Abstract
Objective
Post-thrombotic syndrome (PTS) is a common complication of deep vein thrombosis (DVT) that can result in significant morbidity for the patient with detrimental impact on their quality of life. Evidence supporting lytic catheter-based interventions (LCBI) undertaken for early thrombus reduction in acute proximal DVT for the prevention of PTS is conflicting. Despite this, rates of LCBIs are increasing. To summaries the existing evidence and pool treatment effects, a meta-analysis of randomized controlled trials assessing the efficacy of LCBIs in proximal acute DVT for the prevention of PTS was undertaken.
Methods
This meta-analysis was undertaken aligning with PRISMA guidelines following a protocol pre-registered on PROSPERO. Online searches of Medline and Embase databases, as well as the gray literature, were performed up to December 2022. Included articles were randomized controlled trials that studied the use of LCBIs with additional anticoagulation vs anticoagulation alone and had determined follow-up periods. Outcomes of interest were PTS development, moderate to severe PTS, major bleeding episodes, and quality-of-life measures. Subgroup analyses were performed for DVTs involving the iliac vein and/r common femoral vein. Meta-analysis was performed using a fixed effects model. Quality assessment was performed using the Cochrane Risk of Bias and GRADE assessment tools.
Results
Three trials were included in the final meta-analysis, the Post-thrombotic Syndrome after Catheter-directed Thrombolysis for Deep Vein Thrombosis (CaVenT), Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT), and Ultrasound-accelerated Catheter-directed Thrombolysis Versus Anticoagulation for the Prevention of Post-thrombotic Syndrome (CAVA) trials, comprising 987 patients. Patients undergoing LCBIs had a reduced risk of PTS (relative risk [RR], 0.84; 95% confidence interval [CI], 0.74-0.95; P = .006) and a lower risk of developing moderate to severe PTS (RR, 0.75; 95% CI, 0.58-0.97; P = .03). LBCIs increased the risk of having a major bleed (RR, 2.03; 95% CI, 1.08-3.82; P = .03). In the iliofemoral DVT subgroup analysis, there was a trend toward decreasing the risk of developing PTS and moderate to severe PTS (P = .12 and P = .05, respectively). There was no significant difference in quality-of-life score (as measured by the Venous Insufficiency Epidemiological and Economic Study - Quality of Life/Symptoms) between the two groups (P = .51).
Conclusions
Pooling of current best evidence suggests that LCBIs in acute proximal DVT decreases the rate of PTS and moderate to severe PTS with a number needed to treat of 12 and 18, respectively. However, this is complicated by a significantly higher rate of major bleeding with a number needed to treat of 37. This evidence supports the use of LCBIs in selected patients, including those who are at low risk of major bleeding.
Keywords: Catheter directed thrombolysis, Deep vein thrombosis, Post thrombotic syndrome
Post-thrombotic syndrome (PTS) is a common consequence of deep vein thrombosis (DVT), with some prospective studies estimating an incidence of 20% to 50%.1 PTS manifests as a combination of symptoms and signs of chronic venous disease, including chronic leg pain, oedema, and venous ulceration.2,3 PTS has a major influence on patient quality of life (QOL) that is comparable with patients with angina, heart failure, or cancer.4,5 It has far-reaching economic repercussions, including increased health care expenditures and loss of employment.1
Early thrombus removal may reduce consequent development of PTS, aligning with the open vein theory. Immediate clot removal is thought to decrease PTS development by decreasing valvular injury and scarring.6 There are a variety of catheter-based interventions in use, broadly divided into three categories. Catheter-directed thrombolysis directly bathes the clot with thrombolytic agents. Pharmacomechanical thrombectomy physically breaks down the clot, for example, with a high-powered saline jet or an aspiration technique, in combination with the use of lytic agents.7 The third category uses mechanical means alone without the need for lytic therapy.8 Adjunctive interventions including venous stenting can also be used to improve long-term patency.9
Over the last decade, several randomized controlled trials (RCTs) have been carried out in the United States and Europe investigating the use of catheter-based interventions for the prevention of PTS. The aim of this systematic review and meta-analysis was to review published RCTs and evaluate whether LCBIs are effective in reducing the incidence of PTS in patients with proximal DVTs, alongside providing a thorough overview of included trials.
Methods
Search strategy and selection criteria
This systematic review and meta-analysis was undertaken in accordance with the PRISMA guidelines10 following a pre-registered, publicly available protocol (PROSPERO: CRD42020219737).
Online searches via the Ovid platform were performed on December 5, 2022. Both MEDLINE and EMBASE databases were searched with no restrictions imposed using the search strategy outlined in the Supplementary Table (online only).
