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Low-Molecular-Weight Heparin versus Low-Dose Unfractionated Heparin as Prophylaxis

Low-molecular-weight heparin (LMWH) is derived from standard heparin through either chemical or enzymatic depolymerization. Whereas standard heparin has a molecular weight of 5000 to 30 000 Daltons, LMWH ranges from 1000 to 10 000 Daltons. LMWH binds less strongly to protein, has enhanced bioavailability, interacts less with platelets and yields a very predictable dose response. The clinical advantages of LMWH include predictability, dose-dependent plasma levels, a long half-life and less bleeding for a given antithrombotic effect. Thrombocytopenia is not associated with short-term use of MLWH. LMWH is administered once or twice daily, both during the high-risk period when prophylaxis for DVT is recommended and also while waiting for oral anticoagulation to take effect in the treatment of DVT. The activated partial thromboplastin time does not need to be monitored, and the dose does not need to be adjusted (Rydberg et al. 1999).

Danaparoid sodium (Orgaran) is an alternative anticoagulant for patients who develop heparin-induced thrombocytopenia from heparin therapy. Danaparoid is a low-molecular-weight heparinoid. Its active components consist of heparan sulfate, dermatan sulfate and chondroitin sulfate. The major difference between danaparoid and other LMWHs is that danaparoid is devoid of heparin or heparin fragments. However, it exerts effects similarly to other LMWHs; Danaparoid acts by inactivating thrombin.

Table 4. Generic and Trade-names of Low Molecular Weight Heparin

Generic NameTrade-name
DalteparinFragmin
DanaparoidOrgaran
EnoxaparinLovenox
ArdeparinNormiflo
Parnaparin, ReviparinClivarine
TinzaparinLogiparin, Innohep
CertoporainAlphaparin, Sandoparin

The most commonly studied LMWH for the prophylaxis of venous thromboembolism post SCI is enoxaparin, which was the first used in the USA. The drug has a plasma half-life of 4.4 hours compared with 0.35 hours for LDUH and its subcutaneous bioavailability is 50%, compared to 20% for LDUH (Tomaio et al. 1998). In a meta-analysis, Paciaroni et al. (2008) compared the effectiveness of LDUH to that of LMWH in reducing DVT incidence in individuals post SCI. The study found no significant reduction in DVT between the LDUH group and the control group, or the LDUH group and the LMWH group. However, LMWH was reported to significantly reduce the rate of PE (p=0.04).

Table 5. Low Molecular Weight Heparin Alone in Prophylaxis of Venous Thromboembolism Post SCI

Author Year

Country

Score

Research Design

Total Sample Size

MethodsOutcomes
Chiou-Tan et al., (2003) USA

RCT

PEDro=6

N=95

Population: Mean age=37 yr (Enoxaparin group), mean age=35 yr (Dalteparin group); Gender: males=72%, females=28% (Enoxaparin group), males=80%, females=20% (Dalteparin group); Level of injury: not specified; Severity of injury: complete=53, incomplete=42.

Chronicity: All individuals had sustained acute SCI within 3 mo time; Individuals in the Enoxaparin group were enrolled 1-99 days after injury, and individuals in the Dalteparin group were enrolled 1-84 days after injury. The majority of participants were recruited within 4 weeks of injury, and more than ¾ of individuals were recruited within 6 weeks of injury.

Intervention: Individuals were randomized to either receive 30 mg Enoxaparin subcutaneously every 12 hr (Enoxaparin group), or 5000 IU Dalteparin subcutaneously once daily (Dalteparin group).

Outcome Measures: Incidence of deep vein thromobis (DVT) or pulmonary embolism (PE) and bleeding.

Method of Diagnosis: Duplex ultrasonography.

Timing of DVT onset: Not indicated.

Incidence of DVT:

1.      6% of individuals (Enoxaparin group) and 4% of individuals (Dalteparin group) developed DVT (p=0.51).

2.      No individuals developed PE overall.

3.      4% developed bleeding while receiving Dalteparin and 2% while receiving Enoxaparin (p=0.72).

4.      Similar rates of DVT were found between Enoxaparin and Dalteparin.

 

DiGiorgio et al., (2017)

USA

Observational

N=49

 

Population: Mean age=53.5 yr; Gender: males=65.3%, females=34.7%; Level of injury: not reported; Severity of injury: not reported.

Chronicity:<24 hr post SCI.

Intervention: A retrospective review of individuals with SCI at the UCSF Brain and Spinal Injury Center to determine if administration of enoxaparin (40 mg/day) low-molecular-weight heparin (LMWH) within 24 hr after injury is safe and effective in preventing the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Outcome Measures: Incidence of DVT and PE.

1. There were three DVTs (6.1%) and two PEs (4.1%), with no hemorrhagic complications.

2. No association was observed between DVT and/or PE and age, ASIA grade, sec, race, or having undergone a neurosurgical procedure.

