Endovascular Management of Acute Iliofemoral Deep Vein Thrombosis

Abstract

Lower extremity deep vein thrombosis (DVT) is frequently encountered in clinical practice. Postthrombotic syndrome (PTS) is a common sequela of DVT and encompasses a wide variety of symptoms, including severe pain, edema, and ulceration, all of which may contribute to a negative impact on quality of life. Studies have demonstrated that acute thrombosis of the iliofemoral venous segment is correlated with high rates of PTS, increased severity of symptoms, and high rates of thrombus recurrence, despite patients receiving treatment with standard-of-care anticoagulation therapy. Endovascular interventions, including catheter-directed thrombolysis, pharmacomechanical thrombectomy, and mechanical thrombectomy, have generated significant interest as a method for reduction of short-term symptom severity and potential reduction of downstream PTS severity. While there is high-quality evidence evaluating the role of catheter-directed and pharmacomechanical thrombectomy for acute iliofemoral DVT, newer mechanical-only devices that utilize thrombectomy without fibrinolytic medication are less studied. Currently, there are limited data evaluating the efficacy and safety of these treatment modalities, although investigations are ongoing.

Deep vein thrombosis (DVT) is a common condition which arises in adult populations at an annual incidence of approximately 1 in 1,000. ¹ Postthrombotic syndrome (PTS) is a relatively common sequelae of DVT, occurring in approximately 30 to 50% of patients within 1 to 2 years of the inciting thrombotic event despite receiving optimal anticoagulation. ^{2 3} While the exact mechanism behind PTS is poorly understood, the development of venous hypertension does appear to be a key driver. Initial deposition of thrombus in the veins likely elicits an inflammatory reaction which subsequently damages venous valve leaflets, resulting in reflux. This, paired with wall damage and associated luminal obstruction, results in the long-term clinical manifestations of ambulatory venous hypertension. ⁴

The symptoms of PTS vary widely; when severe, patients may suffer from severe pain, intractable edema, and venous ulceration, which occur in approximately one-quarter to one-third of patients with PTS. ³ These symptoms often have tremendous negative impact on a patients' quality of life (QOL). Prospective assessments have demonstrated similar negative impact on QOL between PTS and diseases like arthritis, chronic lung disease, or diabetes; those with severe PTS symptoms have a similar QOL as patients with cancer or congestive heart failure. ⁵ The financial burden of PTS is also evident: In the United States, the average cost of treating PTS is approximately $7,000 per patient per year. ⁶ PTS patients with severe symptoms have been shown to accrue at least four times greater cost of treatment when compared to those with mild to moderate symptoms. ⁷ PTS patients with ulcerations accrue at least 3.5 times greater annual cost of treatment compared to those with healed ulcers, due to loss of employment and potential need for surgical intervention. ⁸ The negative impact of PTS as it relates to symptoms, QOL, economic burden, and societal burden is clear.

Iliofemoral DVT, defined as thrombosis within the iliac and/or common femoral vein, represents approximately one-quarter of all DVT cases. ^{9 10} Studies have shown that involvement of the common femoral through iliac veins is significantly correlated with higher PTS severity despite optimal medical therapy, including anticoagulation ² ; symptoms that may develop include pain, edema, and stasis ulceration. ^{11 12 13} One series demonstrated that in patients with acute iliofemoral DVT treated with anticoagulation alone, 95% developed venous hypertension, 90% had signs and symptoms of chronic venous insufficiency, 15% developed venous ulcers, and 15% showed signs of venous claudication at 5 years. ¹¹ Similarly, another series demonstrated that 40% of patients with prior iliofemoral DVT treated with anticoagulation alone developed exercise-associated venous claudication. ¹² Furthermore, patients with iliofemoral DVT are shown to have a 2.6-fold higher risk of recurrence as compared to patients with less extensive DVT. ¹⁴

Endovascular Therapy to Reduce PTS Risk/Severity

While the standard of care for lower extremity DVT consists of therapeutic anticoagulation and compression therapy, the severity of PTS with its associated QOL and economic burden has resulted in significant interest in the role of endovascular therapy for acute DVT to mitigate these issues. The use of endovascular therapy is predicated on the “open vein” hypothesis, which posits that early and active removal of thrombus can improve venous flow and prevent PTS development. ¹⁵ Accordingly, catheter-directed therapy (CDT) is a widely studied treatment modality with the goal of actively reducing thrombus burden, thereby removing the nidus for the biological processes that result in PTS. In CDT, a percutaneously inserted multi-side hole catheter is advanced across thrombus for targeted, direct fibrinolytic infusion, resulting in a theoretically higher local concentration of fibrinolytic delivery with a decrease in overall systemic fibrinolytic dosing, theoretically reducing the risk of associated hemorrhagic events. Similarly, pharmacomechanical catheter-directed thrombolysis (PCDT) aims to actively reduce thrombus burden, but with the use of mechanical thrombus disruption such as aspiration or maceration in addition to fibrinolytic infusion.

