Intervention Review

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Antifibrinolytics (lysine analogues) for the prevention of bleeding in patients with haematological disorders

  1. Douglas Wardrop1,
  2. Lise J Estcourt2,*,
  3. Susan J Brunskill3,
  4. Carolyn Doree3,
  5. Marialena Trivella4,
  6. Simon Stanworth2,
  7. Michael F Murphy5

Editorial Group: Cochrane Haematological Malignancies Group

Published Online: 29 JUL 2013

Assessed as up-to-date: 10 JAN 2013

DOI: 10.1002/14651858.CD009733.pub2

How to Cite

Wardrop D, Estcourt LJ, Brunskill SJ, Doree C, Trivella M, Stanworth S, Murphy MF. Antifibrinolytics (lysine analogues) for the prevention of bleeding in patients with haematological disorders. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD009733. DOI: 10.1002/14651858.CD009733.pub2.

Author Information

  1. 1

    Haematology, Oxford Cancer and Haematology Centre, Oxford, Oxfordshire, UK

  2. 2

    NHS Blood and Transplant, Haematology/Transfusion Medicine, Oxford, UK

  3. 3

    NHS Blood and Transplant, Systematic Review Initiative, Oxford, Oxon, UK

  4. 4

    University of Oxford, Centre for Statistics in Medicine, Oxford, UK

  5. 5

    John Radcliffe Hospital, NHS Blood and Transplant, Oxford, UK

*Lise J Estcourt, Haematology/Transfusion Medicine, NHS Blood and Transplant, Level 2, John Radcliffe Hospital, Headington, Oxford, OX3 9BQ, UK. lise.estcourt@nhsbt.nhs.uk. lestcourt@doctors.org.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 29 JUL 2013

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Characteristics of included studies [ordered by study ID]
Avvisati 1989

MethodsParallel RCT. 2 centres (Italy and Netherlands). Enrolment period not stated.


ParticipantsInclusion criteria: patients with newly diagnosed APL who met the following criteria: age 15 to 60 yrs; ventricular ejection fraction > 50%; serum alanine aminotransferase (ALT) < 4 x upper limit of normal; creatinine < 177 μmol/l.

Exclusion criteria: not stated

Arm 1 N = 6 (APL N = 6)

Arm 2 N = 6 (APL N = 6)


InterventionsComparison between TXA and placebo

Arm 1 TXA (2 g given as a continuous infusion every 8 h for the first 6 days of antileukaemic treatment)

Arm 2 Placebo (equal volume of 5% glucose)

RBC transfusion thresholds: packed red cells given to maintain Hb > 9.0 g/dl

Platelet transfusion threshold: 6 to 8 U/m2 (source not stated) routinely given during first 7 days and additionally for overt haemorrhage

Packed red cells and additional platelet concentrates given at the discretion of the attending physician


OutcomesMain or primary outcome not stated

Outcomes reported:

  • Severity of bleeding
  • Thromboembolism
  • Laboratory assessment of fibrinolysis
  • Packed red cell transfusion requirement
  • Platelet concentrate transfusion requirement


Number of days patients from both arms on study: 14


NotesPatients randomised at: not reported

Follow-up of patients: for 14 days from start of antileukaemic treatment

Stopping guidelines: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskPatients were randomised to either TXA or placebo. The article does not state how patients were randomised.

Allocation concealment (selection bias)Unclear riskNot stated

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThe article states that "Patients and attending physicians were blinded to the treatment groups" and that bleeding assessments were examined by the same investigator but it is not clear whether the investigator was one of the attending physicians.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Each patient was examined daily by the same investigator (G.A.) for clinically manifest haemorrhage during the entire study of 14 days". Unclear whether G.A. was blinded to the treatment groups

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data

Selective reporting (reporting bias)Unclear riskThe article states that their efficacy endpoints were "severity of bleeding" and the packed red cell and platelet concentrate transfusion requirement but also reports outcome data for laboratory assessment of coagulation and fibrinolysis. It also states that there were no episodes of thromboembolism. We would be concerned as to what other outcomes were measured and not reported.

Other biasLow riskThe study seemed to be free of other sources of bias

Protocol deviation balanced?Unclear riskProtocol deviations or violations were not commented on

Fricke 1991

MethodsCross-over RCT. USA. Enrolment period and centres not stated.


