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Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-leg immobilization

  1. Mark Testroote1,*,
  2. Willem AH Stigter2,
  3. Loes Janssen3,
  4. Heinrich MJ Janzing4

Editorial Group: Cochrane Vascular Group

Published Online: 25 APR 2014

Assessed as up-to-date: 3 JUN 2013

DOI: 10.1002/14651858.CD006681.pub3


How to Cite

Testroote M, Stigter WAH, Janssen L, Janzing HMJ. Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-leg immobilization. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD006681. DOI: 10.1002/14651858.CD006681.pub3.

Author Information

  1. 1

    Maastricht University Medical Centre, Department of Surgery, Maastricht, Netherlands

  2. 2

    Viecuri Medical Centre of Northern Limburg, Department of Surgery and Orthopaedic Surgery, Venlo, Limburg, Netherlands

  3. 3

    Viecuri Medical Centre of Northern Limburg, Department of Clinical Epidemiology, Venlo, Netherlands

  4. 4

    VieCuri Medical Centre of Northern Limburg, Department of Surgery, Venlo, Limburg, Netherlands

*Mark Testroote, Department of Surgery, Maastricht University Medical Centre, P. Debyelaan 25, Maastricht, 6202 AZ, Netherlands. marktestroote@yahoo.com. marktestroote@gmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 25 APR 2014

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Characteristics of included studies [ordered by study ID]
Jorgensen 2002

MethodsStudy design: randomized, controlled, assessor-blinded, open, multicenter trial.

Method of randomization: random numbers.

Concealment of allocation: sealed envelopes.

Losses to follow up: 95; treatment group 49; control group 46.

Intention-to-treat analysis: no.


ParticipantsCountry: Denmark.

Number: 300 (treatment group 148; control group 152).

Age: adult patients > 18 years (range 18 to 93).

Sex (male/female): treatment group 79/69; control group 93/59.

Inclusion criteria: planned plaster immobilization of the lower leg for at least 3 weeks.

Exclusion criteria: pregnancy; allergy to heparin or contrast media; known liver or renal impairment; uncontrolled hypertension; bleeding disorders; recent GI bleeding; or inability to perform self injection.


InterventionsTreatment group: LMWH 3500 IU anti-Xa of tinzaparin (Innohep) once daily.

Control group: no prophylaxis.


OutcomesAt cast removal unilateral venography was performed.


NotesDose of tinzaparin relatively low; contains both operated and non-operated patients; previous DVT is not excluded; 205/300 were included in final assessment.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskSealed envelopes.

Kock 1995

MethodsStudy design: randomized, controlled, open trial.

Method of randomization: randomization list stratified for varicose veins and obesity.

Concealment of allocation: not reported.

Losses to follow up: 5 refused to take part; 32 excluded due to exclusion criteria; data not evaluated on 52; treatment group 21; control group 31.

Intention-to-treat analysis: yes.


ParticipantsCountry: Germany.

Number: 428 recruited; 5 refused to take part; 32 excluded due to exclusion criteria; 339 (treatment group 176; control group 163).

Age mean + (range): treatment group 34.1 years (18 to 63); control group 33.5 years (range 18 to 64).

Sex (male/female): treatment group 104/72; control group 104/59.

Inclusion criteria: age 18 to 65; conservative treatment of injury with below-knee cast or cylinder cast.

Exclusion criteria: previous DVT; pregnancy; clotting disorders or anticoagulation medication; bleeding; chronic venous insufficiency; contraindications for heparin prophylaxis; plaster cast after surgery.


InterventionsTreatment group: LMWH 32 mg (Mono-embolex NM) once daily.

Control group: no prophylaxis.


OutcomesAt randomization and at plaster removal compression ultrasound and duplex scanning was performed; suspected positive findings were confirmed by phlebography.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported.

Kujath 1993

MethodsStudy design: randomized, controlled, open trial.

Method of randomization: randomization plan "after Sachs".

Concealment of allocation: not reported.

Losses to follow up: 53 excluded post randomization.

Intention-to-treat analysis: no.


ParticipantsCountry: Germany.

Number: 253; treatment group 126; control group 127 (306 admitted to the study; 53 excluded).

Age mean + (range): treatment group 32.9 years (16 to 70); control group 35.6 years (range 16 to 76).

Sex (male/female): treatment group 69/57; control group 77/50.

Inclusion criteria: age over 16 years; injury of the lower limb being treated conservatively; immobilization by a plaster cast applied for at least 7 days.

Exclusion criteria: known thrombopathy; oral anticoagulation; recent brain or GI bleeding; acute pancreatitis; inflammatory heart disease.


