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Hypercoagulability in hematological malignancies

Lauw, M.N.

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Chapter 12 Prophylaxis for venous thromboembolism during asparaginase therapy in patients treated for acute lymphoblastic leukemia

Mandy N. Lauw, Lowiek M. Hubers, Stefano L. Barco, Irene L.M. Klaassen, C. Heleen van Ommen, Barbara A. Hutten, Bart J. Biemond, Saskia Middeldorp

Cochrane Database Syst Rev. 2015

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abstract

Background: Venous thromboembolism (VTE) occurs frequently in patients with

acute lymphoblastic leukemia (ALL). Reported incidences range from 2 to 37%. VTE is

often associated with treatment components, particularly asparaginase. The efficacy,

safety and optimal approach of systemic prophylaxis for VTE during asparaginase

therapy in patients treated for ALL are unclear.

Objectives: Our main objectives were to investigate the efficacy and safety of VTE

prophylaxis during asparaginase therapy in pediatric and adult patients treated for

ALL, and to evaluate the effect of thromboprophylaxis during ALL treatment on

overall survival.

The secondary objectives were to investigate and summarize which thrombopro-

phylactic measure is the most effective and safe during asparaginase therapy for ALL

treatment, and to evaluate the impact of thromboprophylaxis during ALL treatment

on ALL outcome, expressed as complete remission rates.

Search methods: We searched The Cochrane Central Register of Controlled Trials

(CENTRAL, The Cochrane Library, Issue 11 2014), MEDLINE (January 1966 to De-

cember 2014; accessed via PubMed) and EMBASE (January 1980 to December 2014;

accessed via Ovid). We hand searched conference proceedings and references of

relevant papers. In addition, we scanned online registers for ongoing clinical trials.

We contacted authors of identified studies if needed for additional information.

Selection criteria: Randomized controlled trials (RCTs) comparing systemic throm-

boprophylaxis with no intervention or a control intervention during asparaginase

therapy in patients treated for ALL, were eligible. Interventions included any dose

of fresh frozen plasma, cryoprecipitate, antithrombin concentrate, (low-molecular-

weight) heparin, fondaparinux or oral anticoagulants, in comparison with no inter-

vention or placebo, or a comparison of two different interventions.

Data collection and analysis: Three authors independently selected studies, ex-

tracted data and performed risk of bias assessment of the included studies. Discrep-

ancies were resolved by consensus or with the opinion of a fourth author. Analyses

were performed in accordance with the guidelines of the Cochrane Handbook for

Systematic Reviews of Intervention.

Main results: Of 390 identified citations, only 1 RCT was eligible. This RCT com-

pared systemic antithrombin concentrate infusions (once weekly for 4 weeks) with no

intervention to prevent VTE in 109 children treated for ALL. Outcomes were symp-

191

Review: Prophylaxis for VTE in ALL |

12

tomatic and asymptomatic thrombosis (by routine imaging following completion of

the induction phase), laboratory markers and bleeding events. The study had a high

risk of bias.

We found no significant effects of systemic prophylaxis (antithrombin supple-

mentation) compared with no intervention on the risk of VTE, and no differences

in bleeding events. Overall survival, loss of a central venous catheter due to VTE,

VTE-related death, complete remission rates upon end of study treatment, disease-

free survival of ALL patients, or quality of life after completion of treatment for ALL

among participants, were not reported.

Conclusions: We found no significant effects of systemic prophylaxis compared with

no intervention on the risk of VTE during asparaginase therapy in patients treated for

ALL. However, only one RCT was identified with a small sample size and a high risk

of bias. Moreover, this study was not powered to demonstrate efficacy or safety of

prophylactic antithrombin supplementation. No RCTs were found addressing other

blood-derived products or anticoagulants for systemic VTE prophylaxis in patients

treated for ALL.

Based on the currently available evidence, the efficacy and safety of systemic VTE

prophylaxis in patients treated for ALL remain unclear, and we are not able to give

recommendations for clinical practice. Well-designed and sufficiently powered RCTs

are needed to further assess the efficacy and safety of systemic thromboprophylaxis

in patients treated for ALL. Due to the rarity of the disease ALL, such trials will require

multicenter and international collaborations.

backGround

Description of the condition

Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children.

It is characterized by a bimodal age pattern, with a peak incidence at one to four

years of age and a second rise at ages over 60 years.1 The complete remission, cure

and overall survival rates of ALL have significantly increased with advances in combi-

nation chemotherapy and stem cell transplantation technology, both in pediatric and

adult patients.1-3 However, treatment-related complications still represent a major

issue of concern.

Venous thromboembolism (VTE) is one of the most frequent and serious complica-

tions during ALL treatment, leading to morbidity, mortality and premature discon-

tinuation of therapy.3-6 Reported incidences range from 2% to 37%, depending on

differences in VTE definitions (e.g. asymptomatic, symptomatic), study design or

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treatment protocols. Most estimates come from observational studies in pediatric

ALL patients, but the incidence seems to be higher in adults.3, 5, 7-10

VTE complications can lead to suboptimal ALL treatment due to premature

therapy discontinuation or therapy interruptions and, hence, to decreased treatment

outcome, reflected in inferior complete remission or overall survival rates.11 Although

direct mortality is infrequent,3, 4 patients with VTE frequently endure long-term mor-

bidity. Up to 50% of patients develop a lifelong post-thrombotic syndrome, a clinical

syndrome of pain, swelling and skin changes of the affected limb.5 Severe morbidity

specifically applies to patients with VTE in the central nervous system, with 5% direct

mortality, 10% to 20% long-term neurological defects (such as headaches and weak-

nesses) and 3% recurrence.12 Finally, the additional costs related to VTE treatment

are considerable.

The pathogenesis of VTE during ALL treatment is multifactorial and still poorly

understood. Associations have been made with disease, host and treatment modali-

ties.3, 10, 13-15 An increased thrombin generation capacity and decreased fibrinolysis

is observed upon diagnosis in ALL patients.13, 16-22 The highest VTE risk arises in the

first weeks after treatment initiation, especially during the use of asparaginase and

steroids.3, 5, 6, 10, 13, 15, 18, 19, 23

Asparaginase forms a key component of ALL treatment, effectively destroying

human lymphoblasts by inducing a depletion of circulating asparagine, which is

necessary for the survival of lymphoblasts. Asparaginase use has led to superior

complete remission and disease-free survival rates, and is incorporated in nearly

all treatment regimens for pediatric and adult patients.2, 24 However, it also induces

coagulation disorders due to decreased plasma concentrations of hepatic proteins,

most prominently antithrombin and fibrinogen, caused by inhibited biosynthesis and

increased clearance.3, 18, 19, 21, 25 The subsequent antithrombin deficiency, leading to

impaired thrombin inhibition, is thought to play an important role in VTE develop-

ment during ALL treatment.4, 6, 10, 13, 18, 23, 25 Asparaginase therapy in ALL is frequently

used in combination with steroids. Steroids can induce an increase in coagulation

factors, particularly factor VIII and von Willebrand factor, and a decrease in fibrino-

lytic factors.3, 13, 16, 18, 20-22, 26, 27 Thrombophilic mutations of patients may also contribute

to an increased risk of VTE.3, 10, 14 In addition, presence of central venous catheters,

common practice during ALL treatment in children, is strongly associated with an

increased risk of VTE.3, 8, 10, 13, 28-30

Most VTE incidence estimations derive from ALL treatment studies performed

without thromboprophylactic measures.3, 8, 9 Given the high incidence of VTE ob-

served during ALL treatment and its considerable associated morbidity, efficacious

and safe preventive measures are of great importance. Prevention of VTE during ALL

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treatment is complex, as thrombotic and bleeding risk factors need to be balanced.

