Lower-leg immobilization is associated with deep venous thrombosis (DVT) and pulmonary embolism (PE). Is there a role for low molecular weight heparin (LMWH) in patients with lower-leg immobilization to prevent venous thrombosis and its complications?
Pre-disposing risk factors for venous thromboembolism (VTE) can be divided into individual patient factors, trauma, or surgery-related factors. Patient-related factors include obesity; thrombophilia (a hereditary or acquired predisposition to thrombosis); a previous thrombosis; age over 40 years; cardiovascular insufficiency; or post-thrombotic syndrome (PTS) of the lower leg (Clagett 1995; Zagrodnick 1990). Immobilization is considered a significant risk factor for the development of DVT and PE (Knudson 1996; Kudsk 1989; Kujath 1991).
Other factors associated with an increased risk of VTE include: blood transfusion; surgery; fracture of the pelvis, femur or tibia; spinal cord injury; head injury; shock on hospital admission; venous injury; more than three days on ventilation; the time from injury to operation; or operation time (Abelseth 1996; Knudson 2004).
In a group of 102 patients with lower-limb fractures Abelseth found a rate of DVT of 28% (Abelseth 1996). All patients were operated on and mobilized without the use of a plaster cast. Proximal fractures were associated with a higher risk of DVT compared with more distal fractures (Abelseth 1996). Other reported incidences of venographically-proven DVT in patients with lower-limb fractures range from 27% to 78% (Breyer 1984; Geerts 1994; Hjelmstedt 1968; Kudsk 1989; Spieler 1972). The percentages in hospitalized patients are generally higher than in outpatients. In outpatients immobilized in plaster casts without LMWH, the incidence of DVT on ultrasonography ranges from 4.5% to 16.5% (Kock 1995; Kujath 1993; Reilmann 1993; Zagrodnick 1990). The incidence of PE in trauma patients with DVT without prophylaxis is 4.3%, with a high mortality rate (20% to 23.3%). In patients with DVT receiving thromboprophylaxis this incidence can be lowered to 0.3% to 2.0% (Hill 2002).
The primary goal of administering thromboprophylaxis is to prevent PE. Furthermore, prevention of DVT and its possible complications such as postphlebitic syndrome is of great importance. Oral anticoagulants, unfractionated heparin (UFH) and LMWH have been studied for this indication as treatment options. In clinical guidelines, the recommendations on preventing venous thrombosis in patients with isolated lower-leg injuries distal to the knee are sparse. In 2002, the Scottish Intercollegiate Guidelines Network recommended patients with lower-limb fractures for LMWH prophylaxis (SIGN 2002), but in their current version they recommend assessment for thrombosis and bleeding risks. Both the 2004 and 2012 ACCP Antithrombotic Guidelines suggest no prophylaxis rather than pharmacologic thromboprophylaxis (Geerts 2004; ACCP 2012). Their advice is based on the findings of a multicenter study that has remained published only in abstract form (Selby 2010), combined with the data from our own meta-analysis in the previous version of this review (Testroote 2008). In Selby's study (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. The study demonstrates the large discrepancy between trials that utilize venographic outcomes (all DVTs) and CIVTE. However, the ACCP authors performed their own analysis of the combined data and found that the results did not establish the benefit of thromboprophylaxis in the patients enrolled. High-risk patients might still be considered for prophylaxis according to the ACCP. The latter is also advised by the British College of Standards in Haematology (BCSH 2006). A fourth guideline recommends LMWH prophylaxis in lower-limb injury where the leg is immobilized or full weight bearing is not possible (CBO 2006).
Therefore, national guidelines do not come to an evidence-based stand and there remains substantial practice variation amongst surgeons regarding the use of anticoagulation measures (Batra 2006). In daily clinical practice there remains a huge variation in the way thromboprophylaxis is used. A Dutch survey among surgeons shows 79% prescribe prophylaxis for above-knee casts and 30% for below-knee casts (Truijers 2005). In a survey among Italian orthopedic surgeons there was great heterogeneity in terms of timing and duration of prophylaxis since none of the answers were associated with greater than 75% consensus among the respondents (Ageno 2004). A survey performed by the author of this review confirms this view (Testroote 2011).