InterventionsTreatment group: LMWH 36 mg heparin fraction calcium (Fraxiparin ) once daily.

Control group: no prophylaxis.


OutcomesAfter plaster removal or at occurrence of symptoms compression ultrasound to diagnose DVT; in case of doubtful or positive findings a phlebography was carried out. In case of suspected PE scintigraphic analysis was performed.


NotesNone of the patients were operated on.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported.

Lapidus 2007a

MethodsStudy design: randomized, controlled, double blind trial.

Method of randomization: by computer.

Concealment of allocation: not specifically reported but states identical syringes were prefilled with either dalteparin or sodium chloride.

Losses to follow up: 4.

Intention-to-treat analysis: no.


ParticipantsCountry: Sweden.

Number: 105; treatment group 52; control group 53.

Age mean (SD): treatment group 37 years (8); control group 42 years (9).

Sex (male/female): treatment group 41/11; control group 42/11.

Inclusion criteria: age 18 to 75 years; admitted for an acute (0 to 72 hours) Achilles tendon rupture accepted for surgery.

Exclusion criteria: inability or refusal to give informed consent; ongoing treatment with anticoagulant therapy; known allergy for contrast media; kidney disorder; recent thromboembolic event; recent surgery; known malignancy; current bleeding disorder; pregnancy; treatment with platelet inhibitors.


InterventionsTreatment group: LMWH dalteparin 5000 units sc once daily until removal of the plaster cast.

Control group: placebo.


OutcomesDiagnosis of DVT by means of ultrasound and confirmation by venography.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskIdentical syringes were prefilled with either dalteparin or sodium chloride.

Lapidus 2007b

MethodsStudy design: randomized, controlled, double blind trial.

Method of randomization: not reported.

Concealment of allocation: not specifically reported but states identical syringes were prefilled with either dalteparin or sodium chloride.

Losses to follow up: 75.

Intention-to-treat analysis: no.


ParticipantsCountry: Sweden.

Number: 272; treatment group 136; control group 136.

Age mean (SD): treatment group 49 years (14); control group 48 years (14).

Sex (male/female): treatment group 62/74; control group 62/74.

Inclusion criteria: age 18 to 75 years; admitted for an acute (0 to 72 hours) ankle fracture and accepted for surgery.

Exclusion criteria: inability or refusal to give informed consent; ongoing treatment with anticoagulant therapy; known allergy for contrast media; kidney disorder; recent thromboembolic event; recent surgery; known malignancy; current bleeding disorder; pregnancy; treatment with platelet inhibitors; multi-trauma.


InterventionsTreatment group: LMWH dalteparin 5000 units sc once daily until removal of the plaster cast.

Control group: placebo.


OutcomesDiagnosis of DVT by means of ascending venography.


NotesAll patients treated with LMWH one week before randomization.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskIdentical syringes were prefilled with either dalteparin or sodium chloride.

Lassen 2002

MethodsStudy design: randomized, controlled, double blind trial.

Method of randomization: computer (blocks of four).

Concealment of allocation: not specifically reported but states identical syringes were prefilled with either reviparin or placebo.

Losses to follow up: 69 excluded.

Intention-to-treat analysis: no.


ParticipantsCountry: Denmark.

Number: 440; treatment group 217; control group 223.

Age median (interquartile range): treatment group 47 years (37 to 55); control group 47 years (37 to 56).

Sex (male/female): treatment group 112/105; control group 114/108.

Inclusion criteria: age 18 years or older; fracture of the leg or rupture of the Achilles tendon requiring at least 5 weeks of immobilization in a plaster cast or brace within 4 days of the injury.

Exclusion criteria: body weight < 35 kg; pre-existing VTE; systolic BP > 200 mm Hg or diastolic BP > 110 mm Hg; cerebral vascular aneurysm; cerebral vascular accident within the preceding 3 weeks; active gastroduodenal ulcer; bacterial endocarditis; platelet count 1000,000/cu mm; previous treatment with UFH or LMWH, fibrinolytic agents or oral anticoagulants; known hypersensitivity to contrast media; kidney disorder; MI within the preceding 3 months; multiple myeloma; pregnancy; history of drug or alcohol abuse.


InterventionsTreatment group: LMWH reviparin (1750 anti-Xa units) once daily.

Control group: placebo.


OutcomesVenography was performed within one week after removal of the plaster to diagnose DVT. In cases of suspected PE, ventilation-perfusion lung scanning or pulmonary angiography was performed.