Marciniak et al., (2012)

USA

Case Control

N=140

Population: Mean age=46.8 yr (Enoxaparin), mean age=48.4 yr (4500 Tinzaparin), mean age=32.9 yr (3500 Tinzaparin); Gender: males=64.7%, females=35.3% (Enoxaparin), males=74.1%, females=25.9% (4500 Tinzaparin), males=71.4%, females=28.6% (3500 Tinzaparin); Level of injury: not specified; Severity of injury: American Spinal Injury Association Impairment Scale (AIS) A-C, D.

Chronicity: Individuals studied were within 3 mo of sustaining SCI; individuals were admitted at a median of 15 days after injury.

Intervention: Individuals received either Enoxaparin (5000 IU), Tinzaparin (4500 IU), or Tinzaparin (3500 IU). The majority of individuals were on some form of pharmacological prophylaxis before admission.

Outcome Measures: Incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and bleeding.

Method of Diagnosis: Clinical examination, venous duplex scans and computed tomography.

Timing of DVT onset: Individuals developed VTE symptoms at median of 12 days after admission.

Incidence of DVT:

1.     14 individuals developed a DVT and 4 developed a PE.

2.     Individuals receiving Enoxaparin and 4500 IU Tinzaparin had significantly reduced odds of VTE compared with individuals receiving 3500 IU Tinzaparin (OR=0.12 and OR 0.18, respectively); uncontrolled factors may have affected this result.

3.     Bleeding events were low and equivalent in all 3 treatment groups.

Slavik et al., (2007)

Canada

Case Control

N=135

 

Population: Mean age=40.6 yr (Enoxaparin), mean age=45.4 yr (Dalteparin); Gender: males=71.4% (Enoxaparin), males=80.6% (Dalteparin); Level of injury: cervical-thoracic (Enoxaparin), cervical-lumbar (Dalteparin); Severity of injury: American Spinal Injury Association Impairment Scale (AIS A-E) (Enoxaparin), AIS A-C, E (Dalteparin).

Chronicity: Individuals were studied beginning within 72 hr after injury. Hospital length of stay was a median of 42.8 days (Enoxaparin group) and a median of 48.9 days (Dalteparin group).

Intervention: Individuals received either Enoxaparin (30 mg subcutaneously twice daily, n=63, beginning at a median of 4 days after injury) or Dalteparin (5000 IU subcutaneously once daily, n=72, beginning at a median of 3.2 days after injury).

Outcome Measures: Incidence of deep vein thrombosis (DVT) pulmonary embolism (PE) and bleeding.

Method of Diagnosis: Contrast venography, duplex ultrasonography, ventilation-perfusion lung scanning, high-resolution chest tomography, and pulmonary angiography.

Timing of DVT onset: Not indicated.

Incidence of DVT:

1.     1.6% of individuals (Enoxaparin) and 9.7% of individuals (Dalteparin) developed DVT/PE, p=NS.

2.     No significant difference between the two groups in major or minor bleeding was found.

Hebbeler et al., (2004)

USA

Case Control

N=129

 

Population: No demographical information was provided.
Chronicity: Individuals studied were within 2 mo after sustaining injury.Intervention: Individuals received either Enoxaparin 40 mg once daily or Enoxaparin 30 mg twice daily.Outcome Measures: Incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE).Method of Diagnosis: Venous duplex scans and spiral computed tomography imaging.
Timing of DVT onset: Individuals were screened for clinical symptoms of DVT daily. No information was provided specifying when screening was performed.

Incidence of DVT:

1.     DVT occurred in 2.0% of individuals receiving twice daily Enoxaparin, and in 1.25% of individuals receiving once daily Enoxaparin (not significant).

2.     PE only occurred in 2.0% of individuals receiving twice daily Enoxaparin, no individuals in the twice daily Enoxaparin group sustained PE (not significant).

3.     No significant differences were found in bleeding complications between the two groups.

4.     Efficacy of prophylaxis was deemed equivalent between groups.

5.     Individuals who received twice daily Enoxaparin were more likely to have been given Enoxaparin or low dose unfractionated heparin prior to admission (p<0.001).

Harris et al., (1996)

USA

Case Series

N=105

 

Population: Mean age=42 yr; Gender: males=58, females=47; Level of injury: not specified; Severity of injury: complete/incomplete, tetraplegia=35, paraplegia=26.

Chronicity: All individuals were hospitalized 6-104 days (mean=19) after injury.

Intervention: All individuals received 30 mg of Enoxaparin subcutaneously every 12 hr from the time of admission.

Outcome Measures: Incidence of deep vein thrombosis (DVT).

Method of Diagnosis: Clinical examination and venous ultrasonography.

Timing of DVT onset: Not indicated.

Incidence of DVT:

1.     No clinical or ultrasound evidence of DVT.

Table 6. Systematic Reviews and Guidelines on Low-Molecular-Weight Heparinost SCI

Author Year

Country

Research Design

Total Sample Size

AMSTAR Score

MethodsOutcome
Arnold et al., (2017)

USA

Review of published articles up to February 2015

N=9

Method:  A comprehensive literature search was conducted to identify randomized controlled trials (RCT) evaluating the efficacy and safety of antithrombotic strategies. The strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

Databases: MEDLINE; Cochrane Collaboration Library.