ParticipantsInclusion criteria: patients with amegakaryocytic thrombocytopenia who met the following criteria: platelet count < 20,000/microlitre (< 20 x 109/l) with no immediate prospect of recovery and absent/rare megakaryocytes in the bone marrow aspirate/biopsy; at least 1 bleeding episode per month (excluding skin bleeding); a history of platelet transfusions for such bleeding episodes

Exclusion criteria: patients who had any of the following: active bleeding from an anatomical lesion (e.g. peptic ulcer); personal/family history of hypercoagulopathy; pregnancy; DIC; liver failure; personal history of a congenital bleeding disorder

Arms (cross-over RCT): N = 8 (aplastic anaemia N = 7; myelodysplastic syndrome N = 1)


InterventionsComparison between TXA and placebo

Arm 1 TXA (20 mg/kg) 3 x daily for 4 weeks or until a platelet transfusion was required to control bleeding. Followed by a 1-week rest period. Placebo (equivalent number of identical placebo tablets) for 4 weeks or until a platelet transfusion was required to control bleeding. Followed by a 1-week rest period. The method of allocating the randomised patients to further courses of TXA or placebo was not stated.

Arm 2 Placebo (equivalent number of identical placebo tablets) for 4 weeks or until a platelet transfusion was required to control bleeding. Followed by a 1-week rest period. TXA (20 mg/kg) 3 x daily for 4 weeks or until a platelet transfusion was required to control bleeding. Followed by a 1-week rest period. The method of allocating the randomised patients to further courses of TXA or placebo was not stated.

Further cycles of TXA and placebo were repeated until TXA was deemed a success or a failure.

RBC transfusion thresholds: not stated

Platelet transfusion thresholds: platelets (dose and source not stated) given in the event of bleeding as each patient's personal physician deemed necessary


OutcomesMain or primary outcome not stated

Outcomes reported

  • Number of bleeding episodes
  • Severity of bleeding episodes
  • Site of bleeding episodes
  • Platelet transfusion requirement
  • Red cell transfusion requirement
  • Drug side effects


Number of days patients on study: not stated

Defined overall success of TXA in a patient as either 5 failures of placebo and none of drug or 7 failures of placebo and 1 of drug. Defined overall failure of TXA as 2 failed courses of drug. Sequential courses continued until overall success or failure of TXA could be determined.


NotesPatients randomised at: not reported

Follow-up of patients: not reported

Stopping guidelines: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStates that patients were randomised but does not state the mechanism of randomisation. Nor does it state whether they were re-randomised after the initial 2 courses of TXA and placebo or what other method was used to allocate them to successive courses of TXA or placebo.

Allocation concealment (selection bias)Unclear riskStates that patients were randomised but does not state the mechanism of allocation

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStates that study was double-blinded (and the interventions were identical)

However, the article states that drug levels were obtained during 38 of the 49 courses. It does not state that the investigators or patients were blinded to this information during the study. "Plasma tranexamic acid levels were taken weekly and before each platelet transfusion, if possible".

It also states that the study defined overall success of TXA in a patient as either 5 failures of placebo and none of drug or 7 failures of placebo and 1 of drug. Defined overall failure of TXA as 2 failed courses of drug. Sequential courses continued until overall success or failure of TXA could be determined. However, it did not state how this assessment of success or failure was performed without unblinding study personnel.

It is unlikely that patients were informed of these results and therefore blinding of participants is assumed to be at low risk of bias. However, it is not clear that study personnel were not informed of the results and therefore overall risk of bias was classified as unclear.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStates that study was double-blinded (and the interventions were identical)

However, the article states that drug levels were obtained during 38 of the 49 courses. It does not state that the outcome assessors were blinded to this information during the study. "Plasma tranexamic acid levels were taken weekly and before each platelet transfusion, if possible".

It also states that the study defined overall success of TXA in a patient as either 5 failures of placebo and none of drug or 7 failures of placebo and 1 of drug. Defined overall failure of TXA as 2 failed courses of drug. Sequential courses continued until overall success or failure of TXA could be determined. However, it did not state how this assessment of success or failure was performed without unblinding study personnel (including outcome assessors).

