The venous revolution

Where we are and where we’re going

From a basic science perspective, a number of questions remain unanswered regarding deep veins. Venous disease is a cause of morbidity and mortality for patients of all ages, though the past several years have shown marked progress in research and approval of techniques and devices used for the treatment of venous disease. Major areas of research potential include the inflammatory pathway from acute deep venous thrombosis (DVT) to chronic fibrosis, and venous wall biomechanics and flow dynamics in the normal and disease states.

New and emerging research

The inflammatory process of DVT to fibrosis has been an area of active research in recent years. The pathway from acute thrombosis to chronic fibrosis begins with invasion of neutrophils followed by monocytes and macrophages, with subsequent development of myofibroblasts and thickening of the interstitial matrix in the post-thrombotic vein. Substantially more detailed work in the inflammatory pathway has been done, with a particular emphasis on metalloproteinase 9, which appears to have a regulatory function in post-thrombotic vein biomechanics. Knowledge of the inflammatory pathway represents a potential area for medical and interventional prevention of post-thrombotic syndrome after acute DVT.

Within the current body of literature, the understanding of venous wall biomechanics and luminal flow dynamics in the normal and post-thrombotic state is in its infancy. The normal and post-thrombotic veins have been described in animal models and human studies, with the latter demonstrating a predominance of type I collagen, which increases wall stiffness. Venous intervention with the application of radial force by stent placement shows exaggeration of the Poisson effect in veins compared to arteries. This biomechanical phenomenon is due to the relatively lower inherent elasticity of veins and is even further amplified in the post-thrombotic vein wall with increased stiffness. The Poisson effect may limit the overall lumen gain achievable by application of radial force. Understanding these vein wall biomechanics provides a segue into enhanced research on vein flow dynamics, predominantly via computational modeling.

Currently, the understanding of normal venous flow is poor and the quantitation of altered flow dynamics in the post-thrombotic state is markedly limited. As learned from extensive research in the arterial literature, alteration of flow dynamics in the disease states likely contributes to failed outcomes after endovascular interventions. High-yield areas of future research on venous interventions include investigation of the association of such flow dynamic alterations with the inflammatory pathway and subsequent clinical outcomes such as stent thrombosis and in-stent stenosis. Understanding this association will provide invaluable insight for development of next-generation deep venous interventional techniques and devices with improved clinical outcomes.

Superficial venous disease

Superficial venous disease management has undergone evolution over 20 years—beginning with the adoption of thermal ablation modalities to the recent advancement of nonthermal, nontumescent (NTNT) technologies (cyanoacrylate glue closure and chemical ablation), and the development of mechanicothermal techniques. Thermal ablative tools such as endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) have proven records of being safe, effective and durable in eliminating varicose veins with reported success rates of vein obliteration in 88–100% of treated great saphenous veins (GSV) and 88–96% of treated small saphenous veins (SSV). The NTNT technologies have also produced excellent results for vein obliteration and occlusion, at 94.4% at 3 years following glue closure, 87% at 3 years following mechanicothermal techniques, and 86% at 3 months for chemical ablation. These safe and effective treatments performed in conjunction with sclerotherapy and ambulatory phlebectomy are the current standard of practice to achieve quality of life improvement in this large patient group.

Another major advance in superficial venous disease management is the improved classification of the disease and validated scoring systems to assess for changes. The Varicose Vein Symptom Questionnaire (VVSymQ) asks patients to rate heaviness, aching, swelling, throbbing and itching on a scale and produces a validated metric for assessment of the clinical impact of varicose veins and their treatment. The revised Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification has also been updated in 2020 to better reflect the impact of superficial venous disease.

