subtype of blood cancer called acute lymphoblastic leukaemia (ALL) treated with asparaginase-containing chemotherapy.
We are uncertain whether blood-derived products such as antithrombin concentrates for the prevention of blood clots in adults with ALL treated with asparaginase-based chemotherapy are associated with unacceptable harms such as death. Our confidence in the identified studies is limited because of their non-randomised design with few participants and no control for underlying factors that could influence the outcome.
Harms regarding other types of blood clot prevention such as low-molecular-weight heparin could not be evaluated, because death and bleeding were not reported. We did not look at benefits such as reduction in risk of blot clots, given the low quality of identified evidence (no randomised studies). We need high-quality randomised studies, as the conduct of such studies minimises the risk of underlying factors influencing the outcomes.
What was studied in this review?
ALL is a subtype of blood cancer arising from malignant transformation of immature white blood cells of lymphoid origin. Over the last 20 years, the historically poor survival in adults with this disease has markedly improved, primarily due to the introduction of more intensive anti-leukaemic treatment inspired by that used in children with ALL. One of the hallmarks of this treatment is the intensive use of the anti-leukaemic agent called asparaginase. However, nothing comes without a price. Both older age and asparaginase treatment increase the risk of blood clots, which can either block the blood vessels (predominantly in those called veins) and change the normal blood flow or shower fractions of the clot into other veins located in important organs, resulting in serious health problems. Additionally, doctors are prone to stop asparaginase treatment, if blood clots occur—potentially compromising survival in these people.
We do not know if the existing types of blood clot prevention protect against the clots and do not cause bleeding and death in adults with this disease. The medications include heparins, vitamin K antagonists, synthetic pentasaccharides, direct thrombin inhibitors, direct oral anticoagulants, or blood-derived products for antithrombin substitution (decreased production in the body of this anti-blood clotting protein during asparaginase), and mechanical prevention such as graduated elastic stockings.
Therefore, we looked at all currently available research in adults with ALL treated with asparaginase-containing chemotherapy who received blood clot prevention compared to placebo or no prevention. We looked at the following outcomes: first-time symptomatic venous blood clot, all-cause death, major bleeding, blood clot-related death, asymptomatic venous blood clot, clinically relevant non-major bleeding, heparin-induced lowering of blood platelet counts, and quality of life.
What are the results of this review?
We found 23 studies, of which we included two studies in our main analyses to help answer the question and nine studies in an additional analysis to help describe the limitations of the evidence. The remaining 12 studies could not be included due to missing outcomes or critical risk of bias, as people in the control group were not 'real' controls.
The two studies from our main analysis were conducted in UK/Canada and compared antithrombin with no antithrombin concentrates and low-molecular-weight heparin with no low-molecular-weight heparin, respectively, for people with ALL. We are uncertain whether antithrombin concentrates in adults with ALL treated with asparaginase-based chemotherapy improve/reduce all-cause/blood clot-related death, because our confidence in the evidence was very low (one study, 40 adults). Harms in relation to the use of low-molecular-weight heparin could not be evaluated, because all-cause/blood clot-related death, major/clinically relevant non-major bleeding, or heparin-induced lowering of platelets were not reported. None of the studies looked at quality of life.
No studies were found that evaluated any of the other prevention types. We did not look at benefits such as reduction in risk of blood clots, given the low certainty of evidence.
How up to date is this review?
The review authors searched for studies that had been published up to 02 June, 2020.
We do not know from the currently available evidence, if thromboprophylaxis used for adults with ALL treated according to asparaginase-based regimens is associated with clinically appreciable benefits and acceptable harms. The existing research on this question is solely of non-randomised design, seriously to critically confounded, and underpowered with substantial imprecision. Any estimates of effect based on the existing insufficient evidence is very uncertain and is likely to change with future research.
The risk of venous thromboembolism is increased in adults and enhanced by asparaginase-based chemotherapy, and venous thromboembolism introduces a secondary risk of treatment delay and premature discontinuation of key anti-leukaemic agents, potentially compromising survival. Yet, the trade-off between benefits and harms of primary thromboprophylaxis in adults with acute lymphoblastic leukaemia (ALL) treated according to asparaginase-based regimens is uncertain.
The primary objectives were to assess the benefits and harms of primary thromboprophylaxis for first-time symptomatic venous thromboembolism in adults with ALL receiving asparaginase-based therapy compared with placebo or no thromboprophylaxis.
The secondary objectives were to compare the benefits and harms of different groups of primary systemic thromboprophylaxis by stratifying the main results per type of drug (heparins, vitamin K antagonists, synthetic pentasaccharides, parenteral direct thrombin inhibitors, direct oral anticoagulants, and blood-derived products for antithrombin substitution).
