Description of the condition
Digital replantation is an established microsurgical procedure in traumatic hand surgery, with reported success rates as high as 90% (Levin 2008). The success is highly dependent on maintaining the patency of the repaired blood vessels after satisfactory microvascular anastomosis. Microvascular occlusion can result from either venous or arterial thrombosis or, less frequently, a combination of both. Arterial thrombi, which usually present in areas of high or disturbed blood flow or at sites of endothelial damage, are formed primarily of platelet aggregates bound together by thin fibrin strands; thus both platelet activation and the coagulation cascade are important in its thrombogenesis. Venous thrombi, on the other hand, present in areas of stasis and are formed primarily by red blood cells and fibrin, and less so by platelets; thus the coagulation cascade plays a much more prominent role than platelet activation in their etiology (Conrad 2001). Studies on replantation of the digits and free-tissue transfer have indicated that the highest risk of critical thrombosis following microvascular anastomosis is in the first three days following surgery. The risk is then reduced but still exists up to two weeks after surgery (Betancourt 1998; Kroll 1996). Venous thrombosis is reported to occur more often than arterial thrombosis. Nevertheless, 90% of arterial thrombi occur within 24 hours post-replantation while the majority of venous thromboses tend to occur after the first 24 hours (Askari 2006; Kroll 1996; Levin 2008).
The use of prophylactic antithrombotic agents is the most commonly reported strategy for avoiding vascular thrombosis after vascular repair. A variety of anticoagulation protocols are used by microsurgeons. Current protocols include the use of antithrombotic agents such as aspirin, intravenous heparin, low molecular weight heparins (LMWHs) or intravenous dextran, as well as local heparin delivery through direct injection or continuous drip on an open incision (Askari 2006; Barnett 1989; Buckley 2011; Iglesias 1999). However, the optimum dosage and duration of administration of these agents remains complicated by the wide variability of antithrombotic prophylaxis protocols practiced among different surgical units.
Description of the intervention
Unfractionated heparin (UFH) is a glycosaminoglycan polymer of varying lengths and is the most widely used anticoagulant agent for preventing both arterial and venous thrombosis (Stockmans 1997). Heparin maintains the patency of microvascular anastomoses because it inhibits the synthesis of thrombin. This in turn leads to an improved survival rate of digital replantation. However, heparin prophylaxis is limited by an increased risk of haemorrhage from the surgical site, formation of haematoma, heparin-induced thrombocytopenia (Chong 1989) and requirement for transfusion (Isaacs 1977). Low-dose regimens are attractive from the standpoint of bleeding complications (Kroll 1995), but they have been reported as less effective compared to full heparinising doses (Hendel 1984). On the contrary, LMWH is a group of antithrombotic agents with different individual properties. LMWH is derived from UFH and has been reported to be as efficacious as heparin in preventing thrombosis. It has enhanced bioavailability as it binds loosely to protein and interacts less with platelets. In comparison to UFH it has fewer adverse effects. The LMWHs have a long half-life with a very predictable dose-response relationship, which minimises the need for monitoring. Furthermore, LMWH is associated with reduced risk of bleeding and a lower risk of heparin-induced osteoporosis. In addition, it has been shown that short-term use of LMWH is less frequently associated with undesirable heparin-induced thrombocytopenia (HIT) compared with UFH (Franklin 2003; Warkentin 1995).
How the intervention might work
When the vessel wall is injured, collagen and tissue factor become exposed to the flowing blood thereby initiating a proteolytic cascade that leads to the formation of a thrombus (Furie 2008). Exposed tissue factor triggers the formation of thrombin. Unlike the formation of thrombi in large sized vessels, thrombus formation in small sized vessels, such as the digital artery, may completely occlude the blood flow to the tissues supplied by the artery. Similarly, thrombus formation in the digital vein impedes proper venous outflow, which will eventually lead to arterial thrombosis. Both UFH and LMWH exert their anticoagulant activity by activating antithrombin (also known as antithrombin III), which in turn inhibits thrombin and activated factor Xa (factor Xa) to prevent both arterial and venous thrombosis (Hirsh 2001; Wolf 1994). Although systemic anticoagulant therapy does not improve the patency rate when sharply divided vessels are repaired (Elcock 1972; Ketchum 1978), a laboratory study showed a dramatic improvement in the patency rate following repair of traumatized vessels using systemic anticoagulant as an adjunct (Cooley 1985). In a retrospective study of replantation failure, 20% occurred within four hours of discontinuing systemic heparin (Hendel 1984). Although re-endothelialisation begins immediately after vascular repair, some form of anticoagulant therapy should be continued for at least three to five days, that is until the endothelium regenerates and covers the anastomotic site (Chow 1983; Morecraft 1985; Servant 1976). The LMWHs are produced by either chemical or enzymatic depolymerization of UFH resulting in the same inhibitory effect on active factor X but with relatively less anti-IIa (thrombin) activity and thus less effect on the clotting time than UFH (Weitz 1997).