Different approaches are widely used,6 but no guidelines are available.

Description of the intervention

In this review, we evaluated the efficacy and safety of systemic prophylaxis for VTE in

pediatric and adult patients treated with asparaginase therapy for newly diagnosed

ALL, in a hospital setting. Thromboprophylactic measures that were evaluated are

both blood-derived products to supplement deficient natural (anti)coagulation fac-

tors, e.g. fresh frozen plasma, cryoprecipitate and antithrombin concentrate, as well

as pharmacological anticoagulants, e.g. low-molecular-weight heparin, unfraction-

ated heparin, fondaparinux and oral anticoagulants (vitamin K antagonists; warfarin

or acenocoumarol). All measures should be applied systemically with prophylactic

intention. We did not evaluate mechanical preventive measures, such as elastic

compression stockings or intermittent pneumatic compression.

How the intervention might work

Supplementation of deficient natural (anti)coagulation factors by blood-derived

products, e.g. fresh frozen plasma, cryoprecipitate or antithrombin concentrate, may

decrease disease- or treatment-induced deficiencies of pro- and anticoagulant fac-

tors and, thereby, reduce the procoagulant state and possibly the incidence of VTE.

Parental anticoagulants, e.g. low-molecular-weight heparin, unfractionated

heparin and fondaparinux do not have intrinsic anticoagulant activity, but potentiate

the activity of antithrombin in inhibiting activated coagulation factors. They are not

absorbed orally and must be administered parenterally by intravenous infusion or

subcutaneous injections. Oral anticoagulants, e.g. vitamin K antagonists, directly in-

hibit the activity of individual vitamin K-dependent coagulation factors (factor II, VII,

IX and X) and are the mainstay of oral anticoagulant therapy, with proven effective-

ness for primary and secondary prevention of both venous and arterial thrombosis.31

Why it is important to do this review

Each approach for thromboprophylaxis in ALL has its advantages and disadvantages.

Prophylactic supplementation with blood-derived products like fresh frozen plasma,

cryoprecipitate or antithrombin concentrate requires daily infusion of large fluid

volumes during the period of asparaginase therapy, risking transfusion-associated

circulatory overload. Moreover, these products are relatively costly, with prices

varying worldwide from USD 100 per infusion bag of 500 mL fresh frozen plasma,

to more than USD 800 per 500 international unit (IU) of antithrombin concentrate,

respectively. Several infusions of these products are required for daily prophylactic

supplementation. Also, monitoring is advised to assess the necessity and effect of

supplementation. However, the bleeding risk is relatively low with these measures.

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Pharmacological anticoagulants like low-molecular-weight heparin, unfractionated

heparin, fondaparinux or oral vitamin K antagonists encompass a greater bleeding

risk and weight-adjusted dosing, but are relatively cheaper to administer for a longer

period of time, with prices varying from USD 4 to USD 20 per daily required unit.

Moreover, these anticoagulants, except for unfractionated heparin, do not require a

constant intravenous access contrary to blood-derived products.

Several studies, including two Cochrane reviews,32, 33 have been published describ-

ing the use of systemic thromboprophylactic measures for the prevention of central

venous catheter-related thrombosis in cancer patients. However, other manifesta-

tions of VTE, such as central nervous system thrombosis, are also frequently seen in

ALL, while systematic reviews or guidelines for VTE prevention during ALL treatment

are lacking. Therefore, we conducted a systematic review to investigate the clinical

efficacy and safety of the use of systemic VTE prophylaxis in pediatric and adult

patients treated with asparaginase therapy for newly diagnosed ALL.

Objectives

Our main objectives were to investigate the efficacy and safety of VTE prophylaxis

during asparaginase therapy in pediatric and adult patients treated for ALL, and to

evaluate the effect of thromboprophylaxis during ALL treatment on overall survival.

The secondary objectives were to investigate and summarize which thrombopro-

phylactic measure is the most effective and safe during asparaginase therapy for ALL

treatment, and to evaluate the impact of thromboprophylaxis during asparaginase

therapy for ALL treatment on ALL outcome, expressed as complete remission rates.

methods

Criteria for considering studies for this review

Types of studies

Only randomized controlled trials (RCTs) were eligible. Cross-over, quasi-randomized,

cluster randomized, controlled clinical, (historical) cohort, or trials with institutional

distributions were not included. Both full-text and abstract publications, if sufficient

information is available in the abstract on study design, characteristics of partici-

pants, interventions and outcomes, were included.

Types of participants

Pediatric and adult patients with newly diagnosed ALL, according to the French-

American-British (FAB) criteria or World Health Organization (WHO, 2008) clas-

sification of lymphoid neoplasms (with the exclusion of ALL-L3 or Burkitt leukemia/

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12

lymphoma) and treated for this condition in a hospital setting, were eligible. Trials

that included mixed populations, i.e. patients with different hematological malignan-

cies, were only used for ALL subgroups, if sufficient data for patients with ALL were

provided and if 80% of patients or more in the trial were treated for ALL. Patients with

previous VTE or another indication for systemic therapeutic anticoagulation were

excluded from analyses.

Types of interventions

Interventions included either use of blood-derived products, e.g. fresh frozen plasma,

cryoprecipitate or antithrombin concentrate, or anticoagulant agents, e.g. (low-mo-

lecular-weight) heparin, fondaparinux or oral anticoagulants (vitamin K antagonists),

or both, for primary prevention of VTE in patients treated with asparaginase therapy

for ALL, in a hospital setting. Comparison interventions included either an inactive

control (placebo or no intervention), or an active control intervention (prophylaxis

with another blood-derived product or pharmacological anticoagulant, or a different

scheme, regimen or dosage of the same intervention).

Any frequency, duration, timing and dosage of thromboprophylaxis was consid-

ered. In case multiple dosages of thromboprophylaxis were used in one trial, we

attempted to compare each dosage to a separate control intervention. We did not

group different types of interventions together for this comparison.

Other elements of ALL treatment (e.g. chemotherapy, other supportive care) should

have been provided similarly in means and timing in both intervention groups. We

did not evaluate mechanical preventive measures, such as elastic compression stock-

ings or intermittent pneumatic compression.

Types of outcome measures

Primary outcomes

The primary efficacy outcome was symptomatic VTE, including central venous

catheter-related VTE, during ALL treatment, objectively confirmed by imaging

(computerized tomography (CT) or magnetic resonance imaging (MRI) for central

nervous system or abdominal thrombosis, compression or Doppler ultrasonography

or venography for deep vein thrombosis of the leg or upper limb vein thrombosis,

(spiral) CT for pulmonary embolism).

The main safety outcome was clinically relevant or major bleeding, or minor bleed-

ing, as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria (Appendix

1) or the authors’ definitions. Other safety outcomes included thrombocytopenia,

heparin-induced thrombocytopenia, heparin-induced thrombocytopenia with

thrombosis, allergies, or death.

