Gray areas in vein disease: In this series of articles, we discuss the uncertain and the unsure. Eight thoughtful, knowledgeable, and confident vein specialists contemplate four venous disease areas: superficial disease; deep disease, reflux; deep disease, post-thrombotic; and acute DVT.

PATIENTS WITH symptomatic post-thrombotic syndrome (PTS) related to obstruction in the ilio-femoral venous segments may be treated with intervention to reopen obstructed segments of the venous outflow. Patients with PTS comprise a specific subset of patients undergoing venous stenting who are distinctly different from most patients who are treated for non-thrombotic venous outflow obstruction, in which a focal extrinsic compression of the venous outflow occurs. In the absence of a history of associated deep venous disease (DVT), these patients are treated with a less complicated procedure as the vein is typically narrowed but is not completely obstructed. The obstruction is typically focal, requiring less extensive stenting than is commonly encountered in PTS patients.

In recent trials of venous stenting, patients with NT compression achieve excellent results, with very low rates of thrombosis or stenosis of these stents in follow-up. In the VIRTUS trial, 96% of NT patients remained patent one year after stent insertion using the VICI stent.¹ Similar results were reported in trials with several other nitinol venous stents. Given these results, some clinicians do not recommend anticoagulation after stenting in NT patients, preferring to recommend antiplatelet therapy with Plavix and/or aspirin for three to twelve months. However, in a 2018 Delphi consensus project, Milinus et al., surveyed over 100 venous specialists concerning their preferences for the use of anticoagulants and antiplatelet therapies after venous stenting.² The majority of these clinicians reported that they placed their NT patients on anticoagulation, using a variety of anticoagulants for a varying length of time. As the majority of the clinicians in this project were from the United Kingdom or Europe, it is possible that the results reflect regional variations in treatment patterns. It is also clear that the relative benefits and risks of anticoagulation compared to antiplatelet therapies have not been established in a comparative study for NT patients undergoing stenting.

In contrast, treatment in PTS patients is more complex, with more extensive disease that may require recanalization of a chronically occluded iliac outflow tract. Typically, these patients require stenting of a longer segment of the venous outflow tract and a larger inflammatory stimulus related to the procedure performed to recanalize, sequentially dilate and stent this outflow tract. Neglen and Raju previously reported that the risk of stent thrombosis or stenosis in follow-up is significantly higher in PTS than in NT patients.³ In the VIRTUS trial, the patency rate for PTS patients was 73% at two years, significantly lower than the patency rate for NT patients.¹ For this reason, most physicians performing venous stenting consider anticoagulation for patients with PTS, particularly for those with PTS and an occluded venous outflow tract.

Numerous options may be considered for anticoagulation after venous stenting, including Warfarin, direct oral factor X inhibitors, low molecular weight heparins (LMWH), or others. There is little consensus on the optimal method of anticoagulation for these patients. In general, clinical studies such as the ATTRACT trial and the venous stent clinical trials left the choice of anticoagulant to the treating physician’s discretion.^1,4 The lack of comparative evaluation of the anticoagulant options after stenting is a significant knowledge gap in the management of patients with venous obstruction.

The Milinis et al. and Delphi consensus found that anticoagulation is recommended after stenting in post-thrombotic patients but that there was variability in the preferred method of anticoagulation.² The most commonly recommended method was LMWH by 67% of those polled, but the duration of recommended treatment with LMWH varied as it did with all of the anticoagulants recommended. The authors conclude that additional research is needed to support clinical guidelines on the use of anticoagulation after venous interventions.

At the 2021 American Venous Forum virtual meeting, Iles and colleagues from the University of North Carolina reported on outcomes in 106 patients with post-thrombotic disease and complete iliac or inferior vena cava (IVC) occlusion treated with recanalization and stenting of the venous outflow tract.⁵ In this high-risk subgroup, early stent thrombosis occurred within three months of insertion and was significantly associated with the method of anticoagulation. Those treated with a direct oral anticoagulant (DOAC) thrombosed in 38% of cases compared to 5% of cases treated with LMWH for greater than 10 days (typically three to four weeks) before converting to either Warfarin or a DOAC. Based on this information, the authors recommend the use of three to four weeks of LMWH for high-risk patients with extensive venous obstruction requiring venous stenting.

In a study of 136 patients with post thrombotic iliocaval obstruction, Gwozdz et al. routinely treated patients with two weeks of LMWH prior to transitioning to Warfarin for a minimum of six months.⁶ Despite a high frequency of thrombophilia in this high-risk population, cumulative patency of > 80% was achieved at 30 months.

While these retrospective studies provide a suggestion that LMWH is a good choice for post-thrombotic patients and those with more severe venous obstruction undergoing stenting, most of our choices in post-stenting anticoagulation and antiplatelet therapy are not supported by clinical data. Systematic studies comparing treatment strategies are clearly needed to improve our confidence in our treatment recommendations.

Patients with varying types of venous obstruction should be studied in similar groups, as those with less severe disease may not require the same degree of anticoagulation, if any. Likewise, additional information is needed concerning the bleeding risks associated with the use of prolonged anticoagulation in this patient population. As additional data emerges, it is our hope that useful clinical guidelines can be developed to reduce treatment variability and improve outcomes for our patients.

References

1. Razavi MK, Black S, Gagne P, Chiacchierini P, Nicolini P, Marston W. Pivotal study of endovenous stent placement for symptomatic iliofemo-ral venous obstruction. Circ Cariovasc Interv 2019 Dec;12(12):e008268.doi:10.1161/CIRCINTERVENTIONS.119.008268. Epub 2019 Dec 13.
2. Milinis K, Thapar A, Shalhoub J, Davies A. Antithrombotic therapy following venous stenting: International Delphi Consensus. Eur J Endovasc Surg 2018: 55:537-44.
3. Neglen P, Hollis KC, Olivier J, Raju S. Stenting of the venous out-
   flow in chronic venous disease: long-term stent-related outcome, clinical, and hemodynamic result. J Vasc Surg 2007;46:979-90.
4. Vedantham S, Goldhaber SZ, Julian JA, et al. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 2017;377:2240-52.
5. Marston WA, Browder SE, Iles K, Griffith A, McGinigle KL. Early thrombosis after iliac stenting for venous outflow occlusion is related to disease severity and type of anticoagulation. J Vasc
   Surg Venous Lymphat Disord 2021 Mar 2:S2213-333X(21)00098-6. doi: 10.1016/j.jvsv.2021.02.012. Online ahead of print.
6. Gwozdz AM, Doyle AJ, Hunt BJ, Tincknell LG, Jackson N, Saha P, Breen KA, Smith A, Cohen A, Black SA. Effect of thrombophilia on clinical outcomes of chronic post-thrombotic patients after iliofemoral stenting with nitinol venous stents. J Vasc Surg Ven Lymphatic Disord 2020, published online Nov 10, 2020.