Why it is important to do this review
There are conflicting reports on both the efficacy and adverse effects of anticoagulants in preventing microvascular thrombosis (Niibayashi 2000; Veravuthipakorn 2004; Vretos 1995) with little objective evidence to demonstrate their beneficial effects in digital replantation. In addition, many surgeons favour their own particular protocols that are derived by trial and error for perioperative anticoagulation. No consensus or standard exists on the use of LMWH as an antithrombotic agent. As such, there is a strong need to review the efficacy of LMWH in digital replantation.
To assess whether subcutaneous low molecular weight heparin (LMWH) treatment improves the salvage rate of the digits and survival in patients with digital replantation after traumatic amputation.
Criteria for considering studies for this review
Types of studies
We limited our analysis to randomised controlled trials (RCTs), with or without blinding. We also included studies which used alternative methods of randomisation such as alternate days of the week, odd or even dates of birth, or hospital number (quasi-randomised studies). We excluded studies that used historical controls.
Types of participants
We included all patients who suffered from traumatic digital amputation and received salvage microvascular replantation.
Types of interventions
We included studies in which patients with traumatic digital amputation were randomised to receive LMWH versus any other treatment (such as another anticoagulant, placebo or no intervention) after digital replantation in order to prevent microvascular occlusion. We excluded trials that used LMWH for therapeutic purposes in established microvascular occlusion of replanted digits.
Types of outcome measures
- The success rate of replantation, that is, the patency rate of microvascular anastomosis.
- The incidence of compromised microcirculation requiring surgical re-exploration or re-anastomosis, or both.
- Direct cause of microvascular insufficiency (arterial occlusion, venous occlusion, or both).
- Indirect cause of microvascular insufficiency (shock, infection, peripheral vascular pathology, hypercoagulopathy, etc.).
- Complications and side effects related to the interventions (haemorrhage, thrombocytopenia, etc.).
- Coagulation abnormalities.
Search methods for identification of studies
The searches were not limited by language or publication status.
The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched October 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 10), part of The Cochrane Library at www.thecochranelibrary.com. See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com).
The following trial registers were searched by the TSC for ongoing and unpublished trials (November 2012) using the terms (finger or digit) and heparin:
- World Health Organization International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/);
- ClinicalTrials.gov (http://clinicaltrials.gov/);
- Current Controlled Trials (http://www.controlled-trials.com/).
The review authors also searched PubMed using the search strategy which is detailed in Appendix 2, as well as CNKI (China National Knowledge Infrastructure) at http://cnki50.csis.com.tw/kns50/index.aspx and CEPS (Chinese Electronic Periodical Services) at http://www.airitilibrary.com/ using Chinese synonyms modified from the PubMed search strategy (Appendix 3; Appendix 4). PubMed, CNKI and CEPS were searched on 19 January 2013.
Searching other resources
We examined the reference lists of relevant review articles and all included trials to identify further studies.
Data collection and analysis
We considered all the trials identified with our search strategy for inclusion in this review.
Selection of studies
Two review authors (YCC, FCC) independently assessed all titles and abstracts of potentially eligible trials. We obtained the potentially relevant papers and assessed their full texts for inclusion eligibility. We resolved disagreements by discussion.
Data extraction and management
Two review authors (YCC, FCC) independently extracted and checked the data for accuracy. If relevant data could not be extracted, we tried to contact the primary authors of any articles and requested and included the additional unpublished data, when available. We resolved any discrepancies by consensus.
We used a standard data extraction form to capture the following information:
1. characteristics of the study, including design, method of randomisation, allocation concealment, withdrawals or dropouts, and funding source;
2. study participants, including mechanism of amputation and level of amputation;
3. intervention (dosage and route of LMWH administration);
4. comparison intervention (placebo or other anticoagulant medication);
5. outcome measures, including replantation success rate (patency rate of microvascular anastomosis), incidence of microvascular insufficiency demanding surgical re-exploration, cause of microvascular occlusion, and complications.
Assessment of risk of bias in included studies
Two review authors (YCC, FCC) separately assessed the quality of the included studies using the following key domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other sources of bias. For each of these domains we assigned a judgement of 'low risk' of bias, 'high risk' of bias, or 'unclear risk' of bias using guidance from the Cochrane Collaboration risk of bias tool (Higgins 2011). We resolved any disagreement by discussion. We presented this information in the Characteristics of included studies table.
