Combined Physical and Pharmacological Methods

The combination of mechanical methods and pharmacological agents has been studied for their effect on DVT prophylaxis post SCI.

Table 11. Combined Pharmacological and Physical Measures for the Prophylaxis of Venous Thromboembolism Post SCI

Author Year; Country Research Design PEDro Score Sample Size	Methods	Outcome
Halim et al. 2014; India RCT PEDro = 7 N = 74	Population: Mean age: not specified; Gender: males=35, females=2 (group I), males=25, females=12 (group II); Level of injury: not specified; Severity of injury: American Spinal Injury Association Impairment Scale (AIS) A-D. paraplegia=32, tetraplegia=42. Chronicity: Only individuals with acute SCI (≤ 5 days) were studied for a 2-week duration following injury. Chronicity: <7 days post SCI. Intervention: Individuals were randomly allocated to receive only physical measures “like compression stockings” (group I), or low molecular unfractionated heparin (LMWH) (Enoxaparin) 40 mg subcutaneously once daily starting from the day of admission along with physical measures as in group I (group II). Outcome Measures: Incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE). Method of Diagnosis: Clinical examination and color Doppler venous ultrasonography.	Timing of DVT onset: Screening for DVT was done in all subjects at the end of 2 weeks +/-2 days following injury (earlier or later if symptoms arose). Incidence of DVT: Incidence of DVT was 21.6% in group I and 5.4% in group II; this difference was significant (p=0.041). 6/8 individuals in group I had asymptomatic DVT, whereas no asymptomatic DVT events occurred in group II. No PE events occurred overall. Pharmacological prophylaxis decreases the incidence of DVT in acute SCI individuals.
Spinal Cord Injury Thromboprophylaxis Investigators (2003a); USA RCT PEDro = 9 N_Initial= 476; N_Final= 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: American Spinal Injury Association Impairment Scale (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 22h/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: Incidence of DVT was 44.9% for UFH-IPC group versus 60.3% for Enoxaparin group; non-significant difference (p=0.11). Incidence of PE was 18.4% for UFH-IPC group, significantly higher than 5.2% of individuals in the Enoxaparin group (p=0.03). 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).
Spinal Cord Injury Thromboprophylaxis Investigators (2003b); USA Prospective Controlled Trial N_Initial= 172; N_Final= 119	Population: LDUH (n=60): Mean age=34 yr; Gender: males=47, females=13; Level of injury: paraplegic=18, tetraplegic=32; Enoxaparin (n=59): Mean age=30.5 yr; Gender: males=53, females=634; Level of injury: paraplegic=15, tetraplegic=34. Chronicity: 2 weeks post SCI. Intervention: Continuation of study 2003a above. Individuals previously receiving low dose unfractionated heparin (LDUH) continued on this regimen. Those previously on the enoxaparin had an increase in dosage to 40mg. Outcome Measures: Deep venous thrombosis (DVT), pulmonary embolism (PE), major bleeding.	New DVT was demonstrated in 13/60 LDUH versus 5/59 enoxaparin individuals (p=0.052).
Green et al. 1982; USA RCT PEDro = 7 N_Initial= 28; N_Final= 27	Population: Gender: males=24, females=4; Severity of injury: complete=28. Chronicity:<1 mo post SCI. Intervention: Subjects were randomized to one of two regimens: external pneumatic calf compression (EPCC) alone (n=15), or EPCC combined with aspirin (ASA) 300 mg bid and dipyridamole (Dip) 75mg bid (n=13). Outcome Measures: Incidence of deep venous thrombosis (DVT); Factor VIII coagulant activity.	Thrombi developed in 6/15 individuals treated solely with EPCC, and in 3/12 receiving EPCC+ASA/Dip (p<.100). Factor VIII levels of individuals treated with EPCC alone as compared to EPCC+ASA/Dip were higher.
Giorgi Pierfranceschi et al. 2013; Italy Cohort N = 94	Population: Mean age=40.3 yr; Gender: males=80, females=14; Level of injury: not specified; Severity of injury: paraplegia=52, tetraplegia=42. Chronicity: Individuals were monitored during their stay in the neurosurgery unit (NSU, median=20 days after injury) and rehabilitation unit (RU, median=6 mo, admitted after NSU discharge). Intervention: Individuals received prophylactic thigh-length graduate compressive stockings plus low molecular unfractionated heparin (LMWH) (Enoxaparin 4000 U daily or Dalteparin 5000 U daily) within 72 hr upon admission to the RU after neurosurgery (which occurred 48-72 hr after trauma). Outcome Measures: Incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE). Method of Diagnosis: Compression ultrasonography, color Doppler ultrasonography, perfusion lung scintigraphy, and computed tomography pulmonary angiography.	Timing of DVT onset: All VTE events occurred after a median of 15 days from SCI; 90.9% of VTE events occurred during the first 3 mo after SCI. Of 22 VTE events, 59.1% were diagnosed during NSU stay, 27.3% were diagnosed within one week of RU admission, 9% were diagnosed during RU stay, and 5% were detected during follow-up after rehabilitation discharge (>6mo). Incidence of DVT: 23.4% of individuals had VTE events (22 individuals; 19 DVT, 2 PE, 1 DVT/PE).
Germing et al. 2010; Germany Pre-Post N=139	Population: Age range=19-90 yr; Gender: Males=63.5%; Level of injury: not specified; Severity of injury: tetraplegia=68, paraplegia=71. Chronicity: All individuals were studied beginning within the first 36 hr of admission and monitored for 21 days. Intervention: All individuals received low molecular unfractionated heparin (LMWH) (Enoxaparin) 40 mg subcutaneously and compression stockings. Outcome Measures: Incidence of and localization of deep vein thrombosis (DVT). Method of Diagnosis: Color duplex ultrasonography.	Timing of DVT onset: DVT screening was performed within the first 36 hr after admission, and after 7 and 21 days. DVT occurred in 38.1% of individuals within the first 36 hr, in 5% of individuals after 7 days, and in 2% of individuals after 21 days. Incidence of DVT: The cumulative incidence of DVT was 45.3%. 71.4% of DVTs were localized below the knee. 84.5% of distal vein thromboses were in the Vena tibialis. Recanalization occurred in 33.3% of individuals after 3 weeks of prophylaxis, no change in 30.2%, and residual thrombi in 36.5%.
