Catheter-directed thrombolysis for patients with acute lower extremity deep vein thrombosis: a meta-analysis

ABSTRACT Objectives: To evaluate case series studies that quantitatively assess the effects of catheter-directed thrombolysis (CDT) and compare the efficacy of CDT and anticoagulation in patients with acute lower extremity deep vein thrombosis (DVT). Methods: Relevant databases, including PubMed, Embase, Cochrane, Ovid MEDLINE and Scopus, were searched through January 2017. The inclusion criteria were applied to select patients with acute lower extremity DVT treated with CDT or with anticoagulation. In the case series studies, the pooled estimates of efficacy outcomes for patency rate, complete lysis, rethrombosis and post-thrombotic syndrome (PTS) were calculated across the studies. In studies comparing CDT with anticoagulation, summary odds ratios (ORs) were calculated. Results: Twenty-five articles (six comparing CDT with anticoagulation and 19 case series) including 2254 patients met the eligibility criteria. In the case series studies, the pooled results were a patency rate of 0.87 (95% CI: 0.85-0.89), complete lysis 0.58 (95% CI: 0.40-0.75), rethrombosis 0.11 (95% CI: 0.06-0.17) and PTS 0.10 (95% CI: 0.08-0.12). Six studies comparing the efficacy outcomes of CDT and anticoagulation showed that CDT was associated with a reduction of PTS (OR 0.38, 95%CI 0.26-0.55, p<0.0001) and a higher patency rate (OR 4.76, 95%CI 2.14-10.56, p<0.0001). Conclusion: Acute lower extremity DVT patients receiving CDT were found to have a lower incidence of PTS and a higher incidence of patency rate. In our meta-analysis, CDT is shown to be an effective treatment for acute lower extremity DVT patients.


Introduction
Deep vein thrombosis (DVT) in the lower extremities is a common vascular disease. DVT not only affects the treatment and prognosis for patients but also represents a significant clinical and economic disease burden on health care systems (1). The annual incidence of DVT in the leg is between 48 and 182 per 100,000 in the population (2) . As the population ages, the incidence of DVT is steadily increasing (3) . DVT can be complicated by pulmonary embolism (PE) in the short-term and, in the long-term, can cause post-thrombotic syndrome (PTS), which can adversely affect quality of life (2) .
The goals of treatment for acute lower extremity DVT are to prevent PE and reduce the incidence of PTS (4) .
Conventional anticoagulant treatment is mainly aimed at the prevention of PE and recurrent DVT (5) ; nevertheless, over half of DVT patients have developed some degree of PTS in the follow-up period after therapy (6) . Elastic compression stockings had also been recommended by the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for DVT patients to prevent PTS (9th edition) (7) . However, a metaanalysis (six random controlled trails including 1462 patients) recently showed that elastic compression stockings are not sufficient to prevent PTS (1) . Due to the limited effectiveness of anticoagulant therapy for DVT, catheter-directed thrombolysis (CDT) was developed by interventional radiologists as an invasive treatment for DVT in 1994 (8) . Although CDT was suggested by the American College of Chest Physicians Antithrombotic Therapy for Venous Thromboembolism (VTE) Disease CHEST Guideline (6) in 2016, evidence to support CDT for DVT is limited. To evaluate the evidence to support CDT for DVT, we conducted a meta-analysis.
The purpose of this meta-analysis was to (1) evaluate case series studies that quantitatively assess the effects of CDT and (2) compare the efficacy of CDT and anticoagulation in patients with acute lower extremity DVT.
We followed the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) statement for reporting the results of this metaanalysis (9) .
Additional studies were identified from the reference lists from the selected articles. Endnote software was used to manage the citations obtained through the database search.
Two authors (Wang and Zhang) independently established the study eligibility in the meta-analysis; any difference in the opinion about the eligibility was resolved by discussion or by consulting the corresponding author (Mu) and the research team. All abstracts were reviewed using inclusion and exclusion criteria in order to narrow the selection of studies considered for the metaanalysis. The studies had to meet the following eligibility studies was assessed using the Jadad scale. The quality items scored were the following: studies' description of randomization (2 points), blinding (2 points) and attrition information (1 point). Scores ≤2 is divided into low-quality publication and ≥ 3 is divided into highquality publication (10) . All included non-randomized comparative and case series studies were appraised by Wang L, Zhang CL, Mu SY, Ch Yeh, Chen LQ, Zhang ZJ.