Measures of treatment effect
We expressed the data as risk ratio (RR), risk difference (RD), number needed to treat (NNT) and mean difference (MD), where appropriate. The 95% confidence intervals (CI) were used for these estimates of treatment effects.
Unit of analysis issues
We expected to find only studies that used randomisation by individual patients. If studies which randomised by digits had been found, we would apply separate analyses.
Dealing with missing data
We tried to contact the original authors and request the essential information whenever possible. If we were unable to collect the missing data, we would include this fact in the risk analysis.
Assessment of heterogeneity
We planned to examine between-study heterogeneity by inspecting the forest plots and quantifying the impact of heterogeneity using the I
Assessment of reporting biases
When at least 10 relevant trials for a primary outcome were available, we planned to use funnel plots to investigate the presence of publication bias in the included studies, or if any systematic differences existed between small and large studies.
If appropriate, we planned to perform meta-analyses using the Review Manager software (RevMan 5) supplied by The Cochrane Collaboration. For estimates of the RR and RD, we planned to use the Mantel-Haenszel method. For continuous variables, we planned to use the inverse variance method. We planned to use a fixed-effect model for the meta-analyses except in cases where heterogeneity was identified. In those cases we planned to use a random-effects model as described in the Assessment of heterogeneity section.
Subgroup analysis and investigation of heterogeneity
We planned to perform subgroup analyses according to the mechanism of digital amputation (for example guillotine, crush, avulsion or degloving) and the level of digital amputation when data were available. We also planned to perform a comparison of effects of different heparin doses if sufficient numbers of studies, or trials using different dosage regimens, were identified.
We planned to perform sensitivity analysis to explore the influence of the quality of studies on the treatment effect size. We planned to use an intention-to-treat (ITT) approach. We planned to analyse only the data available and consider the dropout rate as a marker of trial quality.
Description of studies
Results of the search
See Figure 1.
|Figure 1. Study flow diagram.|
Two RCTs published in Chinese met our inclusion criteria and were included in this review. Both RCTs (Chen 2001; Li 2012) compared LMWH with UFH. No RCTs comparing LMWH with placebo, no treatment or other anticoagulants were identified.
The first trial (Chen 2001) enrolled 54 participants, including 39 single digit amputations, seven multiple digit amputations, three palm amputations, two forearm amputations and three toe amputations. The inclusion and exclusion criteria were not reported. Twenty-six participants were randomised to the LMWH group (Livaracine 5000 IU subcutaneous injection (SC) 30 min before surgery, followed by 2500 to 5000 IU SC every 12 hours (q12h) for 7 days); the other 28 were randomised to the UFH group (UFH 2500 IU intravenous injection (IV) 0.5 to 1 hour before surgery, followed by 1250 IU q12h for 7 to 10 days). The UFH group also received 500 ml low molecular weight dextran-40 twice a day. No participants with a previous haemorrhagic disorder or preoperative coagulation test that was abnormal were found in either group. The details of the surgical interventions were not reported.
The second trial (Li 2012) enrolled 60 participants with 69 either complete or incomplete amputated digits. The levels of amputation were located between the metacarpophalangeal joint and distal phalangeal base of the digit, and the digital arteries and veins were repaired by interrupted sutures using 9-0 to 12-0 nylon under surgical microscope. In the LMWH group (30 participants with 35 replanted digits), the repair of one artery and two veins was performed on 26 digits of 23 participants; the repair of one artery and one vein was performed on three participants and three digits; and the repair of two arteries and three veins was performed on six digits of four participants. In the UFH group (30 participants with 34 replanted digits), repair of one artery and two veins was performed on 25 digits of 22 participants; repair of one artery and one vein was performed on two participants and two digits; and repair of two arteries and three veins was performed on seven digits of six participants. The participants in the LMWH group received LMWH (exact type unknown) 0.4 ml SC q12h for 7 to 10 days, and participants in the UFH group received UFH 10000 IU SC q12h for 7 to 10 days.
See the Characteristics of included studies tables for further details.
Twenty reports of studies were excluded after examination of the full texts. See the Characteristics of excluded studies for further details.
Risk of bias in included studies
We considered the Chen 2001 trial as having a high risk of bias and the Li 2012 trial a moderate risk of bias based on the various assessed parameters of methodological quality. Details of the methodological quality are reported in the table Characteristics of included studies. A risk of bias summary is presented in Figure 2 with each methodological quality item presented as a percentage across all included trials; Figure 3 shows the separate judgements for each included trial.
|Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
|Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
The method of allocation concealment was not mentioned in either included trial, and the risk of bias for allocation concealment was therefore assessed as unclear.