Incomplete outcome data (attrition bias)
All outcomes
High riskStates that "Three patients completed the randomised portion of the study". "Five of the eight patients did not complete enough courses to determine the efficacy of the drug".

Selective reporting (reporting bias)High riskThe article states that severity of bleeding (as well as number and site) were recorded by the assessor (the patient) but this outcome was not reported in the article

1 patient died of intracranial haemorrhage 4 days after starting the first randomised course. Data from this course were not included in the analysis.

There were 2 courses of TXA or placebo interrupted in 2 patients. One due to an upper respiratory tract infection and the other in which the patient developed an oesophageal haematoma after starting antibiotic treatment for an infection. Data from these courses were not included in the analysis as the investigators felt that the infection/antibiotic treatment may have compromised haemostasis.

Other biasHigh riskOne patient began receiving HLA-matched platelet transfusions 2 months after enrolment and was kept in the study as these transfusions did not completely control the bleeding. This creates bias as the other patients were deemed to have "failed" the course if bleeding necessitating platelet transfusions occurred. 2 other patients were withdrawn after they started to receive HLA-matched platelet transfusions.

The overall success of TXA was defined as either 5 failures of placebo and none of the drug or 7 failures of placebo and 1 of the drug. Overall failure of TXA was defined as 2 failed courses of the drug. Failure of a course was defined as a patient receiving a platelet transfusion for bleeding during a 4-week study period. Patients received a variable number of courses of drug/placebo. The 3 patients who completed the study received between 3 (2 TXA, 1 placebo) and 9 courses (5 TXA, 4 placebo) of treatment. The 5 patients who did not complete the study received between 0 and 20 courses (10 TXA, 10 placebo) of treatment. Of the 3 patients who completed the study, 2 did not have any successful courses of treatment. The third patient had 3/5 successful courses with TXA and 1/4 successful courses with placebo, however this was classified by the study as a failure of TXA (2 failed courses with TXA).

Failure of a course of treatment would be classified in the same way whether patient was on study drug for 1 day before bleeding or 27 days before bleeding that required treatment with a platelet transfusion. More bleeding episodes seen in TXA arm may have been due to more days on study before bleeding requiring a platelet transfusion. Number of days on study drug before bleeding was not reported for individual courses.

Protocol deviation balanced?Unclear riskInsufficient information to determine

Gallardo 1983

MethodsParallel RCT. Abstract. Single centre: USA. Enrolment period not stated


ParticipantsInclusion criteria: patients undergoing remission induction for acute leukaemia. No other inclusion criteria stated.

Exclusion criteria: not stated

N = 19 were eligible. N = 9 in each arm (AML N = 15; ALL N = 4). N = 1 was not evaluable (reason not stated). Distribution of subtypes in to each arm not stated.

Arm 1 N = 9

Arm 2 N = 9


InterventionsComparison between EACA therapy and no EACA therapy.

Arm 1 N = 9 (to receive EACA 100 mg/kg loading dose and 12 to 24 g/day in divided doses)

Arm 2 N = 9 (did not receive EACA)

RBC transfusion threshold: not stated

Platelet transfusion threshold: patients in both arms were administered platelet transfusion (dose and source not stated) when platelet count < 20,000/microlitre. This threshold defined the "days at risk of bleeding".


OutcomesMain or primary outcomes not stated.

Outcomes reported:

  • Bleeding; either as capillary bleeding (CB; skin, mucous membranes, conjunctivae, nose, guaiac in GI or GU tract) or major bleeding (MB; nose bleeding requiring posterior packing, gross GI or GU bleeding and CNS bleeding
  • Monitoring of antifibrinolytic therapy using I125 fibrinogen plasma clot lysis
  • Platelet transfusion requirement
  • Adverse events of antifibrinolytic
  • Thromboembolism


Number of days patients on study: not reported


NotesPatients randomised at: not reported

Follow-up of patients: not reported

Stopping guidelines: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information to permit a judgement of 'high' or 'low' risk.