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The other primary efficacy outcome was overall survival, defined as the time inter-

val from time of inclusion/entry in the ALL study until death from any cause or last

follow-up.

Secondary outcomes

Secondary outcomes included:

- asymptomatic VTE, including central venous catheter-related VTE, during treat-

ment, resulting from screening for VTE with abovementioned imaging methods;

- loss of a central venous catheter due to VTE, defined as loss of central venous

catheter patency (the inability to either infuse or withdraw a sample which could

not be corrected by use of local anticoagulation) or removal of a central venous

catheter due to loss of patency, or due to VTE treatment;

- VTE-related death, measured by death directly accounted by VTE occurrence;

- complete remission rates upon end of study treatment;

- disease-free survival of ALL patients, defined as the time interval from complete

remission until disease relapse, last follow-up or death from any cause;

- quality of life after completion of treatment for newly diagnosed ALL, measured

by validated questionnaires.

Search methods for identification of studies

Electronic searches

We systematically searched The Cochrane Central Register of Controlled Trials

(CENTRAL, The Cochrane Library, Issue 11 of 12, 17 December 2014), MEDLINE

(January 1966 to 17 December 2014; accessed via PubMed), and EMBASE (January

1980 to 17 December 2014; accessed via Ovid). The used search strategies, using a

combination of controlled vocabulary and text words, are shown in the appendices

(Appendix 2, Appendix 3, Appendix 4). We did not apply language restrictions. We

will update the searches every three years.

Searching other resources

We checked references of relevant studies. We hand searched conference proceed-

ings to December 2014 of the International Society on Thrombosis and Haemostasis

(ISTH), American Society of Hematology (ASH), American Society of Clinical Oncol-

ogy (ASCO) and European Haematology Association (EHA). The authors searched

the following clinical trial registers (up to 17 December 2014) to identify studies not

registered in CENTRAL, MEDLINE or EMBASE, either ongoing or unpublished: http://

www.trialregister.nl, http://www.clinicaltrialsregister.eu, http://www.controlled-trials.

com/mrct/, http://www.who.int/ictrp/en/, http://www.clinicaltrials.gov.

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Data collection and analysis

Selection of studies

After employing the search strategies described previously, three review authors

(MNL, LMH and SLB) independently identified studies meeting the inclusion criteria

for this review. They were not blinded to the journal, authors or institutions. Any

discrepancies were resolved by consensus or, if not resulting in agreement, with

the opinion of a fourth author (SM). We screened titles and abstracts of papers for

eligibility for this review, and retrieved the full text of articles that were judged as

potentially eligible by at least one review author.34 We contacted authors for ad-

ditional information if necessary. We clearly stated details of reasons for exclusion of

any study considered for review and showed all excluded studies in a flow diagram

according to the PRISMA statement.35

Data extraction and management

Three review authors (MNL, LMH, SLB) independently extracted relevant data from

eligible studies according to the guidelines by The Cochrane Collaboration,34 using

a standardized data extraction form. Data extraction included general characteristics

of the paper, characteristics of the study design and setting, study participants, study

interventions, the outcomes assessed and the follow-up provided. We contacted

authors for additional information on studies if necessary. We resolved disagree-

ments by consensus or, if not resulting in agreement, with the opinion of a fourth

author (SM).

Assessment of risk of bias in included studies

Three review authors (MNL, LMH, SLB) independently assessed the risk of bias of

included RCTs using the domain-based risk of bias evaluation tool, i.e., selection

bias, performance bias, detection bias, attrition bias and reporting bias, recom-

mended by The Cochrane Collaboration.34 We assessed the methodological qual-

ity of each included RCT using a validity assessment form containing the domains

and corresponding items as suggested in the Cochrane Handbook for Systematic

Reviews of Interventions:34 selection bias (random sequence generation, allocation

concealment), performance bias (blinding of participants, personnel), detection bias

(blinding of outcome assessment), attrition bias (incomplete outcome data), report-

ing bias (selective reporting) and other sources of bias. For every item, we made a

judgement using one of the following three categories: ‘Low risk’ of bias, ‘high risk’

of bias, or ‘unclear risk’ of bias. We contacted authors for additional information on

studies if necessary. We resolved disagreements by consensus or, if not resulting in

agreement, with the opinion of a fourth author (SM).

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Secondly, we assessed the quality of evidence at the outcome level using the

Grading of Recommendations Assessment, Development and Evaluation (GRADE)

approach.34 We contacted authors for additional information on studies if necessary.

We resolved disagreements by consensus or, if not resulting in agreement, with the

opinion of a fourth author (SM). We presented the results of the ‘Risk of bias’ assess-

ment in the ‘Risk of bias’ table and in a methodological quality summary. We took

the risk of bias of included studies into account in the interpretation of the review’s

results.

Measures of treatment effect

For dichotomous outcomes, we expressed the effect estimate as a risk ratio (RR). For

continuous outcomes, we used mean differences (MD) if the same scale was used

for measurement, and standardized mean differences (SMD) if different scales were

used.34 For time-to-event outcomes or survival data, we estimated treatment effects

as hazard ratios (HR). If HR were not provided by the authors, we estimated them

using the methods of Parmar 36 and Tierney.37 If only one study was available and

no events were reported in one of the treatment groups, it was not appropriate to

calculate the RR. For these outcomes, we calculated Fisher’s exact P value instead,

using GraphPad Prism for Windows, version 5 (GraphPad Software Inc, San Diego,

CA, USA, www.graphpad.com). We presented all results with corresponding 95%

confidence intervals (CI). All reported P values are two-sided with significance level

α = 0.05.

Unit of analysis issues

Only RCTs with individual randomization of participants to one of the intervention

groups were considered for this review. As we only included RCTs with a parallel

design, other unit of analysis issues were not applicable.

Dealing with missing data

If relevant data were missing, we attempted to contact the authors to retrieve the

missing data. We tried to distinguish between data ‘missing at random’ and data ‘not

missing at random’.34 We analyzed available data only and, if possible, extracted data

by allocation intervention, irrespective of compliance with the allocated intervention,

to allow an ‘intention-to-treat’ analysis. If outcome data were not presented in an

intention-to-treat fashion, we stated this and performed an available case analysis

based on the primary analysis of the study.34, 38

Assessment of heterogeneity

In meta-analyses with more trials, we aimed to assess statistical heterogeneity by

visual examination of forest plots, and by use of the I2 statistic to quantify possible

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12

heterogeneity (I2 > 30% moderate heterogeneity, I2 > 50% significant heterogene-

ity).34. In case of significant heterogeneity (I2 > 50%), potential causes for it were

explored. However, because we only included one study, this was not applicable.

Assessment of reporting biases

In addition to evaluating reporting bias as described in the ‘Assessment of risk of

bias’ section, we planned to explore reporting bias in meta-analyses with more than

10 studies, by generating funnel plots to graphically illustrate variability between

trials. This is not done if there are fewer studies because the power of the tests is

too low to distinguish chance from real asymmetry, if fewer studies are included.