One trial had a high risk of bias for blinding because LMWH was administered subcutaneously but UFH was administered intravenously (Chen 2001), while the other trial had a low risk of bias for blinding because both the participants and personnel were blinded (Li 2012).
Incomplete outcome data
Both included trials were classified as at unclear risk of bias for incomplete outcome data due to a lack of descriptions about dropouts or withdrawals.
One trial was classified as unclear for risk of selective reporting bias (Li 2012) because 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. The other trial (Chen 2001) did not provide detailed statistics (for example SD) regarding coagulability and platelet counts and was classified as having a high risk of reporting bias.
Other potential sources of bias
One trial had a high risk of bias for other sources (Li 2012) and the other trial had an unclear risk of bias for other sources (Chen 2001). The Li 2012 trial did not report which LMWH product was used, the dosage of LMWH, the mechanism of injury, and the severity of soft tissue damage. The participants had a varying number of repaired vessels. All of these factors may have led to a biased effect estimate. The Chen 2001 trial included amputations of the palm and forearm but the number was small (n = 5). Low molecular weight dextran was used only in the UFH group, which might have biased the results. The details are reported in the 'Risk of bias' tables under Characteristics of included studies.
Effects of interventions
Low molecular weight heparin (LMWH) versus unfractionated heparin (UFH)
Both included trials (Chen 2001; Li 2012) compared LMWH and UFH and reported the efficacy and adverse effects. However, the available data were inadequate for meta-analysis because the trialists used different units of analysis to report the success rate of replantation. In addition, there was a lack of relevant data for the other outcomes planned in this review. For the same reason, subgroup and sensitivity analyses were not performed.
Success rate of replantation
Both RCTs reported data on this outcome. The Chen 2001 trial reported the outcome by considering individual participants: the success rate of replantation was 92.3% in the LMWH group and 89.2% in the UFH group (RR 1.03; 95% CI 0.87 to 1.22). The Li 2012 trial reported this outcome by considering the digits: the success rate of replantation was 94.3% in the LMWH group and 94.15% in the UFH group (RR 1.00; 95% CI 0.89 to 1.13). In both RCTs the success rate of replantation did not significantly differ between the LMWH and UFH groups (see Analysis 1.1). However, neither of the trialists provided the power of the tests.
Incidence of compromised microcirculation
The Chen 2001 trial reported the incidence of postoperative arterial and venous insufficiency separately (see Analysis 1.2), but the authors did not clarify their definitions for these complications. Arterial insufficiency occurred in two out of 26 participants (7.7%) in the LMWH group and two out of 28 participants (7.1%) in the UFH group (RR 1.08; 95% CI 0.16 to 7.10). Compromised venous drainage occurred in three out of 26 participants (11.5%) in the LMWH group and four out of 28 participants (14.3%) in the UFH group (RR 0.81; 95% CI 0.20 to 3.27). The incidence of arterial and venous insufficiency did not significantly differ between the LMWH and UFH groups. A power analysis was not done. The trialists did not report any cases receiving surgical re-exploration or re-anastomosis for salvage of the condition. The Li 2012 trial did not report data relevant to this outcome.
Direct and indirect cause of microvascular insufficiency
Not mentioned in either RCT.
Complications and side effects related to the interventions
The Chen 2001 trial monitored anticoagulation-related bleeding tendency and reported the respective number of participants with various types of haemorrhage ( Analysis 1.3) instead of the number of participants with any haemorrhage. Wound haemorrhage occurred in three participants (11.5%) in the LMWH group and five participants (17.9%) in the UFH group (RR 0.65; 95% CI 0.17 to 2.44). Ecchymoses occurred in one participant (3.8%) in the LMWH group and three participants (10.7%) in the UFH group (RR 0.36; 95% CI 0.04 to 3.24). Haematuria appeared in one participant (3.8%) of the LMWH group and two participants (7.1%) of the UFH group (RR 0.54; 95% CI 0.05 to 5.59). Additionally, nasal bleeding, gingival bleeding, and faecal occult blood were present in two (7.1%), three (10.7%), and one participant (3.6%) of the UFH group, respectively; but none of the LMWH group. Overall, bleeding tendency was increased in the UFH group but this was not statistically significant.
