Low-Dose Alteplase to Treat Blood Clots in Deep Leg Veins

Deep venous thrombosis (DVT) of the lower extremities is routinely treated with anticoagulants, which is very effective in preventing pulmonary embolism, but does not reliably restore venous function in the leg affected by DVT,often leaving permanent vein damage that leads to chronic disability known as post thrombotic syndromes. There is evidence that this may be prevented, and therefore long-term sequelae avoided, if the thrombi are dissolved quickly with thrombolytic agents. In a previous protocol we developed a method using intra-clot injections of alteplase (recombinant tissue plasminogen activator, rtPA) for the treatment of lower extremity DVT. Although the treatment was very successful with few complications, pharmacokinetic data obtained suggest that the regimen can be made safer and perhaps even more effective by using a substantially lower dose of alteplase. The current protocol is a pilot study to test this hypothesis by treating 25 patients with first-time DVT symptomatic for less than or equal to 14 days, accepted from referring physicians both within and outside the National Institutes of Health (NIH). They will be treated with less than or equal to 10 mg alteplase per day for up to four days. Depending on location and extent of the blood clot, catheters are introduced into jugular, femoral, popliteal, and/or posterior tibial vein at the ankle so as to inject alteplase (diluted with normal saline to 0.1mg/ml, throughout the entire length of the clot) once a day with each total daily dose limited to 10mg alteplase per day.The protocol is designed so that if the low-dose regimen is unsuccessful, the patient will subsequently receive the higher-dose regimen that has previously been shown to be effective. During thrombolytic therapy, catheters left in the vein to maintain venous access are also used to infuse unfractionated heparin to provide regional and therapeutic systemic anticoagulation. After completing thrombolytic therapy, the patients will be anticoagulated for approximately 6 months after treatment by conversion from intravenous infusions of unfractionated heparin during thrombolytic therapy to low molecular weight heparin (enoxaparin) and subsequent conversion to oral warfarin anticoagulation for 6 months. Efficacy of treatments will be evaluated at 3 time points (pre- and 1 day post-thrombolytic therapy for initial outcome; at about 6 weeks for short term outcome; and at about 6 months for durability of outcome) by clinical examination (department of Rehabilitation Medicine) and medical imaging through venography and duplex ultrasound sans in department of Radiology. The protocol is also monitored for safety. Safety monitoring is focused on bleeding complications which is the primary risk of all forms of thrombolytic and anticoagulation regimens. As an adverse event, bleeding complications can be classified as either expected (for example, at vascular puncture or access sites as where treatment catheters have been inserted); or unexpected as at remote sites where no instrumentation has been conducted (for example, Intracranial or retroperitoneal bleeding).The latter form of bleeding has been reported and attributed to use of thrombolytic and anticoagulant therapies and is usually much more serious than the former. A second classification is for severity of adverse events. For this protocol a serious adverse event is an event that is life or quality of life threatening, requires additional hospitalization, or surgical intervention, or in the case of thrombolytic therapy requires blood transfusions. A minor adverse event is one that does not have any of above features and will resolve without sequelae with conservative management and without need for invasive interventions. A secondary objective (added to this protocol through an amendment) is to study the rate of recurrent DVT during the 5 year period after treatment. Historical studies show a recurrent venothromboembolism rate of 30% in patients treated with anticoagulation alone. Thrombolytic therapy should improve preservation of venous function which may reduce recurrence rate of venothromboembolism and although the protocol cannot accrue any new patients, the protocol remains active to allow data compilation testing this hypothesis in patients already treated which will be completed by 2014, the expected date of protocol termination.