However, because none of our meta-analyses included 10 or more trials, this was not

applicable. To reduce reporting bias, we searched multiple electronic databases and

sources, proceedings of scientific meetings and trial registries to deal with location

and time lag bias, as described in our search methods for identification of studies.

We excluded duplicate reports of the same study to avoid duplicate publication bias.

Data synthesis

For statistical analysis, we entered data into Review Manager (RevMan) 5.3 (The Nor-

dic Cochrane Centre, The Cochrane Collaboration, Copenhagen 2014), and under-

took analyses according to the guidelines of the Cochrane Handbook for Systematic

Reviews of Interventions.34 We presented results for which data were available in a

table of comparisons and outcomes. We aimed to summarize results by performing

a pooled meta-analysis using a random-effects model; however, if groups were not

comparable or if there were insufficient eligible studies, we summarized the results

descriptively. We aimed to perform an analysis of all results combined together and

a separate analysis for patients treated according to pediatric or adult ALL treat-

ment protocols, because of the major differences in treatment design and dosages.

However, this was not applicable as we only included a study with pediatric patients.

Subgroup analysis and investigation of heterogeneity

We planned to perform a separate analysis for patients treated according to pediatric

or adult ALL treatment protocols, irrespective of the presence of heterogeneity, and

to perform a subgroup analyses for patients with and without asparaginase therapy

in the first remission induction cycle of ALL treatment, for patients with and without

a central venous catheter, and for patients with and without thrombophilic muta-

tions (Factor V Leiden or prothrombin G20210A mutation, or congenital/persistent

deficiencies of antithrombin, protein C or S).

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Sensitivity analysis

We planned to perform a sensitivity analysis with respect to the quality and design of

trials, by excluding studies with a low methodological quality or ‘high risk’ of bias,34

for all meta-analyses that included more than one study. However, this was not ap-

plicable as we only included one study in our analyses.

results

Description of studies

Searches of CENTRAL, MEDLINE and EMBASE identified 390 citations of potentially

relevant papers. We excluded 334 citations based on title and abstract. 56 articles

were selected for full-text evaluation. 17 articles were available as abstract only and

39 articles were screened by full-text analysis. Of these, 17 abstracts and 38 full-text

studies (total = 55) were excluded. Searching of conference proceedings yielded 4

additional relevant abstracts. Checking references of relevant studies yielded an-

other 22 articles. After (full-text) analysis, all 26 additional studies were excluded. We

searched for ongoing studies in online registers http://www.trialregister.nl, http://

www.clinicaltrialsregister.eu, http://www.controlled-trials.com/mrct/, http://www.

who.int/ictrp/en/, http://www.clinicaltrials.gov. There were no ongoing trials relevant

to this review. Thus, we included only one study in our review and for our analysis

[Mitchell 2003].39 Figure 1 shows the flow diagram of selection of studies for this

review, Tables 1A and B list the characteristics of the included study and risk of bias

assessment, and Table 2 shows a complete list of excluded studies with reasons for

exclusion.

Included studies

Characteristics of the selected RCT (N=1; Mitchell 2003),39 including a total number

of 109 participants, are presented in Table 1A. This study compared systemic VTE

prophylaxis by antithrombin supplementation with no intervention in 109 children

treated for ALL (1:2 ratio). Systemic antithrombin infusions, once weekly for 4 weeks

(days 1, 8, 15, 22) were given according to a certain formula (IU required = ((de-

sired – baseline antithrombin levels) x weight (kg) / 1.4), to increase plasma con-

centrations of antithrombin to approximately 3.0 IU/ml but no more than 4.0 IU/

ml. The study investigated the effects of the intervention on the risk of clinically

significant symptomatic or asymptomatic VTE. The primary analysis was performed

on a ‘per-protocol’ and not on an ‘intention-to-treat’ basis, as the authors stated

that the study was set up as “a pilot study designed to assess whether antithrombin

infusions could potentially work using a carefully controlled setting”. Thrombotic

events were categorized as ‘not clinically significant’ in case of a fibrin sheath or

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12loss of central venous catheter patency, which was restored with urokinase therapy.

Thrombotic events were categorized as ‘clinically significant’ in all other events.

Symptomatic VTE events were detected by close monitoring of patients during the

study period and confirmed using appropriate objective imaging tests. No defini-

tions were stipulated for clinical presentation, which was left to the judgement of the

attending physician. Asymptomatic VTE events were detected by routine imaging

(screening) after completion of the induction phase of chemotherapy and during

follow-up (day 28 to a further 3 months). The study describes use of the following

imaging tests: “1) bilateral venography or MRI of the upper body, 2) ultrasound of

the upper body, 3) echocardiogram, 4) MRI of the head.” Occurrence of major and

minor bleeding episodes was also investigated. Major bleeding was defined as overt

bleeding requiring transfusion of red blood cells or any bleed into the central ner-

Citations identified by database searching (N = 390)- CENTRAL (N = 91)- MEDLINE (N = 164)- EMBASE (N = 135)

Articles eligible for full-text evaluation (N = 56)

Articles excluded after titleand abstract evaluation (N = 334)

Studies included based on selection criteria:N = 1

Additional articles obtained from references of relevant studies (N = 22)

Studies excluded after full-text evaluation (N = 81; 60 full-text, 21 abstracts)

Additional abstracts obtained from conference proceedings (N = 4)

Ongoing trials identified byonline registers (N = 0)

Figure 1. Flow diagram of selection of studies

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Table 1. Characteristics of included studies

Table 1A – Mitchell 200339

Methods Open-label, multicenter, randomized, controlled, extended phase II trial

Participants 109 non-selected pediatric patients newly diagnosed with ALL being treated in nine pediatric tertiary centers in Canada and the USA between July 1997 and May 1999. The inclusion criteria were: age > 6 months and <18 years, newly diagnosed patients with ALL at the beginning of the induction chemotherapy (which included ASP), a functioning central venous catheter (CVC) placed within 2 weeks of initiating induction chemotherapy and obtaining informed consent.

Interventions Antithrombin supplementation by antithrombin infusions (N=37; intervention group) versus no intervention (N=72; control group). Patients randomized to antithrombin received infusions of antithrombin (Thrombate III®, Bayer Corporation, USA) once weekly for 4 weeks (days 1, 8, 15, 22) to increase plasma concentrations of antithrombin to approximately 3.0 units/mL but no more than 4.0 units/mL. A pre-infusion blood sample was drawn and an antithrombin level was performed within ± 24 hours of the scheduled antithrombin infusion. The amount of antithrombin required was calculated using the following formula from the product monograph: Units required (IU) = ((desired - baseline antithrombin levels) x weight (kg))/1.4). Baseline antithrombin functional levels were expressed as a percent of normal.All participants received small amounts of unfractionated heparin for prophylaxis of CVC-blockage either by continuous infusion (1-3 units/mL) or intermittent flushes (50-100 units/mL up to 4 times per day) according to local standard of care. As per study protocol, patients did not receive therapeutic doses of heparin or warfarin while on study.

Outcomes • SymptomaticVTEeventsweredetectedbyclosemonitoringofpatientsduringthe study period and confirmed using appropriate objective imaging tests. No definitions were stipulated for clinical presentation, which was left to the judgement of the attending physician.