Change in platelet count
The Li 2012 trial did not directly compare the platelet counts of the LMWH and UFH groups. However, the platelet count significantly decreased postoperatively in the UFH group (preoperative 278.4 ± 18.7 x 10
Chen 2001 monitored coagulability changes before anticoagulation and one hour, three days, and seven days after replantation. The parameters measured before treatment, after LMWH, and after UFH treatment were: antithrombin activity (0.97; 1.22; 1.56), factor Xa activity (1.02; 0.37; 0.58), bleeding time (2 min 24 sec; 3 min 18 sec; 4 min 35 sec), clotting time (8 min 55 sec; 12 min 20 sec; 25 min 32 sec), activated partial thromboplastin time (aPTT) (41 sec; 69 sec; 85 sec), and fibrinogen degradation product (FDP) concentration test (2.6 mg/L; 11.3 mg/L; 18.8 mg/L). No comparison was made between the LMWH and UFH groups but all data consistently showed that coagulability reduced more in the UFH group than in the LMWH group (see Table 1). The authors reported the mean value of the coagulation test by pooling the data at one hour, three days, and seven days after surgery but standard deviations were not available; further statistical analysis was thus not performed. Li 2012 measured the aPTT and found no significant differences in aPTT between both groups on the first postoperative day (LMWH 28.4 ± 3.3 sec, UFH 29.5 ± 3.1 sec; P > 0.05). However, the difference became significant during the second to seventh postoperative days (aPTT on the seventh postoperative day: LMWH 30.2 ± 2.1 sec, UFH 32.5 ± 2.2 sec; P < 0.05) ( Analysis 1.4). It must be noted that aPTT changes were expected in the case of UFH, if given at large doses (such as in the Li 2012 trial), as raised aPTT levels are a therapeutic target for UFH but not for LMWH.
Summary of main results
The objective of this review was to compare LMWH with other anticoagulants or no treatment in terms of efficacy and safety in preventing microvascular occlusion after digital replantation. We found only two relevant RCTs (Chen 2001; Li 2012) comparing LMWH and UFH. In both small trials, the success rate of digital replantation did not significantly differ between the LMWH and UFH groups. Both trials found that LMWH was associated with less heparin-related hypocoagulability or reductions in the platelet count, and Chen 2001 observed an increased bleeding tendency in the UFH group. No trials comparing LMWH to other anticoagulants or no treatment were found. It remains unclear whether routine administration of anticoagulants improves the survival rate of replanted digits by preventing microvascular thrombosis. Compared to other anticoagulants, whether LMWH improves the success rate of replantation or has a reduced incidence of adverse effects is also unknown.
Overall completeness and applicability of evidence
Only two trials were identified for inclusion in this review. Both trials compared LMWH with UFH. No studies comparing LMWH with placebo, no treatment or other anticoagulants were identified. In addition, the two identified trials (Chen 2001; Li 2012) provide very limited evidence on the efficacy of LMWH after digital replantation. Therefore, most of the review question has not yet been resolved.
Although the success rate did not differ between the LMWH and UFH groups in both trials, the authors did not report whether there was any re-exploration and successful salvage of compromised digital perfusion. In those participants who failed replantation, the direct and indirect causes of microvascular occlusion were not reported. Occlusions of the repaired vessels may occur in either arteries or veins, or both. When the arterial inflow is blocked, the replanted digits will turn pale and cool, with decreased skin turgor and sluggish capillary refill. When the venous drainage is blocked, the replanted digits will become congestive and cyanotic. Although the Chen 2001 trial reported the incidence of arterial and venous insufficiency separately, a clear definition of these clinical conditions was not provided. The Chen 2001 trial also reported fewer bleeding events in the LMWH group compared to the UFH group, but the diagnostic criteria were not explicitly stated. This makes the judgement of the actual efficacy and complication rate of LMWH difficult.
We expected that subcutaneous LMWH or other anticoagulants might increase the patency rate of microvascular anastomosis performed on small sized, low-flow and severely injured vessels such as in the repair of digital veins as well as in replanting crushed or avulsed digits or fingertips. However, the available trials did not provide enough data to investigate all relevant types of injuries and the surgical outcomes.
Quality of the evidence
This review included only two RCTs with high or moderate risk of bias based on the various assessed parameters of methodological quality. Blinding and selective reporting (Chen 2001) and other bias (Li 2012) were identified as reasons for a high risk of bias in the included studies. A total of 114 participants with at least 122 completely or incompletely amputated digits, three palms, two forearms and three toes were included. Detailed information about the mechanism and level of amputation was unavailable. Chen 2001 compared the treatment outcomes of microvascular repair at different levels (digit, palm, forearm and toe), which might be a potential source of bias. For each single replanted digit, Li 2012 stated that the number of vessels that were repaired ranged from one artery and one vein to two arteries and three veins. This variation in surgical interventions might be another potential source of bias since complete occlusion of one vessel could have resulted in different outcomes if the number of repaired vessels was different.