Allocation concealment (selection bias)Unclear riskInsufficient information to permit a judgement of 'high' or 'low' risk

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to permit a judgement of 'high' or 'low' risk. The abstract does not state whether investigators and patients were blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit a judgement of 'high' or 'low' risk. The abstract does not state who carried out the bleeding assessments.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information to permit a judgement of 'high' or 'low' risk

Selective reporting (reporting bias)High riskThere are data for thromboembolism and death ("no patient died of thrombosis") but no data given on number episodes of thromboembolism or number of deaths. No data reported monitoring of antifibrinolytic therapy using I125 fibrinogen plasma clot lysis

Other biasUnclear riskThe “at risk of bleeding days” were much higher in the EACA group – 158 vs. 80 due to more severe thrombocytopenia and more cycles of chemotherapy for refractory disease. There may be bias in the randomisation procedure but method of randomisation is not stated.

Protocol deviation balanced?Unclear riskProtocol deviations or violations were not commented on

Shpilberg 1995

MethodsParallel RCT. Enrolment period 1990 to 1992. 2 centres (Israel)


ParticipantsInclusion criteria: de novo AML. All ages.

Exclusion criteria: laboratory signs of DIC; recent history of a thromboembolic event; clinical evidence or suspicion of thromboembolism.

There were 2 parts to the study. The first part investigated patients undergoing induction chemotherapy. The second part investigated patients undergoing consolidation chemotherapy

Induction chemotherapy: N = 38 (FAB M1 N = 5; FAB M2 N = 8; FAB M4 N = 25)

Arm 1 N = 16 (FAB M1 N = 2; FAB M2 N =2; FAB M4 N = 12)

Arm 2 N = 22 (FAB M1 N = 3; FAB M2 N = 6; FAB M4 N = 13)

Consolidation chemotherapy: N = 18 (FAB M2 = 8; FAB M3 = 1; FAB M4 = 9)

Arm 1 N = 10 (FAB M2 N = 5; FAB M3 N =1; FAB M4 N = 4)

Arm 2 N = 8 (FAB M2 N = 3; FAB M4 N = 5)


InterventionsComparison between TXA and placebo in patients receiving (i) induction chemotherapy and (ii) consolidation chemotherapy. Both parts of the investigation had the same intervention.

Arm 1 TXA 1 g every 6 hours

Arm 2 Identically appearing placebo

RBC transfusion threshold: administered to maintain > 9 g/dl

Platelet transfusion threshold: patients in both arms were administered platelet transfusions. (Random donor pooled; 4 units/m2) in the event of clinically significant bleeding, irrespective of platelet count.


OutcomesMain or primary outcomes not stated

Outcomes reported:

  • Number of bleeding events and severity of bleeding (using a scoring system)
  • Platelet concentrate transfusion requirement
  • Red cell transfusion requirement
  • Thromboembolism
  • Adverse events of drug
  • Duration of hospitalisation
  • Duration of significant thrombocytopenia (< 20 x 109/l)
  • Days with fever


Number of days patients on study: not stated


NotesPatients randomised at: not reported

Follow-up of patients: not reported

Stopping guidelines: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStudy states that the trial was randomised but no further details are given as to how this was done

Allocation concealment (selection bias)Unclear riskStudy states that the trial was randomised but no further details are given as to how this was done

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStudy states that the trial was double-blind but no further details are given as to who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStudy states that the patients were carefully examined daily by one of the investigators. The trial was double-blind but no further details are given as to who was blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient data to assess

Selective reporting (reporting bias)Unclear riskInsufficient data to assess

Other biasUnclear riskThe study seemed to be free of other forms of bias

Protocol deviation balanced?Unclear riskInsufficient information to determine

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Amar 2003Wrong patient group - a randomised controlled trial examining the usefulness of antifibrinolytic therapy in patients with non-haematological malignancy undergoing major orthopaedic surgery

Bartholomew 1989Not a RCT - a non-randomised controlled trial on the control of bleeding in patients with immune and non-immune thrombocytopenia with aminocaproic acid

Bates 2011Review

Bedirhan 2001Wrong intervention - a randomised controlled trial investigating the use of aprotinin in postoperative bleeding and the need for blood products in thoracic surgery

Ben-Bassat 1990Not an RCT - non-randomised and non-controlled study of tranexamic acid therapy in acute myeloid leukaemia

Breen 2012Review

Brown 2002Review

Byams 2007Wrong patient group - a cross-over study evaluating the use of desmopressin and tranexamic acid in women with menorrhagia