Level of evidence: High quality study designs such as RCTs and one prospective controlled trial, were the only studies included.

Questions/measures/hypothesis:

1. What is the effectiveness and safety of anticoagulant thromboprophylaxis compared to no prophylaxis, placebo, or another anticoagulant strategy for preventing deep vein thrombosis (DVT) and pulmonary embolism (PE) after acute SCI?

2. What is the comparative effectiveness and safety of mechanical prophylaxis strategies alone or in combination with other prophylactic strategies for preventing DVT and PE after acute SCI?

3. What is the comparative effectiveness and safety of prophylactic inferior vena cava (IVC) filter insertion alone or in combination with other prophylactic strategies for preventing DVT and PE after acute SCI?

4. What is the optimal timing to initiate and/or discontinue anticoagulant, mechanical, and/or prophylactic IVC filter following acute SCI?

What is the cost-effectiveness of the treatment options mentioned above?

Question one:

1.     Seven RCTs reported on the efficacy and/or safety of anticoagulant drug interventions.

2. A single RCT reported the efficacy of LMWH versus no prophylaxis. Individuals treated with enoxaparin has a lower rate of DVT (5.4%) than those who received no LMWH prophylaxis (21.6%).

3. Two RCTs assessed the risk of DVT in individuals receiving unfractionated heparin versus no treatment or placebo and found no significant difference between groups.

4. A single RCT compared the efficacy and safety of two different LMWH drugs (enoxaparin or dalteparin). There was no significant difference in the rate of DVT or PE between groups.

5. One RCT evaluated the efficacy and safety of fixed, low-dose versus adjusted-dose UFH. DVT and PE were observed in 9/29 (31%) and 2/29 (6.9%). The risk of DVT in the fixed, low-dose group was three times greater than the adjusted-dose group (RD=13.8, 95% CI=-3.6-31.2, RR=3.0, 95% CI=0.66-13.7, p=0.25).

6. Two RCTs evaluated the efficacy and safety of LMWH versus UFH and found no statistically significant difference in the rate of DVT or PE between groups.

Question two:

1. One RCT compared the efficacy and safety of mechanical prophylaxis versus mechanical prophylaxis plus antithrombotic drugs. No significant difference in safety or efficacy was observed between groups.

2. Two RCTs compared outcomes between anticoagulant thromboprophylaxis and anticoagulant plus mechanical prophylaxis. Both studies reported significantly higher risk of DVT in the group that received anticoagulant prophylaxis only (50% and 60.3% versus 6.7% and 44.9%).

Question three:

1.     No RCTs were identified that met inclusion criteria.

Question four:

1.     One prospective controlled trial examined the timing of initiation of anticoagulant thromboprophylaxis in individuals with acute SCI. Combined anticoagulant and mechanical prophylaxis initiated within 72 hr of SCI resulted in significantly lower risk of DVT than treatment commenced 72 hr after injury.

Question five:

1.     No RCTs were identified that met inclusion criteria.

Fehlings et al., (2017)

Canada

Clinical Practice Guideline

 

Method: A comprehensive literature search was conducted to address key questions relating to thromboprophylaxis in SCI. The strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

Databases: Not reported.

Level of evidence: …

Questions/measures/hypothesis:

1.     Should anticoagulant thromboprophylaxis be employed to reduce the risk of thromboembolic events in the acute period after SCI?

2.     What anticoagulant thromboprophylaxis should be employed to reduce the risk of thromboembolic events in the acute period after traumatic SCI?

3.     Should enoxaparin versus dalteparin be used to reduce the risk of thromboembolic events in the acute period after traumatic SCI?

4.     Should fixed, low-dose, versus adjusted-dose unfractionated heparin (UFH) be used to reduce the risk of thromboembolic events in the acute period after traumatic SCI?

5.     Should low weight molecular heparin (LWMH) versus UFH be used to reduce the risk of thromboembolic events in the acute period after traumatic SCI?

6.     Should thromboprophylaxis be initiated within 72 hr (vs after 72 hr) of SCI?

Should mechanical or anticoagulant thromboprophylaxis be used in combination or alone?

1.     Three RCTs compared the risk of DVT in individuals treated with LMWH or UFH to those receiving no prophylaxis or placebo. Individuals treated with enoxaparin have a lower rate of DVT (5.45%) than those who received no anticoagulant prophylaxis (21.6%) (p=0.09).

2.     Rates of DVT did not significantly differ between the UFH and the placebo/no prophylaxis group (1.8% and 3% in one trial and 50% and 74% in another).

3.     Anticoagulant thromboprophylaxis should be offered routinely to reduce the risk of thromboembolic events in the acute period after SCI.

4.     There is little to no difference in the rate of DVT, PE, bleeding and mortality between individuals treated with enoxaparin versus dalteparin.

5.     There is low quality evidence that the risk of DVT is three times higher in individuals who received fixed, low-dose UFH compared to adjusted-dose heparin (RD=13.8, 95% CI=-3.6-31.2; RR=3.0, 95% CI=0.66 to 13.7; p=0.25).