The Newcastle-Ottawa scale (NOS) (11) . The quality of a study was judged on the selection of the study groups, the comparability of the groups, and the ascertainment of the outcomes. High quality was deemed if the studies received a star in every domain.
The efficacy outcomes included the occurrence of PTS, the rate of complete lysis, the patency rate and rethrombosis.
(3) The patency rate is the percentage (0-100%) of patency post treatment. Patency was defined as regained when the following findings occurred: Flow in the iliac and femoral vein, compressibility of the vein, and no functional venous obstruction (14) .
(4) Rethrombosis is defined as imaging proven DVT involving a new venous segment or a previously involved venous segment for which symptomatic and imaging improvement had been obtained in a patient with at least one prior episode of DVT (15) .
We used software Stata 12.0 (Stata Corporation, College Station, TX, USA) to perform the metaanalysis. The data on efficacy outcomes in the case series studies were pooled proportions and the data in RCT or nonrandomized comparative studies were extracted to calculate odds ratios (OR) and associated 95% confidence intervals (CIs). All meta-analyses were performed using both fixed and random effects models. Cochrane's Q statistic and I 2 statistics were calculated to provide information about the heterogeneity between studies. I 2 statistics <25% was considered as low heterogeneity, and I 2 statistics >50% was considered as high heterogeneity, according to the method suggested by Higgins and his colleagues (16) .
The publication bias was tested using the Egger's regression asymmetry test (17) and Begg adjusted rank correlation test (18) . Additionally, we performed subgroup analyses based on thrombolytic agent and study design. Several sensitivity analyses were done to test the robustness of our findings. All statistical tests were two-tailed.
(4) Rethrombosis: Among nine studies (19,(22)(23)25,(30)(31)(32)(34)(35) , one study (34) was excluded due to zero event of rethrombosis reported. Rethrombosis occurred in the early weeks or late years during follow-up.  provided in all RCTs. Therefore, the four RCTs (14,(39)(40)(41) were generally of high quality (Appendix 1). All non-RCTs and case series studies were assessed by the Newcastle-Ottawa scale; all of the 12 studies (19)(20)(21)(22)(23)25,28,(31)(32)(34)(35)38) were generally of high quality. Three studies (26,29,37) had outcomes present at the start of the study and two studies (26,33) had no assessment of outcomes. At the same time, five studies (24,27,30,36,42) had no adequate follow-up, and one study (29) had no report of the length of follow-up. These nine studies (24,(26)(27)(29)(30)33,(36)(37)42) were generally of low quality.  to benefit from CDT for its efficacy (6) .However, the evidence is of low quality and requires more studies comparison studies strengthen the conclusion that the CDT group has a significantly higher patency rate than the anticoagulation group. A previous meta-analysis (48) pooling eight RCTs in China suggested that the effective rate of CDT for the treatment of acute lower extremity DVT was significantly higher than that for superficial venous thrombolysis. The reason was thought to be that thrombolytic drugs can directly act on the thrombolysis site to maximize the activation of plasminogen and effectively dissolve the thrombus. The patency rate was gradually decreased from 1 year to 2 years and more than 2 years. Existing studies showed that venous patency was directly correlated with the development of PTS (49)(50) .  (51) . However, the suggested threshold for removal of an entire thrombus is unclear.
The significantly high heterogeneity observed in our paper may vary due to study designs and sample size among studies. A meta-analysis of 11 randomized anticoagulation trials showed that the residual thrombus burden after initial DVT therapy correlated strongly with the risk of recurrent venous thromboembolism (VTE) (52) .
In our meta-analysis of non-comparison studies, eight studies pooled a higher rate of rethrombosis than early recurrent thrombosis in 20 other studies according to the guidelines for the treatment of lower extremity DVT with use of endovascular thrombus removal (51) .
The discrepancy may be caused by the different degree of residual thrombus burden. No evaluable difference in recurrent DVT was found between the CDT and anticoagulation-alone groups in our metaanalysis of two involved studies. The TORPEDO trial (53) found a significant reduction in recurrent VTE comparing percutaneous endovenous intervention plus anticoagulation to anticoagulation alone. Hence, more controlled trials are needed to detect the incidence of rethrombosis for different DVT treatments.
Our subgroup analyses presented a bigger difference in rethrombosis between prospective and retrospective studies: rethrombosis in retrospective studies was 4 times higher than in prospective studies.
The reasons to account for this result were as follows: in the original retrospective studies (1) laboratory hypercoagulability as a known risk factor of recurrent DVT was found in a third of all patients (31) , and (2) a delay in stent placement was considered to be the main reason for early rethrombosis (35)