To assess the effectiveness of low molecular weight heparin for the prevention of venous thromboembolism in patients with lower-leg immobilization in an ambulant setting.
Criteria for considering studies for this review
Types of studies
We considered all randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that describe thromboprophylaxis by means of low molecular weight heparin (LMWH) in adults with lower-leg immobilization in an ambulant setting. Treatment with LMWH could have started in hospital before the patient was discharged.
Types of participants
Adults treated with a leg cast or brace in an ambulant setting. Weight bearing and duration of the leg cast were not considered as criteria for inclusion or exclusion. We performed subgroup analysis of surgically treated and conservatively managed patients.
Types of interventions
Studies comparing LMWH with no prophylaxis or placebo. If statistically feasible, subgroup analysis of different LMWHs will be performed at a later stage when the review is updated. Oral anticoagulants, UFH and aspirin were not considered in our review, and studies using these drugs, as a comparator were excluded.
Types of outcome measures
- Morbidity - symptomatic or asymptomatic DVT (confirmed by venography or ultrasonography), PE (confirmed by ventilation-perfusion scan, CT scan or angiography), or any combination of these items, as a combined symptomatic venous thromboembolism (VTE) endpoint.
- Mortality - PE, confirmed at post mortem; other cause(s) of death.
- Adverse outcomes of treatment: bleeding, heparin induced thrombocytopenia (HIT), allergy, others.
Search methods for identification of studies
For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched June 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 5, part of The Cochrane Library, (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).
Searching other resources
The review authors searched the reference lists of relevant studies.
Data collection and analysis
Selection of studies
Two review authors (MT and WS) independently assessed all studies that met the selection criteria. Disagreements were resolved by discussion.
Data extraction and management
Two review authors (WS and MT) independently extracted data to ensure the objectivity and validity of findings. A third review author (HJ) cross checked the information and disagreements were resolved by discussion. The review authors contacted trial authors for additional information if required.
Quality of trials
The quality of all relevant studies was assessed according to the guidelines for quality of trials from the Dutch Cochrane Centre, using a scoring scheme designed by representatives of the Dutch Cochrane Centre; the Quality Institute for Healthcare CBO; the Dutch General Practitioners Order; the Institute for Medical Technology Assessment; the Workgroup Investigation Quality; the College for Medical Assurances; Health Investigation in the Netherlands (ZonMw); and the Order of Medical Specialists (www.cochrane.nl).
Statistical analysis was carried out using RevMan 5. The fourth author (LJ) co-ordinated and advised on the statistical methods used. We searched for statistical heterogeneity by 'eyeballing'. We quantified heterogeneity by means of an I
Description of studies
Results of the search
See Figure 1.
|Figure 1. Study flow diagram.|
We included six studies (Jorgensen 2002; Kock 1995; Kujath 1993; Lapidus 2007a; Lapidus 2007b; Lassen 2002). The characteristics of these six studies are summarized in the Characteristics of included studies table. All six studies were reported as full papers and included a total of 1490 participants (range 105 to 371). All studies were prospective with quite similar exclusion criteria. The most common exclusion criteria were: pregnancy; allergy to heparin or contrast media; uncontrolled hypertension; pre-existing bleeding disorders; presence of malignancies; recent brain or gastrointestinal bleeding; previous DVT; and chronic venous insufficiency. Each study used a different LMWH as choice of treatment. Nadroparin (Kujath 1993), Mono-Embolex (Kock 1995), tinzaparin (Jorgensen 2002), dalteparin (Lapidus 2007a; Lapidus 2007b) and reviparin (Lassen 2002), were administered once daily until removal of the plaster cast. There were no relevant differences between treatment and control groups regarding demographics or risk factors.
In two studies (Kock 1995; Kujath 1993), plaster cast fitted after surgery was used as an exclusion criterion. In one study (Lassen 2002), patients who underwent surgery before randomization might have had heparin treatment for up to four days before randomization. Another study treated all patients one week with LMWH before randomization (Lapidus 2007b). The included studies differed in the types of plaster cast (upper leg, lower leg, cylinder, or brace). Furthermore, there was a variation in the duration of immobilization: ranging from 15 days (Kujath 1993), up to 43 days (Lapidus 2007a).