Cattan 1963Not an RCT - non-randomised study of EACA in patients with thrombocytopenia

Celebi 2006Wrong patient group - a randomised, double-blind prospective study that examined the role of antifibrinolytic agents in gynaecologic cancer surgery

Chakrabarti 1998Not an RCT - non-randomised and non-controlled trial of EACA in patients with acute leukaemia

Dean 1997Not an RCT - non-randomised and non-controlled trial of EACA and TXA for cancer-associated bleeding problems

Fossa 1978Not an RCT - non-randomised, controlled pilot study on the effect of TXA in patients being treated for various advanced malignancies

Gardner 1980Not an RCT - a series of cases of patients with amegakaryocytic thrombocytopenia treated with EACA to control bleeding

Garewal 1985Not an RCT - non-randomised and non-controlled trial of EACA for the control of bleeding in thrombocytopenic patients

Jeserschek 2003Wrong intervention - a randomised controlled trial examining the role of high-dose aprotinin in the reduction of bleeding in major orthopaedic surgery

Kalmadi 2006Not a RCT - retrospective study of the effect of EACA on transfusion requirements in patients with thrombocytopenic haemorrhage

Katzel 1998Wrong intervention - a prospective, controlled, double-blind pilot study examining the role of aprotinin during thoracic surgery for malignant lung disease

Levy 2005Review

Marti-Carvajal 2011Review

McConnell 2011Wrong patient group - a randomised controlled trial examining the reduction of blood loss in primary hip arthoplasty with tranexamic acid fibrin spray

McConnell 2012Wrong patient group - a randomised controlled trial examining the reduction of blood loss in primary knee arthoplasty with tranexamic acid fibrin spray

Mevio 1983Wrong patient group - a double-blind study examining the role of tranexamic acid in the prevention of radiomucositis in head and neck cancer patients submitted for radiotherapy

Movafegh 2011Wrong patient group - a randomised, double-blind study examining the effect of intravenous tranexamic acid on blood loss during and after caesarian delivery

Rickles 2007Review

Sanz 2010Not an RCT - non-randomised with historical control evaluating the use of tranexamic acid in patients with promyelocytic leukaemia

Schwartz 1986Not an RCT - a non-randomised, non-controlled trial of the effect of EACA in patients with acute promyelocytic leukaemia and acquired alpha-2-plasmin inhibitor deficiency

Wassenaar 2008Not an RCT - a retrospective study of the use of EACA in patients with acute promyelocytic leukaemia and acquired alpha-2-plasmin inhibitor deficiency

Yang 2001Wrong patient group - a randomised, comparative trial examining the efficacy of tranexamic acid in reducing post-partum blood loss in primigravid women

 
Summary of findings for the main comparison. Antifibrinolytics (lysine analogues) compared to placebo to prevent bleeding in patients with haematological disorders

Antifibrinolytics (lysine analogues) compared to placebo to prevent bleeding in patients with haematological disorders

Patient or population: patients with haematological disorders
Settings: hospital
Intervention: antifibrinolytics (lysine analogues)
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)§
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboAntifibrinolytics (lysine analogues)

Number of patients with any bleedingSee commentSee commentNot estimable86
(3 studies)
⊕⊝⊝⊝
very low1,2
Gallardo 1983 saw a reduction in minor bleeding; Avvisati 1989 and Shpilberg 1995 saw a reduction in the number of bleeding events

Number of patients with thromboembolismSee commentSee commentNot estimable68
(2 studies)
⊕⊝⊝⊝
very low1,2
No patients within the Avvisati 1989 or Shpilberg 1995 studies had an episode of thromboembolism. Gallardo 1983 only reported no deaths due to thrombosis.

Mortality (all-cause)See commentSee commentNot estimable0
(0)
See commentNone of the studies reported all-cause mortality. Shpilberg 1995 reported no deaths due to bleeding and Gallardo 1983 reported no deaths due to thrombosis.

