Source: Mastoris I, Kokkinidis DG, Bikakis I, et al. Catheter-directed thrombolysis vs. anticoagulation for the prevention and treatment of post-thrombotic syndrome in deep vein thrombosis: an updated systematic review and meta-analysis of randomized trials. Phlebology. 2019; 34(10): 675-682.
Study Population: 4 trials of 1005 patients with deep vein thrombosis
Efficacy Endpoints: Postthrombotic syndrome, patent iliofemoral veins, future venous thromboembolism
Harm Endpoints: Bleeding, all-cause mortality
Narrative: Clot formation in deep veins (deep vein thrombosis [DVT]), such as large veins in the lower extremities and pelvis, is common with an annual incidence approximating 900,000 in the United States.1, 2 Some patients with DVT (20%–50%) develop long-term complications such as postthrombotic syndrome (PTS).1, 2, 3 PTS is manifested by signs and symptoms including swelling of the affected limb, pain, cramps, burning or prickling sensations (paresthesias), itching, redness, skin color change, and varicose vein formation.4 The severe form of PTS can cause skin ulcers from venous stasis.4 These chronic symptoms can reduce patient mobility, affect quality of life, and increase health care costs, particularly with moderate and severe disease. The severity of PTS is determined by grading systems such as the Villalta score.1, 2, 3, 5 This scoring system is composed of signs and symptoms of PTS, with scores of 5, 6, 7, 8, 9 defined as mild and scores of ≥10 defined as moderate to severe.5 Drugs that prevent clot formation (anticoagulants) can treat DVT but do not prevent PTS in all patients, and residual clots and venous valvular incompetence due to the dilatation of the veins can increase the risk of PTS and recurrent VTE.6, 7, 8, 9 Dissolving the existing clot (thrombolysis) may reduce the risk of PTS but may also increase the risk of bleeding complications.10 To reduce the risk of bleeding, a clot-dissolving medication can be applied directly next to the clot, a strategy called catheter-directed thrombolysis (CDT).11, 12
The systematic review and meta-analysis summarized here included randomized controlled trials (RCTs) comparing CDT plus anticoagulation versus anticoagulation alone for adult patients with DVT.13 Prespecified outcomes included overall occurrence of PTS, iliofemoral vein patency, overall rates of recurrent VTE, bleeding rates, and all-cause mortality. The authors also preplanned a subgroup analysis based on severity of PTS (mild vs moderate to severe). The severity of PTS was determined by the Villalta score.5
The meta-analysis identified four RCTs comprising 1005 patients with DVT in aggregate. The trials were published between 2002 and 2017.13 Of the included patients, 491 underwent CDT plus anticoagulation and 514 were treated with anticoagulation only. Mean patient age was 53 years, and women accounted for 38% of patients. CDT devices varied. Three trials used alteplase for clot lysis via CDT and one used streptokinase. The anticoagulation regimens included unfractionated heparin or low-molecular-weight heparin with warfarin, although the largest trial (ATTRACT) utilized direct oral anticoagulants (DOACs).12
CDT reduced the risk of overall PTS (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.12 to 0.85, absolute risk difference [ARD] = 9.9%, number needed to treat [NNT] = 10). When only data for patients with moderate-to-severe PTS were analyzed, CDT did not offer any preventive benefit and also did not reduce the risk of future VTE. However, patients undergoing CDT were more likely to have patent iliofemoral veins (OR = 2.69, 95% CI = 1.07 to 6.75, ARD = 20.8%, NNT = 5). The rates of death or bleeding were not different between the groups in the overall study population.
The largest trial included in the systematic review (ATTRACT), composed of 692 patients (365 with mild PTS and 327 with moderate-to-severe PTS), showed no difference in PTS or recurrent VTE between the CDT and standard anticoagulation groups.12 However, this trial reported a greater bleeding risk in the CDT group compared to the anticoagulation-only group (1.7% vs 0.3%).12 Bleeding sites included gastrointestinal (two patients), retroperitoneal (two patients), and the device access site (two patients).
A recent Cochrane review published in 2021 evaluated systemic, locoregional, CDT, and pharmacomechanical thrombolysis for treatment of DVT.14 While the Cochrane review found that thrombolysis in general reduced the risk of PTS (risk ratio [RR] = 0.78, 95% CI = 0.66 to 0.93, ARD = 3.2%, NNT = 32, 6 months’ to 5 years’ follow-up, six trials), no reduction in PTS was detected in the CDT subgroup. Combined data from both systemic and local thrombolysis with CDT also suggested that this intervention was associated with increased risk of bleeding compared to standard anticoagulation (RR = 2.45,95% CI = 1.58 to 3.78, ARD = 4.4, number needed to harm = 22). This Cochrane review included only two of the studies from the systematic review by Mastoris et al. which we have summarized here.12, 13, 14, 15
Caveats: There was clinical heterogeneity with regard to devices, thrombolytic agents, and anticoagulation regimens among the different studies. Time to CDT may be an important variable in preventing PTS, as recently formed clots may respond better to thrombolysis.16 Thus, some have recommended that thrombolysis optimally should be performed within 10 days of the onset.16 However, included trials varied concerning time to treatment initiation (within 10 days in ATTRACT trial and 21 days in CaVenT).12, 15 Duration of follow-up also varied, ranging from 6 months to 5 years. Importantly, the ATTRACT trial utilized DOACs, compared to the other included trials that utilized unfractionated or low-molecular-weight heparin and warfarin.12 The ATTRACT trial also accounted for over half of the included patients, and it did not find a benefit for using CDT to reduce PTS in the overall population.12 Interestingly, this trial found no difference in thrombus removal success rate with CDT compared with anticoagulation alone. Therefore, it is possible the lack of benefit for preventing PTS may have been due to issues with the CDT approach and modality.12 Additional limitations for the meta-analysis include variations in PTS classification, which may have further influenced the outcomes and subgroup analyses. Of note, none of the included trials separated upper versus lower DVT and PTS, and this distinction may impact therapeutic approach and patient morbidity. Finally, the majority of patients analyzed in the systematic review suffered from mild PTS, and the overall number of patients with moderate-to-severe PTS was small. Therefore, the absence of benefit from CDT might be due to a type II error.
Based on the existing evidence, we have assigned a color recommendation of yellow (data Inadequate) for use of CDT to reduce risk of PTS in patients with DVT. This was based on several factors. Overall, CDT was associated with reduced risk of PTS, but there was a lack of benefit for moderate-to-severe PTS in the meta-analysis by Mastoris et al.13 Moreover, data were conflicting in the 2021 Cochrane review, which demonstrated reduced risk of PTS but increased risk of bleeding. The potential benefits and harms of CDT likely vary based on several factors, such as severity of DVT (patient symptoms, comorbidities, venous system involvement), patient activity levels, duration of DVT, and risk of bleeding. Further data from larger trials are needed to assess available devices, more current anticoagulation strategies with DOACs, and patient with various DVT severities.
The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.
Author: Brit Long, MD; Michael Gottlieb, MD
Supervising Editors: Shahriar Zehtabchi, MD
Published/Updated: October 26, 2021
The title bar is color-coded with our overall recommendation.