In the included studies the primary outcome parameter was VTE. Deep venous thrombosis, both symptomatic and asymptomatic, was diagnosed by means of ascending venography (Jorgensen 2002; Lapidus 2007b; Lassen 2002) or ultrasound (Kock 1995; Kujath 1993; Lapidus 2007a). If ultrasound was used suspect findings had to be confirmed by venography. Clinically suspected PE had to be confirmed by ventilation-perfusion scintigraphy, angiography or spiral CT-scanning. Information concerning the number of patients with symptomatic and asymptomatic VTE and the extent of the DVT was collected. Secondary outcome parameters were mortality and side effects in both treatment and control groups.
For this update we excluded an additional five studies (Ahmad 2003; Goel 2009; Marlovits 2007; NCT00843492; Selby 2010) making a total of 39 excluded articles. The reasons for exclusion are stated in the Characteristics of excluded studies table. The previous version of this review (Testroote 2008) reported that 74 articles were excluded. This number included guidelines, multiple study reports of included studies and cohort studies therefore, where appropriate, these articles have now been removed from as excluded studies.
Risk of bias in included studies
We used the scoring scheme provided on the website of the Dutch Cochrane Centre to assess the validity and 'quality' of the included randomized controlled trials (www.cochrane.nl). Although we found the general quality of the six included studies good, some remarks should be added.
The true thromboembolic rate in unprotected patients was not really obtained because in all six studies the high-risk patients were excluded from participation. Therefore the incidence in unprotected patients and the effect of LMWHs might be underestimated.
In four studies the included patients had a wide variety of different traumas, ranging from fractures to soft tissue injuries and tendon ruptures (Jorgensen 2002; Kock 1995; Kujath 1993; Lassen 2002). Since the risk of DVT is found to be related to the presence and type of fracture, as well as the extent of soft tissue injury and type and duration of surgery, heterogeneity might be introduced. However, by randomization this effect should be minimized. Two studies focused on a specific group of trauma patients (Lapidus 2007a, Lapidus 2007b). Furthermore, the drop-out rate in the studies was on the high side.
Three studies used ultrasound (Kock 1995; Kujath 1993, Lapidus 2007a), and three used venography (Jorgensen 2002; Lapidus 2007b; Lassen 2002), for diagnosis of DVT. The latter is considered the 'Gold Standard', but in routine practice is rarely used as first line investigation for DVT. Duplex ultrasonography and compression ultrasonography have a lower sensitivity and specificity compared to venography, especially for diagnosing calf vein thrombosis (CBO 2008; Lensing 1989). This might be the reason for the differences in the results between Kock 1995 and the studies that used venography (Jorgensen 2002; Lapidus 2007b; Lassen 2002), since there were no other major differences in patient characteristics and interventions. However, it does not explain the differences between the results of Kock, Kujath and Lapidus (Kock 1995; Kujath 1993, Lapidus 2007a). Also, investigations with different sensitivities and specificities were used to diagnose potential PE .
Lassen 2002 included patients who received up to four days of LMWH (32% of patients). Another study treated all patients with LMWH for one week prior to randomization (Lapidus 2007b). This might equalize the effects in the two groups and lead to an underestimation of the treatment effect. The study of Lapidus therefore merely focused on duration of treatment and not on the indication of treatment itself (Lapidus 2007b).
The dose of 3500 anti-Xa IU of tinzaparin that Jorgensen 2002 used might be too low, since another study showed equal antithrombotic effect using 4500 anti-Xa IU of tinzaparin compared with 40 mg of enoxaparin, which is the standard dose in orthopedic surgery (Eriksson 2001). This possibly creates an underestimation of the effect of prophylaxis.
