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Low-Dose Unfractionated Heparin

Heparin is a naturally occurring anticoagulant that is produced by basophils and mast cells. Two types of heparins are commonly used as anticoagulants to prevent thrombosis: LDUH and LMWH. The mechanism of action of LDUH includes binding to antithrombin III, and together this heparin/antithrombin complex then binds to factor Xa, causing inactivation. LMWH is synthesized from unfractionated heparin (UFH) by depolymerization, and thus has a reduced size and molecular weight (3000-7000 daltons) in comparison to LDUH (3000-30000 daltons). LDUH also binds to and inactivates thrombin (factor II), although this process requires larger heparin molecules (at least 18 saccharide units in length). Therefore, LMWH has a reduced ability to inhibit thrombin due to the smaller molecular structure not being able to simultaneously bind antithrombin and thrombin. However, this reduced binding to plasma proteins contributes to a more predictable dose-dependent response for LMWH. Pharmacokinetically, LMWH has a higher and more efficient bioavailability compared to LDUH, although LMWHs are themselves a heterogeneous class of compounds that differ in weight, anticoagulant activity and pharmacokinetic properties. Various LMWHs exist including Enoxaparin, Dalteparin, Ardeparin, Nadroparin, Parnaparin, Reviparin, and Tinzaparin. A major complication associated with the use of heparin for thromboprophylaxis is the risk of hemorrhaging, although LMWH is associated with a lower incidence of hemorrhaging as a result of reduced binding to platelets and endothelium (Hirsh & Raschke 2004, Quader et al. 1998). Additionally, spinal epidural hematoma is a rare but devastating complication that has been reported to occur after spinal surgery; this may potentially be associated with pre-operative use of chemical thromboprophylaxis although evidence has shown this to be a rare occurrence. Nevertheless, the benefits of thromboprophylaxis must be weighed against the risk of potential hematoma formation (Al-Dujaili et al. 2012, Awad et al. 2005, Cunningham et al. 2011).

Table 2. Efficacy of Low-Dose Unfractionated Heparin as Prophylaxis

Author Year

Country

Score

Research Design

Total Sample Size

MethodsOutcomes
Agarwal & Mathur (2009)

India

RCT

PEDro=4

N=297

Population: Mean age=32 yr; Gender: males=87% (study group), males=74% (control group); Level of injury: not specified; Severity of injury: AIS A-E.

Chronicity: Individuals studied were within an average of 8 days (range: 3-40 days) after injury; 80% and 77% individuals in the study and control groups entered the study within 10 days after injury, respectively.

Intervention: Individuals were randomly allocated into the treatment group receiving 5000 IU low dose unfractionated heparin (LDUH) every 12 hr for 3 mo from time of admission, or the control group (no heparin). Physical therapy measures were advised for both groups.

Outcome Measures: Incidence of Deep Vein Thrombosis (DVT).

Method of Diagnosis: Color Doppler studies.

Timing of DVT onset: DVT was detected within 6-10 days after injury in the study group, and within 5-28 days after injury in the control group.

Incidence of DVT:

1.      1.8% of individuals in the treatment group and 3% of individuals in the control group developed DVT (>0.05).

2.      Heparin prophylaxis was found to have no significant correlation with DVT incidence (p<0.05).

 

Green et al., (1988)

USA

RCT

PEDro=7

NInitial=75; NFinal=58

Population: Age=3-81yr; Gender: males=63, females=12; Severity of injury: complete=75.

Chronicity: Unknown

Intervention: Individuals were randomized to one of two regimens of heparin treatment: fixed dose or adjusted dose heparin.

Outcome Measures: Incidence of Deep Venous Thrombosis (DVT) and bleeding.

1.     Individuals on the adjusted-dose regimen received a mean of 13200±2200 U of heparin per dose and had an activated partial thromboplastin time 1.5 times higher than those on a fixed-dose regimen.

2.     Thromboembolism was detected in 9/29 individuals randomized to the fixed-dose regimen and 2/29 on the adjusted-dose regimen.

3.     While no individual who received the adjusted-dose and whose activated partial thromboplastin time reached the target level had a thrombosis, bleeding occurred in 7 individuals; no individual on the fixed-dose regimen bled.

Merli et al., (1988)

USA

RCT

PEDro=4

NInitial=53; NFinal=48

Population: Not available.

Chronicity:<2 weeks post SCI

Intervention: Randomly assigned to one of three groups: 5000 IU low dose unfractionated heparin (LDUH) alone, 5000 IU LDUH combined with electrical stimulation, or no treatment.

Outcome Measures: Incidence of Deep Venous Thrombosis (DVT).

1.     Electric stimulation plus heparin significantly lowered (p<0.05) the incidence of DVT.

2.     No differences were noted between the heparin and placebo group.

Frisbie & Sasahara (1981)

USA

Prospective Controlled Trial

N=32

 

Population: Mean age=27yr (treatment), 28yr (control); Level of injury: cervical-lumbar; paraplegic=8, tetraplegic=24.

