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Venous Thromboembolism (Rehab Phase)

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

Several studies have been found which examined LMWH alone or compared different dosages or types of LMWHs.

Author Year; Country
Research Design
PEDro Score
Sample Size

Methods Outcome

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: (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, (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: (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.
Author Year; Country
Research Design
Total Sample Size
AMSTAR Score
Methods Outcome

Arnold et al. 2017; USA
Review of published articles up to Febreuary 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:

  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 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:

  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: 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?
  7. 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.

Discussion

Several studies have examined the thromboprophylactic effectiveness of LMWH compared to that of LDUH on the incidence of DVT and PE in the acute phase (<3 months) of SCI. Two studies evaluated the efficacy of Logiparin compared to LDUH. One RCT by Green et al. (1990) included individuals who were within 72 hours of sustaining SCI, and who were randomly assigned to receive 5000 IU LDUH every 8 hours or 3500 anti-Xa U Logiparin once daily. Significantly more individuals receiving LDUH (24%) developed DVT/PE compared to individuals receiving LMWH (0%, p=0.02). Green et al. (1994) studied 48 individuals who were given 3500 anti-Xa U Logiparin once daily for 8 weeks, beginning within 72 hours of injury. These individuals, combined with 20 individuals receiving the same regimen in the previously mentioned study (1990), were compared to individuals receiving LDUH (also from the previously mentioned study by Green et al. (1990)). Although not significant, a trend was reported in terms of fewer thrombotic events occurring for LMWH, which compared favourably to LDUH for VTE prophylaxis.

Several studies evaluated the efficacy of Enoxaparin compared to LDUH. In a case control study, Arnold et al. (2010) retrospectively reviewed individuals who were admitted greater than 72 hours post-SCI, and who received either 5000 U LDUH three times a day or Enoxaparin (30 mg twice daily or 40 mg once daily). A significant difference between groups in incidence of DVT was not observed (p=0.357). Thumbikat et al. (2002) also conducted a case control study in which individuals were studied, on average, 12 days post-injury. Participants received either 5000 IU LDUH twice daily, or 20 or 40 mg Enoxaparin. The authors reported that 13% of individuals receiving LDUH and 18% of individuals receiving Enoxaparin developed VTE, with peak incidences occurring at 20 to 30 days and 90 to 100 days following injury for both groups overall; however, no statistical analyses were reported.

In an RCT by the Spinal Cord Injury Thromboprophylaxis Investigators (2003a), individuals were randomly assigned to receive either 5000 IU LDUH every 8 hours along with IPC, or 40 mg of Enoxaparin every 12 hours without IPC. All individuals studied had sustained an SCI within 72 hours, were monitored for approximately two weeks, and were screened for DVT/PE. In individuals receiving LDUH, the incidence of DVT was 44.9%, which was not significantly different from 60.3% of individuals receiving Enoxaparin (p=0.11). The incidence of PE was significantly higher (18.4%) in individuals receiving LDUH compared to Enoxaparin (5.2%, p=0.03). Further to the previous study, the Spinal Cord Injury Thromboprophylaxis Investigators (2003b) investigated the effect of 6 more weeks of pharmacological prophylaxis following the initial 2-week protocol. Individuals previously receiving 5000 IU LDUH every 8 hours continued to do so, but without concurrent IPC. Individuals previously receiving Enoxaparin continued this regimen, but at a dose of 40 mg once daily. Screening for DVT and PE was performed at the conclusion of the additional 6-week protocol. In individuals receiving LDUH, the incidence of DVT was 18.3% which was not significantly different from 6.8% of individuals receiving Enoxaparin (p=0.067). The incidence of PE was also not significantly different between groups (3.3% and 1.7% of individuals receiving LDUH and Enoxaparin, respectively, p=0.576).

Finally, a case control by Worley et al. (2008) evaluated the efficacy of Dalteparin compared to LDUH. Individuals in acute care (time post-injury otherwise not specified) were retrospectively reviewed; individuals received either 5000 U LDUH twice daily or 5000 U Dalteparin daily. No significant difference in DVT incidence was found between the groups (p=0.7054).

A systematic review by Chen and Wang (2013) examining 18 studies with 2578 individuals compared the effect of different pharmacological VTE prophylactic options. It was concluded that LMWH is similar to LDUH in 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 Chen and Wang (2013), there is still strong evidence based on five studies that LMWH is more effective than LDUH.

Conclusions

There is level 1b evidence (from one RCT: Green et al. 1990) that Logiparin (low molecular weight heparin) is more effective than low-dose unfractionated heparin as prophylaxis for venous thromboembolism in acute SCI individuals.

There is level 1b evidence (from one RCT: Spinal Cord Injury Thromboprophylaxis Investigators 2003a) that Enoxaparin (low molecular weight heparin) is more effective than low-dose unfractionated heparin as prophylaxis for pulmonary emboli in acute SCI.

There is level 1b evidence (from one RCT: Spinal Cord Injury Thromboprophylaxis Investigators 2003a; one prospective controlled trial: Spinal Cord Injury Thromboprophylaxis Investigators 2003b; and two case controls: Arnold et al. 2010; Thumbikat et al. 2002) that Enoxaparin (low molecular weight heparin) is equally as effective as low-dose unfractionated heparin as prophylaxis for deep venous thrombosis in acute SCI.

There is level 3 evidence (from one case control: Worley et al. 2008) that Dalteparin (low molecular weight heparin) is equally as effective as low-dose unfractionated heparin as prophylaxis for venous thromboembolism in acute SCI individuals.

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