Effects of interventions
Kujath et al included 253 participants in their study, of whom 126 received a subcutaneous injection of Fraxiparin daily, and 127 patients received no prophylaxis (Kujath 1993). Incidences of VTE were 16.5% (n = 21) in the control group and 4.8% (n = 6) in the LMWH group (odds ratio (OR) 0.25; 95% confidence interval (CI) 0.10 to 0.65) (Kujath 1993). Kock et al included 163 patients in the control group (no treatment), and 176 patients were assigned to receive LMWH once daily (Kock 1995). The incidence of DVT in the prophylaxis group was 0% versus 4.3% (n = 7) in the control group (OR 0.06; 95% CI 0.00 to 1.04). In 2002, Jorgensen et al published the results of their venographic-controlled study, and diagnosed DVT in 10 out of 99 patients in the treatment group and in 18 out of 106 patients in the control group (Jorgensen 2002). This difference was not significant (OR 0.55; 95% CI 0.24 to 1.26). Finally, in 2002 Lassen et al found an incidence of 35 of 188 patients randomly assigned to receive placebo (18.6%) and in 17 of 183 patients (9%) in the LMWH group (OR 0.45; 95% CI 0.24 to 0.83) (Lassen 2002). Lapidus et al published two studies in 2007 (Lapidus 2007a; Lapidus 2007b). The study on thromboprophylaxis after surgical treatment of Achilles tendon rupture revealed a high incidence of thromboembolic events: 37% in the treatment group versus 40% in the placebo group. The results were not significant (P = 0.8) (Lapidus 2007a). The study on prolonged thromboprophylaxis during immobilization after ankle surgery also did not reveal a significant difference: 21% in the treatment group versus 31% in the placebo group (P = 0.07) (Lapidus 2007b).
We conducted a meta-analysis to establish whether there was evidence of a thromboprophylactic effect of LMWH, estimated the size of this effect, and investigated whether it was consistent across the included studies. We analyzed all patients together and subsequently the effect for different subcategories: surgically treated patients; patients with conservative treatment; patients with below-knee casts; patients with cylinder or above-knee casts; patients with fractures; patients with soft tissue injuries; PE; distal or proximal DVT; and finally the number of patients with symptomatic VTE.
All patients: Analysis 1.1
Six studies (Jorgensen 2002; Kock 1995; Kujath 1993; Lapidus 2007a; Lapidus 2007b; Lassen 2002) with a total of 1490 patients had incidences of injuries of the lower limb immobilized by a plaster cast or brace. The control group (n = 740) received no prophylaxis or placebo, the prophylaxis group received LMWH once daily (n = 750). The incidence of thromboembolic events in the control group ranged from 4.3% to 40% (134/740) and from 0% to 37% (75/750) in the prophylaxis group (OR 0.49:, 95% CI = 0.34 to 0.72), P = 0.00020.
Only patients with below-knee casts: Analysis 1.2
It was possible to obtain data on specific analyses of DVT in below-knee casts or braces from five studies (Jorgensen 2002; Kock 1995; Lapidus 2007a; Lapidus 2007b; Lassen 2002). In the studies of Lassen 2002 and Kujath 1993 the relation between the type of cast and occurrence of thrombosis was not part of the study design. However, from the study of Lassen 2002 the subgroup with rupture of the Achilles tendon could still be added. The incidence in the LMWH group of DVT ranged from 0% to 37%% and from 3.6% to 40% in controls (OR 0.54; 95% CI 0.37 to 0.80).
Only one study provided data on patients with cylinder or above-knee casts only (Kock 1995), with an incidence of 0% in the LMWH group and 2/24 (8.3%) in the control group.
Pulmonary embolism: Analysis 1.3
In the studies under review, PE was a rare complication in immobilization of the lower extremity. Lassen 2002 reported on four symptomatic patients in the control group; in two of them PE was confirmed by ventilation-perfusion scan. Kujath 1993 reported that in one patient in the group without prophylaxis there were clinical signs of a PE, but this diagnosis could not be proven by scintigraphic imaging.
Only patients with conservative treatment: Analysis 1.4
Four included studies provided incidences of DVT in conservatively treated patients (Jorgensen 2002; Kock 1995; Kujath 1993; Lassen 2002). When analyzed without consideration of type of cast or brace, the incidence ranged from 0% to 11.8% in the LMWH group and from 4.3% to 17.3% for the controls (OR 0.35; 95% CI 0.19 to 0.62), P = 0.00039.
Only surgically treated patients: Analysis 1.5
Information about surgically treated patients could be obtained from four studies (Jorgensen 2002; Lapidus 2007a; Lapidus 2007b; Lassen 2002). Both Kujath 1993 and Kock 1995 only analyzed conservatively treated patients. The incidence of DVT ranged from 7.2% to 37% in the LMWH group and from 18.0% to 40% in the control group (OR 0.54; 95% CI 0.37 and 0.80), P = 0.0018.
