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Venous Thromboembolism (Rehab Phase)

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). Several types of LMWH are available (Table 5).

Generic name Trade-name
Daltaperin Fragmin
Danaparoid Orgaran
Enoxaparin Lovenox
Ardeparin Normiflo
Parnaparin, Reviparin Clivarine
Tinzaparin Logiparin, Innohep
Certoporain Alphaparin, Sandoparin

Danaparoid sodium (Orgaran) is an alternative anticoagulant for individuals 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.

The most commonly studied LMWH for the prophylaxis of VTE post SCI is enoxaparin, which was the first used in the United States. 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).

Author Year; Country
Score
Research Design
Total Sample Size

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

  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?
  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.
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

Several studies have examined the independent thromboprophylactic effectiveness of LMWH on the incidence of DVT and PE in acute SCI. Various forms of LMWH have been investigated including Enoxaparin, Dalteparin, and Tinzaparin.

Two studies compared the effectiveness of Enoxaparin versus Dalteparin in preventing VTEs. Chiou-Tan et al. (2003) conducted an RCT in which acute SCI individuals (<3 months post-SCI) were randomized to receive either 30 mg Enoxaparin every 12 hours or 5000 IU Dalteparin once daily. The authors found that 6% of individuals receiving Enoxaparin and 4% of individuals receiving Dalteparin developed DVTs (p=0.51); however, no individuals developed PE. A case control study conducted by Slavik et al. (2007) also compared the efficacy of Enoxaparin and Dalteparin. Individuals were studied within 72 hours post-SCI and received either 30 mg Enoxaparin twice daily or 5000 IU Dalteparin once daily. No significant difference regarding the incidence rate of DVT or PE was found between these groups, indicating equivalent prophylactic efficacy.

A case control study by Marciniak et al. (2012) compared the effect of Enoxaparin versus Tinzaparin on incidence of VTE events. All individuals were within 3 months of sustaining an SCI and were admitted to inpatient rehabilitation at a median of 15 days after injury. Individuals received either 5000 IU Enoxaparin, 4500 IU Tinzaparin (high-dose), or 3500 IU Tinzaparin (low-dose). The results revealed that individuals who received either Enoxaparin or the high dose of Tinzaparin had a significantly reduced risk of developing VTE complications compared with individuals receiving 3500 IU Tinzaparin. The authors indicated that uncontrolled factors may have affected this result, although these were not specified. The findings suggested an association between developing VTE and having had no prophylaxis prior to admission to inpatient rehabilitation, despite using prophylaxis after admission. Prophylaxis prior to admission may be protective of VTE, with no particular type of prophylaxis being significantly different in terms of protective efficacy.

A case control study by Hebbeler et al. (2004) compared two dosages of Enoxaparin. Individuals were within 2 months of sustaining SCI and received either 40 mg once daily or 30 mg twice daily of Enoxaparin. There were no significant differences found in DVT or PE incidence between groups and therefore the prophylactic efficacy of Enoxaparin was equivalent between the two dosages studied.

In a case series by Harris et al. (1996), individuals who were hospitalized for an average of 19 days following injury received 30 mg of Enoxaparin every 12 hours from admission. No individuals developed DVT in this study population. In a recent observational study, DiGiorgi et al. (2017) found that just 6.1% of their sample experienced a DVT and 4.1% a PE after 40 mg daily enoxaparin administration.

One systematic review evaluated the ideal time for initiating DVT treatment with LMWH. Christie et al. (2011) concluded that LMWH prophylaxis for DVT should be administered within 72 hours post-SCI. However, this conclusion should be interpreted with caution, as it was based on a single, small (N=5) systematic review.

Conclusion

There is level 1b evidence (from one RCT and one case control: Chiou-Tan et al. 2003; Slavik et al. 2007) that 30 mg twice daily Enoxaparin and 5000 IU daily Dalteparin are equally effective as prophylaxis for venous thromboembolism in acute SCI individuals.

There is level 4 evidence (from one case control: Hebbeler et al. 2004) that twice daily 30 mg Enoxaparin is equally as effective as 40 mg daily Enoxaparin as prophylaxis for venous thromboembolism in acute SCI individuals.

There is level 4 evidence (from two observational studies: DiGiorgio et al. 2017; Harris et al. 1996) that 40 mg daily enoxaparin is effective in reducing risk of thromboembolism.

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