6.     The rate of bleeding is significantly higher in individuals treated with adjusted-dose heparin (24.1%) than in those receiving low-dose (0%) (RD=24.1, 95% CI=8.6-39.7; p=0.01).

7.     Anticoagulant thromboprophylaxis, consisting of either subcutaneous LMWH or fixed, low-dose UFH, should be offered to reduce the risk of thromboembolic events in the acute period after SCI.

8.     The authors caution against use of adjusted-dose UFH, due to the potential pf increased bleeding events.

9.     One prospective observational study evaluated the risks of DVT and PE in individuals who received prophylaxis initiated within or after 72 hr of injury. Based on low quality evidence, the rate of DVT was significantly lower in individuals treated early (n=2) compared with late (n=46). There was insufficient evidence to compare the groups.

10.   Anticoagulant thromboprophylaxis should be commenced within the first 72 hr after injury, if possible, to minimize the risk of VTE complications during acute hospitalization.

11.   Individuals who received a combination of UFH and electronic calf stimulation had a lower risk of DVT than individuals treated with UFH alone (RD=43.3, 95% CI=15.8-70.9; RR=7.5, 95% CI=1.06-53.03, p=0.02).

12.   Individuals treated with LMWH alone have a lower risk of PE compared with individuals who receive UFH plus IPC (RD=13.2, 95% CI=0.9-25.4; RR=0.28, 95% CI=0.08-0.98; p=0.06).

13.   A higher percentage of individuals experienced a DVT when treated with IPC alone (40%) compared with IPC plus aspirin and dipyridamole (25%); however, this difference was not statistically significant.

Christie et al., (2011)

Canada

Date included in the review not stated

N=5

AMSTAR=5

Method: Comprehensive literature search of English RCT, Cohort studies, case series, and review articles of relating to prophylaxis low molecular unfractionated heparin (LMWH) for deep venous thrombosis (DVT) in traumatic SCI in adult age group (+18yr).

Databases: PubMed.

Questions/measures/hypothesis: Examine the ideal time for initiation of deep venous thrombosis (DVT) prophylaxis with LMWH after SCI or after surgery.

1.     DVT prophylaxis should be instituted within 72hr post injury.

2.     LMWH should be held on the morning of surgery and resumed within 24hr following surgery.

 

Discussion

LMWH is the newest treatment for prophylaxis of venous thromboembolism. Given that LMWH appears to offer advantages (e.g. decreased incidence of DVT/PE and reduced costs; Spivack & Aisen 1997) over LDUH as the standard of care, it is not surprising that there are a number of trials comparing the two treatments.

There have been seven trials that have compared LDUH and LMWH. The SCI Thromboprophylaxis Investigators (2003a) conducted an RCT of 107 SCI patients who were assigned to receive thromboprophylaxis with either a combination of LDUH (5000 IU) plus intermittent pneumatic compression (IPC) 22 hr/day, or enoxaparin 30 mg s/c q12h. The incidence of DVT was 63.3% and 65.5% for the LDUH and enoxaparin groups, respectively (p=0.81), whereas the incidence of PE was 18.4% and 5.2%, respectively (p=0.03). Among all the randomized patients, the incidence of major bleeding was 5.3% in the LDUH group versus 2.6% in the enoxaparin group (p=0.14). This may be the result of the added benefit of intermittent pneumatic compression. Nonetheless, the incidence of PEs was still significantly greater in the LDUH group. In their follow-up prospective controlled trial, the enoxaparin group increased their dosage to 40 mg once daily (SCI Thromboprophylaxis Investigators 2003b). A new DVT was detected in 21.7% of LDUH and 8.5% of enoxaparin patients (p=0.052). Enoxaparin appeared to be more effective in this population than LDUH (SCI Thromboprophylaxis Investigators 2003b).

The results by the SCI Thromboprophylaxis Investigators have been supported by earlier studies. In a case series by Maxwell et al. (2002), individuals with SCI using a combination of sequential compression devices and LMWH produced a fewer number of DVTs and PEs (7.4% and 0%, respectively) compared to those receiving sequential compression devices and LDUH.

An RCT by Green et al. (1990) on 41 SCI subjects also compared LDUH to LMWH. Five patients in the standard heparin group had thrombotic events including two patients with fatal pulmonary embolism. Two other patients had bleeding severe enough to necessitate withdrawal of the heparin. The cumulative event rate was 34% in the LDUH group while the LMWH group had no thrombotic events or bleeding. The difference between the two groups was significant (p=0.006). In a follow-up study, Green et al. (1994) studied 48 acute SCI patients with complete motor paraplegia who all received LMWH (3500 IU). Treatment began within 72 hours of injury and continued for eight weeks. In total, eight suffered a thrombotic event which consisted of two pulmonary emboli, four proximal DVTs, and two distal calf DVTs. When combining data from a previous study (68 LMWH (20 from previous study) and 79 LDUH), the differences in bleeding and thrombotic events were significant (p=0.04 and p=0.015, respectively) favoring LMWH.

