Catheter-Directed Thrombolysis for Deep Vein Thrombosis: Serving at Break Point

Catheter-Directed Thrombolysis Protocols for Deep Venous Thrombosis of the Lower Extremities—A Systematic Review and Meta-analysis

Venous thromboembolism (VTE), inclusive of both deep vein thrombosis (DVT) and pulmonary embolism, is a common, morbid, and sometimes deadly condition. It is estimated that more than 1 million Americans and more than 700,000 Europeans experience a VTE event annually.[1] Lifetime estimated risk of VTE in the United States is 8.1%, notably higher in black persons. Other important risk factors for developing VTE include obesity,[2] postsurgical populations,[3] recently hospitalized, cancer,[4] and those with sleep apnea.[5] Recent focus has included the associations of VTE to pregnancy and family history in women of childbearing age[6] [7] as well as those with assisted reproductive technology.[8] When patients experience a DVT, it negatively impacts their quality of life and limits their ability to participate as a productive member of society.[9]

While most patients with acute DVT can be safely treated with anticoagulation therapy, some patients require more aggressive thrombus removal.[10] While this has long been recognized for patients with a threatened limb from acute DVT (e.g., phlegmasia cerulea dolens), thrombus removal is increasingly being utilized to reduce the risk of the postthrombotic syndrome (PTS).

The most commonly used and studied modality is catheter-directed thrombolysis (CDT). However, consensus has not yet been reached as to which patients are most likely to benefit from this therapy. Furthermore, the protocols for use of these devices and the methods for assessing efficacy outcomes are heterogeneous and often not specified in many publications.

To help address the heterogeneity in CDT use for acute DVT, Duarte-Gamas et al performed a systematic review and meta-analysis of CDT study protocols and outcomes.[11] Of note, they focused only on studies of acute and subacute thrombosis of the inferior vena cava (IVC) or thrombus in the lower limbs, excluding any studies using these devices for pulmonary embolism or arterial disease. They included a wide variety of study types, including randomized clinical trials, nonrandomized prospective studies, and observational studies.

The systematic review identified 46 studies with a total of 49 different protocols since 1991. Nearly all (92%) of the study protocols were focused on patients with acute DVT (2–14 days following diagnosis). Enrolled patients most often included iliofemoral DVT across the various protocols and were predominantly treated with urokinase in 71 to 80% of the protocols. Prophylactic use of IVC filters was considered “routine” in only 18% of protocols, yet even fewer (10%) explicitly excluded their use. Most protocols allowed for “selective deployment” of IVC filters, a practice that increased with frequency over the study period.

A key finding from this systematic review was the highly heterogenous way in which CDT procedures were considered “successful” across the study protocols. For instance, different protocols looked specifically for the presence of antegrade flow while others required complete thrombus dissolution, lysis of ≥90% of thrombus, residual stenosis <30%, and changes in key scoring systems (e.g., Venous Registry Index). The Venous Registry Index was used in 19/41 protocols, with a wide range of reported success (0–88% reported complete thrombolysis). Across the various studies, minor bleeding complications were common (8.7% of all patients) and more frequent in protocols using recombinant tissue plasminogen activator or tissue plasminogen activator than with urokinase. On the other hand, major bleeding complications were rare (1.0%) when low-dosage thrombolysis protocols were used but more common (2.3%) for high-dosage thrombolysis protocols.

A leading justification for CDT therapy in acute and subacute DVT is to prevent or reduce the burden of PTS. This outcome was most commonly assessed using the Villalta score in 17/35 protocols, with many having no specified scoring system in the protocol. Across the 35 studies assessing these outcomes, just over one in five developed the PTS within 6 to 89 month assessment period following CDT therapy. PTS incidence was not explained by variability in the follow-up intervals.

This systematic review highlights some of the major shortcomings in the available CDT data, namely, the reliance on low-quality data (e.g., single-center case series) and lack of standard, agreed upon definitions of technical success and disease-related outcomes. In these data, only 13% of the cited studies were randomized control trials, and nearly one-third of the studies did not report consecutive inclusion of patients, suggesting the possibility of selection and/or reporting bias. Definitions of technical success varied from dichotomous criteria (complete thrombus resolution or not) to segmental scoring systems such as the Venous Registry Index. A majority of studies (76%) reported on the incidence of PTS. PTS definitions ranged from clinical diagnosis to use of various scoring systems—some PTS- or venous-specific and others more generic. Consequently, PTS severity, which can range from mild edema to life-limiting chronic venous ulceration, was not assessed in the review.

CDT for arterial disease is largely utilized for limb salvage. In contrast, CDT in the setting of venous disease is most commonly employed as a strategy to prevent the long-term morbidity associated with PTS. Whereas limb preservation interventions have long been measured by straightforward outcomes, such as freedom from major amputation, the clinically relevant outcomes related to venous CDT are less precise. The mostly widely used PTS measurement in this series was the Villalta score. The Villalta score suffers from a number of well-described shortcomings. First, it does not account for venous claudication. Second, it does not take into account fluctuations in symptoms.[12] Third, the signs/symptoms comprising the score overlap significantly with findings in chronic venous disease related to valvular insufficiency rather than thrombotic disease.[13] In 2010, standardized diagnostic criteria for patients with advanced venous disease were recognized as a research priority at the Pacific Vascular Summit 6.[14] In the intervening 13 years, no improved, specific measure of limb symptoms after DVT has emerged. In contrast, there has been an exponential increase in articles related to venous thrombus removal strategies. A major gap currently exists between our level of technical innovation and ability to consistently measure disease-specific outcomes related to alleviating thrombus burden.

