Low molecular weight heparin for preventing blockage of blood vessels in replanted fingers or toes after amputation injuries

Background

Microvascular surgery refers to any surgery involving small-sized blood vessels that is performed under the operating microscope, allowing, for example, for the repair of arteries and veins of amputated parts to the body. These vessels are typically 1 mm to 2 mm in diameter. Replantation is the reattachment of a completely detached body part, with fingers and thumbs being the most commonly replanted body parts. This is often referred to as digital replantation. In principle, digital replantation involves not only restoring the blood flow through the arteries and veins but also restoring the bony skeleton of the toes, fingers or thumbs, along with repairing the tendons and nerves, if necessary. Occlusion (blockage) of one or more of the repaired vessels due to the formation of a clot within the blood vessel can result in failure of the replantation. Anticoagulant medications are used to reduce clotting, and they could potentially prevent such a complication. Anticoagulants such as unfractionated heparin (UFH) have therefore been used to prevent clot formation after digital replantation. It is unclear if low molecular weight heparin (LMWH) has similar benefit.

Key results

A randomised controlled trial (RCT) is a clinical study in which people have an equal chance of receiving the treatment or a comparator. This systematic review identified four RCTs comparing LMWH with either UFH or no LMWH. The trials included a total of 258 people with at least 273 replanted fingers or toes (digits). The evidence is up-to-date to 17 March 2020. The trials differed in which results they reported and how they reported them, so we could not combine all the information.

Three trials showed no evidence of a benefit of LMWH when compared with UFH in the success rate of replantation, microvascular insufficiency due to vessel occlusion (poor blood flow due to blockages in the small-sized blood vessels), and side effects such as bleeding. There was no evidence of clear differences between the use of LMWH or no LWMH in the success rate of replantation in one study. Similarly, no evidence of clear differences in the incidence of reduced blood flow (compromised microcirculation) requiring further microvascular surgery (re-exploration or incision), or causes of microvascular insufficiency due to vessel blockage, were detected in the study which analysed by digits or people.

The limited evidence, which we judged to be of low to very low certainty, suggests there is no clear benefit of LMWH in increasing the success rate of replantation or preventing microvascular occlusion in digital replantation when compared to UFH or no LMWH.

Certainty of the evidence

The overall certainty of evidence is very low due to limitations in study design and reporting. For example, the studies did not take measures to hide from a person which treatment they had, and they reported results that were not stated in the original plan. The sample size of included studies was not large enough to provide precise effect estimates. There is a need for large studies that are designed to reduce these study limitations.

Authors' conclusions: 

There is currently low to very low-certainty evidence, based on four RCTs, suggesting no evidence of a benefit from LMWH when compared to UFH on the success rates of replantation or affect microvascular insufficiency due to vessel occlusion (analysed by digit or participant). LMWH had similar success rates of replantation; and the incidence rate of venous and arterial microvascular insufficiency showed no evidence of a difference between groups when LMWH was compared to no LMWH (analysed by digit). Similar rates of complications and adverse effects were seen between UFH and LMWH. There was insufficient evidence to draw conclusions on any effect on coagulation when comparing LMWH to UFH or no LMWH. The certainty of the evidence was downgraded due to performance and reporting bias, as well as imprecision in the results. Further adequately powered studies are warranted to provide high-certainty evidence.

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Background: 

The success of digital replantation is highly dependent on the patency of the repaired vessels after microvascular anastomosis. Antithrombotic agents are frequently used for preventing vascular occlusion. Low molecular weight heparin (LMWH) has been reported to be as effective as unfractionated heparin (UFH) in peripheral vascular surgery, but with fewer adverse effects. Its benefit in microvascular surgery such as digital replantation is unclear. This is an update of the review first published in 2013.

Objectives: 

To assess if treatment with subcutaneous LMWH improves the salvage rate of the digits in patients with digital replantation after traumatic amputation.

Search strategy: 

The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, AMED and CINAHL databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers, to 17 March 2020. The authors searched PubMed, China National Knowledge Infrastructure (CNKI) and Chinese Electronic Periodical Services (CEPS) on 17 March 2020 and sought additional trials from reference lists of relevant publications.

