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

Condition(s) targeted: Venous Thrombosis

Intervention: Alteplase (Activase, Genentech) (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: National Institutes of Health Clinical Center (CC)

Overall contact:
Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

This study will test the effectiveness of low-dose recombinant tissue plasminogen activator (rtPA, or alteplase) in dissolving blood clots in deep leg veins. rtPA is given to patients with heart attacks to dissolve blood clots in blocked coronary arteries. Blood clots that develop in the deep leg veins can cause pain and swelling and may break loose and lodge in the lungs. Current Routine treatments use anticoagulants (blood thinners) such as heparin, or rtPA to dissolve the clots to stop the clots from enlarging. In an earlier study we showed that rtPA could be used to actually dissolve the clots. This study will determine whether lower doses of rtPA can effectively dissolve clots with fewer bleeding complications than the current previous higher-dose regimen.

Patients 18 years of age and older who have blood clots in a deep vein of the pelvis or leg may be eligible for this study if they have had symptoms for 14 days or less and if they have never had clots in their deep veins before.

Participants are admitted to hospital for 3 to 5 days. On the first treatment day, the patient has a venogram to show the location of the clots. The radiologist injects an x-ray contrast material into a small vein in the foot and watches the dye by x-ray as it moves up the leg, revealing the clot(s). A catheter (plastic tube) is then inserted into a vein either behind the knee, in the groin, or in the neck, and advanced until it reaches the clots. When the catheter is in place, rtPA is injected while the radiologist watches the vein under the x-ray image. The amount of rtPa needed will depends on the size of the clot. Up to five venograms may be done if the clot requires the maximum four rtPA treatments allowed in this study. During the treatments, patients receive standard doses of heparin, given continuously by vein, and Coumadin, another blood thinner, taken by mouth. Patients continue taking Coumadin for 6 months.

Blood samples are drawn shortly before the first dose of rtPa and at five time points afterward to measure the rtPa in the circulation and other factors that indicate whether the rtPa is affecting clotting ability. Blood also is drawn at least once a day to monitor heparin levels.

To evaluate the impact of treatment on the function of the leg, patients are evaluated in the Rehabilitation Medicine Department before receiving rtPA and again at the end of the hospitalization. Patients are also fitted for a compression stocking for the leg, which should be worn to reduce the chance of swelling.

Official title: The Treatment of Deep Vein Thrombosis of the Lower Extremities With "Low-Dose" Alteplase: a Pilot Study

Study design: Treatment, Open Label, Single Group Assignment, Safety/Efficacy Study

Primary outcome: Efficacy: ability to restore venous function in lower extremities affected by deep vein thrombosis.

Secondary outcome: Safety

Detailed description: Deep venous thrombosis (DVT) of the lower extremities is routinely treated with anticoagulants, which typically yield a satisfactory result, at least in the short term. However, DVT often causes permanent vein damage that leads to late complications. There is evidence that this may be prevented, and therefore long-term sequellae 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 usually successful and complications were uncommon, we think 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. Up to 25 patients with first-time DVT symptomatic for less than or equal to 14 days will be accepted from referring physicians both within and outside the NIH. They will be treated with less than or equal to 10 mg alteplase per day for up to four days. 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. The patients will be anticoagulated for approximately 6 months and re-evaluated after approximately 6 weeks and approximately 6 months with venography and/or duplex sonography.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA

Only adult patients (18 years old or older) are included.

Patients must have thrombosis documented by ultrasound or venography to involve the deep veins of the pelvis and/or a lower extremity proximal to the calf veins, i. e., the popliteal vein or above.

The thrombosis must be the patient's first DVT.

The thrombosis must have been symptomatic for no more than 14 days.

Patients must be able to give informed consent and be able to follow the prescribed anticoagulation regimen.

Patients on concurrent NIH protocols will be eligible as well as patients from the community and the rest of the U. S. who are not already on NIH protocols.

EXCLUSION CRITERIA

Pregnant patients are not eligible, although postpartum mothers over 10 days from delivery are eligible if they refrain from breast feeding their infants for 24 hours after each study with x-ray contrast material.

Serum creatinine greater than than 2 mg/dL.

Any current bleeding diathesis not attributable to heparin or warfarin. Fibrinogen less than 150 mg/dL. Any patient with a prothrombin time greater than 15 s, an aPTT greater than 35 s, or a platelet count less than 100,000/microL must be evaluated by the Hematology Service for a coagulopathy before being included.

Within the previous 10 days: major surgery or trauma, puncture of a noncompresssible vessel, organ biopsy, or cardiopulmonary resusitation.

Within the previous 2 months: cerebrovascular infarction or hemorrhage, or intracranial or intraspinal surgery or trauma.

Within the previous 6 months: major internal bleeding.

Active intracranial disease (aneurysm, vascular malformation, neoplasm).

Life expectancy less than 6 months.

Patients with hemoglobin concentration less than 9g/dL will not participate in the pharmacokinetic portion of the protocol.

Uncontrolled systolic blood pressure greater than 180 mm Hg or diastolic greater than 100 mm Hg.

Atrial fibrillation, unless a cardiac echocardiogram excludes the presence of intracardiac thrombus.

Known right-to-left intracardiac shunt.

Pericarditis, infective endocarditis.

History of heparin-induced thrombocytopenia within 6 months or the presence of persistent anti-heparin antibodies by ELISA.

History of anaphylactic reactions to x-ray contrast media.

Known retinopathy unless cleared by an ophthalmologist at NIH.

Evidence of uncontrolled congestive heart failure or a history of diabetes mellitus.

Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting

NIH Clinical Center Detailed Web Page

Related publications:

Schafer AI. Venous thrombosis as a chronic disease. N Engl J Med. 1999 Mar 25;340(12):955-6. No abstract available.

Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996 Jul 1;125(1):1-7.

Levine M, Hirsh J, Weitz J, Cruickshank M, Neemeh J, Turpie AG, Gent M. A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest. 1990 Dec;98(6):1473-9.

Starting date: May 2004
Ending date: March 2010
Last updated: August 24, 2009