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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

MethodsOutcomes
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:

1.     Incidence of DVT was 21.6% in group I and 5.4% in group II; this difference was significant (p=0.041).

2.     6/8 individuals in group I had asymptomatic DVT, whereas no asymptomatic DVT events occurred in group II.

3.     No PE events occurred overall.

4.     Pharmacological prophylaxis decreases the incidence of DVT in acute SCI individuals.

Spinal Cord Injury Thromboprophylaxis Investigators (2003a)

USA

RCT

PEDro=9

NInitial=476; NFinal=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:

1.     Incidence of DVT was 44.9% for UFH-IPC group versus 60.3% for Enoxaparin group; non-significant difference (p=0.11).

2.     Incidence of PE was 18.4% for UFH-IPC group, significantly higher than 5.2% of individuals in the Enoxaparin group (p=0.03).

3.     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

NInitial=172; NFinal=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.

1.     New DVT was demonstrated in 13/60 LDUH versus 5/59 enoxaparin individuals (p=0.052).
Green et al., (1982)

USA

RCT

PEDro=7

NInitial=28; NFinal=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.

1.     Thrombi developed in 6/15 individuals treated solely with EPCC, and in 3/12 receiving EPCC+ASA/Dip (p<.100).

2.     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:

1.     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:

1.     The cumulative incidence of DVT was 45.3%.

2.     71.4% of DVTs were localized below the knee.

3.     84.5% of distal vein thromboses were in the Vena tibialis.

4.     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:

1.     The incidence of DVT and PE in individuals using compression alone was 7.1% and 2.4%, respectively.

2.     The incidence of DVT and PE in individuals using compression and LDUH was 11.1% and 2.8%, respectively.

3.     The incidence of DVT and PE in individuals using compression and LMWH was 6.9% and 0%, respectively.

4.     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:

1.     DVT incidence was 2% for EAP.

2.     DVT incidence was 26% for LAP.

3.     65% of detected DVTs had no clinical signs evident.

4.     Individuals with ASIA A SCIs were more likely to develop DVTs (36%).

5.     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:

1.     6 (2.2%) individuals developed DVT, 2 (0.7%) individuals developed DVT while still receiving Enoxaparin.

2.     2 (0.7%) of individuals developed PE (1 individual developed PE while still receiving Enoxaparin).

Merli et al., (1992)

USA

Case Control

NInitial=38; NFinal=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:

1.     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.

2.     6 individuals (35%) in the control group had positive fibrinogen scans for DVT, all of which were confirmed by venography.

3.     The incidence of thrombosis was significantly lower in the treatment group compared to the control group (p=0.04).

4.     A significant difference favouring the treatment group was found in terms of the extent of the clot (p=0.02).

Discussion

Various combinations of physical and pharmacological treatments to prevent DVTs post SCI have been studied. Three studies examined LDUH paired with mechanical methods. Merli et al. (1992) studied 36 SCI patients who received either prophylaxis (LDUH 5000 IU) combined with external pneumatic compression and gradient elastic stockings or no treatment for two weeks. The incidence of thrombosis was significantly lower in the treated group (p=0.04). Spinal Cord Injury Thromboprophylaxis Investigators conducted an RCT (2003a) and follow-up prospective controlled trial (2003b) both of which examined the effect of 5000 IU LDUH plus intermittent pneumatic compression versus enoxaparin alone. In the first study (2003a), the authors found no significant difference between the two groups in DVT incidence. However, in the second study the dosage of enoxaparin was increased and they found that high-dose enoxaparin resulted in fewer DVTs than the combined LDUH-IPC treatment (Spinal Cord Injury Thromboprophylaxis Investigators 2003b).

Three types of LMWH (enoxaparin, dalteparin, and Nadroparine) combined with physical methods have also been studied. In a prospective cohort study, Giorgi et al. (2013) found that among 94 individuals receiving either dalteparin or enoxaparin in combination with physical methods, a high rate of DVTs (22%) still occurred. However, the rate of DVTs declined significantly after three months post rehabilitation stay. Aito et al. (2000) studied 275 SCI patients, 99 of who were treated within 72 hours of injury while 176 were treated 8-28 days post SCI. The treatment involved permanently dressed gradient elastic stockings, subcutaneous LMWH (Nadroparine), and external sequential pneumatic compression (ESPC) of the lower limbs. There was early mobilization of the lower limbs. The complete prophylactic treatment lasted at least 30 days post SCI; LMWH and ESPC were continued for two more months depending on the patient’s progress. A 2% DVT incidence in the early treatment group compared to a 26% incidence in the later treatment group demonstrated that early treatment was clearly important. In a retrospective study by Deep et al. (2001), the authors reported that just 2.9% of patients developed a DVT/PE between admission and discharge from rehabilitation after being treated with anti-thromboembolic stockings and 40 mg of enoxaparin.

Finally, Green et al. (1982) randomized 27 SCI patients to either external pneumatic calf compression alone, or in combination with 300 mg acetylsalicylic acid twice daily plus 75 mg dipyridamole twice daily. Thrombi developed in 6/15 patients treated solely with external calf compression (EPCC) and in 3/12 receiving ASA/Dipyridamole as well as EPCC (p<0.100).

Early application of pharmacological agents, along with mechanical treatments, has been shown to reduce the risk of DVT complications. Maxwell et al. (2002) demonstrated that in comparison to individuals receiving only sequential compression devices, those using compression combined with LMWH developed fewer DVTs and PEs. Given the results by the Spinal Cord Injury Thromboprophylaxis Investigators (2003b) showing better outcomes with high-dose Enoxaparin (alone), future studies comparing LMWH to LMWH plus mechanical methods are warranted. In a recent RCT, Halim et al. (2014) compared individuals using only compression stockings to another group receiving prophylactic LMWH with the physical compression. Patients were screened at a two week intervals for DVT using Doppler ultrasound. The incidence of DVT was significantly lower in the group receiving both prophylactic LMWH and physical compression compared to the compression-only group.

Conclusions

There is level 3 evidence (from one case control study and one case series study; Merli et al. 1992; Maxwell et al. 2002) that a comprehensive prophylactic treatment of external pneumatic compression, gradient pressure stockings and low dose unfractionated heparin reduces venous thrombosis post SCI.

There is level 4 evidence (from one pre-post study; Aito et al. 2000) that a comprehensive prophylactic regimen of pharmacological and physical measures is more effective in preventing venous thrombosis post SCI when instituted earlier rather than later.

There is level 1b evidence (from one RCT; Halim et al. 2014) that a comprehensive prophylactic treatment of gradient pressure stockings and low molecular weight heparin is more effective than pressure stockings alone in reducing venous thrombosis post SCI.

A combined regiment of pneumatic compression, pressure stockings and low-dose heparin or low molecular weight heparin given prophylactically may reduce the incidence of venous thrombosis and this effect is better in early post SCI.