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Three Part Question

In [patients with lower extremity injury requiring temporary immobilisation] does [prophylactic anticoagulation with LMWH] increase the incidence of [fatal, major or minor bleeding episodes].

Clinical Scenario

You have seen a 34 year old female with a lateral malleolus fracture, which is suitable for immobilisation in a below knee plaster cast. She had a previous DVT several years ago when her other leg was in plaster following a fracture. She is anxious not to have another one.
You are aware of recent evidence suggesting that heparin prophylaxis may be beneficial in this situation. When you discuss this with the patient she asks you to quantify the risks of bleeding. You are unsure, but resolve to find out immediately.

Search Strategy

MEDLINE and EMBASE databases were searched using the OVID interface the week ending the 8th July 2011 using the following strategies.
MEDLNE: (exp Casts, Surgical OR plaster cast$.mp OR exp immobilization OR immobilisation$) AND (exp Heparin, low-molecular-weight OR exp enoxaparin OR exp Dalteparin OR LMWH.mp OR low molecular weight heparin.mp OR clexane.mp OR dalteparin.mp OR fragmin.mp OR tinzaparin.mp OR enoxaparin.mp)

EMBASE:(exp plaster cast OR plaster cast$.mp OR exp immobilization OR immobilisation.mp) AND (exp low molecular weight heparin OR low molecular weight heparin.mp OR LMWH.mp OR exp enoxaparin OR enoxaparin.mp OR clexane.mp OR exp dalteparin OR dalteparin.mp OR fragmin. mp OR exp tinzaparin OR tinzaparin.mp)

All searches were limited to human studies only

Search Outcome

101 and 460 records were found respectively. Four unique randomised controlled trials (RCTs) examining the study population were found, along with one prospective observational review and 2 meta-analyses. The two meta-analyses [1,3] include the same six papers, four of which are the RCTs identified. Therefore the Cochrane review, along with the prospective observational study, is presented below as it gives the most complete data regarding adverse events.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Testroote M et al 2008 Netherlands	Patients with lower limb injuries managed as outpatients in lower limb plaster casts or braces.	Six studies included (1490 patients) of which 4 studies included patients treated non-surgically (788 patients). 750 patients were given thromboprophylaxis with LMWH. (level of evidence 1a)	Incidence of major bleeding	LMWH group: 2 patients (0.26%), Control group: 1 patient (0.14%)	Statistical and clinical heterogeneity. The numbers of patients included in the studies are small. The assessment of safety includes patients managed surgically. One of the studies included uses as a sub-prophylactic dose of LMWH.
			Incidence of minor bleeding	LMWH group: 14 patients (1.87%), Control group: 12 patients (1.62%)
Otero-Fernandez R et al 2008 Spain (157 centres)	Orthopaedic patients requiring out-patient thromboprophylaxis with Bemiparin. Included 6456 patients, of which 1789 patients were managed conservatively with cast immobilisation.	Prospective uncontrolled multicenter cohort (Level of evidence 2b)	Incidence of major Bleeding	Overall: 0.17%, Plaster-cast group: 0.11%	No control group. Two different doses of Bemiparin used (2500IU and 3500IU) selected at clinicians discretion.
			Incidence of minor Bleeding	Overall: 4.57%, Plaster-cast group: 1.51%
			Incidence of Thrombocytopenia	Overall: 0.51%, Plaster-cast group: 0.17%

Comment(s)

The use of prophylactic low molecular weight heparin (LMWH), for the prevention of venous thromboembolism (VTE), is widely employed in both the inpatient and outpatient setting. As with all anticoagulant therapy, its use is associated with an increased risk of bleeding and additionally a theoretical risk of heparin induced thrombocytopenia (HIT) is present, although this is less common with low molecular weight than with unfractionated heparin. The evidence presented demonstrates the use of LMWH to be safe in the target population: a risk of major bleeding of 0.11 – 0.27% is reported [1,2], with a number needed to harm of 769 [1]. When this is compared with the estimated number needed to treat of 14 [1] to prevent one VTE event in the same cohort, it follows that the benefits of LMWH prophylaxis outweigh the risks. In addition no deaths from bleeding were reported in either of the presented studies as well as minimal rates of minor bleeding (1.51 – 2.7%) and HIT (0 – 0.17%) [1,2]. Furthermore it is worth noting that LMWH thromboprophylaxis has been proven to be equally safe in the elderly (a sub-group which can cause particular concern) with studies demonstrating rates of major bleeding and HIT of 0.4 – 0.49% and 0.54 - 1.4% respectively [4,5], although it is important to note that these studies have been carried out in medical patients and not the target cohort. As persuasive as these figures regarding the benefits and risks of LMWH thromboprophylaxis are, it is important to consider each patient on an individual basis and it is worth remembering that high risk patients, both for bleeding and VTE risk, have been excluded from the studies likely resulting in an exaggeration of the overall benefit and risk ratio.

Editor Comment

BAF using for February submission

Clinical Bottom Line

Low molecular weight heparin is safe to use as thromboprophylaxis in patients with lower limb plaster casts. Associated rates of major bleeding and thrombocytopenia are low, less than 0.2% in the related cohort.

References

1. Testroote M et al Low Molecular Weight Heparin for Prevention of Venous Thromboembolism in Patients with Lower-Leg Immobilisation (Review) The Cochrane Database of Systematic Reviews 2008; (4): CD006681.
2. Otero-Fernandez R et al Evaluation of the Effectiveness and Saftey of Bemiparin in a Large Population of Orthopaedic Patients in a Normal Clinical Practice Clin App Thomb Haem 2008; 14(1): 75 - 83
3. Ettema HB et al Prevention of Venous Thromboembolism in Patients with Immobilization of the Lower Extremities: A Meta-Analysis of Randomized Controlled Trials J Thromb Haemost 2008; 6: 1093–8.
4. Leizorovicz A, Cohen AT, Turpie AGG et al Randomized, Placebo-Controlled Trial of Dalteparin for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients Circulation 2004; 110: 874-879
5. Rodriguez-Manas L, Gomez-Huelgas R, Veiga-Fernandez F et al Thromboprophylaxis with the Low-Molecular-Weight Heparin Bemiparin Sodium in Elderly-Medical Patients in Usual Clinical Practice. The ANCIANOS Study Clinical Drug Investigation 2010; 30(5): 337-345