Residual rates of reflux and obstruction and their correlation to post-thrombotic syndrome in a randomized study on catheter-directed thrombolysis for deep vein thrombosis.

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Haig Y, Enden T, Slagsvold CE, Sandvik L, Sandset PM, Kløw NE. J Vasc Surg:
Venous Lymphat Disord. 2014;2:123-130.

Catheter-directed thrombolysis, venous abnormalities, and postthrombotic syndrome

Despite appropriate anticoagulant therapy, at least 1 of every 2 to 3 patients with proximal deep vein thrombosis (DVT) of the lower extremities will develop (severe) postthrombotic sequelae (PTS). Among parameters that have been found to be associated with an increased risk of PTS are venous thrombosis of the common femoral or iliac vein, obesity, previous ipsilateral DVT, older age, and female sex.1,2 By contrast, the role played by the development of venous reflux and/or the longstanding persistence of venous obstruction is controversial.1,2 Accordingly, whether, and to what extent, the earlier restoration of vein patency has the potential to reduce the incidence of late manifestations after an episode of DVT is uncertain.

Recently, the results of the CaVenT study (Catheter-directed Venous Thrombolysis in acute iliofemoral vein thrombosis), the first randomized controlled trial to address the value of catheter-directed thrombolysis (CDT ) for reducing the incidence of PTS in 209 consecutive patients with iliofemoral DVT, have been published.3 The CaVenT study showed a statistically significant 15% reduction in PTS development after 24 months in patients treated with additional CDT compared with those allocated to anticoagulation alone. Iliofemoral patency after 6 months was more often regained in the CDT group and patency after 24 months correlated with the remaining thrombus load after completed CDT treatment. Severe or clinically relevant bleeding complications developed in 8% of patients allocated to CDT and 0% of patients receiving heparin alone.3

Very recently, the authors of the CaVenT study assessed whether regained venous patency and development of deep venous reflux differed between patients treated with additional CDT and those receiving standard treatment alone.4 All 189 patients available for long-term investigation underwent ultrasonography and air plethysmography after 6 and 24 months to evaluate venous reflux and patency. There was an absolute risk reduction in venous reflux of 12% after 6 months and 16.5% after 24 months in the CDT arm when compared with controls. Correspondingly, venous patency was regained in 18.5% more patients after 6 months and 15% more patients after 24 months compared with controls. Both the reduction in venous reflux and the increase in venous patency were statistically significant. Independent of treatment allocation, patients with fully recanalized and competent deep veins at 6-months had a 40.5% absolute risk reduction of developing PTS compared with patients with an abnormal vein assessment.45 Then, this strategy has gradually been replaced by direct infusion of a plasminogen activator into the thrombus using ultrasound-guided access to the deep venous system and fluoroscopic positioning of the catheter into the thrombus. Avoiding systemic infusion has resulted in fewer major bleeding complications, and direct infusion of the lytic agent has been associated with improved efficacy.2

Is CDT the future of DVT treatment? Recently, the results of a large observational study that included patients with a principal discharge diagnosis of proximal or caval DVT from 2005 to 2010 in the US have been published.6 Patients treated with CDT plus anticoagulation were compared with patients treated with anticoagulation alone. Propensity scores were used to construct 2 matched groups, each containing 3594 patients, for a comparative outcomes analysis. While in-hospital mortality was not significantly different between the CDT and the anticoagulation groups, the rates of blood transfusion were found to be significantly higher in patients receiving CDT , as was the incidence of pulmonary embolism, intracranial hemorrhage, and vena cava filter placement. Are these complications a price to be paid for the prevention of PTS? I do not think so. In a scenario where novel direct oral anticoagulants are increasingly streamlining the treatment of venous thromboembolism due to the simplicity of use, coupled with an attractive benefit-to-risk ratio for all of the patient’s presentation and location of thrombosis,7 the use of CDT raises concerns. At best, CDT requires the identification of a highly selected group of patients who are reputed to carry an unusually high risk of late complications while having a low hemorrhagic risk.

1. Kahn SR, Comerota AJ, Cushman M, et al; American Heart Association Council on Peripheral Vascular Disease, Council on Clinical Cardiology, and Council on Cardiovascular and Stroke Nursing. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014;130:1636-1661.
2. Nicolaides AN, Fareed J, Kakkar AK, et al. Prevention and treatment of venous thromboembolism— International Consensus Statement. Int Angiol. 2013;32:111-260.
3. Enden T, Haig Y, Kløw NE, et al; CaVenT Study Group. Long-term outcome after additional catheterdirected thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet. 2012;379:31-38.
4. Haig Y, Tone E, Slagsvold CE, Sandvik L, Sandset PM, Kløw NE. Residual rates of reflux and obstruction and their correlation to post-thrombotic syndrome in a randomized study on catheter-directed thrombolysis for deep vein thrombosis. J Vasc Surg: Venous Lymphat Disord. 2014;2:123-130.
5. G oldhaber SZ, Buring JE, Lipnick RJ, Hennekens CH. Pooled analyses of randomized trials of streptokinase and heparin in phlebographically documented acute deep venous thrombosis. Am J Med. 1984;76:393-397.
6. Bashir R, Zack CJ, Zhao H, Comerota AJ, Bove AA. Comparative outcomes of catheter-directed thrombolysis plus anticoagulation vs anticoagulation alone to treat lower-extremity proximal deep vein thrombosis. JAMA Intern Med. 2014;174:1494-1501.
7. van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124:1968-1975.