Interestingly, some studies (Arnold et al. 2010; Worley et al. 2008) report no difference in the incidence of DVT or bleeding complications among individuals with SCIs receiving LDUH or LMWH (enoxaparin and dalteparin, respectively). A systematic review by Chen and Wang (2015) examining 18 studies with 2578 patients compared the effect of different pharmacological VTE prophylactic options. It was concluded that LMWH is similar to LDUH in the VTE prevention but has less bleeding complications. There was no difference in VTE prophylaxis using various types and/or doses of LMWH, including enoxaparin, tinzaparin and dalteparin. Despite the conflicting results presented by Thumbikat et al. (2002) and Chen and Wang (2015), there is still strong evidence based on five studies that LMWH is more effective than LDUH.

Table 7. Low-Molecular-Weight Heparin versus Low-Dose Unfractionated Heparin as Prophylaxis

Author Year

Country

Research Design

PEDro Score

Sample Size

MethodsOutcomes
Spinal Cord Injury Thromboprophylaxis Investigators  (2003a)

USA

RCT

PEDro=9

N=107

Population: Mean age=40.6 yr (unfractionated heparin (UFH)-intermittent pneumatic compression (IPC) group), mean age=38.5 yr (Enoxaparin group); Gender: males=79.6% (UFH-IPC group), males=89.7% (Enoxaparin group); Level of injury: not specified; Severity of injury: American Spinal Injury Association Impairment Scale (AIS) A-D.

Chronicity: All individuals were studied beginning within 72 hr of sustaining injury and monitored for approximately 2 weeks during acute treatment (mean=13.4 days for UFH-IPC group, mean=14 days for Enoxaparin group).

Intervention: Individuals were assigned to receive either low-dose UFH (5000 IU subcutaneously every 8 hr) plus IPC (used at least 22hr/day), or only Enoxaparin (30 mg subcutaneously every 12 hr).

Outcome Measures: Incidence of deep vein thrombosis (DVT), pulmonary embolism (PE), and major bleeding.

Method of Diagnosis: Doppler ultrasonography, venography, ventilation-perfusion lung scanning, spiral computed tomographic scanning, and pulmonary angiography.

Timing of DVT onset: DVT/PE screening/data collection was performed at the end of the 2-week acute treatment phase or within 2 days of the last dose of acute-phase medication.

Incidence of DVT:

1.     Incidence of DVT was 44.9% for UFH-IPC group versus 60.3% for Enoxaparin group; nonsignificant difference (p=0.11).

2.     Incidence of PE was 18.4% for UFH-IPC group, significantly higher than 5.2% of individuals in the Enoxaparin group (p=0.03).

3.     Among all randomized individuals, the incidence of major bleeding was 5.3% for low dose unfractionated heparin IPC group versus 2.6% for Enoxaparin group (p=0.14).

Green et al., (1990)

USA

RCT

PEDro=8

NInitial=41; NFinal=32

Population: Mean age=31 yr (LDUH group), mean age=28 yr (LMWH group); Gender: males=4, females=17 (LDUH group), males=3, females=17 (LMWH group); Level of injury: cervical-lumbar; Severity of injury: not specified.

Chronicity: All individuals were studied beginning within 72 hr of sustaining injury and monitored for 8 weeks.

Intervention: Individuals were randomly assigned to receive either low dose unfractionated heparin (LDUH) (5000 IU) subcutaneously every 8 hr or low molecular unfractionated heparin (LMWH) (Logiparin, 3500 anti-Xa units) subcutaneously once daily.

Outcome Measures: Incidence of deep vein thrombosis (DVT), pulmonary embolism (PE), and major bleeding.

Method of Diagnosis: Impedance plethysmography, Doppler flow measurements and duplex ultrasonography.  

Timing of DVT onset: DVT events occurred on days 4, 7, and 32 after admission; PE events occurred on days 21 and 38 after admission.

Incidence of DVT:

1.     33% of the LDUH group had thrombosis or hemorrhage; 24% (5/21) of individuals in this group had DVT/PE.

2.     No individuals treated with LMWH had a documented thrombotic event.

3.     The difference between the two groups in terms of frequency of developing thrombosis was significant (p=0.02).

 

Arnold et al., (2010)

USA

Case Control

N=476

Population: Acute SCI individuals were a subset of the study population (n=24); no further information was provided.

Chronicity: Individuals studied were admitted after>72 hr post injury.

Intervention: Retrospective review of individuals who received either 5000 U low dose unfractionated heparin (LDUH) three times a day or low molecular unfractionated heparin (LMWH) (Enoxaparin, 30 mg twice daily or 40 mg once daily).

Outcome Measures: Incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE).

Method of Diagnosis: Duplex ultrasonography.

Timing of DVT onset: Not indicated.

Incidence of DVT:

1.     15.4% of the LDUH and 36.4% of the LMWH groups developed DVT (NS, p=0.357).