Fractures or soft tissue injuries: Analyses 1.6 and 1.7
Five studies provided information on patients with fractures (Jorgensen 2002; Kock 1995; Kujath 1993; Lapidus 2007b; Lassen 2002). These groups of patients contain both operated and conservatively treated patients. Results were significant (OR 0.53; 95% CI 0.36% to 0.78%), P = 0.0012. When analyzing the results from the patients with soft tissue injuries (Jorgensen 2002; Kock 1995; Kujath 1993; Lapidus 2007a; Lassen 2002), there is a significant difference as well (OR 0.39; 95% CI 0.22% to 0.68%), P = 0.00091.
Distal or proximal deep vein thrombosis: Analyses 1.8 and 1.9
Five studies provided information on the segment in which the thrombus was located (Jorgensen 2002; Kock 1995; Lapidus 2007a; Lapidus 2007b; Lassen 2002). The incidence of distal segment DVT, defined as below-knee DVT, ranged from 0% to 34.7% in participants who received LMWH and from 2.5% to 34.0% in the control group (OR 0.61; 95% CI 0.42 to 0.89), P = 0.0091. Proximal DVT (above knee) was rare; there were eight events in a total of 614 patients who received LMWH (incidences ranging from 0% to 4.0%) versus 20/603 (incidences ranging from 0.9% to 6.4%) in the controls (OR 0.41; 95% CI 0.19 to 0.91), P = 0.027.
Patients with symptomatic VTE: Analysis 1.10
All studies but one reported on patients with symptomatic VTE (Jorgensen 2002; Kock 1995; Kujath 1993; Lapidus 2007b; Lassen 2002). Lapidus 2007a did not report on patients with a symptomatic DVT due to fact that it was clinically not possible to differentiate symptoms of a possible DVT from those of normal postoperative findings. Lapidus 2007b reported on two events in the LMWH group and six events in the placebo group. Lassen 2002 mentioned two patients with PE and four with symptomatic DVT, all of them in the placebo group. Kujath 1993 reported on nine symptomatic patients, however, it is not clear whether they were in the treatment group or not. For that reason, this study is not included in analysis 1.10. Kock 1995 did not report on symptomatic patients in the Lancet publication, but additional information from five of the seven patients with thrombosis was found in a former publication. Jorgensen 2002 did not find any symptomatic VTE.
Symptomatic VTE was observed in two of 658 (0.3%) patients receiving LMWH versus 16 out of 645 (2.5%) patients in the control group (OR 0.16; 95% CI 0.05 to 0.56). If full information were available percentages might have been higher.
The results of the six eligible RCTs were fairly consistent (Jorgensen 2002; Kock 1995; Kujath 1993; Lapidus 2007a; Lapidus 2007b; Lassen 2002). When quantifying the results, there was some evidence of heterogeneity: I
3. Adverse outcomes of treatment
Major side effects, such as hematoma, acute bleeding, allergy and thrombocytopenia were rare. Major bleeding did occur in two of 750 patients. Lassen reported major bleeding in two patients in the LMWH group (retroperitoneal bleeding in one and permanent discontinuation of LMWH due to minor bleeding in another) and in one patient in the placebo group (permanent discontinuation of LMWH due to minor bleeding). Fourteen patients in the LMWH group and twelve in the placebo group had a minor bleeding event (Lassen 2002).
Altogether, there were no significant differences between the treatment and control groups. Kock reported on five patients with minor complications (four small local hematomas, one facial eczema) (Kock 1995). Jorgensen saw four patients in the treatment group with a wound infection compared with one in the control group (Jorgensen 2002). Kujath did not observe any side effects (Kujath 1993). Lapidus did not report any major bleeding. In one study he mentioned one patient with a nosebleed after two days of dalteparin (Lapidus 2007b) and in the other he reported on two patients (one in the dalteparin group and one in the placebo group) who discontinued medication due to minor bleeding (Lapidus 2007a).
As early as 1944 the first study on deep venous thrombosis (DVT) following leg injuries was published reporting incidences of 7% to 18% (Bauer 1944). Nonfatal and fatal pulmonary embolism (PE) complicate DVT of the lower extremities. Fatal PE used to be a common cause of death in hospitals because of the often clinically occult nature of DVT.