Selection criteria: 

We included randomised or quasi-randomised controlled trials comparing treatment with LMWH versus any other treatment in participants who received digital replantation following traumatic digital amputation.

Data collection and analysis: 

Two review authors (PL, CC) independently extracted data and assessed the risk of bias of the included trials using Cochrane's 'Risk of bias' tool. Disagreements were resolved by discussion. We assessed the certainty of evidence using the GRADE approach.

Main results: 

We included two new randomised trials in this update, bringing the total number of included trials to four. They included a total of 258 participants, with at least 273 digits, from hospitals in China. Three studies compared LMWH versus UFH, and one compared LMWH versus no LMWH. The mean age of participants ranged from 24.5 to 37.6 years. In the studies reporting the sex of participants, there were a total of 145 men and 59 women. The certainty of the evidence was downgraded to low or very low because all studies were at high risk of performance or reporting bias (or both) and there was imprecision in the results due to the small numbers of participants.

The three studies comparing LMWH versus UFH reported the success rate of replantation using different units of analysis (participant or digit), so we were unable to combine data from all three studies (one study reported results for both participants and digits). No evidence of a benefit in success of replantation was seen in the LMWH group when compared with UFH, regardless of whether the outcomes were reported by number of participants (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.87 to 1.10; 130 participants, 2 studies; very low-certainty evidence); or by number of digits (RR 0.97, 95% CI 0.90 to 1.04; 200 digits, 2 studies; low-certainty evidence). No studies reported the incidence of compromised microcirculation requiring surgical or non-surgical therapy, or any systemic/other causes of microvascular insufficiency. There was no evidence of a clear difference between the LMWH and UFH groups in occurrence of arterial occlusion (RR 1.08, 95% CI 0.16 to 7.10; 54 participants, 1 study; very low-certainty evidence) or venous occlusion (RR 0.81, 95% CI 0.20 to 3.27; 54 participants, 1 study; very low-certainty evidence). Two studies reported adverse effects. The LMWH and UFH groups showed no evidence of a difference in wound bleeding (RR 0.53, 95% CI 0.23 to 1.23; 130 participants, 2 studies; low-certainty evidence), haematuria (RR 0.43, 95% CI 0.09 to 2.11; 130 participants, 2 studies; very low-certainty evidence), ecchymoses (RR 0.82, 95% CI 0.21 to 3.19; 130 participants, 2 studies; very low-certainty evidence), epistaxis (RR 0.27, 95% CI 0.03 to 2.32; 130 participants, 2 studies; very low-certainty evidence), gingival bleeding (RR 0.18, 95% CI 0.02 to 1.43; 130 participants, 2 studies; very low-certainty evidence), and faecal occult blood (RR 0.27, 95% CI 0.03 to 2.31; 130 participants, 2 studies; very low-certainty evidence). We could not pool data on coagulation abnormalities as varying definitions and tests were used in the three studies.

One study compared LMWH versus no LMWH. The success rate of replantation, when analysed by digits, was reported as 91.2% success in the LMWH group and 82.1% in the control group (RR 1.11, 95% CI 0.93 to 1.33; 73 digits, 1 study; very low-certainty evidence). Compromised microcirculation requiring surgical re-exploration, analysed by digits, was 11.8% in the LMWH group and 17.9% in the control group (RR 0.86, 95% CI 0.21 to 3.58; 73 digits, 1 study; very low-certainty evidence). Compromised microcirculation requiring incision occurred in five out of 34 digits (14.7%) in the LMWH group and eight out of 39 digits (20.5%) in the control group (RR 0.72, 95% CI 0.26 to 1.98; 73 digits; very low-certainty evidence). Microvascular insufficiency due to arterial occlusion, analysed by digits, was 11.8% in the LMWH group and 17.9% in the control group (RR 0.66, 95% CI 0.21 to 2.05; 73 digits, 1 study; very low-certainty evidence), and venous occlusion was 14.7% in the LMWH group and 20.5% in the control (RR 0.72, 95% CI 0.26 to 1.98; 73 digits, 1 study; very low-certainty evidence). The study did not report complications or adverse effects.

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