NotesStudy contains both operated and non-operated patients; up to four days of LMWH prophylaxis was allowed before randomization.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskIdentical syringes were prefilled with either reviparin or placebo.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abelseth 1996Prospective incidence study, not a randomized or controlled clinical trial; operated patients without plaster immobilization and LMWH. Clinical and not outpatients.

Ageno 2004Survey on thrombosis prophylaxis by Italian orthopedic surgeons.

Ahmad 2003This study focuses on pathophysiology of heparin-induced thrombocytopenia (HIT) syndrome. The object was to determine the relative generation and functionality of AHPF4 antibodies in patients who were immobilized with plaster casts receiving 1750 IU of clivarin (reviparin) or a placebo. It is a substudy of the included study Lassen 2002.

Anonymous 1991Not a randomized or controlled clinical trial.

Anonymous 1995Not a randomized or controlled clinical trial.

Armbrecht 1993Patients operated for tendon rupture, one group treated with plaster and LMWH; the other group with early functional mobilization without prophylaxis. No clinical DVTs seen.

Bauer 1944Not a randomized or controlled clinical trial.

Breyer 1984Not a randomized or controlled clinical trial.

Bridges 2003LEAP-study (LMWH expedited Anticoagulation Program) to decrease number of inpatient days on warfarin and total hospital days for trauma patients requiring DVT. Case-control study.

Eriksson 2001Randomized controlled trial. Comparison of fondaparinux and enoxaparin after hip-fracture surgery.

Freeark 1967Not a randomized or controlled clinical trial.

Geerts 1994Prospective study of VTE after major trauma. No prophylaxis against VTE.

Geerts 1996Randomized controlled clinical trial of LMWH and low-dose heparin. Focus on major trauma, not outpatients.

Gehling 1994Prospective clinical study to determine incidence of DVT, no antithrombotic treatment.

Gehling 1998Randomized controlled clinical trial. Comparison of acetylsalicylic acid with LMWH in plaster immobilized trauma patients.

Giannadakis 2000Prospective clinical study to determine incidence of DVT in selected patients, no antithrombotic treatment.

Goel 2009A prospective randomized double-blind controlled trial using LMWH with saline injection as placebo in adults who had sustained an isolated fracture below the knee that required operative fixation. Study authors did not focus on immobilization of the lower leg in plaster-cast, so this study does not meet our inclusion criteria. The study authors included 238 patients and all underwent bilateral venography for diagnosis of DVT. There was no statistically significant difference in the incidence of DVT between the patients treated with LMWH or placebo (P = 0.22). However, owing to a cessation of funding, recruitment had to be ended before the necessary sample size was established (another reason for exclusion). The study results could not categorically exclude a potentially beneficial role of LMWH-treatment, and the authors recommend a further randomized controlled trial is undertaken.

Greenfield 1997Randomized controlled clinical trial. Clinical trauma patients randomized to low-dose UFH, LMWH, pneumatic compression devices, or foot pumps with or without vena caval filters.

Haas 1989Observational study on the use and tolerance of LMWH in ambulant patients. Not focused on trauma.

Harenberg 1998Prospective cohort study to determine the clinical incidence of VTE and the tolerance to LMWH in operated and not operated surgical and orthopedic patients.

Hjelmstedt 1968Not a randomized or controlled clinical trial.

Kannus 1991Review on treatment for acute tears of the lateral ligaments of the ankle. Not focused on subject of thrombosis prophylaxis.

Knudson 1996Randomized controlled clinical trial; LMWH in high-risk trauma patients, compared with mechanical methods of prophylaxis.

Knudson 2004Retrospective study to identify VTE incidence and risk factors in trauma patients using the American College of Surgeons National Trauma Data Bank.

Kudsk 1989Not a randomized or controlled clinical trial. Focuses on multi trauma patients.

Lassen 2000Not a randomized or controlled clinical trial.

Lippert 1995Not a randomized or controlled clinical trial.

Marlovits 2007This study focused on prolonged thrombosis prophylaxis after arthroscopic surgery rather than immobilization of the lower leg after trauma and was excluded for that reason.

Martinole 2003Not a randomized or controlled clinical trial.

Micheli 1975Case report, expert opinion.

NCT00843492The purpose of this ongoing study sponsored by GlaxoSmithKline is to evaluate the efficacy and safety of fondaparinux in comparison with a LMWH (nadroparin) in preventing VTE in patients with leg injuries below the knee that require a cast or other type of immobilization but not surgery. This study does not meet our inclusion criteria (LMWH versus placebo or no prophylaxis),

Nesheiwat 1996Case report and literature review.