By meta-analysis of the data obtained from the six included studies (Jorgensen 2002; Kock 1995; Kujath 1993; Lapidus 2007a, Lapidus 2007b; Lassen 2002), we found an incidence of venous thromboembolism (VTE) ranging from 4.3% to 40% diagnosed by means of compression ultrasound and/or venography in patients who had a leg injury that had been immobilized in a plaster cast or a brace for at least one week and who received no prophylaxis, or placebo. This number was significantly lower (ranging from 0% to 37%) in patients who received daily subcutaneous injections of LMWH during the entire period of immobilization.
Comparable results were seen in the following subcategories: patients with a below-knee cast; surgically treated patients; conservatively treated patients; patients with fractures; patients with soft-tissue injuries; and patients with proximal or distal DVT. The odds ratios (OR) between the individual subgroups were rather similar, with an overlap of the confidence intervals (CI). Therefore it is not possible to indicate a subgroup where prophylaxis is not indicated. Numbers were too small for statistically significant results in the subgroups of only cylinder or above-knee casts, and for PE.
The discussion on the use of LMWH in immobilization of the lower leg focuses on two issues: the reduction of symptomatic VTE and the relevance of distal DVT. By meta-analysis we were able to show that in the treatment group a significant difference was obtained. The incidence of symptomatic VTE was reduced from 2.5% to 0.3% (OR 0.16; 95% CI 0.05 to 0.56).
Over eighty percent of DVTs diagnosed were located distally. Calf vein thrombosis propagates and becomes proximal in between 0% and 25% of patients, accounting for a mean of 10%. Up to 10% of proximal DVTs embolize massively and are potentially fatal, so this disorder can be very dangerous (Anonymous 1986; Schellong 2007). Opinions differ about the risk of post-thrombotic syndrome (PTS) after distal DVT. It is stated that the risk is considerably lower than in proximal DVT. Results are inconsistent on the relationship between the location of the initial thrombus and the subsequent development of PTS. Some prospective studies reported rates of PTS after distal DVT that were as high as 20% to 80% (McLafferty 1998; Schulman 1986). Hence, distal DVT appears to be associated with a substantial risk of subsequent PTS. Further research is indicated to elicit the exact role of distal DVT in the development of PTS (Kahn 2006).
The incidence of complications in the review seemed to be low compared with data in the literature. Major bleeding was reported in 0.27% (two out of 750 patients) and minor bleeding in up to 5.5% of patients (Lassen 2002). In contrast Reilmann reported up to 14% of patients with hematomas due to injections (Reilmann 1993). Another study even described it up to 28%, although part of the patients were not treated with LMWH but with unfractionated heparin (Zagrodnick 1990). In our six included studies no cases of heparin-induced thrombocytopenia were described, which is in concordance with the observation that this condition is seldom seen in combination with LMWH.
The six studies used different types of LMWH. The total number of patients was insufficient to evaluate which type of LMWH to choose. Evidence published so far indicates that any differences between LMWH preparations, if they exist, must be extremely small (Geerts 2004). It is unlikely that a properly sized and designed study comparing the various LMWHs will ever take place. Sample size calculations quickly reach over 10,000 if one considers appropriate definitions of 'non inferiority' when comparing the various antithrombotic regimens (Vaitkus 2004).
Venography is considered the most accurate method of diagnosing DVT (Abelseth 1996; Bergqvist 2002). It is an invasive procedure and there is a reported incidence of serious adverse reactions to the contrast media in the range of 0.4% to 2% (Lensing 1990). Duplex ultrasound is the most common non-invasive test used to diagnose venous thrombosis of the extremities. Compared with venography, ultrasound has been shown to be reliable in the diagnosis of proximal symptomatic DVT, with a sensitivity and specificity of over 90%. However, for distal thrombosis a sensitivity of 73% can be reached when combining compression ultrasound with color-doppler ultrasound (CBO 2008). Considering the properties of the imaging methods used to diagnose PE, a recent systematic review showed a sensitivity of 86% for the ventilation-perfusion scintigraphy and a specificity of 46% compared with pulmonary angiography. For the CT scan the percentages were respectively 85% and 94% (Hayashino 2005). Consequently, the number of instances of DVT and PE missed seems to be acceptable when including studies with different diagnostic procedures and should not influence our conclusions to a major extent. However, an underestimation of the incidence of VTE can occur when using ultrasound, CT-scan or ventilation-perfusion scanning.
