What the trials have taught us about aggressive therapy of deep venous thrombosis

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By Stephen Kee and Adam Plotnik

Deep venous thrombosis occurs in 3–600,000 patients per year in the USA, and is associated with significant rates of short (pulmonary embolus) and long-term morbidity (post-thrombotic syndrome). Post-thrombotic syndrome has been reported to develop in over 50% of patients within two years following deep venous thrombosis despite standard therapy. The syndrome results from venous obstruction and inflammatory destruction of the valves. Manifestations include chronic limb pain, swelling, heaviness, early fatigue, skin pigmentation and/or venous ulceration. Consequently, there is significant impairment on the patient’s quality of life and the care required places a major economic burden on both the patient and healthcare providers.


Conventional therapy

Standard treatment of acute deep venous thrombosis is anticoagulation, which prevents pulmonary embolus and the propagation of thrombus, but does not affect the outcome or severity of post-thrombotic syndrome. Historically the only treatment for post-thrombotic syndrome with level one evidence is compression stockings. Thrombolysis, initially published in 1994 by Semba and colleagues in Radiology, has also been used to treat extensive deep venous thrombosis, however, the data supporting its use to prevent post-thrombotic syndrome is limited. Ongoing research and recently published studies are changing the treatment landscape for this devastating disease. This article provides an update of this data.


Data on thrombolysis and acute deep venous thrombosis

A 2014 Cochrane review evaluating randomised controlled trials, with a total of 1103 patients from 17 studies, examined thrombolysis and anticoagulation vs. anticoagulation alone in the setting of acute deep venous thrombosis. They demonstrated significantly less post-thrombotic syndrome in those receiving thrombolysis compared with anticoagulation alone. However, it identified significantly increased bleeding complications (10% vs. 8%). Notably, most of these bleeding complications occurred in early studies (pre-1990), whereas recent adaptations in the standard practice of thrombolysis (lower dose rates and reduced concomitant heparin administration) should mitigate many of these issues.

Only two randomised controlled trials have specifically compared catheter-directed thrombolysis with anticoagulation. Elsharawy and Elzayat (European Journal of Vascular and Endovascular Surgery, 2002) published data from 35 patients, half treated with catheter-directed thrombolysis and anticoagulation, half with anticoagulation alone. They found significantly less reflux and higher patency in the catheter-directed thrombolysis group although numbers were small and short follow-up precluded evaluation of post-thrombotic syndrome. The other more significant randomised controlled trials was CaVent, a Norwegian study that included 209 patients. Half were treated with catheter-directed thrombolysis and anticoagulation, half with standard anticoagulation. Post-thrombotic syndrome was significantly lower in the catheter-directed thrombolysis group. Other observational studies have demonstrated improvement in long-term quality of life following catheter-directed thrombolysis, including Comerota in 2000 (54 patients) and Grewal in 2010 (42 patients). Despite this data, there continues to be widespread reluctance to change the paradigm of treatment for deep venous thrombosis, based mainly on the concerns regarding bleeding risks.

Unresolved questions as to the benefits and risks of catheter-directed thrombolysis may be answered by an ongoing National institute of Health sponsored, multicentre trial, ATTRACT (Acute venous thrombosis: thrombus removal with adjunctive catheter- directed thrombolysis). Patients with an iliofemoral and femoropopliteal deep venous thrombosis are being stratified into catheter-based techniques of thrombolysis vs. anticoagulation alone. The primary endpoint is the development of post-thrombotic syndrome at 24 months, and there will also be a cost-benefit assessment. Their study hypothesis targets a reduction in post-thrombotic syndrome of 33% in the lysis group, with hopefully, a low incidence of bleeding complications. Should this large multicentre randomised controlled trials result in clinical improvement with acceptable risk and an overall cost-benefit, it may shift the playing field in favour of aggressive thrombolytic therapy for deep venous thrombosis.


Why are we not doing more thrombolysis?

The challenge to incorporating catheter-directed thrombolysis into standard practice lies in the fact that post-thrombotic syndrome develops long after the patient’s acute hospital admission for deep venous thrombosis. Many physicians dealing with the acute stage have a low-level of appreciation of the long-term sequelae. Data from trials clearly show a significant reduction in post-thrombotic syndrome with catheter-directed thrombolysis and ATTRACT will hopefully demonstrate further improvement with the added inclusion of pharmacomechanical techniques, and cost-benefit data. Furthermore, with strict adherence to thrombolysis exclusion criteria, meticulous interventional techniques, and close treatment monitoring, the risk of bleeding complications can be minimised. Although current evidence in favour of catheter-directed thrombolysis for deep venous thrombosis may not be robust enough to allow for a shift in clinical practice, that may soon change.

 


Stephen T Kee is associate professor of Radiology and section chief, Interventional Radiology, David Geffen School of Medicine at UCLA, Los Angeles, USA. Adam Plotnik is a radiologist at the same institution. The authors have reported no disclosures pertaining to the article