Potential biases in the review process
We conducted the review according to the published protocol. We tried to avoid publication bias by searching a wide range of databases including two databases in Mandarin (CNKI and CEPS). However, it is still possible that some relevant trials published in different languages may not have been identified. Only two RCTs were identified and an objective assessment of publication bias was not performed. We could not obtain additional data from the trialists of the included studies since their contact information was not available. Outcomes from replantation of three palms and two forearms were included in this review because Chen 2001 pooled these results with the results from digital replantation and they could not be extracted. However, since this trial was a RCT, we assumed these five amputations (5/54) were randomly distributed and were evenly represented in the LMWH and UFH groups. We were unable to establish contact with the trialists to confirm this.
The type of study included in this review was only the RCT. It should be kept in mind that the systematic evaluation of adverse effects of LMWH or other anticoagulants may require other types of studies, such as cohort and case-control studies (Chi 2009; Cochrane Adverse Effects Methods Group 2012; Loke 2007).
Agreements and disagreements with other studies or reviews
Currently there is little evidence to guide perioperative anticoagulation in digital replantation. The best available evidence consists mainly of retrospective studies (Buckley 2011; Fukui 1989; Fukui 1994; Han 2000; Niibayashi 2000; Noguchi 1999; Oufquir 2006; Poole 1977; Rapoport 1985; Veravuthipakorn 2004; Vretos 1995), comparative studies (Azolov 1983; Furnas 1992; Gao 2007; Maeda 1991; Nikolis 2011; Yang 2008; Yu 2012; Zhang 2002; Zhang 2004), prospective cohort studies (Loisel 2010), or animal studies (Rooks 1994). Most of these studies compared anticoagulants other than LMWH, and many of the authors included major limb replantation or free flap transfer in their studies (Askari 2006; Azolov 1983; Fukui 1994; Khouri 1998; Maeda 1991; Pederson 2008). One RCT compared UFH with no treatment (Shu 2011). In the Shu 2011 trial, 24 patients with 42 digital replantations were randomised to the UFH group (50 IU/kg IV bolus) versus 25 patients with 35 digital replantations randomised to the control group. A per protocol analysis yielded three versus three arterial occlusions (RR 0.83; 95% CI 0.18 to 3.87), two versus one venous occlusions (RR 1.67; 95% CI 0.16 to 17.62), and four versus three replantation failures (RR 1.11; 95% CI 0.27 to 4.63). The results showed that single-dose UFH had no positive effect on microvascular patency and the success rate of replantation. It is worth noting that 85.7% (36/42 in the UFH group and 30/35 in the control group) of the amputations were incomplete, and 72.7% (30/42 and 26/35 respectively) of the injury mechanisms were crushing and avulsion. To date, no other systematically reviewed evidence concerning LMWH and digital replantation can be found.
The efficacy of antithrombotic agents for preventing thrombosis had been reviewed systematically for patients that received infrainguinal arterial bypass surgery (Geraghty 2011). Three trials comparing LMWH to UFH were included (Norgren 2004; Samama 1994; Swedenborg 1996). Meta-analysis of 507 participants (Norgren 2004; Samama 1994) failed to demonstrate a significant difference on early patency, and only marginally favoured LMWH versus UFH for early graft thrombosis on day 30 (odds ratio (OR) 0.54; 95% CI 0.33 to 0.90). Another included trial (Jivegard 2005) compared the primary graft patency in 229 patients. One hundred and sixteen participants were randomised to receive LMWH (dalteparin 5000 IU SC once daily for three months) versus 113 that received placebo; all participants received aspirin. The bypass occlusions at one month (8 versus 11; OR 0.69; 95% CI 0.27 to 1.78), three months (20 versus 25; OR 0.75; 95% CI 0.39 to 1.44), and 12 months (44 versus 46; OR 0.97; 95% CI 0.56 to 1.69) revealed no significant differences between the groups at any of these time points. One included trial in the Geraghty 2011 review (Edmondson 1994) compared LMWH with acetylsalicylic acid and dipyridamole (ASA and DIP). Ninety-four patients were randomised to receive 2500 IU SC LMWH (Fragmin) once daily, and 106 patients to receive 300 mg aspirin and 100 mg dipyridamole, both three times per day for three months. Bypass occlusions at six months (12 versus 30; OR 0.39; 95% CI 0.20 to 0.78) and 12 months (21 versus 38; OR 0.52; 95% CI 0.29 to 0.96) showed a significant positive effect for LMWH. Further subgroup analysis found that this positive effect was only significant in patients undergoing operations for limb salvage and not in patients having operations for claudication. It remains unclear whether the efficacy of LMWH in maintaining the patency of large-sized vessels is consistent with the findings when treating much smaller sized vessels, such as digital arteries and veins.
