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. 2015 Jun 24;2015(6):CD008562. doi: 10.1002/14651858.CD008562.pub3

Aoki 2002.

Methods Design: parallel (2 groups)
Study phase: III
Country: Japan
Follow‐up period: 28 days after the end of the infusion or until death
Randomization unit: patient
Participants Randomized: 132

  1. Activated protein C: 63 (48%)

  2. Heparin: 69 (52%)


Excluded post‐randomization (likely): 21.2% (28/132)

  1. Without evidence of DIC: 5 (received infusion?)

  2. Withdrawals: 13 (within 3 days of the infusion)

  3. Protocol violation: 10


Analyzed patients for efficacy: 79% (104/132)

  1. Activated protein C: 78% (49/63)

  2. Heparin: 80% (55/69)


Analyzed patients for safety: (107/132)

  1. Activated protein C: (52/63)

  2. Heparin: (55/69)


Age (mean ± SD)

  1. Activated protein C: 60.0 ± 18.8 years

  2. Heparin: 56.9 ± 18.8 years


Gender

  1. Activated protein C (male/female): 31/18

  2. Heparin (male/female): 34/21


Patient with leukemia:
1. Activated protein C:
Acute promyelocytic leukemia: 6
Non‐leukemias: 17
2. Heparin:
 Acute promyelocytic leukemia: 6
 Non‐leukemias: 26
Inclusion criteria:
Patients with DIC diagnosed primarily on the basis of criteria established by the DIC research group of the Ministry of Health and Welfare of Japan.
Exclusion criteria:

  1. Children younger than 15 years;

  2. Pregnant women and women suspected of being pregnant;

  3. Allergic patients;

  4. Patients with a history of allergic shock reaction to preparations from human blood;

  5. Patients judged as unsuitable for the clinical trial;

  6. Patients receiving the following agents: anticoagulant agents, antiplatelet agents, antifibrinolytic agents, and others that might affect the evaluation of the test drugs (these other agents include heparin, aprotinin, tranexamic acid, gabaxate mesylate, antithrombin concentrate, argatroban, aspirin, ticlopidine, cilostazole, dipyridamole, plasminogen activators, urinastatin, and nafamostat mesylate).
Interventions Experimental:

  1. Human activated protein C (freeze‐dried preparation containing 10,000 units of human activated protein C in each vial (the Chemo‐Sero‐Therapeutic Research Institute, Kumamoto, Japan). One unit of Human activated protein C was defined as the amount of human activated protein C required to double the activated partial thromboplastin time of 1 mL of normal standard plasma. One unit was equivalent to 0.2 μg of human activated protein C. Dosage: 12.5 U (2.5 μg)/kg bodyweight per hour


Comparison:

  1. Heparin (unfractionated sodium heparin prepared by Fuso Pharmaceutical Company (Osaka, Japan). Each vial contained 10,000 units of heparin in 10 mL of solution. Dosage: 8 U/kg bodyweight per hour

  2. Placebo preparations were identical in appearance.


The test drug (Human activated protein C, heparin or placebo) was added to 500 mL to 1000 mL of infusion fluid (5% glucose, physiological saline or electrolyte solution) and was administered intravenously at a constant rate for a total duration of 6 days.

  • Co‐intervention: fresh frozen plasma and platelet concentrates
Outcomes Symptoms
 DIC score and coagulation/fibrinolysis parameters
 Death from any cause during treatment or within 28 days after treatment
 Safety
Notes Identifier trial number: not reported
Sample size calculation a priori: not declared
Conduction time date: no reported
Sponsor: not given
This trial included 'leukemic group' patients and 'non‐leukemic group'. However, details of deaths in the 'leukemic group' were not given. On 19 August 2010 and 18 February 2014, we sent an e‐mail to the main trial author (aoki.hema@med.tmd.ac.jp), but we were unable to make contact.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information to permit judgment of 'low risk' or 'high risk'.
Allocation concealment (selection bias) Unclear risk Insufficient information to permit judgment of 'low risk' or 'high risk'.
Blinding (performance bias and detection bias) 
 All outcomes Unclear risk Insufficient information to permit judgment of 'low risk' or 'high risk'.
The trial was described as "double blind", however details were not reported.
Incomplete outcome data (attrition bias) 
 All outcomes High risk Lost patients: 21.3%.
 There were no details of withdrawals by groups.
Selective reporting (reporting bias) High risk One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis.
For leukemic patients there is no information on death from any cause.
Other bias High risk

  1. Confounding bias (Porta 2008);

  2. Bias in the presentation of data (Porta 2008);

  3. Design bias (Porta 2008).