Maxwell et al. 2002; USA Case Series N = 111	Population: Mean age=37.5 yr; Gender: males=81%, females=19%; Level of injury: not specified; Severity of injury: paraplegia=41.4%, tetraplegia=58.6%. Chronicity: Individuals were hospitalized and monitored for an average of 23 days following injury. Intervention: Retrospective review of individuals using sequential compression devices alone or in combination with 5000 IU low dose unfractionated heparin (LDUH) subcutaneously every 12 hr or low molecular unfractionated heparin (LMWH) (Enoxaparin) 30 mg subcutaneously every 12 hr. Outcome Measures: Incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE). Method of Diagnosis: Venous duplex ultrasonography.	Timing of DVT onset: Screening for DVT was performed on average 2.3 times during each admission. No other information was provided. Incidence of DVT: The incidence of DVT and PE in individuals using compression alone was 7.1% and 2.4%, respectively. The incidence of DVT and PE in individuals using compression and LDUH was 11.1% and 2.8%, respectively. The incidence of DVT and PE in individuals using compression and LMWH was 6.9% and 0%, respectively. No significant difference was found among these groups (p>0.05).
Aito et al. 2002; Italy Pre-Post N = 275	Population: Mean age=41.3 yr (early admitted individuals (EAP)), mean age=42.3 yr (late admitted individuals (LAP)); Gender: males=81, females=20 (EAP), males=185, females=37 (LAP); Level of injury: not specified; Severity of injury: AIS A-D. Chronicity: Individuals were either EAP (within 72 hr from injury) or LAP (on average 12 days after injury, range=8-28 days). Intervention: All individuals received permanently dressed gradient elastic stockings (GES), external sequential pneumatic compression and low molecular unfractionated heparin (LMWH) (Nadroparine) beginning within 72 hr post injury for EAP and upon admission for LAP, lasting for at least 30 days from injury. Outcome Measures: Incidence of deep vein thrombosis (DVT). Method of Diagnosis: Color Doppler ultrasonography.	Timing of DVT onset: Examinations to detect the presence of DVT were performed immediately on admission, after 45-60 days and when requested. DVT was detected 25 and 29 days after injury in EAP; 60% of LAP had DVT detected on admission, 40% developed DVT within 6 weeks. Incidence of DVT: DVT incidence was 2% for EAP. DVT incidence was 26% for LAP. 65% of detected DVTs had no clinical signs evident. Individuals with ASIA A SCIs were more likely to develop DVTs (36%). No comparisons between the two groups were done due to lack of homogeneity of treatment, however a dramatic reduction in thromboembolic events was observed in the EAP group, supporting the use of pharmacological and mechanical treatment early after injury.
Deep et al. 2001; UK Case Series N = 276	Population: Mean age=39.8 yr; Gender: not specified; Level of injury: cervical=150, thoracic and lumbar=126; Severity of injury: not specified. Chronicity: All individuals were studied beginning upon admission to the spinal injuries unit. Intervention: A retrospective review of SCI individuals receiving full length anti-thromboembolic stockings (up to mid-thigh) from admission to discharge and 40mg of Enoxaparin once daily beginning the day of injury or admission. Outcome Measures: Incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE). Method of Diagnosis: Venous ultrasonography, venography, ventilation-perfusion scanning, and computed tomography angiography.	Timing of DVT onset: DVT developed 8-30 days after discontinuing Enoxaparin in 6 individuals (which was stopped after 26-46 days); 1 episode of PE developed 33 days after discontinuing Enoxaparin (which was stopped after 56 days). Incidence of DVT: 6 (2.2%) individuals developed DVT, 2 (0.7%) individuals developed DVT while still receiving Enoxaparin. 2 (0.7%) of individuals developed PE (1 individual developed PE while still receiving Enoxaparin).
Merli et al. 1992; USA Case Control N_Initial= 38; N_Final= 36	Population: Age range=15-69 yr (control), age range=18-70 yr (treatment); Gender: males=11, females=6 (control), males=14, females=5 (treatment); Level of injury: not specified; Severity of injury: Frankel A-B. Chronicity: Individuals were studied beginning within 48 hr of acute SCI for the duration of the first 2 weeks following injury. Intervention: Individuals received external pneumatic compression with gradient elastic stockings (GES) and low dose unfractionated heparin (LDUH) 5000 U subcutaneously every 12 hr (treatment group, n=19), and were compared to a group of individuals from a previous study receiving no treatment (control group, n=17). Outcome Measures: Incidence of deep vein thrombosis (DVT). Method of Diagnosis: 125 I fibrinogen scanning and venography.	Timing of DVT onset: Screening was performed beginning within 18 hr of admission and daily thereafter for 2 weeks. Incidence of DVT: 2 individuals (11%) in the treatment group developed a positive fibrinogen scan on days 6 and 8 of the study, only 1 individual (5.2%) was confirmed to have DVT by venography. 6 individuals (35%) in the control group had positive fibrinogen scans for DVT, all of which were confirmed by venography. The incidence of thrombosis was significantly lower in the treatment group compared to the control group (p=0.04). A significant difference favouring the treatment group was found in terms of the extent of the clot (p=0.02).