• AsymptomaticVTEeventsweredetectedbyroutineimaging(screening)followingcompletion of the induction phase of chemotherapy and during follow-up (day 28 to a further 3 months), with the following imaging tests: “1) bilateral venography or MRI of the upper body, 2) ultrasound of the upper body, 3) echocardiogram, 4) MRI of the head.”

• Laboratorymarkers:surrogateoutcomesforthromboticeventswereassessedby measurement of plasma concentrations of markers of endogenous thrombin generation.

• Majorbleedingwasdefinedasovertbleedingrequiringtransfusionofredbloodcells or any bleed into the central nervous system or retro peritoneum. Minor bleeding was any bleeding not considered major.

Notes The primary analysis of the study was performed on a per-protocol basis. The primary objective of the study was to determine the prevalence of thrombosis in the non-antithrombin arm (control arm). The second objective of the study was to acquire some preliminary data on efficacy and safety of prophylaxis with antithrombin. The study was not powered to prove efficacy or safety of antithrombin supplementation, but rather to look for trends. The outcomes for the secondary objective were assessed by comparing antithrombin-treated patients to the non-antithrombin treated arm: first by clinical outcomes 1) whether there was a trend to reduction in the incidence of thrombotic events, 2) whether there was a trend to comparable incidences of bleeding events and finally, 3) using surrogate outcome for thrombotic events by measuring markers of thrombin generation.

ALL = acute lymphoblastic leukemia; ASP = asparaginase; CVC = central venous catheter; MRI = magnetic resonance imaging; VTE = venous thromboembolism.

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12vous system or retro-peritoneum. Minor bleeding was any bleeding not considered

major bleeding.

Risk of bias in the included study

Data on the risk of bias assessment are described in Table 1B and presented in

Figure 2. The included study [Mitchell, 2003]39 was found to have substantial meth-

odological limitations.

Table 1B – Mitchell 200339; Risk of bias

BiasAuthors’

judgement Support for judgement

Random sequence generation (selection bias)

Low risk “Patients were block randomized (n=3) by hospital and stratified by ALL risk group (high or standard). Randomization was performed by the pharmacist-on-call using a computer generated random number list.”

Allocation concealment (selection bias)

Low risk “Randomization was performed by the pharmacist-on-call using a computer generated random number list.”

Blinding of participants and personnel (performance bias)All outcomes

High risk “Use of a placebo in the study was considered unethical as this would involve four intravenous infusions of albumin solutions, and multiple extra blood sampling in the non-treated patients.” Therefore, this was an open study whereby attending physicians, nurses and other health care providers knew patient treatment allocation.”

Blinding of outcome assessment (detection bias)VTE symptomatic

High risk Symptomatic thrombotic events were detected by close monitoring of patients during the study period and confirmed using appropriate objective imaging tests. No definitions were stipulated for clinical presentation, which was left to the judgement of the attending physician.

Blinding of outcome assessment (detection bias)VTE asymptomatic

Low risk Asymptomatic thrombotic events outcomes were adjudicated centrally by committees consisting of physicians with appropriate expertise, who were not involved with study patients’ care and were blinded to treatment groups.

Blinding of outcome assessment (detection bias)Major or minor bleeding

High risk Major or minor bleeding events were detected by close monitoring of patients during the study period. No blinding of outcome assessors was performed.

Incomplete outcome data (attrition bias)All outcomes

High risk 24 patients were excluded from analysis, 12 (17%) were in the non-antithrombin treated group and 12 (32%) in the antithrombin-treated group.

Selective reporting(reporting bias)All outcomes

High risk No complete reporting of outcome events, as symptomatic VTE, asymptomatic VTE, and bleeding were not reported for excluded participants.

ALL = acute lymphoblastic leukemia; VTE = venous thromboembolism.

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Table 2. Characteristics of excluded studies (ordered by study year)

No. Study (full-text) Year Reasons for exclusion

1 Kucuk 1985 design: case report; outcome: hemostatic parameters

2 Zaunschirm 1986 design: retrospective cohort study; outcome: hemostatic parameters

3 Ribiero 1986 design: prospective observational cohort study

4 Gugliotta 1990 design: prospective cohort study / case series

5 Mattioli Belmonte 1991 design: prospective cohort study; outcome: hemostatic parameters

6 De Stefano 1993 design: prospective observational cohort study

7 Riseeeuw-Appel 1994 intervention: no investigation of systemic VTE prophylaxis (asparaginase comparison)

8 Korte 1994 design: prospective observational cohort study

9 Halton 1994 design: prospective cohort study; outcome: hemostatic parameters

10 Nowak-Göttl 1994 intervention: no investigation of systemic VTE prophylaxis (asparaginase comparison)

11 Mazzucconi 1994 design: prospective cohort study; outcome: hemostatic parameters

12 Pogliani 1995 design: prospective cohort study

13 Nowak-Göttl 1995 design: prospective cohort study; outcome: hemostatic parameters

14 Parma 1995 design: prospective case-control study; outcome: hemostatic parameters

15 Nowak-Göttl 1996 design: prospective cohort study

16 Elhasid 2001 design: prospective controlled-cohort study

17 Duval 2002 intervention: no investigation of systemic VTE prophylaxis (asparaginase comparison)

18 Chojnowski 2002 outcome: hemostatic parameters

19 Matsuzaki 2002 design: retrospective cohort study; outcome: hemostatic parameters

20 Massicotte 2003 participants: ALL patients <80% (children with CVCs)

21 Nowak-Göttl 2003 design: prospective observational cohort study

22 Mitchell 2003 design: prospective observational cohort study

23 Male 2003 design: prospective observational cohort study

24 Attarbaschi 2003 design: prospective observational cohort study

25 Imberti 2004 design: retrospective cohort study

26 Elliott 2004 design: retrospective cohort study

27 Verso 2005 participants: ALL patients <80% (cancer patients with CVCs)

28 Cortelezzi 2005 design: prospective observational cohort study

29 Couban 2005 participants: ALL patients <80% (cancer patients with CVCs)

30 Athale 2005 design: prospective observational cohort study

31 Appel 2006 intervention: no investigation of systemic VTE prophylaxis (asparaginase comparison)

32 Massicotte 2006 design: review

33 Ruud 2006 participants: ALL patients <80% (children with cancer and CVCs)

34 Payne 2007 design: review

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Table 2. Characteristics of excluded studies (ordered by study year) (continued)


35 Fagnani 2007 design: prospective cohort study; participants: ALL patients <80% (cancer patients with CVCs)

36 Niers 2007 design: prospective cohort study; participants: ALL patients <80% (cancer patients with CVCs)

37 Dinndorf 2007 intervention: no investigation of systemic VTE prophylaxis (asparaginase comparison)

38 Rickles 2007 design: review

39 Falanga 2007 design: review

40 Meister 2008 design: prospective controlled-cohort study

41 Hunault-Berger 2008 design: retrospective study

42 Abbott 2009 design: prospective controlled-cohort study

43 Cesaro 2009 intervention: no systemic VTE prophylaxis; participants: ALL patients <80% (children with cancer and CVCs)