Chronicity:<1 week post SCI

Intervention: Individuals were assigned to receive 5000 IU low dose unfractionated heparin (LDUH) every 12hr until 60 days post SCI or no treatment.

Outcome Measures: Incidence of Deep Venous Thrombosis (DVT).

1.     DVT incidence was unexpectedly low in both the control (1/17) and treatment (1/15).
Winemiller et al., (1999)

USA

Case Series

N=285

 

Population: Mean age=26 yr (VTE), mean age=25 yr (no VTE); Gender: males=88% (VTE), males=72% (no VTE); Level of injury: cervical-lumbar; Severity of injury: Frankel scores A-B.

Chronicity: All individuals were studied for the initial 6 week duration following injury.

Intervention: Retrospective review of individuals who were administered antithrombotic prophylaxis (sequential compression devices (SCD)/gradient elastic stockings (GES)) or unfractionated heparin (UFH) for 42 days-6 weeks after injury.

Outcome Measures: Incidence of DVT/PE.

Method of Diagnosis: Fibrinogen scans, impedance plethysmography, Doppler studies, venography, and ventilation-perfusion scanning.

Timing of DVT onset: DVT/PE was first detected at a median of 14.5 days after injury; 63% of initial DVT/PE events occurred within the first 3 weeks.

Incidence of DVT:

1.     Overall incidence of DVT/PE was 84/428 (19.6%); 59 DVT and 25 PE.

2.     A multivariate analysis suggested a reduced risk of thromboembolism in individuals with SCI treated with heparin within the first 14 to 42 days after injury.

3.     The effect of heparin may be most effective within the first 14 days after injury.

Gunduz et al., (1993)

Turkey

Post-Test

N=31

Population: Mean age=27 yr; Gender: males=27, females=4; Level of injury: cervical-lumbar; Severity of injury: Frankel complete=24, Frankel partial=6.

Chronicity: Individuals were admitted within an average of 27 days post injury; 12 individuals were admitted within the first 2 weeks (mean=12.25 days ± 2.2 days), 18 individuals were admitted within the first 2 mo (mean=40.98 ± 3.75 days).

Intervention: All individuals received 5000 IU low dose unfractionated heparin (LDUH) every 12h for 12 weeks from time of admission.

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

Method of Diagnosis: Venography.

Timing of DVT onset: Not indicated.

Incidence of DVT:

1.     Incidence of DVT was 53.3%.

 

Kulkarni et al., (1992)

England

Case Series

N=97

 

Population: Mean age: not specified; Gender: males=80, females=20; Level of injury: cervical-lumbar; Severity of injury: not specified.

Chronicity: Most individuals studied were admitted<24 hr following injury; 33 individuals were admitted within 2-87 days following injury.

Intervention: All individuals received 5000 IU low dose unfractionated heparin (LDUH) every 8 hr from time of admission.

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

Method of Diagnosis: Clinical examination.

Timing of DVT onset: Not indicated.

Incidence of DVT:

1.     26 individuals developed thromboembolic complications (17 DVT, 7 PE, 2 DVT + PE).

2.     Delayed arrivals (>24 hr post SCI) were more at risk of developing thromboembolic complications.

Table 3. Systematic Reviews and Guidelines on 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?

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: …

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 dose unfractionated 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.

Discussion

Unfractionated heparin has been the standard treatment for VTE post SCI for years. Evidence for its effectiveness, however, is unclear. Using LDUH alone is not recommended as a prophylactic treatment (Dhall et al. 2013) and is associated with high rates of DVTs and PEs in individuals with acute SCI (Kulkarni et al. 1992). Seven studies examined the independent prophylactic effectiveness on the incidence of DVT and PE in acute SCI individuals.

Agarwal and Mathur (2009) conducted a randomized controlled trial (RCT) in which acute SCI individuals who had sustained injury within an average of 8 days were randomly allocated into either the experimental group receiving 5000 IU LDUH every 12 hours for 3 months, or the control group (receiving no intervention). The results showed that 1.8% of participants who received LDUH developed DVT (within 6-10 days after injury), while 3% of participants in the control group developed DVT (within 5-28 days after injury); the two groups were not significantly different in terms of DVT incidence (p>0.05). This low incidence rate in the control group can perhaps be attributed to the study being conducted within an Asian population, where it is believed that Eastern populations have lower incidence rates of DVT compared to Western populations (Rathore et al. 2008).

Green et al., (1988) studied 75 individuals with SCI who were randomized to receive either a fixed dose or an adjusted dose of unfractionated heparin. The fixed dose heparin was 5000 IU; the adjusted heparin group started off at 5000 IU and was adjusted according to (activated partial thromboplastin time to a maximum of 15000 IU (mean=13200 IU). Thromboembolism was detected in 9/29 on fixed-dose regimen with no bleeding complications while 2/29 on the adjusted-dose regimen developed thromboembolism and 7/29 had bleeding complications.