Discussion

Several studies have examined the prophylactic effectiveness of various combinations of mechanical and pharmacological methods on the incidence of DVT and PE in acute SCI. Two studies investigated the combined effect of LDUH with mechanical methods for VTE prophylaxis. In an RCT by the Spinal Cord Injury Thromboprophylaxis Investigators (2003a), individuals were randomly assigned to either receive 5000 IU LDUH every 8 hours along with IPC, or 40 mg of Enoxaparin every 12 hours. All individuals studied had sustained SCI within 72 hours and were monitored for a duration of approximately 2 weeks of acute treatment, at the end of which screening for DVT and PE was performed. 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). Merli et al. (1992) conducted a case control study in which individuals received external pneumatic compression with gradient elastic stockings and 5000 U LDUH every 12 hours and were compared to a control group of individuals receiving no intervention. All individuals were studied beginning within 48 hours of injury for the initial 2-week duration following injury. The incidence of DVT was found to be significantly lower in individuals receiving mechanical and pharmacological prophylaxis as compared to the group of control individuals (p=0.04). However, in the second study by The Spinal Cord Injury Thromboprophylaxis Investigators (2003b) dosage of enoxaparin was increased, and they found that high-dose enoxaparin resulted in fewer DVTs than the combined LDUH-IPC treatment.