46 Mitchell 2010 design: prospective observational cohort study

47 Castelli 2010 design: review

48 Qureshi 2010 design: prospective observational cohort study

49 Athale 2010 design: prospective observational cohort study

50 Harlev 2010 design: retrospective study

51 Astwood 2011 design: review

52 Akl 2011 design: review

53 Chalmers 2011 design: review


55 Santoro 2013 design: prospective observational cohort study; outcome: hemostatic parameters

56 Zia 2013 design: review

57 Ranta 2013 design: retrospective study

58 Lauw 2013 design: retrospective study

59 Bhojwani 2014 design: prospective observational cohort study; outcome: hypertriglyceridemia

60 Ranta 2014 design prospective observational cohort study

No. Study (abstract) Year Reasons for exclusion

1 Casonato 1988 design: prospective observational cohort study; outcome: hemostatic parameters

2 Castaman 1993 design: prospective observational cohort study; intervention: no investigation of systemic VTE prophylaxis (asparaginase comparison)

3 Moricke 2009 design: prospective observational cohort study

4 Korte 2009 design: prospective observational cohort study; outcome: hemostatic parameters

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Selection bias

For evaluation of selection bias, we assessed random sequence generation and allo-

cation concealment. Investigators of the included study [Mitchell, 2003]39 performed

random and concealed sequence allocation; hence, a low risk of selection bias was

present.

Performance bias and detection bias

For evaluation of performance bias, we assessed the blinding of participants and

personnel. The included study [Mitchell, 2003]39 was open-label; neither participants,

nor personnel were blinded for patient treatment allocation. Therefore, the risk of

performance bias was high.

For evaluation of detection bias, we assessed the blinding of outcome assessors.

Blinding was assessed for all outcomes separately (symptomatic VTE, asymptomatic

Table 2. Characteristics of excluded studies (ordered by study year) (continued)


5 Harlev(full-text no. 50)

2009 design: retrospective study

6 Scott 2010 design: prospective observational cohort study

7 Sakaguchi 2010 design: retrospective study

8 Larsen 2011 intervention: no investigation of systemic VTE prophylaxis (steroids comparison)

9 Lauw(full-text no. 58)






12 Simmons 2011 design: retrospective study / review

13 Rodeghiero 2011 design: review

14 De Stefano 2011 design: review

15 Nayiager 2012 design: prospective observational cohort study; outcome: hemostatic parameters

16 Mc Cullough 2013 design: retrospective study

17 Barreto 2013 design: retrospective study

18 Bigliardi 2014 design: retrospective study

19 Andersson 2014 design: prospective observational cohort study

20 Musgrave 2014 design: retrospective study

21 Ranta(full-text no. 60)

2014 design prospective observational cohort study

ALL = acute lymphoblastic leukemia; CVC = central venous catheter; VTE = venous thromboembo-lism.

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VTE, bleeding events). Symptomatic VTE and bleeding events were assessed by

regular clinicians. Because the study was open-label, these clinicians were aware

of the treatment allocation (high risk of detection bias). Imaging tests of asymp-

tomatic VTE were adjudicated centrally by committees consisting of physicians with

appropriate expertise, who were not involved with study patients’ care and who were

blinded to treatment groups (low risk of detection bias).

Attrition bias

For evaluation of attrition bias, we assessed the completeness of outcome data.

The included study [Mitchell, 2003]39 excluded 24 participants from analyses after

randomization because they did not satisfy the ‘per-protocol’ analysis. Although

reasons for exclusion were stated, their outcome data is unknown, which represents

a high risk of attrition bias.

Reporting bias

For evaluation of reporting bias, we assessed selective reporting of findings. The

included study [Mitchell, 2003]39 did not provide complete reporting of all outcome

events investigated, as symptomatic VTE, asymptomatic VTE, and bleeding events

were not reported for excluded participants, representing a high risk of reporting bias.

Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for the included study

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Effects of interventions

Symptomatic VTE

Data on the number of patients with symptomatic VTE could not be extracted from

the included study [Mitchell, 2003]39, because a clear distinction between the number

of symptomatic or asymptomatic VTE events cannot be made, as no specifications

are provided in the results whether events were symptomatic or asymptomatic.

Therefore, symptomatic and asymptomatic VTE were assessed together.

Symptomatic or asymptomatic VTE

Data on the number of patients with symptomatic or asymptomatic VTE could be

extracted from the included study [Mitchell, 2003].39 This RCT compared systemic

VTE prophylaxis (antithrombin supplementation) with no intervention in ALL patients.

Systemic prophylaxis for VTE versus no intervention

Results from the included RCT [Mitchell, 2003]39 were evaluated in an analysis with

a total of 109 participants. The primary analysis was performed on a ‘per-protocol’

basis and reporting of outcome data was incomplete. Hence, we performed an avail-

able case (per-protocol) analysis. A total of 37 participants were randomly assigned

to systemic prophylaxis (antithrombin) and 72 to no intervention. Outcomes were

reported for 25 participants in the intervention group and 60 in the control group. We

found no significant difference between systemic prophylaxis and no intervention on

the risk of VTE (RR 0.76; 95% CI 0.38-1.55; p=0.46; Figure 3). Tests for heterogeneity

were not applicable.

Adverse events

Major bleeding

Major bleeding was reported as an outcome measure in the included study [Mitchell,

2003].39 The primary analysis was performed on a ‘per-protocol’ basis and reporting

of outcome data was incomplete. Hence, we performed an available case analysis. A

total of 37 participants were randomized to systemic prophylaxis (antithrombin) and

72 to no intervention. Major bleeding complications were reported for 25 and 60

participants, respectively. The difference between interventions was not statistically

significant (Fisher’s exact test, p=1.00).

Minor bleeding

Minor bleeding was reported as an outcome measure in the included study [Mitchell,

2003].39 The primary analysis was performed on a ‘per-protocol’ basis and reporting

of outcome data was incomplete. Hence, we performed an available case analysis. A

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total of 37 participants were randomized to systemic prophylaxis (antithrombin) and

72 to no intervention. Minor bleeding complications were reported for 25 and 60

participants, respectively. The difference between interventions was not statistically

significant (Fisher’s exact test, p=0.084).

Overall survival

The included study [Mitchell, 2003]39 did not report on survival outcomes or differ-

ences between interventions.

Loss of a central venous catheter due to VTE

The included study [Mitchell, 2003]39 did not report on loss of a central venous cath-

eter due to VTE or differences between interventions.

VTE-related death

The included study [Mitchell, 2003]39 did not report any death due to VTE or differ-

ences between interventions.

Complete remission rates upon end of study treatment

The included study [Mitchell, 2003]39 did not report on complete remission rates or

differences between interventions.

Disease-free survival of ALL patients

The included study [Mitchell, 2003]39 did not report on disease-free survival rates or

differences between interventions.

Quality of life after completion of treatment for newly diagnosed ALL

The included study [Mitchell, 2003]39 did not report on quality of life or differences

between interventions.

Figure 3. Forest plot of comparison: Systemic prophylaxis versus no intervention in patients treated for acute lymphoblastic leukemia; outcome: Symptomatic or asymptomatic venous thromboembo-lism (VTE)

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Subgroup analyses

The included study [Mitchell, 2003]39 was performed in pediatric patients only, who all

received asparaginase therapy, and who all had a central venous catheter. Inherited

thrombophilia was not assessed. Hence, no subgroup analyses were performed.