Typically, prophylactic treatment involves 5000 IU of heparin. Two RCTs and one controlled study examining the efficacy of this dose and a placebo found no difference in the incidence of venous thrombosis in both the treatment and the placebo groups. Interestingly, Merli et al., (1988) found that heparin plus electrical muscle stimulation significantly reduced the incidence of venous thrombosis when compared to heparin alone. Finally, one RCT (Green et al. 1988) has shown that while 5000 IU of heparin was not an effective dose in reducing the incidence of thromboembolism, higher doses were more effective but had a higher risk of bleeding complications. In a recent systematic review and meta-analysis, Chen and Wang (2013) conclude that among individuals with acute SCI, LDUH has no thromboprophylaxis effect compared with placebo or no treatment.

Merli et al., (1988) evaluated 53 individuals with acute SCI who were randomly assigned to one of three groups: placebo saline (n=17), 5000 IU LDUH (n=16), or 5000 IU LDUH plus electrical stimulation of the tibialis anterior and gastrocnemius muscles (n=15) over 28 days. There was no difference between the placebo saline and heparin groups in the incidence of DVT while there was a significant improvement in the heparin and electrical stimulation group. The study was prematurely discontinued because of the benefit of the heparin plus electrical stimulation group and lack of efficacy in the control group.

Frisbie and Sasahara (1981) conducted a non-randomized trial of 32 individuals with SCI receiving either no treatment or 5000 IU of LDUH until day 60 post SCI. Incidence of DVT was rare in both the control (1/17) and the LDUH group (1/15).

A case series by Winemiller et al., (1999) retrospectively reviewed individuals who were administered LDUH for the initial 42 days to 6 weeks after injury (dosage unspecified). VTE events were first detected at a median of 14.5 days after injury. A multivariate analysis suggested that these individuals had a reduced risk of thromboembolism when treated with LDUH within the first 14 to 42 days after injury, suggesting that LDUH may be most effective within the first 14 days after injury in preventing thromboembolic events.

In a post-test study conducted by Gunduz et al., (1993), all SCI individuals also received 5000 IU LDUH every 12 hours, administered for 12 weeks from the time of admission. All participants were admitted within an average of 27 days after injury. The incidence of DVT was 53.3% but the onset timing was not indicated.

In a case series study, Kulkarni et al., (1992) examined SCI individuals who were admitted<24 hours following injury. Participants received 5000 IU LDUH every 8 hours. The researchers noted that 27% of individuals still developed thromboembolic complications, including 17 DVT, 7 PE and 2 DVT + PE events.

According to the most recent clinical practice guidelines (Fehlings et al. 2017)213S, the following conclusions and recommendations have been made:

We suggest that anticoagulant thromboprophylaxis be offered routinely to reduce the risk of

thromboembolic events in the acute period after SCI.

Quality of Evidence: Low

Strength of Recommendation: Weak

 

We suggest that anticoagulant thromboprophylaxis, consisting of either subcutaneous low-

molecular-weight heparin or fixed, low-dose unfractionated heparin, be offered to reduce the

risk of thromboembolic events in the acute period after SCI. Given the potential

for increased bleeding events with the use of adjusted-dose unfractionated heparin, we

suggest against this treatment option.

Quality of Evidence: Low

Strength of Recommendation: Weak

 

We suggest commencing anticoagulant thromboprophylaxis within the first 72 hours after

injury, if possible, in order to minimize the risk of venous thromboembolic complications

during the period of acute hospitalization.

Quality of Evidence: Low

Strength of Recommendation: Weak

Conclusions

There is level 2 evidence (from one RCT; (Agarwal & Mathur 2009)) that low-dose unfractionated heparin is not effective as prophylaxis for venous thromboembolism in acute SCI individuals; However, there is level 4 evidence (from one case series; (Winemiller et al. 1999) that low-dose unfractionated heparin is effective as prophylaxis for venous thromboembolism if provided early (within 14 days after injury).

There is level 1b evidence (from one RCT; (Green et al. 1988) that adjusted (higher) dose unfractionated heparin is more effective in prophylaxis of venous thromboembolism than 5000 IU low-dose unfractionated heparin but has a higher incidence of bleeding complications.

There is level 2 evidence (from two RCTs and one prospective controlled trial; (Agarwal & Mathur 2009, Frisbie & Sasahara 1981, Merli et al. 1988) that 5000 IU of low-dose unfractionated heparin is no more effective than placebo in the prophylaxis of venous thrombosis post SCI.

  • Low-dose unfractionated heparin may effectively prevent the risk of developing venous thromboembolic events during the acute phase post SCI if provided early after injury.