Surrogate endpoints for the assessment of efficacy in venous thromboembolism treatment trials.

For the assessment of the efficacy of anticoagulant therapy in patients with symptomatic venous thrombosis, the incidence of symptomatic venous thromboembolic complications is the outcome measure of choice. However, the low incidence of such complications necessitates the inclusion of a prohibitively large number of patients in randomized trials evaluating anticoagulant regimens. Therefore, alternative efficacy outcome measures are desirable. This paper discusses the validity of the following alternative tests: venography and compression ultrasound for deep vein thrombosis; and pulmonary angiography and perfusion lung scanning for pulmonary embolism. It is concluded that a combination of one of the deep vein thrombosis tests and perfusion lung scanning is the optimal approach. A thrombotic burden assessment, using repeat venography and perfusion lung scanning, has been performed at the end of treatment (day 10) with low-molecular-weight heparin and unfractionated heparin in 170 patients with symptomatic proximal deep vein thrombosis. An improved thrombotic burden was associated with a low number of subsequent symptomatic venous thromboembolic complications (4%), whereas this figure gradually increased for patients with an unchanged (10%) and deteriorated (29%) outcome (p < 0.005). It is concluded that the thrombotic burden assessment has potential to replace symptomatic outcomes, especially in dose-finding studies.