Implications for practice
The current limited evidence showed no significant differences in the efficacy of LMWH and UFH in preventing microvascular occlusion after digital replantation, but LMWH was associated with a lower risk of postoperative bleeding and hypocoagulability. There are many unclear risks of bias, which make the quality of evidence uncertain.
Implications for research
No placebo-controlled trials were identified by this systematic review. Further double-blind RCTs should be conducted to compare LMWH with placebo and to evaluate the efficacy of LMWH in reducing the risk of anastomotic thrombosis. Detailed information regarding the size and quality of the involved vessels and the interventions used should be reported for subgroup analysis in order to limit the risk of bias and to provide conclusive evidence. Prospective cohort studies and case-control studies would also be useful in assessing the adverse effect of LMWH and should be included in future reviews. Further reviews that include all anticoagulants and their application in replantation or microsurgery are warranted. A cost-effectiveness analysis of these interventions should also be considered.
We acknowledge the Cochrane Peripheral Vascular Diseases Review Group and Marlene Stewart for their assistance in the development of this review.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor: [Hand] explode all trees 1847
#2 MeSH descriptor: [Finger Injuries] this term only 84
#3 hand 14816
#4 finger 2728
#5 thumb 548
#6 digit 1931
#7 (radial or digital or pollicis or ulnar or palmar) near/4 arter* 912
#8 MeSH descriptor: [Radial Artery] this term only and with qualifiers: [Blood supply - BS, Surgery - SU] 81
#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 19219
#10 MeSH descriptor: [Amputation] explode all trees 297
#11 amput* 1237
#12 avuls* 179
#13 mutilat* 112
#14 MeSH descriptor: [Ischemia] explode all trees 775
#15 ischaemi* 4842
#16 ischemi* 12915
#17 MeSH descriptor: [Replantation] explode all trees 37
#18 MeSH descriptor: [Reconstructive Surgical Procedures] this term only 494
#19 replant* or *attach* 4439
#20 revascular* 4562
#21 salvag* 1734
#22 anastomosis 1643
#23 reconstruct* or re-construct* 4158
#24 re-vascula* 20
#25 MeSH descriptor: [Microsurgery] this term only 354
#26 microsurg* 609
#27 micro-surg* 17
#28 #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 31500
#29 MeSH descriptor: [Heparin, Low-Molecular-Weight] explode all trees 1608
#30 heparin* 7684
#31 LMWH 823
#32 nadroparin* or fraxiparin* or enoxaparin 1380
#33 Clexane or klexane or lovenox 77
#34 dalteparin or Fragmin or ardeparin 582
#35 normiflo or tinzaparin or logiparin 226
#36 Innohep or certoparin or sandoparin or reviparin 182
#37 clivarin* or danaproid or danaparoid 94
#38 antixarin or ardeparin* or bemiparin* 63
#39 Zibor or cy 222 or embolex or monoembolex 73
#40 parnaparin* or rd 11885 or RD1185 41
#41 tedelparin or Kabi-2165 or Kabi 2165 68
#42 emt-966 or emt-967 or pk-10 169 or pk-10169 or pk10169 19
#43 fr-860 or cy-216 or cy216 80
#44 seleparin* or tedegliparin or seleparin* or tedegliparin* 12
#45 wy90493 or "wy 90493" 9
#46 ("kb 101" or kb101 or lomoparan or orgaran) 64
#47 parnaparin or fluxum or lohepa or lowhepa 49
#48 op 2123 or parvoparin 13
#49 ave 502 63
#50 calciparin* 28
#51 #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 8304
#52 #9 and #28 and #51 11 in Trials
Appendix 2. Authors' PubMed search strategy
1. hand[MeSH Terms] OR hand[All Fields] OR hands[All Fields] 341314
2. fingers[MeSH Terms] OR fingers[All Fields] OR finger[All Fields] 83476
3. thumb[MeSH Terms] OR thumb[All Fields] OR thumbs[All Fields] 14272
4. digit[All Fields] OR digits[All Fields] OR digital[All Fields] 90873
