AA

Low-Molecular-Weight Heparin (LMWH) vs. LDUH 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.

Generic (Trade) Names of Low-Molecular-Weight Heparin
Dalteparin (Fragmin)
Danaparoid (Orgaran)
Enoxaparin (Lovenox)
Ardeparin (Normiflo)
Parnaparin, Reviparin (Clivarine)
Tinzaparin (Logiparin, Innohep)
Certoporain (Alphaparin, 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 6 LMWH vs. Unfractionated Heparin as Prophylaxis

Discussion

 

There have been seven trials that have compared LDUH and LMWH. The SCI Thromboprophylaxis Investigators (2003a) conducted a 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.

A 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, two studies (Arnold et al. 2010; Worley et al. 2008) reported no difference in the incidence of DVT or bleeding complications among individuals with SCIs receiving LDUH or LMWH (enoxaparin and dalteparin, respectively). Despite the conflicting results presented by Thumbikat et al. (2002), there is still strong evidence basedon five studies that LMWH is more effective than LDUH.

Table 7 Studies Evaluating Low Molecular Weight Heparin vs. Unfractionated Heparin

Conclusions

There is level 1a evidence (from 2 RCTs, 1 prospective controlled trial, 1 pre-post, and 1 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.