Further advances in saphenous vein ablative techniques continue to occur, including endovenous microwave ablation (EMA), high intensity focused ultrasound (HIFU), endovenous steam ablation and novel sclerosant devices. EMA has shown promising results in initial comparative studies with EVLA resulting in a shorter procedure time, decreased induration and ecchymosis, and lower rates of parasthesias with successful vein closure up to 1 year. HIFU may be the next disruptive technology in venous ablation due to the entirely noninvasive nature of the technique, which generates heat at a precise point via a linear ultrasound array transducer without the need for invasive tools or tumescent anesthesia. Endovenous steam ablation has been studied for several years without widespread adoption or advancement. Novel sclerosant devices allow for simultaneous aspiration of blood and administration of sclerosant to induce a chemical ablation.

Due to the high number of patients suffering from superficial venous disease throughout the world and the desire to obtain optimal results with the least patient discomfort, it is important to constantly strive to improve on the already high-quality care offered by current techniques and technologies. 

Inferior vena cava filters

Despite the broad availability of inferior vena cava filters (IVCFs) for over three decades, including design iterations that introduced devices that could be retrieved once the indication for mechanical caval prophylaxis passes, there remains equipoise regarding optimal practices surrounding filter placement and retrieval. There are three randomized controlled trials which have examined filter usage: two assessing the benefits of IVCF in addition to anticoagulation in risk reduction for pulmonary embolism (PE), and a third examining prophylactic IVCF usage in trauma patients. Though the results of these trials have provided valuable guidance on IVCF utilization, basic questions remain, including which populations may benefit from a prophylactic filter placement, as well as optimal retrieval windows for retrievable IVCF.

All retrievable and convertible IVCFs have received clearance for permanent implantation. However, data from the past 15 years suggests that some of these devices may be subject to device-related adverse events. It is probable that the majority of patients with such devices in situ no longer need mechanical caval prophylaxis, thus leaving them with devices where the risk/benefit ratio has been tilted unfavorably. Negative outcomes are further magnified by historically low IVCF retrieval rates.The United States Food and Drug Administration (FDA) recognized this issue and released safety communications in 2010 and 2014, followed by mandating post-market surveillance studies, one of which is the PRESERVE (Predicting the Safety and Effectiveness of Inferior Vena Cava Filters) study. This forthcoming data will be important in describing modern IVCF utilization and retrieval practices with currently available filters. In the meantime, novel device design efforts are underway to specifically address the question of devices remaining in situ beyond their period of clinical benefit.

Filter retrieval rates have been historically low for a variety of reasons, including poor clinical follow-up and the necessity for a second procedure. A novel IVCF featuring absorbable components which temporarily maintain caval filtration for a minimum of 60 days (Sentry, Boston Scientific, Marlborough, MA) was designed to specifically address the issue of low retrieval rates. Endogenous hydrolysis of the poly-p-diaxanone filament occurs, resulting in opening of the nitinol filtration arms. The IVCF frame remains as a permanent implant.16 The device holds promise with an excellent safety profile in their trial data; however, the need for long-term data remains paramount. Several IVCF investigational device exemption studies have shown excellent device safety profiles only to find issues once the device is subjected to “real-world” use. Further, given that there is variability in endogenous bioconversion, there is loss of clinical control of the duration of the mechanical caval prophylaxis, leading to variable periods of PE protection. Nevertheless, clinical interest in absorbable IVCF designs persist, with first-in-human placements of fully absorbable IVCF having recently occurred, where after hydrolysis, no significant endocaval foreign body should remain.     

Considerable interest remains in IVCF device development and practice refinement. As new devices continue to be developed, it is important to maintain focus on the most basic clinical issues that surround IVCF utilization, including optimal patient and device selection and diligent follow-up of patients with devices in situ.

Thrombectomy and venous reconstruction

In 2017, the ATTRACT trial failed to show a benefit of pharmacomechanical catheter-directed thrombolysis (CDT) in reducing post-thrombotic syndrome (PTS) compared to anticoagulation alone as first-line therapy in proximal deep vein thrombosis. However, the subgroup analyses of these patients that came in the following years showed better short-term recovery from deep venous thrombosis (DVT), reduced severity of PTS, slowed PTS progression and improved long-term quality of life in selected patients with acute iliofemoral DVT, especially after stent placement. With these discoveries, new devices, techniques and strategies surrounding the treatment of venous thromboembolic disease have emerged in the years since the ATTRACT trial and are beginning to offer patients immediate and long-term relief from symptoms of acute and chronic DVT.