Number of platelet transfusions per patientSee commentSee commentNot estimable0
(0)
See commentNone of the studies reported the number of platelet transfusions per patient

Adverse events of transfusionsSee commentSee commentNot estimable0
(0)
See commentNone of the studies reported adverse events due to blood transfusions

Adverse events of antifibrinolytic agentsSee commentSee commentNot estimable74
(2 studies)
⊕⊝⊝⊝
very low1,2
Shpilberg 1995 reported no side effects were observed and Gallardo 1983 stated side effects were minimal but no further information was provided

*No meta-analyses were performed within this review and therefore no comparative risks could be calculated.

§One study (Fricke 1991) was included within the review but no data were extracted from this study. This was because Fricke 1991 had significant flaws within the study design (see Risk of bias in included studies and Characteristics of included studies) and no viable data could be extracted from the study report.
CI: confidence interval

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1A full assessment of the quality of the evidence was limited by a lack of reporting. However, selective outcome reporting was present in Gallardo 1983.
2Within all three studies there were only 86 participants. This is significantly below the optimal information size (OIS) (Pogue 1997).
 
Table 1. Study characteristics

StudyType of studyNo. of patientsNo. of patients receiving antifibrinolyticNo. of patients platelet refractory/ allo-immunisationDiagnosis of patientsTreatment of underlying diseaseAntifibrinolytic doseAntifibrinolytic frequencyAntifibrinolytic routeTreatment startedTreatment stoppedPlatelets given

Tranexamic acid studies

Avvisati 1989RCT126NR

 
APLChemo2 g8-hourlyIV in 500 ml 5% glucose1st day of antileukaemic RxAfter 6 daysProphylactic

Fricke 1991RCT Cross-over8

Only 3 completed study
8At least 37 AA

1 MDS
NR20 mg/kg8-hourlyOralAfter 4-day trial period to assess drug toleranceSuccessive 4/52 courses or until grade 2 bleedingTherapeutic

Shpilberg 1995RCT5626NRAML

38 induction

18 consolidation
Chemo1 g6-hourlyOralPlatelets < 20 or rapidly falling and < 50Platelet count > 20 for 2 consecutive countsTherapeutic

EACA studies

Gallardo 1983RCT199NR15 AML

4 ALL

(1 patient not evaluable)
ChemoLoading dose 100 mg/kg

12 to 24 g/day thereafter
NRNRPlatelet count < 20 x 109/lPlatelet count ≥ 20 x 109/lPlatelet count < 20 x 109/l

 AA: aplastic anaemia
ALL: acute lymphocytic leukaemia
AML: acute myeloid leukaemia
APL: acute promyelocytic leukaemia
C: control
EACA: epsilon aminocaproic acid
IV: intravenous
MDS: myelodysplastic syndrome
NR: not reported
RCT: randomised controlled trial
TXA: tranexamic acid
 
Table 2. Results of studies (primary outcomes of review)

StudyType of studyNumber of patientsType of patientsNumber, site and severity of bleedingThromboembolism (venous and arterial)






Tranexamic acid studies

Avvisati 1989RCT12APLCumulative haemorrhagic scores

TXA 3

C 42

(P = 0.0045)
No thromboembolic events observed






Shpilberg 1995RCT56AML

38 induction

18 consolidation
Mean number of bleeding events per patient :

Induction

TXA 6.2 ± 2.9

C 4.5 ± 3.6

Consolidation

TXA 1.1 ± 1.4

C 2.6 ± 2.2

(P < 0.05)
Cumulative haemorrhagic scores:

Induction

TXA 8.3 ± 4.8

C 5.6 ± 4.8

Consolidation

TXA 1.3 ± 1.8

C 5.1 ± 3.6

(P < 0.05)

 
No thromboembolic events observed

EACA Studies

Gallardo 1983RCT1915 AML

4 ALL
Capillary bleeding+

EACA 31% of days at risk@

Placebo 50% of days at risk@
Major bleeding

EACA 15%

Placebo 19%
No deaths due to thromboembolic disease

 @Days at risk defined as days when platelet count fewer than 20 x 109/l.
+Capillary bleeding defined as bleeding in skin, mucous membranes, conjunctivae, nose and guaiac in gastrointestinal or genitourinary tract.
Major bleeding defined as nose bleeding requiring posterior packing, gross gastrointestinal or genitourinary tract bleeding and central nervous system bleeding.
ALL: acute lymphocytic leukaemia
AML: acute myeloid leukaemia
APL: acute promyelocytic leukaemia
C: control
EACA: epsilon aminocaproic acid
RCT: randomised controlled trial
TXA: tranexamic acid
 