Searches for grey literature were undertaken using Google Scholar using the same keywords. Reference screening of all included articles was performed to further identify eligible articles.
Eligibility criteria
Included articles had the following characteristics.
-
1.
Study design is an RCT.
-
2.
Articles report on the use of LCBIs for early thrombus removal in acute DVT in addition to anticoagulation, in comparison with standard therapy with anticoagulation alone.
-
3.
Articles reporting on adult patients with proximal DVTs, defined as a thrombosis involving the femoral, common femoral or iliac vein, or iliofemoral DVTs, defined as a thrombosis involving the iliac veins and/or the common femoral vein.
-
4.
Articles reporting on adult patients diagnosed with DVT presenting within 14 days of symptom onset (ie, acute).
-
5.
Articles must include a follow-up period to determine the rate of PTS development within the study group.
-
6.
Articles reporting a QOL measure (nonessential).
Articles were excluded if they had the following characteristics.
-
1.
Articles with a nonrandomized study design that are at a high risk of bias (ie, prospective nonrandomized studies).
-
2.
Articles failing to report a follow-up period to assess the outcome measure.
-
3.
Articles reporting on participants with chronic venous outflow obstruction.
-
4.
Articles where the full text is not available in English.
-
5.
Articles that are duplicate publications (ie, have been previously published as full-text publications).
-
6.
Articles conducted using data from animals (ie, nonhuman studies).
Identified articles were screened against the inclusion criteria by two reviewers (A.J., M.M.) independently. Mediation of included articles was carried out independently by a third reviewer (A.G.).
Data analysis
Study-level data from included articles were extracted using a standardized template in Microsoft Excel (Richmond, VA) by two reviewers (A.J., M.M.) independently. Discrepancies in extracted data were mediated by a third reviewer (A.G.). Data extracted included author, title, year, location, study design, participant number, randomization, inclusion criteria, interventions performed, assessor blinding, follow-up, outcomes, end points, rate of PTS, rate of moderate to severe PTS, major bleeding events, QOL measures, statistical analysis, loss to follow-up, and procedural complications.
For a given outcome, the last follow-up was used as the timepoint unless outcome measures had a common timepoint across several studies. Primary outcome measures included rates of PTS, moderate to severe PTS, QOL measures, and major bleeding events. Heterogeneity was assessed using the I2 test. Meta-analysis was performed using a fixed effects model as prespecified in the protocol. A fixed effects model was chosen based on the assumption that the number of studies would be low, with similar interventions for the same indication. Subgroup analyses were also performed on trials reporting on iliofemoral DVTs alone. Risk ratios were used as the effect measure.
The online platform GradePro was used to assess the certainty of the outcomes according to the GRADE principles. The Cochrane Risk of Bias assessment was undertaken by two reviewers (A.J., M.M.) independently to assess the quality of evidence of the included articles.
Results
Study selection
The study selection process is detailed in the PRISMA flow diagram (Fig 1).
Fig 1.
Flow diagram detailing study selection process.
Study designs
Six studies from three different trials were included in the systematic review, two each from the Post-thrombotic Syndrome after Catheter-directed Thrombolysis for Deep Vein Thrombosis (CaVenT),11,12 Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT),13,14 and Ultrasound-accelerated Catheter-directed Thrombolysis Versus Anticoagulation for the Prevention of Post-thrombotic Syndrome (CAVA) trials15,16 published between 2012 and 2021. All three trials were multicenter RCTs. Table I provides details of the included studies.
Table I.
Study characteristics of included studies in main analysis
| Study Name, author | Year | Type of study | Location | Participant number | Male, % | Age, median | Iliofemoral DVTs, % | Follow-up, months |
|---|---|---|---|---|---|---|---|---|
| CaVenT, Haig | 2016 | RCT | Norway | 176 | 63 | 53, 58a | 39 | 60 |
| ATTRACT, Vedantham | 2017 | RCT | USA | 691 | 62 | 53 | 57 | 24 |
| CAVA, Notten | 2021 | RCT | Netherlands | 120 | 48 | 49 | 100 | 39b |
DVT, Deep vein thrombosis; RCT, randomized controlled trial.
Age for the CaVenT trial is median value of the control and LCBI arm, respectively.
Median follow-up.