Among surgeons there is a consensus that prophylaxis should be prescribed to moderate and high risk patients. Opinions differ, however, on the definitions of moderate and high risk. Several attempts have been made to stratify the risk for VTE of immobilized patients (Gearhart 2000; Zagrodnick 1990). Knudson developed a scheme, based on analysis of 1602 episodes of VTE using the National Trauma Data Bank, to identify trauma patients with a high risk of thrombosis (Knudson 2004). Fracture of the lower limb and an age of over 40 years were among the factors used for selection. However, she also stated that in this way 90% of cases of patients with VTE would be identified and 10% would be missed (Knudson 2004). By contrast, in another study patients under 40 years of age with soft tissue injuries also sustained DVT (Kock 1995). Up to now no stratification method has proven its superiority or has gained general acceptance.
In most cases where prophylaxis was prescribed, it was administered throughout the period of immobilization. Only Lapidus randomized patients after administration of LMWH for one week. No significant result was obtained between the treatment and the placebo group (Lapidus 2007b). Although it is clear that the former strategy works, there are no data on the optimal period of administration of LMWH.
The finding of an increased incidence of DVT in an untreated population calls for measures and thromboprophylaxis seems necessary if immobilization in a cast or brace is needed. Post-traumatic DVT can lead to PE or long-term damage in the form of PTS (Kakkar 1994). Low molecular weight heparin has not shown to be effective in reducing the incidence of VTE. The possible complications of major bleeding events (2/750 patients or 0.3%) and heparin-induced thrombopenia (none in this review) have shown to be extremely rare, and do not outweigh the beneficial effect of reduction of thromboses.
Implications for practice
Use of low molecular weight heparin (LMWH) in outpatients significantly reduces the number of venous thromboembolic events when a plaster cast or brace is required. Because DVT venous thrombosis can lead to serious morbidity, we advise administration of LMWH during the entire period of immobilization of the lower extremity. This advice accounts for both lower and above-knee casts or braces.
Implications for research
Even with LMWH as a prophylactic measure, incidences of DVT ranging from 0% to 10% mean a very high absolute rate of morbidity in the population, given the enormous frequency of trauma to the leg. Immobilization should be avoided as much as possible, and treatment requiring less immobilization should always be considered. In order to further reduce the number of venous thromboembolic events we encourage all research to develop less immobilizing treatment options, and to develop even more effective and safe thromboprophylactic drugs.
Development of even more effective LMWHs might be a challenge. At this moment it remains difficult to prove superiority of a specific LMWH since the research needed will require a huge number of patients. Of interest is the development of new groups of drugs.
This review did not focus on the ongoing discussion on the clinical relevance of calf vein thrombosis. It simply confirmed its more frequent occurrence in immobilized patients. Future research might bring more clarity in the discussion on the significance of calf vein thrombosis.
Since the optimal period of treatment is unclear, further research should be performed to get more insight into this matter.
In this analysis we did not focus on scoring systems and individual risk factors. Future research might give more directives on specific advice for the different subgroups based on patient and trauma characteristics.
We are indebted to Mrs S Morrenhof-Atkinson for carefully reviewing the text of the review on its grammatical content.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. CENTRAL search strategy
Anticoagulant feedback, 14 February 2011
Feedback received on this review, and other reviews and protocols on anticoagulants, is available on the Cochrane Editorial Unit website at http://www.editorial-unit.cochrane.org/anticoagulants-feedback.
Last assessed as up-to-date: 3 June 2013.
Protocol first published: Issue 3, 2007
Review first published: Issue 4, 2008
Contributions of authors
MT assessed trial quality, extracted data.
WS assessed trial quality, extracted data.
HJ crosschecked information.
LJ coordinated and advised on statistical methods.
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.
Medical Subject Headings (MeSH)
Anticoagulants [*therapeutic use]; Heparin, Low-Molecular-Weight [*therapeutic use]; Immobilization [*adverse effects]; Leg Injuries [*therapy]; Randomized Controlled Trials as Topic; Venous Thromboembolism [*prevention & control]
MeSH check words
* Indicates the major publication for the study