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Low molecular weight heparin for prevention of microvascular occlusion in digital replantation

  1. Yi-Chieh Chen1,2,
  2. Ching-Chi Chi1,3,
  3. Fuan Chiang Chan4,*,
  4. Yu-Wen Wen5

Editorial Group: Cochrane Peripheral Vascular Diseases Group

Published Online: 8 JUL 2013

Assessed as up-to-date: 19 OCT 2012

DOI: 10.1002/14651858.CD009894.pub2


How to Cite

Chen YC, Chi CC, Chan FC, Wen YW. Low molecular weight heparin for prevention of microvascular occlusion in digital replantation . Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD009894. DOI: 10.1002/14651858.CD009894.pub2.

Author Information

  1. 1

    Chang Gung University, College of Medicine, Taoyuan, Taiwan

  2. 2

    Chang Gung Memorial Hospital, Department of Plastic and Reconstructive Surgery, Taoyuan, Taiwan

  3. 3

    Chang Gung Memorial Hospital, Department of Dermatology and Centre for Evidence-Based Medicine, Chiayi, Taiwan

  4. 4

    Temple Street Children's University Hospital, Department of Plastic and Reconstructive Surgery, Dublin, Ireland

  5. 5

    Chang Gung University, Clinical Informatics and Medical Statistics Research Centre, Taoyuan, Taiwan

*Fuan Chiang Chan, Department of Plastic and Reconstructive Surgery, Temple Street Children's University Hospital, Temple Street, Dublin, Ireland. fchan910@gmail.com. fchan@eircom.net.

Publication History

  1. Publication Status: New
  2. Published Online: 8 JUL 2013

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Characteristics of included studies [ordered by study ID]
Chen 2001

MethodsDesign: RCT

Randomisation: method unknown

Blinding: nil
Intention-to-treat/Loss to follow up: unclear. The authors did not report if some patients were randomised but did not complete the trial.


ParticipantsSetting: China Railway Group's four innings second hospital, Fuyang City, Anhui Province, China

Study period: 1999 Oct - 2000 Jun

54 participants of replantation including 39 single digits, 7 multiple digits, 3 palms, 2 forearms and 3 toes were randomised into two groups: group A (LMWH) aged 4.5 - 57 yrs, mean 25.8, group B (UFH) aged 8-55 yrs, mean 26.6 yrs
Inclusion criteria:

- no history of major bleeding disorders

- normal bleeding time and clotting time before replantation
Exclusion criteria: not reported


Interventions2 intervention groups
Treatment (group A , n = 26): livaracine (Lee's Pharmaceutical Holdings Ltd, Hong Kong, China) 5000 IU SC 30 min before surgery, followed by 2500-5000 IU SC q12h x 7 days
Control (group B, n = 28): UFH 2500 IU IV 0.5 - 1 hr before surgery, followed by 1250 IU q12h x 7 -10 days; also received low molecular weight dextran 500ml twice a day


Outcomes1. Success rate of replantation: LMWH = 24/26 (89.2%), UFH = 25/28 (92.3%), P > 0.05
2. Bleeding tendency:

- LMWH group: 3 wound bleeding, 1 ecchymosis, 1 haematuria

- UFH group: 5 wound bleeding, 3 ecchymosis, 2 nasal bleeding, 3 gingival bleeding, 2 haematuria, 1 faecal occult blood

3. Coagulation abnormality (assessed by antithrombin activity, factor Xa activity, bleeding time, clotting time, aPTT, FDP concentration test): UFH > LMWH (see also  Table 1)


NotesThe study authors reported that success rate was calculated by individual patients; the mean value of coagulation test was obtained by pooling the data of 1hr, three days and seven days after surgery; statistical evaluation was not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote p. 53: "...patients were randomised into group A and B... (author's translation)"

Comment: Method not described

Allocation concealment (selection bias)Unclear riskComment: Method of allocation not described

Blinding of participants and personnel (performance bias)
All outcomes
High riskComment: LMWH was administered subcutaneously but UFH was administered intravenously

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: No description of blinding of outcome assessment

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: No description of dropouts or withdrawals

Selective reporting (reporting bias)High riskComment: Standard deviation of aPTT, bleeding time and FDP (mg/L) were not reported, platelet count change not reported

