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Three Part Question

In [below knee fractures treated conservatively by plaster and immobilisation] does [administration of low molecular weight heparin] prevent [deep vein thrombosis]?

Clinical Scenario

A 20 years old gentleman presents with a swollen ankle after an inversion injury. Clinically you suspect a fracture of lower one third of fibula. Radiograph confirms a Weber A fracture which is treated conservatively in a below knee back slab and crutches. You refer him to fracture clinic and very well know that operative fixation is highly unlikely and he will be changed into a full plaster soon. You wonder if giving him low molecular weight heparin might prevent development of deep vein thrombosis.

Search Strategy

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations April 23, 2010
Ovid MEDLINE(R), 1950 to April Week 2, 2010
Ovid OLDMEDLINE(R) 1947 to 1965

tibia.mp. or exp Tibia/ OR fibula.mp. or exp Fibula/ OR exp Ankle/ or exp Ankle Joint/ or ankle.mp. OR talus.mp. or exp Talus/ OR exp Calcaneus/ or calcaneum.mp. or exp Heel/ OR exp Tarsal Bones/ or navicular.mp. OR exp Tarsal Bones/ or cuboid.mp. or Tarsal Joints/ (9638) OR metatarsal$.mp. or exp Metatarsal Bones/ OR exp Foot/ or exp Foot Bones/ or foot.mp. OR toe phalanges.mp. or exp Toes/ or exp Toe Phalanges/ (9196)

AND
fracture.mp. (107730) OR bone fracture.mp. or exp Fractures, Bone/

OR
plaster of paris.mp. or exp Calcium Sulfate/ OR surgical cast.mp. or exp Casts, Surgical/ OR exp Casts, Surgical/ or cast.mp. OR backslab.mp. OR exp Bandages/ OR exp Immobilization/ or immobilisation.mp. OR exp Leg/ or lower leg.mp.


AND
bemiparin.mp. OR dalteparin sodium.mp. or exp Dalteparin/ OR exp Enoxaparin/ or enoxaparin sodium.mp. OR tinzaparin sodium.mp.OR heparin, low-molecular-weight/ or exp dalteparin/ or exp enoxaparin/ or exp nadroparin/ OR lmwh.mp. or exp Heparin, Low-Molecular-Weight/

AND

deep vein thrombosis.mp. or exp Venous Thrombosis/ OR exp Venous Thrombosis/ or dvt.mp. OR clot.mp. or exp Thrombosis/

Limit to English language and Humans

Search Outcome

918 papers – 6 relevant. Out of these 2 were a Meta-analysis and Cochrane review which are in the table below. (and four randomised controlled trials even though were appraised individually I did not include them in the table as they were included in meta-analysis and Cochrane review) .

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
H.B. Ettema 2008 USA	6 randomised controlled trials between January 1985 and July 2007 were identified by 2 independent assessors after looking through MEDLINE and EMBASE. Literature in English, German and Dutch were included. Inclusion Criteria – Proper randomisation, enrolled patients with lower limb immobilisation, Compared prophylaxis with LWMH, unfractionated Heparin or coumarin derivative with placebo or untreated control and using objective methods of confirming deep vein thrombosis. Data on asymptomatic deep vein thrombosis was included if systematic screening was carried out with ascending lower limb contrast venography or duplex scan. 1456 patients were analysed.	meta analysis	Prophylaxis with LMWH for immobilisation of lower extremities reduces the risk of DVT.Prophylactic dose of LMWH does not increase the incidence of bleeding	Risk of deep vein thrombosis decreased from 17.1% to 9.6% with use of LMWH.Compared to placebo and untreated,RR -0.58, CI – 0.39 – 0.86 .P=0.006	In one study the duration of plaster is 15.8 days only which is not a true of the patients treated for fracture in a cast conservatively In some of the clinical trials high risk patients for deep vein thrombosis were not included. Type of cast was not mentioned
Mark Testroot 2008 canada	The Cochrane Peripheral Vascular Disease Groups Specialized Register, the Central Register of Controlled Trials, MEDLINE, EMBASE and reference lists of articles were searched. Relevant studies were requested from pharmaceutical companies. Two authors independently assessed the data collected. All randomized control trials and controlled clinical trials that have used low molecular weight heparin with lower limb immobilization were included. Exclusion Criteria – Studies using Aspirin, anticoagulation and unfractionated heparin.	Cochrane systematic review	Dvt and PE , Morbidity, mortality, adverse effect of treatment	Odd’s Ratio for Pulmonary embolism – 0.20,Deep vein thrombosis in non operated patients – 0.35 Deep vein thrombosis in patients with fractures – 0.53, Mortality – Nil, Adverse outcomes – No incidence of heparin induced thrombocytopenia was noted.Major bleeding in 2 patients out of 750 patients.Minor bleeding 14/750 in treatment group and 12 in Placebo group.
D. P. Goel 2009 canada	238 patients with unilateral isolated fractures below the knee which required operative fixation between December 2000 and July 2006. 127 in Fragmin group . 111 in placebo group. Follow up after two weeks included bilateral venography on all patients.	Double blinded RTC	incidence of DVTs demonstrated by bilateral venography by day 14.	Incidence of DVT: (12.6%) in placebo (8.7%) in Fragmin group , [no statistically significant difference , Fisher’s exact test, p = 0.22)]	Study only included half the required number of patients due to withdrawal of funding Study excluded high risk patients Study included only surgically treated patients
			Incidence of bleeding	no adverse events in secondary outcome ( one patient in fragmin group died few months later due to reasons unrelated to DVT)

Comment(s)

There is increased incidence of deep vein thrombosis in patients with fractures of lower limb immobilised in plaster cast or brace or back slab. One study has used 3,500 units of Tinzaparin for prophylactic group but still found deep vein thrombosis in the group but there was higher incidence in control group. So it was difficult to say what the prophylactic dose of LMWH to prevent DVT was. In some clinical trials the patients with high risk were not included in the study and some dropped out of the study because of the administration of injection. In one clinical trial some patients were excluded because it was difficult to perform an ascending venous phlebography and some patients were already on Aspirin. I wondered if all these taken into account the actual incidence of deep vein thrombosis might be under reported. I think further work is needed to determine the dose of LMWH to decrease the incidence of deep vein thrombosis to the maximum possible extent. Administration of LMWH for this patient group will have an impact on the financial aspect of the hospital and Primary Care Trust. This will start from the cost of the drug itself, administration in the community, input from radiology and follow up clinics. Risk assessment of patients for a venous thromboembolism might be the way forward by giving LMWH to high and medium risk patients. Verbal and written advice to the low risk patient group can be given and they can be asked to see their general practitioner for further concerns. The trial by Goel et al was one of few that found no significant difference , however this trial was not completed due to financial reason, and should some reduction of the incidence of DVT in patients receiving LMWH without adverse effect.

Clinical Bottom Line

Low molecular weight heparin decreases the incidence but does not prevent deep vein thrombosis in patients with below knee fractures treated conservatively by plaster and immobilisation.

References

1. Ettema HB, Kollen BJ, Verheyen CCPM, Bu¨ ller HR 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.
2. Testroote M, Stigter WAH, de Visser DC, Janzing HMJ Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-leg immobilization Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD006681
3. D. P. Goel Prophylaxis of deep-vein thrombosis in fractures below the knee Journal of Bone and Joint Surgery 2009;91-B:388-94