Sensitivity analyses for the used risk of bias criteria

No sensitivity analyses for the used risk of bias criteria were possible because only

one study was included in the analyses.

discussion

Patients treated for ALL are at high risk of VTE, particularly during asparaginase

therapy. VTE complications lead to mortality, morbidity, and suboptimal ALL treat-

ment and treatment outcome due to premature therapy discontinuation, therapy

interruptions or loss of a central venous catheter. Given the high incidence of VTE

during ALL treatment and its consequences, efficacious and safe preventive mea-

sures for VTE are of great importance.

In this review, we evaluated the evidence on efficacy and safety of systemic VTE

prophylaxis in pediatric and adult patients treated with asparaginase therapy for

newly diagnosed ALL. We identified only one RCT, which compared antithrombin

supplementation with no intervention [Mitchell, 2003].39 This study did not find a

significant difference between systemic prophylactic antithrombin supplementa-

tion and no intervention for the incidence of symptomatic or asymptomatic VTE.

The study also investigated major and minor bleeding episodes, but showed no

significant differences between the interventions. The study did not report on overall

survival, loss of a central venous catheter due to VTE, VTE-related death, complete

remission rates upon end of study treatment, disease-free survival of ALL patients,

or quality of life after completion of treatment for newly diagnosed ALL among

participants. However, the sample size of this included study was small. The study

was part of the larger PARKAA (Prophylactic Antithrombin Replacement in Kids with

ALL treated with Asparaginase) study. The primary objective of the PARKAA study

was to determine the prevalence of thrombosis in the non-antithrombin arm (control

arm), of which the results were published in another paper.40 The aim of the included

study – to acquire some preliminary data on efficacy and safety of prophylaxis with

antithrombin –39 was the second objective of the PARKAA study, for which the study

was not powered. Therefore, the included study may have missed a clinically impor-

tant effect. Moreover, the study analyzed outcomes on a per-protocol basis and did

not report outcomes on excluded patients. We were unable to retrieve missing data

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from the study authors, and hence, performing an intention-to-treat analysis was not

possible. This may have had a significant impact on the results of the study if data

were not missing at random. It does not affect the conclusions of this review as the

study remains underpowered.

No RCTs were identified investigating other blood-derived products or anticoagu-

lants for systemic VTE prophylaxis in ALL patients. Hence, although the identified

study did not find a significant effect of systemic antithrombin supplementation on

VTE incidence, no firm conclusions can be drawn on the efficacy of systemic prophy-

laxis in reducing the risk of VTE in patients treated for ALL with asparaginase therapy.

Well-designed and sufficiently powered RCTs are therefore needed to further investi-

gate the value of systemic prophylaxis compared with no intervention for prevention

of VTE in patients treated for ALL. Due to the rarity of the disease ALL, such trials

will require multicenter and international collaborations. Furthermore, it is uncertain

whether the incidence of symptomatic VTE in ALL patients is high enough to allow for

a feasible sample size in sufficiently powered RCTs on systemic thromboprophylaxis

in ALL patients. Selecting those patients with the highest risk of VTE may therefore

be worthwhile,41 but the variables necessary for a proper risk prediction model are

not clear yet, particularly if there is a homogeneous cohort of ALL patients.

In addition, the included study assessed the incidence of symptomatic and asymp-

tomatic VTE. Asymptomatic, or incidental, VTE is increasingly found in cancer pa-

tients with the currently enhanced imaging techniques, particularly chest computed

tomography (CT) scans. However, the clinical relevance, i.e. the mortality risk and risk

of recurrence, is unknown for asymptomatic VTE in cancer patients, particularly in

patients with hematological malignancies. Recent studies have estimated the preva-

lence of incidental VTE at up to 4% in hospitalized cancer patients.42, 43 Rates of recur-

rence and bleeding seem similar in cancer patients with incidental and symptomatic

VTE.44, 45 However, these studies have only been performed in patients with solid

cancers, and mostly for patients with incidental pulmonary emboli. The relevance

of asymptomatic VTE in the upper extremities and upper central system has not

been properly investigated. Until this has been clarified, it seems reasonable to aim

studies on the efficacy and safety of systemic VTE prophylaxis in patients with ALL at

symptomatic VTE events.

We elected to only include RCTs for this review. By choosing this strategy, we found

only one study that fulfilled our inclusion criteria. We may have missed valuable infor-

mation by not including case-controlled or controlled clinical trials. However, there is

a high risk of bias involved with designs other than a RCT for assessment of efficacy

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and safety of an intervention. Hence, including other designs may have offered more

information, but also more biased evidence.

authors’ conclusions

Implications for practice

In this systematic review, we found no significant effects of systemic prophylaxis

compared with no intervention on the risk of VTE during asparaginase therapy in

patients treated for ALL. We also did not find a difference in bleeding between

patients with systemic VTE prophylaxis compared with no intervention during

ALL treatment. However, we identified only one small study that randomized 109

participants between systemic antithrombin supplementation and no intervention.

This study was not powered to prove efficacy or safety of prophylactic antithrombin

supplementation. The study also did not report on overall survival, loss of a central

venous catheter due to VTE, VTE-related death, complete remission rates upon

end of study treatment, disease-free survival of ALL patients, or quality of life after

completion of treatment for newly diagnosed ALL among participants.

Based on currently available evidence, we are not able to make any recommenda-

tions for clinical practice.

Implications for research

Well-designed and sufficiently powered randomized trials are needed to investigate

the value of systemic prophylaxis compared with no intervention for prevention of

VTE during asparaginase therapy in patients treated for ALL, as well as the optimal

measure for thromboprophylaxis. Due to the rarity of the disease ALL, such trials

will require multicenter and international collaborations. Furthermore, with the in-

troduction of the newer non-vitamin K oral anticoagulants (NOACs), which directly

target thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban), more

measures for systemic thromboprophylaxis are currently available and require evalu-

ation for this indication. However, the efficacy and safety of NOACs for secondary

prevention of VTE in cancer patients still await confirmation.

acknowledGements

The authors would like to thank Ina Monsef (Trials Search Coordinator of the Co-

chrane Haematological Malignancies Group) for assistance in developing the search

strategies for the different databases.

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Appendix 1. TIMI criteria (as defined in 2010)

Hemorrhage - bleeding classified by the TIMI hemorrhage classification scheme:

• Minimal: any clinically overt sign of hemorrhage (including imaging) that is as-

sociated with a fall in hemoglobin < 3 g/dL (or, when hemoglobin is not available,

a fall in hematocrit of < 9%)*.

• Minor: any clinically overt sign of hemorrhage (including imaging) that is asso-

ciated with a fall in hemoglobin of 3 to ≤ 5 g/dL (or, when hemoglobin is not

available, a fall in hematocrit of 9 to ≤ 15%)*.

• Major: 1. if it is intracranial, or

2. clinically significant overt signs of hemorrhage associated with a drop in

hemoglobin of > 5 g/dL (or, when hemoglobin is not available, an absolute

drop in hematocrit of > 15%)*.

3. if coronary arterial bypass grafting related: fatal bleeding or perioperative

intracranial bleeding or reoperation following closure of the sternotomy

incision for the purpose of controlling bleeding or transfusion of > 5 units

of whole blood or packed red blood cells within a 48-hour period (cell saver

transfusion will not be counted in calculations of blood products) or chest

tube output > 2 L within a 24-hour period.