Other biasUnclear riskComment: Outcomes of digital amputation (n = 46) were mixed with amputation of palm (n = 3), forearm (n = 2) and toe (n = 3) and cannot be extracted. The mean value of coagulation test was obtained by pooling the data of 1h, 3d and 7d; SD value was not available; statistic evaluation was not reported. Low molecular weight dextran was used only in the control group, which might have biased the results. The definition or arterial and venous insufficiency was not described

Li 2012

MethodsDesign: RCT

Randomisation: method unknown
Blind assessment: double blind
Intention-to-treat/loss to follow-up: unclear. The authors did not report if some patients were randomised but did not complete the trial


ParticipantsSetting: Integrative Medicine Hospital of Guangdong Province, Foshan City, China

Study period: since 2006
60 participants (46 male, 14 female) aged 17- 43 yrs (mean 24.5 yrs) with 69 complete or incomplete amputated digits
Inclusion criteria: amputation of digit(s) between the level of metacarpophalangeal joint and distal phalangeal base, non-salvageable without vascular anastomosis
Exclusion criteria: not stated


Interventions2 intervention groups
Treatment (30 participants with 35 replanted digits): LMWH (exact type unknown) 0.4 ml SC q12h x 7-10 days
Control (30 participants with 34 replanted digits): UFH 10000 IU SC q12h x 7-10 days
Both groups also received:
- papaverine 60 mg/IM/q6h x 7-10 days
- low molecular weight dextran 500ml IV q12h x 7-10 days
- dipyridamole 25mg po tid x 7-10 days
- aspirin 50mg po qd x 7-10 days


Outcomes1. Success rate of replantation:
LMWH = 33/35 (94.3%), UFH = 32/34 (94.15), P > 0.05
2. aPTT prolongation: UFH > LMWH (between 2nd-7th postoperative days), P < 0.05
3. Platelet count: LMWH unchanged, UFH dropped significantly than before surgery


NotesSuccess rate was calculated by digits


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote p. 205: "...participants were randomised into two groups... (author's translation)"

Comment: Method not described

Allocation concealment (selection bias)Unclear riskComment: Method of allocation not described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote p. 205: "...double blind principle was followed... (author's translation)"

Comment: The outcome is not likely to be influenced

Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote p. 205: "...double blinding principle was followed... (author's translation)"

Comment: Outcome measurement is not likely to be influenced

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: No description of dropouts or withdrawals

Selective reporting (reporting bias)Unclear riskComment: The trialists did not report the incidence of compromised microcirculation requiring surgical re-exploration or re-anastomosis. The direct or indirect cause of microvascular insufficiency was also not provided

Other biasHigh riskComment: The LMWH used in this trial was not reported. The dosage of LMWH was not reported; only the volumetric dosage was provided. The specific mechanisms of injury leading to amputation and the severity of soft tissue damage between each group were not mentioned. In some replanted digits only one digital artery and one digital vein were repaired, while in some other cases two digital arteries and three digital veins were repaired. Occlusion of a repaired vessel might result in different outcome if the number of repaired vessels was different

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Azolov 1983Comparative study, compared coumarin, nitrofarin, aspirin and dextrans; not focused on LMWH [Article in Russian]

Buckley 2011Case report and review of evidence

Fukui 1989Case series, 13 cases (replantations and damaged digital arteries) received daily intra-arterial infusion of (1) 240,000 U of urokinase, (2) 40 micrograms of prostaglandin E1, (3) 10,000 U (maximum) of heparin, and (4) low molecular weight dextran for 10 consecutive days

Fukui 1994Retrospective survey conducted among 94 members of the Japanese Society of Reconstructive Microsurgery on the present status of replantation in Japan and included 9,664 replanted extremities (157 upper arms, 415 forearms, 471 hands, 8,320 digits, 33 thighs, 103 calves, 37 feet, and 128 toes). Outcomes of continuous local intra-arterial infusion of various anticoagulant and thrombolytic agents at Nara Medical University were reviewed

Furnas 1992Comparative study, compared the incidence of blood loss and blood transfusion between patients with replanted digits receiving one anticoagulant in addition to aspirin (n = 40) and two or more anticoagulant in addition to aspirin (n = 15)

Gao 2007Comparative study, compared the incidence of vascular insufficiency after digital replantation between two groups: the experimental group (n = 76) received clexane 40 mg SC daily as well as low molecular weight dextran and papaverine, the control group receive the same treatment but clexane [Article in Chinese]

