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Time to turn attention to post-thrombotic syndrome
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HemOnc Today recently convened its well-respected Section Editors to present on ‘hot’ or controversial topics they deemed important to their subspecialty area. Presented here is Gregory M. Vercellotti, MD’s, discussion of his hit list of topics that he believed fulfilled this qualification. HemOnc Today will continue to follow and expand coverage of these topics in the ensuing months. We hope you find these executive overviews informative.
The time has probably come for hematologist/oncologists to think more about post-thrombotic syndrome. The main issue involved in post-thrombotic syndrome is the treatment of patients after they have a deep vein thrombosis and their leg swells up. Physicians who treat people with these conditions realize that it is a big problem. These patients experience chronic limb swelling, pain, heaviness, fatigue and ulceration. Unfortunately, there are not a lot of treatment options for these patients.
Normally, veins have one-way valves that include perforating veins that prevent deep to superficial flow. When a patient gets a DVT, even when they are prescribed anticoagulant drugs, the blood clots permanently damage these valves. Patients get reflux. Blood comes down and blocks venous return. Physicians see this time and time again with varicosities and venous ulcerations. It is a desperate situation for many individuals.
Effect of post-thrombotic syndrome
The costs are significant. Venous stasis syndrome is estimated to affect about 150,000 people annually, with a direct medical cost of about $261 million. Venous ulcers affect more than 20,000 patients, with a direct medical cost of $153 million. These ulcers are challenging to take care of. Even after hip surgery, there is a per patient direct cost of about $3,817 per year in year one, and $1,677 per year in subsequent years. It is estimated that there is a loss of 2 million work days annually.
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The incidence of post-thrombotic syndrome is 23% to 46% after first DVT, according to the literature. That means this happens frequently, despite our use of heparin and low–molecular weight heparin, oral antithrombins, warfarin, etc. Prandoni and colleagues published that the cumulative incidence of post-thrombotic syndrome over the years has been quite significant, especially the occurrence of severe post-thrombotic syndrome after first episode of DVT.
The question remains: Why is this happening? We know it is likely happening due to venous hypertension, whether it is primary or secondary. But what is the role of inflammation? The role of inflammation from the white cells, platelet, oxidants, cytokines, matrix metalloproteinases within the vessel wall that leads them to the altered cellular function could be in the dermal pathology ulceration, but also could be in the whole post-thrombotic syndrome.
One possible hypothesis that has been around for some time is the open vein hypothesis: Does immediate clot removable speed the relief of initial DVT, save the venous valves and prevent post-thrombotic syndrome?
When looking at the literature, many studies that have been conducted are relatively small studies in which people have used streptokinase, tissue plasminogen activator or thrombectomy. It appears that in many of these small studies that the post-thrombotic syndrome rate is less when some kind of clot removing procedure is used, whether it is linux or mechanical removal. One example is the use of the AngioJet Catheter (Medrad). The AngioJet Catheter goes into the clot and acts like a drill. It drills through the clot, disrupting it.
ATTRACT
One trial that is looking at pharmacomechanical catheter-directed thrombolysis just recently started enrollment. The ATTRACT — the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis — trial is a trial conducting by Suresh Vedantham, MD, at Washington University.
The objective of the study is to determine if the initial adjunctive use of pharmacomechanical catheter-directed thrombolysis in symptomatic patients with acute proximal DVT reduces the occurrence of the post-thrombotic syndrome during 24 months of follow-up.
The secondary objectives include looking at resolution of acute DVT symptoms, venous disease-specific and general quality of life, safety, cost-effectiveness between the two treatment arms; identifying pretreatment predictors of heightened therapeutic response to pharmacomechanical catheter-directed thrombolysis; and determining if post-thrombotic syndrome scores and quality of life change scores are correlated with post-treatment thrombus burden, recurrent DVT and valvular reflux.
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Photo courtesy of MEDRAD Interventional/Possis |
The eligibility in this trial include anybody with proximal DVT in the iliac, common femoral or femoral vein, and anyone ready to start anticoagulation. Patients are excluded if they have high bleeding risk, central nervous system lesions and patients with cancer.
The trial is multicenter. Patients will either be assigned to pharmacomechanical catheter-directed thrombolysis with tissue plasminogen activator or standard anticoagulation.
Gregory M. Vercellotti, MD, is professor in the division of hematology-oncology-bone marrow transplant at the University of Minnesota and is the HemOnc Today Vascular Disorders Section Editor.
The ATTRACT trial addresses several important questions regarding the use of catheter-directed thrombectomy/thrombolysis for iliofemoral deep vein thrombosis. These include: Is there an overall long-term benefit to using the procedure compared with standard anticoagulation? Are there certain subgroups that are more likely to benefit? And is the procedure cost effective when compared with the long-term medical and productivity costs of post-thrombotic syndrome? The eventual results from this trial will provide much needed data to guide physicians involved in the initial management of patients with large proximal DVTs.
– Yvonne H. Datta, MD
Hematology Oncologist, University of Minnesota
A recent study suggests that newer anti-Factor Xa agents might be beneficial beyond their anticoagulant effect. That is, Scotten and colleagues (J Clin Invest. 2009;119;2550) have shown that Factor Xa promotes fibrosis, as well as acting as an important procoagulant moiety. The “woody” swelling of the post-thrombotic syndrome is likely due to excessive fibrogenesis and might be a previously unsuspected target of therapy. Thus, a “twofer” benefit might accrue with anti-Xa drugs in the treatment of DVT (when they become FDA-approved in this country).
– Harry S. Jacob, MD
HemOnc Today Chief Medical Editor