Bleeding requiring medical attention - any bleeding that requires medical treat-

ment, surgical treatment, or laboratory evaluation and does not meet criteria for

major or minor bleeding.

• Significant: the combination of major bleeding, minor bleeding, or bleeding

requiring medical attention.

• Instrumented: any hemorrhage that occurs as a result of an invasive procedure.

• Spontaneous: any hemorrhage that is not the direct result of an invasive proce-

dure (e.g. gingival bleeding, epistaxis, gastrointestinal bleeding).

*To account for transfusion, hemoglobin and hematocrit measurements will be ad-

justed for any PRBCs or whole blood given between baseline and post-transfusion

measurements. A transfusion of one unit of blood will be assumed to result in an

increase of 1 g/dl in hemoglobin (Hb) or of 3% in hematocrit (Ht). Thus, to calcu-

late the true change in hemoglobin or hematocrit if there has been an intervening

transfusion between two blood measurements, the following calculations should be

performed:

• Hemoglobin=[baselineHb–posttransfusionHb]+[numberoftransfusedunits]

• Hematocrit=[baselineHt–posttransfusionHt]+[numberoftransfusedunitsx

3]

217


12

Appendix 2. Search strategy for The Cochrane Library, issue 11 of 12 (17 December 2014)

ID Search

#1 MeSH descriptor: [Leukemia] explode all trees

#2 (leukem* or leukaem* or leucem* or leucaem*)

#3 MeSH descriptor: [Leukemia, Lymphoid] explode all trees

#4 MeSH descriptor: [Precursor Cell Lymphoblastic Leukemia-Lymphoma] explode all trees

#5 (lymphoblast* or lymphoid* or lymphocyt* or lymphat*)

#6 (acut* or akut*)

#7 (#2 AND #5)

#8 (#2 AND #6)

#9 (#1 OR #2 OR #3 OR #4 OR #7 OR #8)

#10 MeSH descriptor: [Thrombosis] explode all trees

#11 MeSH descriptor: [Venous Thrombosis] explode all trees

#12 MeSH descriptor: [Thromboembolism] explode all trees

#13 (thrombos* or trombos* or thrombus* or trombus* or thromboembol*)

#14 (phlebothrombos* or phlebotrombos* or procoagul* or coagul* or hypercoag*)

#15 (#10 OR #11 OR #12 OR #13 OR #14)

#16 (prophyla* or prevent* or support* or inhibit*)

#17 (anticoag* or antithromb* or thromboproph* or thromboprev*)

#18 (plasma* or fresh frozen plasma* or cryoprecip* or FFP*)

#19 (heparin* or UFH* or low molecular weight heparin* or LMWH*)

#20 (fondaparinux* or enoxaparin* or nadroparin* or dalteparin* or tinzaparin*)

#21 (vitamin K antagonist* or warfarin* or coumarin* or acenocoumarol* or phenprocoumon*)

#22 (#16 OR #17 OR #18 OR #19 OR #20 OR #21)

#23 (#9 AND #15 AND #22)

#24 “accession number” near pubmed

#25 (#23 NOT #24)

| Chapter 12

218

Appendix 3. Search strategy for MEDLINE (from 1945 to 17 December 2014, accessed via PubMed)

ID Search

#1 “Leukemia”[Mesh:NoExp]

#2 (leukem* OR leukaem* OR leucem* OR leucaem*)

#3 “Leukemia, Lymphoid”[Mesh]

#4 “Precursor Cell Lymphoblastic Leukemia-Lymphoma”[Mesh]

#5 (lymphoblast* or lymphoid* or lymphocyt* or lymphat*)

#6 (acut* or akut*)

#7 #2 AND #5

#8 #2 AND #6

#9 #1 OR #2 OR #3 OR #4 OR #7 OR #8

#10 “Thrombosis”[Mesh:NoExp]

#11 “Venous Thrombosis”[Mesh]

#12 “Thromboembolism”[Mesh]

#13 (thrombos* or trombos* or thrombus* or trombus* or thromboembol*)

#14 (phlebothrombos* or phlebotrombos* or procoagul* or coagul* or hypercoag*)

#15 #10 OR #11 OR #12 OR #13 OR #14

#16 (prophyla* or prevent* or support* or inhibit*)

#17 (anticoag* or antithromb* or thromboproph* or thromboprev*)

#18 (plasma* or fresh frozen plasma* or cryoprecip* or FFP*)

#19 (heparin* or UFH* or low molecular weight heparin* or LMWH*)

#20 (fondaparinux* or enoxaparin* or nadroparin* or dalteparin* or tinzaparin*)

#21 (vitamin k antagonist* OR warfarin* OR coumarin* OR acenocoumarol* OR phenprocoumon*)

#22 #16 OR #17 OR #18 OR #19 OR #20 OR #21

#23 #9 AND #15 AND #22

#24 ((((((randomized controlled trial [pt]) OR controlled clinical trial [pt]) OR randomized [tiab]) OR placebo [tiab]) OR clinical trials as topic [Mesh: NoExp]) OR randomly [tiab]) OR trial [ti]

#25 (animals [mh]) NOT humans [mh]

#26 #24 NOT #25

#27 #23 AND #26

219


12

Appendix 4. Search strategy for EMBASE (from 1980 to 17 December 2014, accessed via Ovid)

ID# Search

#1 LEUKEMIA/

#2 (leuk?em$ or leuc?em$).tw.

#3 exp LYMPHATIC LEUKEMIA/

#4 exp ACUTE LYMPHOBLASTIC LEUKEMIA/

#5 (lymphoblast$ or lymphoid$ or lymphocyt$ or lymphat$).tw.

#6 (acut$ or akut$).tw.

#7 2 and 5

#8 2 and 6

#9 1 or 2 or 3 or 4 or 7 or 8

#10 THROMBOSIS/

#11 exp VEIN THROMBOSIS/

#12 exp THROMBOEMBOLISM/

#13 (thrombos$ or trombos$ or thrombus$ or trombus$ or thromboembol$).tw.

#14 (phlebothrombos$ or phlebotrombos$ or procoagul$ or coagul$ or hypercoag$).tw.

#15 or/10-14

#16 (prophyla$ or prevent$ or support$ or inhibit$).tw.

#17 (anticoag$ or antithromb$ or thromboproph$ or thromboprev$).tw.

#18 (plasma$ or fresh frozen plasma$ or cryoprecip$ or FFP$).tw.

#19 (heparin$ or UFH$ or low molecular weight heparin$ or LMWH$).tw.

#20 (fondaparinux$ or enoxaparin$ or nadroparin$ or dalteparin$ or tinzaparin$).tw.

#21 (vitamin K antagonist$ or warfarin$ or coumarin$ or acenocoumarol$ or phenprocoumon$).tw.

#22 or/16-21

#23 9 and 15 and 22

#24 (random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.

#25 RETRACTED ARTICLE/

#26 or/24-25

#27 (animal$ not human$).sh,hw.

#28 (book or conference paper or editorial or letter or review).pt. not exp randomized controlled trial/

#29 (random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not exp randomized controlled trial/

#30 26 not (27 or 28 or 29)

#31 23 and 30

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