Han 2000Retrospective study, used topical and systemic anticoagulation to maintain external bleeding for fingertip replantation to overcome venous congestion in 140 cases without venous repair or in cases in which there is obstruction of a repaired vein

Loisel 2010Prospective study without control group, enrolled 13 cases of replantation (one devascularisation of hand, two complete amputations of hand, four ring fingers and six complete amputations of finger) using local irrigation of anastomosis with urokinase and LMWH to reduce the thrombosis rate [Article in French]

Maeda 1991Comparative study, compared intra-arterial, intravenous infusion of urokinase, heparin and PGE1 in 44 patients. IA group included 24 replantation (17 digit, 4 hand, one forearm and 2 toe replantations) and 5 open fracture cases; IV group included 10 replantations; control group were 5 patients with hand injuries

Niibayashi 2000Retrospective study, 252 consecutive digital replantations and revascularisations in 201 patients were reviewed to determine factors influencing survival, including the application of anticoagulant agents

Nikolis 2011Historical control study, the retrospective review group included 175 digits (104 revascularisations and 71 amputations), IV heparin was used in 35.1% of the cases; the prospective group included 106 digits (45 revascularisations and 61 amputations), IV heparin was used in 14.6% of the cases. The two cohorts were compared with regards to demographics, injury characteristics, postoperative thromboprophylaxis medication as well as complication and success rates

Oufquir 2006Retrospective study, 15 amputated digits developed "no reflow phenomenon" after replantation and received intra-arterial infusion of antithrombotic and fibrinolytic agents [Article in French]

Pomerance 1997Retrospective study, 127 digits and 24 thumbs in 106 patients were reviewed to assess early results and complications, and to determine if a short course (minimum 3 days) of dextran-40 anticoagulation adversely affected digit survival

Rooks 1994Double-blind animal study, used a rat femoral artery crush-avulsion model to analyse the efficacy of intra-arterially delivered anticoagulants against similar systemically administered intra-venous anticoagulants

Shu 2011Randomised controlled trial, 49 patients were randomised to receive single dose IV UFH (50 IU/kg) (24 participant with 42 digits), or no treatment (25 participant with 35 digits) [Article in Chinese]

Vretos 1995Retrospective study. 43 patients received replantation, revascularization or free flap transfer. Antithrombotic medication included (1) aspirin and dipyridamole; (2) low molecular weight dextran; (3) streptokinase and streptodonase; (4) diclofenac. No control group

Yang 2008Historical control study, 40 patients with 56 amputated digits received replantation and fasudil treatment were included as the experimental group; comparison was made with retrospective data reviewed from 32 patients with 45 digital replantation who received postoperative LMWH and papaverine as the control group

Yu 2012Comparative study, 41 cases with 44 amputated digits in the control group received IM injection of heparin and papaverin after replantation; another 41 cases with 44 digital replantation received continuous local infusion of solution with heparin, lidocaine and dexamethasone via a catheter inserted into the flexor tendon sheath [Article in Chinese]

Zhang 2002Comparative study, compared the efficacy and adverse effect between two groups: 12 cases with 17 amputated digits received LMWH, the other 12 cases with 19 digits received UFH [Article in Chinese]

Zhang 2004Comparative study, included 45 cases with 60 digital amputations which were caused by avulsion or crush injury or happened on the fingertips. Twenty-three cases received postoperative LMWH, the other 22 cases received UFH

 
Comparison 1. LMWH versus UFH

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Success rate of replantation2Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Unit of analysis: numbers of participants
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Unit of analysis: numbers of digits
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Compromised microcirculation1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 Arterial
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Venous
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Haemorrhage1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 wound bleeding
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 hematuria
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 gingival bleeding
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.4 fecal occult blood
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.5 nasal bleeding
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.6 ecchymosis
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 aPTT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 
Table 1. Coagulability measures (Chen 2001)

Coagulability measuresbefore treatmentafter LMWH treatmentafter UFH treatment

Antithrombin activity0.971.221.56

Factor Xa activity1.020.370.58

Bleeding time2 min 24 sec3 min 18 sec4 min 35 sec

Clotting time8 min 55 sec12 min 20 sec25 min 32 sec

aPTT41 sec69 sec85 sec

FDP concentration test2.6 mg/l11.3 mg/l18.8 mg/l

 aPTT: activated partial thromboplastin time
FDP: fibrinogen degradation product
LMWH: low molecular weight heparin
UFH: unfractionated heparin