Worley et al., (2008)

Canada

Case Control

N=90

Population: Mean age=46yr (LDUH group), mean age=38 yr (LMWH group); Gender: males=40, females=7 (LDUH group), males=39, females=4 (LMWH group); Level of injury: cervical-sacral; Severity of injury: tetraplegia=35, paraplegia=12, American Spinal Injury Association Impairment Scale (AIS) A-D.

Chronicity: Individuals studied were under acute care following acute SCI. No other information was provided.

Intervention: Individuals reviewed received either 5000 U low molecular unfractionated heparin (LMWH) (Dalteparin) subcutaneously daily or 5000 U low dose unfractionated heparin (LDUH) subcutaneously twice daily.

Outcome Measures: Incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE).

Method of Diagnosis: Compression ultrasonography, ventilation-perfusion lung scanning, computed tomography, and pulmonary angiography.

Timing of DVT onset: Not indicated.

Incidence of DVT:

1.     7.8% of all individuals developed DVT/PE: 3 in LDUH group, and 4 in LMWH group.

2.     No significant difference was found in terms of incidence of DVT and type of prophylaxis received (p=0.7054).

3.     No association was found between type of prophylaxis used and localization of DVT.

Spinal Cord Injury Thromboprophylaxis Investigators (2003b)

USA

Prospective Controlled Trial

N=119

 

Population: Mean age=34 yr (unfractionated heparin (UFH) group), mean age=30.5 yr (Enoxaparin group); Gender: males=78.3% (UFH group), males=89.8% (Enoxaparin group); Level of injury: not specified; Severity of injury: American Spinal Injury Association Impairment Scale (AIS) A-D.

Chronicity: All individuals were studied from 2-8 weeks following injury (in continuation of study 2003a, above).

Intervention: Continuation of study 2003a (above): Individuals previously receiving unfractionated heparin (UFH) continued on this regimen (5000 IU subcutaneously every 8 hr), but intermittent pneumatic compression (IPC) was discontinued. Those previously receiving Enoxaparin continued this regimen, but at a dose of 40mg once daily (instead of 30 mg twice daily).

Outcome Measures: Incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE).

Method of Diagnosis: Doppler ultrasonography, venography, ventilation-perfusion lung scanning, spiral computed tomographic scanning, and pulmonary angiography.

Timing of DVT onset: DVT/PE screening/data collection was performed at the end of the 6-week rehabilitation treatment phase (8 weeks following injury).

Incidence of DVT:

1.     Incidence of DVT was 18.3% in the UFH group versus 6.8% in the Enoxaparin group; (p=0.067).

2.     Incidence of PE was 3.3% in the UFH group versus 1.7% of individuals in the Enoxaparin group (p=0.576).

 

 

 

 

Thumbikat et al., (2002)

UK

Case Control

N=173

Population: Age range=10-60 yr (27 individuals were over 60); Gender: males=129, females=44; Level of injury: cervical-lumbar; Severity of injury: not specified.

Chronicity: Individuals in the heparin group commenced treatment “soon after admission,” and individuals in the Enoxaparin group received treatment on the day of admission. Individuals were studied beginning within an average of 12 days following injury (range 0-80). Average period of anticoagulation was 57 days for individuals in the heparin group and 52 days for individuals in the Enoxaparin group.

Intervention: Individuals received either a combination of heparin 5000 IU twice daily followed by warfarin, or only Enoxaparin 20 mg (n=40) or 40 mg (n=32).

Outcome Measures: Incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE) and other complications.

Method of Diagnosis: Doppler ultrasonography and ventilation-perfusion scanning.

Timing of DVT onset: Peak incidences of VTE occurred at 20-30 and 90-100 days following injury for both groups studied.

Incidence of DVT:

1.     13% of individuals in the heparin group and 18% of individuals in the Enoxaparin group developed VTE episodes, respectively.

2.     25% of individuals receiving 20 mg Enoxaparin and 9.4% of individuals receiving 40 mg Enoxaparin developed DVT/PE, respectively.

3.     6 of the 13 thrombotic events in the Enoxaparin group occurred after the individuals had been mobilized and anticoagulation stopped.

 

 

 

Green et al., (1994)

USA

Pre-post

N=48

Population: No demographical information was provided.

Chronicity: Individuals were studied beginning within 72 hr post injury and monitored for 8 weeks.

Intervention: All individuals received low molecular unfractionated heparin (LMWH) (Logiparin) at a dose of 3500 anti-Xa U subcutaneously once daily, beginning within 72 hr of injury for 8 weeks.

Outcome Measures: Incidence of deep vein thrombosis (DVT), pulmonary embolism (PE), and bleeding in these 48 individuals combined with 20 individuals receiving LMWH in the study by Green et al., 1990 (above) were compared to previously studied individuals treated with standard heparin.

Method of Diagnosis: Impedance plethysmography Doppler flow measurements and duplex ultrasonography.  

Timing of DVT onset: DVT screening was done at the conclusion of the 8 week timeframe post injury.

