TREATMENT OF DEEP VENOUS THROMBOSIS AND ECONOMIC ASPECTS
Authors: Hull Russell D , Raskob Gary E 
Published: August 2018

Initial therapy with intravenous heparin, followed by long-term anticoagulant therapy for three months or more, is the treatment of choice for most patients with acute venous thrombosis. Inferior vena caval interruption, using a transvenously inserted filter, is the management of choice for preventing pulmonary embolism in patients in whom anticoagulant therapy is contraindicated, and in the very rare patient in whom anticoagulant therapy is ineffective. The role of thrombolytic therapy has not been completely resolved. It was hoped that thrombolytic therapy would minimize or prevent the post-phlebitic syndrome; unfortunately, this may not be the case because the critical factor in the development of the post-phlebitic syndrome appears to be venous valve damage, which occurs early in the formation of venous thrombosis. Thrombolytic therapy should be considered in selected patients with acute massive venous thrombosis (eg. the patient with phlegmasia cerulea dolens).

Intravenous heparin administered in doses which prolong the activated partial thromboplastin time (APTT) to 1.5 to 2 times control is highly effective and is associated with a low frequency (2%) of recurrent venous thromboembolism. A recent randomized trial (1) in patients with proximal-vein thrombosis indicates that failure to achieve an adequate anticoagulant response (APTT > 1.5 times control) is associated with a high risk (20%) of recurrent venous thromboembolism. Therefore, sufficient heparin should be administered to maintain the APTT above 1.5 times the control value.

Intravenous heparin is continued for 7 to 10 days, overlapped with oral anticoagulant therapy for 4 to 5 days before heparin is stopped. Multiple randomized clinical trials in patients with proximal-vein thrombosis indicate that when heparin is administered for 7 to 10 days, followed by adequate long-term anticoagulant therapy, the frequency of recurrent venous thromboembolism is very low (2%). An alternative approach is to commence heparin and oral anticoagulants together at the time of diagnosis, and to discontinue heparin on the fourth or fifth day. If this latter approach is effective, it would avoid 4 to 5 days of unnecessary hospitalization in many patients, and would markedly reduce the cost of initial heparin therapy. A recent randomized trial (2) in patients with submassive venous thromboembolism suggests that 4 to 5 days of initial heparin therapy is effective and safe, but this approach must be evaluated by further randomized clinical trials before it is routinely recommended.

Recent clinical trials indicate that inadequate long-term therapy in patients with proximal-vein thrombosis results in a high frequency (40-50%) of recurrent venous thromboembolism and is cost-ineffective because of the diagnostic and treatment costs of recurrent venous thromboembolism (3). The risk of recurrence is markedly reduced to 2% by adequate long-term anticoagulant therapy with warfarin sodium or adjusted subcutaneous heparin; both of these approaches are markedly more cost-effective than inadequate long-term therapy (3). Oral anticoagulant therapy with warfarin sodium for three months (or longer in selected patients), is less expensive than adjusted subcutaneous heparin and is preferred in most patients with acute proximal-vein thrombosis. The risk of bleeding associated with oral anticoagulant therapy can be reduced to less than 5%, without loss of effectiveness for preventing recurrent venous thromboembolism, by adjusting the dose of warfarin sodium to achieve a less intense anticoagulant effect (PT 1.25 to 1.5 times control using a rabbit brain thromboplastin such as Simplastin or Dade-C, corresponding to an INR of 2.0 to 3.0). Less intense warfarin sodium therapy is the most cost-effective of the alternative long-term anticoagulant regimens (3). Adjusted dose subcutaneous heparin is an effective and safe alternative to warfarin sodium; although slightly more expensive, it is the long-term regimen of choice in pregnant patients, and in patients returning to geographically remote areas lacking the facilities for anticoagulant monitoring (in whom the dose is adjusted during the first few days of long-term therapy and then fixed). REFERENCES: (1) Hull R, Raskob G, Hirsh J et al. N Engl J Med 1986;315:1109-1114. (2) Gallus A, Jackaman J, Tillett J et al.

Lancet 1986;2:1293-1296. (3) Hull R, Raskob G, Hirsh J, Sackett DL. JAMA 1984;252:235-239.