We conducted a comprehensive literature search on 02 June 2020, with no language restrictions, including (1) electronic searches of Pubmed/MEDLINE; Embase/Ovid; Scopus/Elsevier; Web of Science Core Collection/Clarivate Analytics; and Cochrane Central Register of Controlled Trials (CENTRAL) and (2) handsearches of (i) reference lists of identified studies and related reviews; (ii) clinical trials registries (ClinicalTrials.gov registry; the International Standard Randomized Controlled Trial Number (ISRCTN) registry; the World Health Organisation's International Clinical Trials Registry Platform (ICTRP); and pharmaceutical manufacturers of asparaginase including Servier, Takeda, Jazz Pharmaceuticals, Ohara Pharmaceuticals, and Kyowa Pharmaceuticals), and (iii) conference proceedings (from the annual meetings of the American Society of Hematology (ASH); the European Haematology Association (EHA); the American Society of Clinical Oncology (ASCO); and the International Society on Thrombosis and Haemostasis (ISTH)). We conducted all searches from 1970 (the time of introduction of asparaginase in ALL treatment). We contacted the authors of relevant studies to identify any unpublished material, missing data, or information regarding ongoing studies.
Randomised controlled trials (RCTs); including quasi-randomised, controlled clinical, cross-over, and cluster-randomised trial designs) comparing any parenteral/oral preemptive anticoagulant or mechanical intervention with placebo or no thromboprophylaxis, or comparing two different pre-emptive anticoagulant interventions in adults aged at least 18 years with ALL treated according to asparaginase-based chemotherapy regimens. For the description of harms, non-randomised observational studies with a control group were eligible for inclusion.
Using a standardised data collection form, two review authors independently screened and selected studies, extracted data, assessed risk of bias for each outcome using standardised tools (RoB 2.0 tool for RCTs and ROBINS-I tool for non-randomised studies) and the certainty of evidence for each outcome using the GRADE approach. Primary outcomes included first-time symptomatic venous thromboembolism, all-cause mortality, and major bleeding. Secondary outcomes included asymptomatic venous thromboembolism, venous thromboembolism-related mortality, adverse events (i.e. clinically relevant non-major bleeding and heparin-induced thrombocytopenia for trials using heparins), and quality of life. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. For non-randomised studies, we evaluated all studies (including studies judged to be at critical risk of bias in at least one of the ROBINS-I domains) in a sensitivity analysis exploring confounding.
We identified 23 non-randomised studies that met the inclusion criteria of this review, of which 10 studies provided no outcome data for adults with ALL. We included the remaining 13 studies in the 'Risk of bias' assessment, in which we identified invalid control group definition in two studies and judged outcomes of nine studies to be at critical risk of bias in at least one of the ROBINS-I domains and outcomes of two studies at serious risk of bias.
We did not assess the benefits of thromboprophylaxis, as no RCTs were included. In the main descriptive analysis of harms, we included two retrospective non-randomised studies with outcomes judged to be at serious risk of bias. One study evaluated antithrombin concentrates compared to no antithrombin concentrates. We are uncertain whether antithrombin concentrates have an effect on all-cause mortality (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.26 to 1.19 (intention-to-treat analysis); one study, 40 participants; very low certainty of evidence). We are uncertain whether antithrombin concentrates have an effect on venous thromboembolism-related mortality (RR 0.10, 95% CI 0.01 to 1.94 (intention-to-treat analysis); one study, 40 participants; very low certainty of evidence). We do not know whether antithrombin concentrates have an effect on major bleeding, clinically relevant non-major bleeding, and quality of life in adults with ALL treated with asparaginase-based chemotherapy, as data were insufficient. The remaining study (224 participants) evaluated prophylaxis with low-molecular-weight heparin versus no prophylaxis. However, this study reported insufficient data regarding harms including all-cause mortality, major bleeding, venous thromboembolism-related mortality, clinically relevant non-major bleeding, heparin-induced thrombocytopenia, and quality of life.
In the sensitivity analysis of harms, exploring the effect of confounding, we also included nine non-randomised studies with outcomes judged to be at critical risk of bias primarily due to uncontrolled confounding. Three studies (179 participants) evaluated the effect of antithrombin concentrates and six studies (1224 participants) evaluated the effect of prophylaxis with different types of heparins. When analysing all-cause mortality; venous thromboembolism-related mortality; and major bleeding (studies of heparin only) including all studies with extractable outcomes for each comparison (antithrombin and low-molecular-weight heparin), we observed small study sizes; few events; wide CIs crossing the line of no effect; and substantial heterogeneity by visual inspection of the forest plots. Although the observed heterogeneity could arise through the inclusion of a small number of studies with differences in participants; interventions; and outcome assessments, the likelihood that bias due to uncontrolled confounding was the cause of heterogeneity is inevitable. Subgroup analyses were not possible due to insufficient data.