Incidence of DVT:

1.     A trend toward less thrombotic events was reported for LMWH (p=0.15).

2.     LMWH and standard heparin were significantly different in terms of bleeding, favouring LMWH (p=0.04).

3.     LMWH compares favourably with low dose unfractionated heparin as VTE prophylaxis.

 

 

Table 8. Systematic Reviews and Guidelines comparing Low-Molecular-Weight Heparin to Low-Dose Unfractionated Heparin

Author Year

Country

Research Design

Total Sample Size

AMSTAR Score

MethodsOutcome
Arnold et al., (2017)

USA

Review of published articles up to February 2015

N=9

Method:  A comprehensive literature search was conducted to identify randomized controlled trials (RCT) evaluating the efficacy and safety of antithrombotic strategies. The strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

Databases: MEDLINE; Cochrane Collaboration Library.

Level of evidence: High quality study designs such as RCTs and one prospective controlled trial, were the only studies included.

Questions/measures/hypothesis:

1.  What is the effectiveness and safety of anticoagulant thromboprophylaxis compared to no prophylaxis, placebo, or another anticoagulant strategy for preventing deep vein thrombosis (DVT) and pulmonary embolism (PE) after acute SCI?

2.  What is the comparative effectiveness and safety of mechanical prophylaxis strategies alone or in combination with other prophylactic strategies for preventing DVT and PE after acute SCI?

3.  What is the comparative effectiveness and safety of prophylactic inferior vena cava (IVC) filter insertion alone or in combination with other prophylactic strategies for preventing DVT and PE after acute SCI?

4.  What is the optimal timing to initiate and/or discontinue anticoagulant, mechanical, and/or prophylactic IVC filter following acute SCI?

5.  What is the cost-effectiveness of the treatment options mentioned above?

Question one:

1.     Seven RCTs reported on the efficacy and/or safety of anticoagulant drug interventions.

2.     A single RCT reported the efficacy of LMWH versus no prophylaxis. Individuals treated with enoxaparin has a lower rate of DVT (5.4%) than those who received no LMWH prophylaxis (21.6%).

3.     Two RCTs assessed the risk of DVT in individuals receiving unfractionated heparin versus no treatment or placebo and found no significant difference between groups.

4.     A single RCT compared the efficacy and safety of two different LMWH drugs (enoxaparin or dalteparin). There was no significant difference in the rate of DVT or PE between groups.

5.     One RCT evaluated the efficacy and safety of fixed, low-dose versus adjusted-dose UFH. DVT and PE were observed in 9/29 (31%) and 2/29 (6.9%). The risk of DVT in the fixed, low-dose group was three times greater than the adjusted-dose group (RD=13.8, 95% CI=-3.6-31.2, RR=3.0, 95% CI=0.66-13.7, p=0.25).

6.     Two RCTs evaluated the efficacy and safety of LMWH versus UFH and found no statistically significant difference in the rate of DVT or PE between groups.

 

Question two:

7.     One RCT compared the efficacy and safety of mechanical prophylaxis versus mechanical prophylaxis plus antithrombotic drugs. No significant difference in safety or efficacy was observed between groups.

8.     Two RCTs compared outcomes between anticoagulant thromboprophylaxis and anticoagulant plus mechanical prophylaxis. Both studies reported significantly higher risk of DVT in the group that received anticoagulant prophylaxis only (50% and 60.3% versus 6.7% and 44.9%).

Question three:

9.     No RCTs were identified that met inclusion criteria.

Question four:

10.   One prospective controlled trial examined the timing of initiation of anticoagulant thromoboprophylaxis in individuals with acute SCI. Combined anticoagulant and mechanical prophylaxis initiated within 72 hr of SCI resulted in significantly lower risk of DVT than treatment commenced 72 hr after injury.

Question five:

11.   No RCTs were identified that met inclusion criteria.

Fehlings et al., (2017)

Canada

Clinical Practice Guideline

 

Method: A comprehensive literature search was conducted to address key questions relating to thromboprophylaxis in SCI. The strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

Databases: Not reported.

Level of evidence: Weak, Moderate, Strong

Questions/measures/hypothesis:

1.      Should anticoagulant thromboprophylaxis be employed to reduce the risk of thromboembolic events in the acute period after SCI?

2.      What anticoagulant thromboprophylaxis should be employed to reduce the risk of thromboembolic events in the acute period after traumatic SCI?

3.      Should enoxaparin versus dalteparin be used to reduce the risk of thromboembolic events in the acute period after traumatic SCI?

4.      Should fixed, low-dose, versus adjusted-dose unfractionated heparin (UFH) be used to reduce the risk of thromboembolic events in the acute period after traumatic SCI?

5.      Should low molecular weight heparin (LWMH) versus UFH be used to reduce the risk of thromboembolic events in the acute period after traumatic SCI?

6.      Should thromboprophylaxis be initiated within 72 hr (vs after 72 hr) of SCI?

Should mechanical or anticoagulant thromboprophylaxis be used in combination or alone?

1.     Three RCTs compared the risk of DVT in individuals treated with LMWH or UFH to those receiving no prophylaxis or placebo. Individuals treated with enoxaparin have a lower rate of DVT (5.45%) than those who received no anticoagulant prophylaxis (21.6%) (p=0.09).

