The Role of the Treatment of Established DVT/PE with Anticoagulation in the Trauma Patient

I.   Statement of the Problem

In a patient with a diagnosed DVT, the goals of therapy are to prevent progression of the thrombosis and subsequent PE. Objective evidence to support the treatment of DVT with intravenous heparin comes from a prospective randomized trial by Hull and coworkers¹ in which the efficacy of intravenous heparin was compared to subcutaneous heparin in the initial treatment of established DVT. Recurrent VTE occurred in 19.3% of those treated with subcutaneous heparin and in 5.2% of those treated with intravenous heparin (p<0.024). In another prospective controlled trial of anticoagulant therapy for PE,² there were no deaths due to PE in the group receiving heparin anticoagulation compared to a mortality rate of 26% in those who did not receive heparin. This landmark study could never be repeated today for ethical reasons.

The data supporting anticoagulation for established VTE is incontrovertible. The dosage, timing, duration and route of anticoagulant therapy may be subject to some circumspection.

II.   Process

A Medline search from 1966 to present revealed several thousand articles related to anticoagulant treatment for DVT/PE. Ten of these were felt to be of significant quality on which to base the following recommendations.

III.   Recommendations

A.   Level I

For a documented DVT or PE in a patient with a contraindication to and/or complication of anticoagulation, vena caval interruption with a mechanical device is warranted.

B.   Level II

1. For a documented first episode of DVT/PE and no contraindication to receiving anticoagulation, at least six months duration of anticoagulation therapy is warranted.
2. Patients with congenital deficiency of antithrombin III, protein C or protein S, or who, due to the nature of their injuries (such as those with spinal cord injury and permanent neurologic deficit), are at permanent high risk for DVT/PE or recurrent VTE, should receive anticoagulant therapy indefinitely. An alternative to anticoagulant therapy in these patients is vena caval interruption with a mechanical device.

C.   Level III

Low molecular weight heparin administered subcutaneously at home may be substituted for unfractionated intravenous heparin in the hospital as the initial anticoagulant treatment for established DVT.

IV.   Scientific Foundation

Heparin acts by enhancing antithrombin III, so that the inhibitor more efficiently combines with and inactivates thrombin (IIa), factor IXa and X.⁴ The goal of treatment with heparin is to keep the APTT more than 2.0 times the control value. Failure to reach therapeutic levels of anticoagulation within 24 hours increases the risk of recurrent venous thromboembolism by up to 15 times.¹ In Hullís study¹, failure to achieve an adequate anticoagulant response (APTT >1.5 times control) was associated with a high risk (25%) of recurrent venous thromboembolism. Five days of heparin therapy is followed by an oral vitamin K antagonist (e.g. warfarin). Warfarin acts by inhibiting the synthesis of the vitamin K-dependent coagulant proteins (II, VII, IX, X) and 2 vitamin K dependent anticoagulant factors , protein C and S. Patients may actually become more thrombogenic in the first 24-48 hours of anticoagulation with warfarin because of the early initial depletion of protein C.⁵ Therefore, after starting warfarin, there is need for a continuation of heparin therapy until the third or fourth day of warfarin treatment. In the past, the suggested therapeutic range for warfarin anticoagulation was a prolongation of the prothrombin time of between 1.5-2.5 times the base line value (INR of 3-7). ⁶ Newer studies suggest that a prothrombin time prolongation of 1.3-1.5 times baseline (INR of 2.0-3.0)⁷ is effective. Recent literature supports continuation of oral anticoagulant treatment for 6 months after a first episode of venous thromboembolism. Schulman et al⁸, compared six weeks of anticoagulation to six months in a randomized prospective study in 898 patients who experienced a first episode of venous thromboembolism. All patients with congenital clotting abnormalities were excluded. After two years of follow-up there were 80 recurrent episodes of venous thromboembolism in the six week group (18%; 95% CI, 14.5-21.6%) and 43 in the six month group (9.5%; 95% CI, 6.8-12.2). This represented a significant reduction in thromboembolism when the duration of anticoagulation was extended from 6 weeks to 6 months for a first episode of venous thromboembolism.

It should be noted that two recent studies^9,10 support the use of low molecular weight heparin, administered primarily at home, in the initial anticoagulant treatment in patients with DVT. In a randomized prospective study by Levine et al.⁹ 253 patients were assigned to receive intravenous heparin in-hospital and 247 patients received low molecular weight heparin primarily at home for the initial treatment of a proximal DVT. All patients were begun on warfarin on the second day. Recurrent thromboembolism was 5.3% in the low molecular weight heparin group vs. 6.7% (95% CI; for the absolute difference - 3.0% to 5.7%) rate in the intravenous heparin group. The number of patients with bleeding complications were not significantly different between groups. In a similar randomized prospective study by Koopman et al.,¹⁰ in 400 patients, there was an 8.6% recurrent thromboembolism rate in those who received intravenous heparin compared to a 6.9% rate in the low-molecular weight heparin group (95% CI; 3.6% to 6.9%). Bleeding complications were not significantly different between groups. Overall there was a mean reduction in total hospital stay for the treatment of DVT of 67% in the group treated with low- molecular weight heparin at home. The implication of these two studies are enormous on how DVT is to be treated. Whereas previously patients with DVT were admitted for a 5-10 day course of intravenous heparin, they can now be treated as out-patients, safely resulting in decreased hospital stay, decreased costs and improved quality of life.

The major risk of anticoagulation treatment for venous thromboembolism is hemorrhage. The risk of bleeding on oral anticoagulants is directly related to the intensity of the anticoagulant therapy. In a randomized trial⁷ patients receiving a lower dose of warfarin (target INR, 2.0-2.5) had a 4% incidence of bleeding, as compared with those treated with a higher dose (INR, 2.5-4.5) who had a bleeding complication rate of 22%. Certainly this risk of bleeding is no more manifest than in the trauma patient. Any patient who has an injury in which a bleeding diathesis could exacerbate or extend that injury (e.g. incomplete spinal cord injuries, head injuries, ocular trauma, non-operatively managed solid organ injuries) has a contraindication to anticoagulation for the treatment of venous thromboembolism. These patients should be considered for alternative mechanical interruption of the vena cava. Brathwaite et al.³ looked at a group of low-risk trauma patients who were treated for PE with anticoagulation. There was 36% bleeding complication rate in this group of patients many of which were life-threatening including : 3 subdural hematomas, 2 hemothoraces, 1 hemorrhagic pericardial effusion, 1 retroperitoneal hematoma, and 1 patient who lapsed into shock. Of note, those at particular risk were those elderly trauma patients who received anticoagulation. In this study the authors also note there were 34 other patients who received inferior vena cava filters with no related complications or deaths. These authors concluded that anticoagulation for DVT/PE should be used selectively in trauma patients and avoided in elderly patients, who should undergo early vena cava filter placement instead.

V.   Summary

Anticoagulation is a well-established treatment for DVT/PE. Current evidence suggests that a three to six-month period provides adequate treatment for a first time DVT/PE in a patient without clotting abnormality. Those in whom the risk of recurrent VTE extends beyond six months may have anticoagulation extended indefinitely. In addition, those patients whose injuries preclude the use of anticoagulants because bleeding would exacerbate their injuries, should have consideration given to placement of a vena cava filter. Recent evidence also supports initial treatment of VTE with low molecular weight heparin as an outpatient.

VI.   Future Investigations

Future studies should target the timing and duration of intravenous and oral anticoagulant therapies. In addition, studies comparing initial therapy with intravenous heparin should be compared with subcutaneous heparin.

V.   References

Reference Conclusions