Investigations on the Role and Outcomes of Endovascular Therapy

One of the landmark studies assessing endovascular therapy for iliofemoral DVT, the Post-Thrombotic Syndrome After Catheter-Directed Thrombolysis for Deep Vein Thrombosis (CaVenT) trial, examined whether additional treatment with CDT using alteplase reduced development of PTS. The primary analysis of CaVenT assessed two primary endpoints: iliofemoral patency at 6 months and the development of PTS at 24 months as defined by the Villalta score. This randomized controlled trial assessed 209 patients with iliofemoral DVT, 108 receiving standard treatment consisting of anticoagulation/compression stockings and 101 receiving standard treatment plus CDT. At 24 months, 41% (95% confidence interval [CI]: 31.5–51.4) of patients in the CDT group presented with PTS as compared to 55.6% (95% CI: 45.7–65.0) in the conventional group ( p  = 0.047). Iliofemoral patency at 6 months was 65.9% (95% CI: 55.5–75.0) in the CDT group versus 47.4% (95% CI: 37.6–57.3) in the conventional group ( p  = 0.012). In patients with iliofemoral patency at 6 months, the rate of PTS at 24 months was 36.9% (95% CI: 28.2–46.5) versus 61.3% (95% CI: 50.3–71.2) in partially recanalized limbs. The CaVenT data suggested that patients treated with CDT had increased rates of iliofemoral patency at 6 months and decreased rates of PTS at 24 months; in addition, it demonstrated that a fully recanalized iliofemoral segment was correlated with decreased rates of PTS. At 5-year follow-up, data were available for 84% of patients, demonstrating that 43% (95% CI: 33–53%) of patients in the CDT group developed PTS versus 71% (95% CI: 61–79%) of patients in the conventional group ( p  < 0.0001). ¹⁶ However, there was no significant difference in the QOL measurements at any point beyond 6 months.

CaVenT was characterized by extended lytic administration times in critical care settings. With the advent of devices that included a component of mechanical thrombectomy, there was interest in evaluating the role of PCDT in the treatment of proximal DVT. The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial, a phase III, National Institutes of Health, assessor-blinded, open-label, randomized controlled trial, assessed whether PCDT resulted in decreased PTS relative to standard therapy consisting of anticoagulation and compression. ¹⁷ A total of 692 patients with proximal DVT (iliofemoral or femoropopliteal segment) were randomized across 56 medical centers in the United States. Three-hundred fifty-five patients received conventional therapy with anticoagulation alone and 337 received conventional therapy plus PCDT. While PCDT included infusion of recombinant tissue–plasminogen activator followed by catheter-based mechanical thrombectomy, most patients in the PCDT treatment arm received treatment with rheolytic thrombectomy (AngioJet, then Bayer Healthcare, Leverkusen, Germany; now Boston Scientific, Marlborough, MA). Balloon angioplasty and stent placement were at operator discretion. The primary outcomes under investigation were the Villalta scores at both 6 and 24 months. While the study initially demonstrated no significant difference in composite Villalta scores (47% in PCDT and 48% in conventional therapy, p  = 0.56), there did appear to be a difference in the rates of moderate to severe symptoms (Villalta ≥10) between the PCDT and conventional groups (18 and 24%; risk ratio, 0.73; 95% CI: 0.54–0.98; p  = 0.04). Bleeding events at 10 days were, however, found to be significantly higher in the PCDT group (1.7 vs. 0.3% of patients, p  = 0.049); no bleeding-related mortality occurred. Despite the failure of the trial to demonstrate a significant difference in the primary outcome of PTS risk reduction, it did demonstrate reduction in PTS severity in patients with iliofemoral DVT who presented with moderate-to-severe symptoms or greater. Subgroup analysis examining patients with iliofemoral DVT found that while PCDT did not decrease occurrence of PTS or recurrent venous thromboembolism, PCDT significantly reduced leg pain and swelling at 30 days ( p  < 0.01) and, over 24 months, reduced PTS severity scores ( p  < 0.01), reduced development of moderate-or-severe PTS (18 vs. 28%; risk ratio, 0.65; 95% CI: 0.45–0.94; p  = 0.021), and resulted in greater improvement in venous disease-specific QOL ( p  = 0.029). ¹⁸ Subgroup analysis of patients with femoropopliteal DVT receiving PCDT revealed no improvement of early leg pain or swelling and no difference in PTS occurrence, moderate-or-severe PTS, severity of PTS scores, or venous disease-specific QOL, though there was an increase in bleeding (8 vs. 2 patients; p  = 0.032). ¹⁹ Another ATTRACT trial subanalysis found that PCDT use across all proximal DVT patients leads to greater improvement in venous disease-specific QOL at 1 month (difference, 5.7; p  = 0.0006) and 6 months (5.1; p  = 0.0029) only. However, the iliofemoral DVT subgroup experienced greater improvement in venous disease-specific QOL throughout 24 months (intention-to-treat analysis at 1 month, p  < 0.0001 and 6 months, p  < 0.0001; per-protocol analysis at 18 months, p  = 0.0086 and 24 months, p  = 0.0067) while the femoropopliteal DVT subgroup did not achieve change in QOL score from baseline. ²⁰ In summary, patients with a favorable risk profile for thrombolytic therapy who present with moderate-severe symptoms and acute iliofemoral DVT may benefit from intervention to reduce the risk of PTS severity.