2.      Rates of DVT did not significantly differ between the UFH and the placebo/no prophylaxis group (1.8% and 3% in one trial and 50% and 74% in another).

3.      Anticoagulant thromboprophylaxis should be offered routinely to reduce the risk of thromboembolic events in the acute period after SCI.

4.      There is little to no difference in the rate of DVT, PE, bleeding and mortality between individuals treated with enoxaparin versus dalteparin.

5.      There is low quality evidence that the risk of DVT is three times higher in individuals who received fixed, low-dose UFH compared to adjusted-dose heparin (RD=13.8, 95% CI=-3.6-31.2; RR=3.0, 95% CI=0.66 to 13.7; p=0.25).

6.      The rate of bleeding is significantly higher in individuals treated with adjusted-dose heparin (24.1%) than in those receiving low-dose (0%) (RD=24.1, 95% CI=8.6-39.7; p=0.01).

7.      Anticoagulant thromboprophylaxis, consisting of either subcutaneous LMWH or fixed, low-dose UFH, should be offered to reduce the risk of thromboembolic events in the acute period after SCI.

8.      The authors caution against use of adjusted-dose UFH, due to the potential pf increased bleeding events.

9.      One prospective observational study evaluated the risks of DVT and PE in individuals who received prophylaxis initiated within or after 72 hr of injury. Based on low quality evidence, the rate of DVT was significantly lower in individuals treated early (n=2) compared with late (n=46). There was insufficient evidence to compare the groups.

10.    Anticoagulant thromboprophylaxis should be commenced within the first 72 hr after injury, if possible, to minimize the risk of VTE complications during acute hospitalization.

11.    Individuals who received a combination of UFH and electronic calf stimulation had a lower risk of DVT than individuals treated with UFH alone (RD=43.3, 95% CI=15.8-70.9; RR=7.5, 95% CI=1.06-53.03, p=0.02).

12.    Individuals treated with LMWH alone have a lower risk of PE compared with individuals who receive UFH plus IPC (RD=13.2, 95% CI=0.9-25.4; RR=0.28, 95% CI=0.08-0.98; p=0.06).

13.    A higher percentage of individuals experienced a DVT when treated with IPC alone (40%) compared with IPC plus aspirin and dipyridamole (25%); however, this difference was not statistically significant.

Chen & Wang (2013)

China

Review of published articles up to February 2013

N=18

AMSTAR=9

 

 

Method: Comprehensive literature search of randomized controlled trials (RCT), quasi-RCTs, cohort studies, case control studies, and cross-sectional studies of individuals with acute SCI receiving heparin to prevent the risk venous thromboembolism (VTE) and major bleeding.

Databases: MEDLINE.

Level of evidence: High quality study designs such as RCTs, prospective cohort studies; moderate quality study designs such as case control studies were included. Cross-sectional observational studies were the only type of low quality study design included into the search. Low quality study designs such as case series, case reports, and reviews were excluded.

Questions/measures/hypothesis:

1.     Examine the effectiveness of low-dose unfractionated heparin (LDUH) in SCI in preventing VTE.

2.     To compare the effectiveness of LDUH with low-molecular-weight heparin (LMWH) in preventing VTE and major bleeding.

3.     To compare the effectiveness of different types of LMWH in preventing VTE and major bleeding.

1.     Two RCTs and two case-control studies compared LDUH with a placebo or untreated condition but no significant differences were reported between the two conditions in the prevalence of VTE (p=.259).

2.     Nine studies, including four case-control studies, three RCTs, one quasi-RCT, and one cohort study, compared LDUH and LMWH. No significant difference was reported between the two in regards to development of VTE (p=.162) but LMWH was associated with significantly lower instances of major bleeding (p=0.044).

3.     One study compared fixed-dose LDUH with adjusted-dose LMWH and reported a significantly higher prevalence of VTE in the fixed-dose LDUH group (p=0.019). Major bleeding was also significantly higher in the fixed-dose LDUH group compared to the adjusted-dose LMWH group (p=0.0048).

4.     Three studies compared three different types of LMWH (Enoxaparin, Tinzaparin, and Dalteparin) but no significant differences were found between Enoxaparin and Tinzaparin (p=.130), and Enoxaparin and Dalteparin (p=.866) in prevalence rates of VTE.

5.     No significant differences were found between Enoxaparin and Dalteparin for major bleeding (p=.496). Prevalence of major bleeding was not investigated in the comparison between Enoxaparin and Tinzaparin.

Conclusions

There is level 1a evidence (from two RCTs, one prospective controlled trial, one pre-post, and one case series; SCI Thromboprophylaxis Investigators 2003a, 2003b; Green et al. 1990, 1994; Maxwell et al. 2002) that low-molecular-weight heparin, in particular enoxaparin, is more effective in reducing venous thromboembolic events, when compared to the standard subcutaneous heparin prophylaxis. Moreover, the incidence of bleeding complications was less in the LMWH group.

  • Low-molecular-weight heparin reduces the risk of venous thromboembolism post SCI more effectively than standard or unfractionated heparin prophylaxis with fewer bleeding complications.