5. radial[All Fields] OR digital[All Fields] OR pollicis[All Fields] OR ulnar[All Fields] OR palmar[All Fields] AND Arter* 14401
6. ((((#1) OR #2) OR #3) OR #4) OR #5 469579
7. amput* 37758
8. avuls* 8871
9. mutilat* 6659
10. ischaemia[All Fields] OR ischemia[MeSH Terms] OR ischemia[All Fields] OR ischemic[All Fields] 276229
11. replantation[MeSH Terms] OR replantation[All Fields] OR replantat* 7276
12. revascular* 43186
13. salvage* 35015
14. microsurgery[MeSH Terms] OR microsurgery[All Fields] OR microsurg* 35573
15. Reconstruct* 198775
16. ((((((((#7) OR #8) OR #9) OR #10) OR #11) OR #12) OR #13) OR #14) OR #15 592309
17. heparin[MeSH Terms] OR heparin[All Fields] OR heparin* 86953
18. anticoagulants[MeSH Terms] OR anticoagulants[All Fields] OR anticoagulant[All Fields] OR anticoagulants[Pharmacological Action] OR anticoagula* 206013
19. antithrombo* 12404
20. UFH OR UH OR LMWH 15916
21. nadroparin* OR fraxiparin* OR enoxaparin 3957
22. Clexane OR klexane OR lovenox 3444
23. dalteparin OR Fragmin OR ardeparin 1226
24. normiflo OR tinzaparin OR logiparin 395
25. Innohep OR certoparin OR sandoparin OR reviparin 533
26. clivarin* OR danaproid OR danaparoid 589
27. antixarin OR ardeparin* OR bemiparin* 108
28. Zibor OR cy 222 OR embolex OR monoembolex 216
29. parnaparin* OR rd 11885 OR RD1185 44
30. tedelparin OR Kabi-2165 OR Kabi 2165
31. emt-966 OR emt-967 OR pk-10 169 OR pk-10169 OR pk10169 1048
32. fr-860 OR cy-216 OR cy216 1555
33. seleparin* OR tedegliparin OR seleparin* OR tedegliparin* 1010
34. wy90493 OR wy 90493 0
35. kb 101 OR kb101 OR lomoparan OR orgaran 1022
36. parnaparin OR fluxum OR lohepa OR lowhepa 54
37. op 2123 OR parvoparin 46
38. ave5026 4
39. calciparin* 53
40. ((((((((((((((((((((((#17) OR #18) OR #19) OR #20) OR #21) OR #22) OR #23) OR #24) OR #25) OR #26) OR #27) OR #28) OR #29) OR #30) OR #31) OR #32) OR #33) OR #34) OR #35) OR #36) OR #37) OR #38) OR #39 240139
41. ((#6) AND #16) AND #40 654
Appendix 3. Authors' CNKI search strategy
(((題名= 低分子肝素 OR 關鍵詞 = 低分子肝素 OR 摘要 = 低分子肝素) OR (題名= 低分子量肝素 OR 關鍵詞 = 低分子量肝素 OR 摘要 = 低分子量肝素)) AND ((題名 =斷指 OR 關鍵詞 =斷指 OR 摘要 =斷指 OR 全文 =斷指) OR (題名 = 再植 OR 關鍵詞 = 再植 OR 摘要 = 再植 OR 全文 = 再植))) 32
Appendix 4. Authors' CEPS search strategy
(肝素 AND 斷指)=所有欄位 5
Contributions of authors
Yi-Chieh Chen (YCC), Fuan Chiang Chan (FCC), and Yu-Wen Wen (YWW) wrote the protocol. YCC and FCC selected trials, assessed trial quality, and extracted the data. YCC and Ching-Chi Chi (CCC) interpreted the data and conducted statistical analyses. YCC drafted the final review with contributions from CCC.
Declarations of interest
Sources of support
- No sources of support supplied
- Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.The PVD Group editorial base is supported by the Chief Scientist Office.
Differences between protocol and review
Outcomes from replantation of three palms and two forearms were included in this review because Chen 2001 pooled these results with the results from digital replantation and could not be extracted. However, since this trial was a RCT, we assumed these five amputations were randomly distributed evenly in the LMWH and UFH groups. We were unable to establish contact with the trialists to confirm this.
One secondary outcome (coagulability assessed by antithrombin activity, factor X
Medical Subject Headings (MeSH)
Anticoagulants [adverse effects; *therapeutic use]; Blood Coagulation Disorders [chemically induced]; Fingers [blood supply; *transplantation]; Heparin [therapeutic use]; Heparin, Low-Molecular-Weight [adverse effects; *therapeutic use]; Microvessels [*surgery]; Peripheral Arterial Disease [epidemiology]; Postoperative Hemorrhage [chemically induced]; Randomized Controlled Trials as Topic; Replantation [*adverse effects]; Venous Insufficiency [epidemiology]
MeSH check words