Future of Iliofemoral DVT Investigation

As investigation into DVT intervention continues, a particular emphasis on delineating the pathophysiology of venous obstruction, venous hypertension, PTS, and symptom development is necessary. While pivotal trials such as CaVenT and ATTRACT have shown benefits of CDT or PCDT in acute DVT in support of the open-vein hypothesis, these trials have not demonstrated sustained improvements in QOL. Furthermore, these two studies demonstrated that 44% of lysed patients subsequently developed PTS. These findings suggest a mechanism behind the pathophysiology of PTS and its clinical manifestations that needs further exploration. An understanding of the pathologic process could also identify key therapeutic targets for further research and translate into clinical objectives that providers can use as predictive factors to stratify patients and direct management.

More recently, there has been keen interest in the development of mechanical-only DVT intervention devices and strategies. Options include rheolytic devices (Angiojet ZelanteDVT; Boston Scientific, Maple Grove, MN), aspiration devices (Indigo and Indigo Lightning, Penumbra, Alameda, CA; QuickClear, Philips, Minneapolis, MN) and clot capture devices (ClotTriever; Inari Medical, Irvine, CA). These devices all have the goal of rapid thrombus elimination for reestablishment of flow in the vein. Rheolytic devices inject pressurized saline to draw thrombus into the catheter via the Bernoulli effect ( Figs. 1 Fig. 2 Fig. 3 Fig. 4 ), current generation aspiration devices use pressure sensors to optimize continuous or intermittent thrombus aspiration, and clot capture devices deploy a catheter to core the thrombus and remove clot with a self-expanding mesh funnel.

Fig. 1.

Digital subtraction left femoral venography demonstrating subtotal acute thrombotic occlusion.

Fig. 2.

Digital subtraction left common femoral venography demonstrating subtotal acute thrombotic occlusion.

Fig. 3.

Digital subtraction venography demonstrating subtotally restored patency in the left femoral vein after rheolytic thrombectomy.

Fig. 4.

Digital subtraction venography demonstrating subtotally restored patency in the left external and common iliac veins after rheolytic thrombectomy and stent placement.

Outcomes of mechanical-only devices are limited to single-arm trials. The multicenter, prospective, single-arm ClotTriever Outcomes (CLOUT) registry was established to assess the safety and efficacy of the ClotTriever System for acute or nonacute lower extremity DVT of any symptom duration in all patients, including those with bilateral DVT or prior unsuccessful DVT treatment. ²¹ This registry is ongoing, with the primary effectiveness endpoint of complete or near-complete (≥75%) thrombus removal determined by core lab-adjudicated Marder scores. Interim analysis at 6 months examined results of the first 250 patients with 260 treated limbs, of which 99.6% were treated in a single session and none received thrombolytics. Eighty-six percent of treated lower extremities achieved complete or near-complete thrombus removal, with Marder scores reduced by a median of 100% (interquartile range [IQR]: 82.1–100%; baseline score: 8.8, IQR: 6.8–12.5 to 0.0, IQR: 0.0–1.3; p  < 0.0001). Safety outcomes were notable for one device-related serious adverse event, fatal pulmonary embolus, at 30 days. At 6 months, 24% of patients had PTS. Trials for other mechanical devices, including “BOLT,” a prospective multicenter study of patients with DVT to evaluate the safety and efficacy of the Indigo aspiration system, are currently enrolling.

However, these trials are limited to device efficacy and have no comparator arm, limiting their validity. In addition to valid comparator arms, future studies investigating the efficacy of these devices should also employ uniform treatment arms to minimize bias.

Conclusion

Endovascular intervention for lower extremity DVT has seen tremendous growth in research and innovation over the past two decades. While there has been a refinement in patient selection and procedural technique to improve outcomes, future investigations remain vital in further refining the therapy, with particular attention to the rapid expansion of venous-specific thrombectomy devices. These devices must be critically evaluated to assess their safety and efficacy through studies that have taken sincere efforts to minimize bias, thereby producing data that can be confidently applied to the care of future patients with DVT.