One study by Maxwell et al. (2002) compared LDUH and LMWH, each in combination with mechanical methods of prophylaxis. Individuals hospitalized for an average of 23 days after injury were retrospectively reviewed in terms of their use of SCD in combination with either 5000 IU LDUH every 12 hours or 30 mg Enoxaparin every 12 hours. The incidence of DVT and PE in individuals using SCD and LDUH was 11.1% and 2.8%, respectively. The incidence of DVT in individuals using SCD and Enoxaparin was 6.9%; no PE was observed in this group of individuals. There were no significant differences in incidence rates for DVT or PE between groups.

Five studies investigated LMWH in combination with mechanical methods of prophylaxis. Giorgi Pierfranceschi et al. (2013) studied individuals who had received graduate compressive stockings in combination with either 4000 U Enoxaparin daily or 5000 U Dalteparin daily. Treatment was administered within 72 hours of admission after surgery, which occurred 48-72 hours after injury. The authors found that 23.4% of individuals developed VTE events, 90.9% of which occurred within the first 3 months after SCI. Halim et al. (2014) conducted an RCT in which individuals were randomly assigned to receive either only physical modalities of prophylaxis (not specified further) or 40 mg Enoxaparin once daily along with the same form of physical prophylaxis. Individuals enrolled in this study had sustained an SCI no more than 5 days prior to entering the study and were monitored for the initial 2-week duration following injury. The incidence of DVT was significantly higher in individuals receiving only mechanical prophylaxis (21.6%) compared to individuals receiving a combination of mechanical and pharmacological prophylaxis (5.4%, p=0.041). PE occurrences were nonexistent. Germing et al. (2010) enrolled individuals within the first 36 hours of admission in a pre-post study; all individuals received 40 mg Enoxaparin together with compression stockings. The cumulative incidence of DVT was reported to be 45.3%, with 38% of DVT events occurring within the first 36 hours of admission; no statistical analysis was reported. A case series by Deep et al. (2001) retrospectively investigated individuals on admission to a spinal injury unit. On admission or at the time of injury, individuals received anti-thromboembolic stockings and 40 mg Enoxaparin once daily. Of this study population, 2.2% and 0.7% of individuals developed DVT and PE, respectively. Finally, in a pre-post study by Aito et al. (2002), individuals, who were classified as either early admitted (i.e., 72 hours post-injury) or late admitted (mean=12 days post-injury), received a combination of permanently dressed gradient elastic stockings, external sequential pneumatic compression, as well as Nadroparine. The incidence of DVT was 2% and 26% for early admitted and late admitted individuals, respectively; no statistical analysis was reported.

Conclusion

There is level 1b evidence (from one RCT: Spinal Cord Injury Thromboprophylaxis Investigators 2003a) that low-dose unfractionated heparin in combination with intermittent pneumatic compression is as effective as Enoxaparin as prophylaxis for deep vein thrombosis in acute SCI individuals.

There is level 3 evidence (from one case control: G. J. Merli et al. 1992) that pneumatic compression in combination with gradient elastic stockings and low-dose unfractionated heparin is effective in reducing the incidence of deep vein thrombosis in acute SCI individuals.

There is level 1b evidence (from one RCT: Halim et al. 2014) that Enoxaparin in combination with physical measures is more effective than physical measures alone as prophylaxis for deep venous thrombosis in acute SCI individuals. However, there is level 4 evidence (from one case series: Maxwell et al. 2002) that Enoxaparin plus sequential compression devices, low-dose unfractionated heparin plus sequential compression devices, and sequential compression devices alone are similarly effective as venous thromboembolism prophylaxis in acute SCI individuals.

A combination of low-dose unfractionated heparin with intermittent pneumatic compression seems equally as effective as low-molecular-weight heparin alone at reducing this risk.

There is conflicting evidence regarding the effectiveness of the combination of low- molecular-weight heparin with physical measures at reducing the risk of venous thromboembolism compared to physical measures alone during the acute phase post SCI.