Table 3. Results of studies (secondary outcomes of review)

StudyType of studyNumber of patientsType of patientsMortality (all causes)Mortality (secondary to bleeding)Mortality (secondary to thromboembolism)Laboratory assessment of fibrinolysisNumber of platelet transfusionsNumber of red cell transfusionsAdverse events of antifibrinolytic agentsAdverse events of transfusions

(e.g. transfusion reactions, antibody development)
DICQoL

Tranexamic acid studies

Avvisati 1989RCT12APLNRNRNRNo difference in the coagulation and fibrinolysis indices between the 2 groups apart from FDPs*.  FDPs decreased in TXA arm but increased in the placebo arm (P < 0.01)Platelet Tx

TXA = 45 Tx

C = 246 Tx

 

P = 0.045

 
Reduction in overall RBC transfusions required in TXA group:

(units)

TXA 21

C 56
NRNRNRNR

Shpilberg 1995RCT56AML

38 induction

18 consolidation
NRNo fatal bleeding in either groupNRNRInduction (units)

TXA 22.1 ± 13.2

C 23.1 ± 11.7

Consolidation

(units)

TXA 3.7 ± 4.1

C 9.3 ± 3.3

(P < 0.05)
No reduction RBC transfusion requirements

Induction

(units)

TXA 7.5 ± 4.7

C 7.3 ± 3.3

Consolidation

(units)

TXA 4.1 ± 2.8

C 4.1 ± 3.4
No side effects were observedNRNRNR

EACA studies

Gallardo 1983RCT1915 AML

4 ALL
NRNRNo patient died of thrombosisMonitored with the I125 fibrinogen plasma clot lysis assay  but no further data described.EACA

1 every 13.3 days at risk@

Placebo

1 every 10.5 days at risk@
NRSide effects were stated as minimalNRNRNR

 *Blood coagulation tests were prothrombin time, activated partial thromboplastin time, fibrinogen, FDP, antithrombin III activity, thrombin-antithrombin III complexes, protein C activity and α2-antiplasmin. These were carried out daily for the first 10 days.
@Days at risk defined as days when platelet count fewer than 20 x 109/l.
+Capillary bleeding defined as bleeding in skin, mucous membranes, conjunctivae, nose and guaiac in GI or GU tract.
Major bleeding defined as nose bleeding requiring posterior packing, gross gastrointestinal or genitourinary tract bleeding and central nervous system bleeding.
ALL: acute lymphocytic leukaemia
AML: acute myeloid leukaemia
APL: acute promyelocytic leukaemia
C: control
DIC: intravascular coagulation
EACA: epsilon aminocaproic acid
FDPs: fibrin degradation products
GI: gastrointestinal
GU: genitourinary
QoL: quality of life
NR: not reported
RBC: red blood cell
RCT: randomised controlled trial
TXA: tranexamic acid
Tx: transfusion
 
Table 4. Laboratory assessment of fibrinolysis - Avvisati 1989

Coagulation factorsTimingTreatment groups

Median (range)

Tranexamic acidPlacebo

Fibrinogen (mg/dl)Baseline80 (55 to 395)70 (50 to 190)

Day 355 (20 to 125)62 (45 to 150)

Day 553 (35 to 80)78 (36 to 150)

Day 760 (50 to 65)85 (17 to 160)

Thrombin-antithrombin complex (ng/ml)Baseline32 (4 to 58)22 (15 to 26)

Day 350 (20 to 100)22 (11 to 52)

Day 541 (5 to 51)17 (5 to 34)

Day 710 (5 to 31)21 (3 to 37)

α2-antiplasmin (%)Baseline39 (29 to 80)50 (29 to 58)

Day 327 (17 to 40)35 (27 to 47)

Day 532 (27 to 34)36 (29 to 51)

Day 733 (19 to 53)42 (32 to 59)

Fibrin/fibrinogen degradation products (μg/dl)Baseline40 (10 to 80)80 (40 to 160)

Day 3NRNR

Day 5NRNR

Day 7NRNR

 NR: not reported