Reilmann 1988Not a randomized or controlled clinical trial. Prospective study in which patients received LMWH plus dihydroergotamine (DHE) versus heparin alone or low-dose continuous intravenous heparin.

Reilmann 1993Not a randomized or controlled clinical trial. Study of 97 trauma patients who received heparin fragment calcium during admission and continued afterwards throughout cast period, compared with two groups without prophylaxis: Achilles tendon ruptures and talofibular ruptures.

Schultz 2004Focus on multi trauma patients.

Selby 2010In this study (known as the D-KAF trial) consecutive patients with isolated fractures of the distal leg requiring surgery were randomized to dalteparin 5000 IU or placebo once daily SC. Patients were screened using proximal ultrasound (only of the upper leg, not the calf) at day 14. The researchers were interested in clinically important venous thromboembolism (CIVTE). The study authors found that the overall incidence of CIVTE was so low (1.9%; 95% CI 0.7 to 4.7%) with no observed differences between dalteparin and placebo, that recruitment was stopped early. For this reason, we did not include this study in our meta-analysis. However, the study demonstrates the large discrepancy between trials that utilize venographic outcomes (all DVTs) and CIVTE.

Spieler 1972Not a randomized or controlled clinical trial.

Wolf 1992Cohort of 515 patients with plaster immobilization of the lower leg treated with LMWH; no comparison.

Zagrodnick 1990Retrospective data and prospective study to evaluate self-injection of UFH and LMWH .

 
Characteristics of ongoing studies [ordered by study ID]
NCT00881088

Trial name or titlePROTECT: Prophylaxis of thromboembolic complications trial

MethodsA prospective, randomized, controlled, single blinded, multi-center trial. The purpose of this study is to determine the need for thromboprophylaxis in patients with a fracture of the lower extremity being treated conservatively in a below-knee plaster cast and to assess if both of the two tested prophylactic treatments are effective for this indication.

ParticipantsPatients of at least 18 years with a nonsurgical fracture of the lower extremity requiring immobilization in a below-knee plaster cast for a minimum of 4 weeks.

InterventionsPatients will be randomly assigned to one of three groups: one receiving nadroparin (2850 IE anti-Xa = 0.3 ml, given once daily), one receiving fondaparinux (2.5 mg = 0.5 ml, given once daily) and one receiving no prophylaxis.

OutcomesAt the time of removal of the plaster cast symptoms or signs suggestive of DVT or PE will be noted and a color duplex ultrasonography of the treated limb will be performed in all patients by an experienced technician according to a strict diagnostic test protocol. When there is incompressibility of a vein or lack of flow the diagnosis of DVT is made. The technician will be blinded to treatment.
In case of a suspected pulmonary embolism pulmonary angiography will be performed.

Starting dateMay 2009

Contact informationDepartment of Surgery
VU Medisch Centrum
P.O. Box 7057
1007 MB Amsterdam
The Netherlands
Phone: +31(0)20-4444444 (pager *7310)
E-mail: marlieke.bruntink@gmail.com

NotesA study from the Netherlands, investigating the need for thromboprophylaxis in patients with a fracture of the lower extremity being treated conservatively in a below-knee plaster cast. Both fondaparinux and nadroparin are analysed for this indication, versus no prophylaxis.

 
Comparison 1. Low molecular weight heparin versus no prophylaxis/placebo

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

 1 DVT: irrespective of type of plaster, whether operated or not61490Odds Ratio (M-H, Random, 95% CI)0.49 [0.34, 0.72]

 2 DVT: in below-knee cast, whether operated or not5894Odds Ratio (M-H, Fixed, 95% CI)0.54 [0.37, 0.80]

 3 PE3896Odds Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.23]

 4 DVT: only non-operated patients4788Odds Ratio (M-H, Fixed, 95% CI)0.35 [0.19, 0.62]

 5 DVT: operated patients4699Odds Ratio (M-H, Fixed, 95% CI)0.54 [0.37, 0.80]

 6 DVT: fractures5817Odds Ratio (M-H, Fixed, 95% CI)0.53 [0.36, 0.78]

 7 DVT: soft-tissue injuries5658Odds Ratio (M-H, Fixed, 95% CI)0.39 [0.22, 0.68]

 8 DVT: distal segment51208Odds Ratio (M-H, Fixed, 95% CI)0.61 [0.42, 0.89]

 9 DVT: proximal segment51217Odds Ratio (M-H, Fixed, 95% CI)0.41 [0.19, 0.91]

 10 Symptomatic VTE41303Odds Ratio (M-H, Fixed, 95% CI)0.16 [0.05, 0.56]