Venous stent reconstruction

Endovascular venous stent reconstruction is now first-line therapy for chronic IVC thrombosis, with incidences reported at 4–15% in patients presenting with lower extremity DVT. Caval thrombosis is accompanied by multiple comorbidities including recurrent lower extremity DVT with swelling, pain, and venous ulceration.

Venous stents are designed with a balance between radial force and flexibility and must conform to the venous anatomy into which they are deployed. Several new stents that are FDA approved have accomplished this balance with diameters and lengths designed to accommodate upper and lower extremity veins as well as venae cavae.

The 12-month data from the VIVO study, a prospective, non-randomized, international multicenter study of one such stent found freedom from 30-day major adverse event rate of 96.7% and primary patency rate of 89.9% in patients with symptomatic obstruction of one iliofemoral venous segment. The study also demonstrated improvement in Venous Clinical Severity Score (VCSS) at 1 and 12 months. This stent has been FDA approved as of October 15, 2020.

There are also two bare-metal stents which show similar promise when used for iliocaval reconstruction. One features a closed cell design and uniform end-to-end strength and shape. The results of the VIRTUS study demonstrates 12-month overall patency rates of 100% in patients with post-thrombotic syndrome with a large percentage of patients with clinical iliac vein compression syndrome (25%). Safety data from this cohort showed a 12-month adverse event freedom rate of 98.8%. Alternatively, the other bare-metal stent has an open-cell design. Results from the VERNACULAR study examined patients with post-thrombotic syndrome and non-thrombotic iliac vein lesions treated with this stent and showed a composite primary safety outcome of 93.5% and a primary patency rate of 88.3%. All treated lesions achieved over 50% residual stenosis at the end of the procedures, and VCSS pain score reductions in all patients at 1, 6, and 12 months with similar short- and long-term results described by Lichtenberg et al.

Technical challenges in managing complex iliofemoral venous diseases are continuing to be addressed with promising new equipment. One venous stent is currently undergoing clinical evaluation with 200 patients, 44% of whom with stent placement extending below the inguinal ligament into the common femoral vein. Primary patency rate at 12 months is 88% with a major adverse event freedom rate of 98% at 30 days and significant reductions in Villalta and VCSS scores at 6 and 12 months. Venous stent placement to treat lesions across the inguinal ligament appears to be safe and effective at least in the short term.

Novel techniques of caval stent reconstruction are becoming more commonly used to treat non-thrombotic and thrombotic venous lesions. Iyer et al. reported a technical success rate of 98.1% and a mean decrease of 9.5 mmHg in pre- and post-hepatocaval pressure gradients in 53 patients with malignant IVC compression involving the intrahepatic cava with one stent. Chronic central venous occlusions of the chest and pelvis have also been remedied with recanalization and Z-stent reconstruction in patients with upper and lower extremity edema, superior vena cava syndrome, and stenosis related to hemodialysis fistula or indwelling central venous catheter. In a study by McDevitt et al., 137 patients were reconstructed with 208 Z-stents in the upper and lower body with technical success rates of 97.1% and a severe adverse event rate of 1.5%. The 1, 3, and 5-year primary stent patency rates were reported at 84.2, 84.2 and 82.1% respectively.

Conclusion

Venous disease patients demand clinical focus and commitment to treatment excellence. While significant advances have been made in the basic science, superficial venous, IVCF, thrombectomy and deep venous spaces, the understanding and implementation of venous disease–specific therapies remains in its infancy. The interventional radiology community looks forward to its continued involvement in the advancement and success of venous disease treatments.

To learn more about the evolution of IVC filters, listen to Warren Krackov, MD, FSIR, speak with SIR President Matthew S. Johnson, MD, FSIR, about the upcoming IVC filter clinical practice guidelines and the status of the FDA-requested PRESERVE Study.

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