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Pharmacological Modalities

Pharmacological methods are the most widely used form of thromboprophylaxis (Chen & Wang, 2013). The aim of this method of prophylaxis is to inhibit the formation of the clot itself, or to prevent the progress of the coagulation cascade which ultimately leads to venous thrombi (Tai et al. 2013). Antithrombotic prophylaxis is given to individuals with acute SCI in an effort to lower the coagulability of the blood by maintaining the concentration of factor Xa, a key factor in the coagulation cascade, below the critical level. High levels of factor Xa result in thrombus formation, leading to thromboembolic complications (Kulkarni et al. 1992).

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).

Evaluation of Low-Dose Unfractionated Heparin as Thromboprophylaxis in Acute SCI

Discussion

Four studies have examined the independent prophylactic effectiveness of LDUH 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). 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.

Finally, 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.

Conclusion

There is level 2 evidence (from one RCT; Agarwal and 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).

  • 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.

Evaluation of Low-Molecular-Weight Heparin as Thromboprophylaxis in Acute SCI

 

Discussion

Five studies have examined the independent thromboprophylactic effectiveness of LMWH on the incidence of DVT and PE in acute SCI individuals. 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 a 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 a 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.

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. 

  • Enoxaparin and Dalteparin are equally effective in reducing the risk of venous thromboembolism during the acute phase post SCI..

Evaluation of Low-Molecular-Weight Heparin compared to Low-Dose Unfractionated Heparin as Thromboprophylaxis in Acute SCI

 

Discussion

There have been seven studies to examine the thromboprophylactic effectiveness of LMWH compared to that of LDUH on the incidence of DVT and PE in acute SCI individuals. The forms of LMWH investigated include Logiparin, Enoxaparin and Dalteparin. 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 (Green et al. 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.

Four 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 a 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 a 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).

Conclusion

There is level 1b evidence (from one RCT; Green et al. 1990) that Logiparin 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 is more effective than low-dose unfractionated heparin as prophylaxis for pulmonary emboli in acute SCI individuals, but equally as effective for deep venous thrombosis in acute SCI individuals; However, there is level 2 evidence (from one prospective controlled trial and two case controls; Spinal Cord Injury Thromboprophylaxis Investigators 2003b; Arnold et al. 2010; Thumbikat et al. 2002) that Enoxaparin is equally as effective as low-dose unfractionated heparin as prophylaxis for venous thromboembolism in acute SCI individuals. 

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

  • Logiparin may be more effective than low-dose unfractionated heparin as venous thromboembolism prophylaxis during the acute phase post SCI.

  • There is conflicting evidence regarding the effectiveness of Enoxaparin compared to low-dose unfractionated heparin at reducing the risk of venous thromboembolism during the acute phase post SCI.

  • Dalteparin seems equally as effective as low-dose unfractionated heparin as venous thromboembolism prophylaxis during the acute phase post SCI.