Perhaps the most important revelation from this work is the scale of unrealized opportunity from failing to standardize protocol reporting requirements and patient-centric, clinically relevant outcomes. Until these standards are met, we will fail to capitalize on knowledge gained through our collective patients' lived experiences to better select the right patient for the right intervention in the future. There are several low-cost methods that could improve data collection, including (1) establishing a patient safety organization registry for deep vein interventions with consecutive patient reporting requirements; (2) standardized protocol reporting and minimal follow-up intervals for disease; and (3) assessing patient-reported outcomes rather than only clinician-assessed outcomes ([Fig. 1]).[15] Economic incentives for medical device innovation and governmental-based funding opportunities often determine the quality and quantity of research in a particular subject area. Professional societies may help direct efforts toward unmet areas of need by identifying, publicizing, and sponsoring disease or procedural-specific initiatives.

Fig. 1 Post-thrombotic Syndrome Trial Design. RCT, randomized clinical trial; PTS, post-thrombotic syndrome.

As Duarte-Gamas et al have highlighted, the ball is now in our court: maximizing the benefits of CDT and newer thrombus reduction strategies requires putting in collective effort toward refining our definition of success and consistently reporting standardized outcomes.

Publication History

Received: 14 September 2023

Accepted: 14 September 2023

Article published online:
09 October 2023

• References

• 1 Benjamin EJ, Muntner P, Alonso A. et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2019 Update: a report from the American Heart Association. Circulation 2019; 139 (10) e56-e528
• 2 Wang J, Tan J, Hua L, Sheng Q, Huang X, Liu P. Genetic predisposition of both waist circumference and hip circumference increased the risk of venous thromboembolism. Thromb Haemost 2023; 123 (03) 347-361
• 3 Gurunathan U, Barras M, McDougall C, Nandurkar H, Eley V. Obesity and the risk of venous thromboembolism after major lower limb orthopaedic surgery: a literature review. Thromb Haemost 2022; 122 (12) 1969-1979
• 4 Lecumberri R, Ruiz-Artacho P, Tzoran I. et al; RIETE Investigators. Outcome of cancer-associated venous thromboembolism is more favorable among patients with hematologic malignancies than in those with solid tumors. Thromb Haemost 2022; 122 (09) 1594-1602
• 5 Trzepizur W, Gervès-Pinquié C, Heudes B. et al; Pays de la Loire Cohort Study Group. Sleep apnea and incident unprovoked venous thromboembolism: data from the Pays de la Loire sleep cohort. Thromb Haemost 2023; 123 (04) 393-401
• 6 Grandone E, Antonucci E, Colaizzo D. et al. Venous thromboembolism in women of childbearing age: insights from the START registry. Thromb Haemost 2023; 123 (11) 1060-1068
• 7 Hwang H-G, Lee JH, Bang S-M. Incidence of pregnancy-associated venous thromboembolism: second nationwide study. Thromb Haemost 2023; 123 (09) 904-910
• 8 Goualou M, Noumegni S, de Moreuil C. et al. Venous thromboembolism associated with assisted reproductive technology: a systematic review and meta-analysis. Thromb Haemost 2023; 123 (03) 283-294
• 9 Braekkan SK, Grosse SD, Okoroh EM. et al. Venous thromboembolism and subsequent permanent work-related disability. J Thromb Haemost 2016; 14 (10) 1978-1987
• 10 Goldhaber SZ, Magnuson EA, Chinnakondepalli KM, Cohen DJ, Vedantham S. Catheter-directed thrombolysis for deep vein thrombosis: 2021 update. Vasc Med 2021; 26 (06) 662-669
• 11 Duarte-Gamas L, Jácome F, Dias LR. et al. Catheter-directed thrombolysis protocols for deep venous thrombosis of the lower extremities - a systematic review and meta-analysis. Thromb Haemost 2024; 124 (02) 105-107
• 12 Engeseth M, Enden T, Sandset PM, Wik HS. Limitations of the Villalta scale in diagnosing post-thrombotic syndrome. Thromb Res 2019; 184: 62-66
• 13 Ning J, Ma W, Fish J, Trihn F, Lurie F. Biases of Villalta scale in classifying post-thrombotic syndrome in patients with pre-existing chronic venous disease. J Vasc Surg Venous Lymphat Disord 2020; 8 (06) 1025-1030
• 14 Moneta GL. Decreasing venous ulcers by 50% in 10 years: five critical issues in the diagnosis and investigation of venous disease. J Vasc Surg 2010; 52 (5, Suppl): 44S-46S
• 15 Lurie F, Obi A, Schul M, Hofmann LV, Kasper G, Wakefield T. Venous disease patient registries available in the United States. J Vasc Surg Venous Lymphat Disord 2018; 6 (01) 118-125