Participant characteristics
Participant characteristics of the studies included in the main analysis can be found in Table I. The CaVenT trial carried out in Norway included 176 participants and had the longest follow-up of 5 years in their long-term study. The ATTRACT trial carried out in the United States was the largest study with 691 participants but had the shortest follow-up at 2 years. The most recent trial was the CAVA trial in the Netherlands, which included 120 participants in their long-term follow-up study with a mean follow-up of 39 months. The CaVenT trial included patients with an objectively diagnosed DVT (via ultrasound examination and, if inconclusive, by computed tomography scan or venography) above the mid-thigh level. The ATTRACT trial included patients with a DVT in the femoral, common femoral, or iliac veins. The CAVA trial included patients with iliofemoral DVTs only, defined as a thrombus involving the common femoral vein or above.
The median age of the participants across the three trials ranged from 49 to 58 years. CaVenT and ATTRACT participants were predominantly men (63% and 62%, respectively), with men comprising 48% of the CAVA trial participants. All the CAVA participants had iliofemoral DVTs, compared with 57% and 39% of the patients in the ATTRACT and CaVenT trials, respectively. The median duration of symptom onset to inclusion was 6 days in the ATTRACT and CAVA trials, and a mean of 6.6 days in the CAVENT trial. The studies included in the subgroup analysis are discussed separately elsewhere in this article.
Interventions undertaken
Details of the interventions undertaken are outlined in Table II. The CaVenT trial used an alteplase infusion without any mechanical techniques. The ATTRACT trial used delivery of alteplase in a single session using the Angiojet or Trellis system followed by a slow alteplase infusion if there was residual thrombus. The CAVA trial used the Ekos Endowave pharmacomechanical system to deliver a thrombolytic infusion.
Table II.
Procedure characteristics of included studies
| Study Name, author | Year | Detail of procedure used in intervention arm | Details of additional procedures used | Additional procedures | Stenting |
|---|---|---|---|---|---|
| CaVenT, Enden | 2012 | Catheter-directed infusion of alteplase at 0.01 mg/kg/h for maximum duration of 96 h. Daily venography and infusion continued until complete lysis achieved or no progression of lysis. Adjunctive procedures at discretion of physician. | Balloon angioplasty, venous stenting, thrombus aspiration | 39 (43) | 15 (17) |
| ATTRACT, Vedantham | 2017 | If popliteal vein occluded or inferior vena cava involved, then an alteplase infusion first method for maximum of 30 h. | Balloon venoplasty, balloon maceration, venous stenting, catheter aspiration, thrombectomy with the use of AngioJet or Trellis System. | 297 (88) | 82 (24) |
| If above criteria not met, then a single session thrombus removal with rapid delivery of alteplase through the AngioJet or Trellis System and if residual thrombus present an alteplase infusion for maximum of 24 h. | |||||
| Stenting encouraged for lesions causing ≥50% narrowing of lumen, robust collateral filling or mean pressure gradient of >2 mm Hg. | |||||
| ATTRACT, Comerotaa | 2019 | As above | As above | 178 (91) | 70 (36) |
| CAVA, Notten | 2019 | Urokinase in combination with Ekos Endowave system (multiple high-frequency ultrasound transducers). A 250,000 IU bolus given immediately after insertion followed by 100 000 IU/h continuous infusion for a maximum duration of 96 h. Infusion terminated if patency of ≥90% was achieved, no progression of patency in 48 h as determined by daily venography or APPT, fibrinogen or plasma fibrinogen persistently deranged beyond acceptable limits. Adjunctive procedures at discretion of physician but encouraged if persistent lumen reduction of >50%. | Angioplasty, venous stenting, thrombo-suction, endophlebectomy, fistula formation | 42 (55) | 35 (45) |
APPT, Activated partial thromboplastin time.
Values are number (%).
Subgroup analysis of the ATTRACT trial on iliofemoral deep vein thromboses only.
In all three trials, adjunct procedures were performed at the physicians’ discretion, with both the ATTRACT and CAVA trials encouraging stenting for lesions causing >50% residual venous lumen reduction. The CAVA trial had the highest rate of stenting (45% of the patients in the intervention arm), compared with ATTRACT (24%) and CaVenT (17%).
Definitions of PTS
The ATTRACT and CaVenT trials used the International Society on Thrombosis and Haemostasis consensus criteria to diagnose PTS.17 This was defined as a Villalta score of 5 or higher, or the presence of an ulcer in the ipsilateral lower limb ≥6 months after DVT. The definition of PTS in the CAVA trial was according to the Villalta criteria, which required two time-spaced (≥3 months apart) assessments of a Villalta score of ≥5 at ≥3months after DVT.18 CAVA also provided results for the rates of PTS according to the International Society on Thrombosis and Haemostasis criteria, which were used in the meta-analysis, allowing a homogenous outcome measure across all three included trials.
Rate of PTS
Individual rates of PTS and moderate to severe PTS in the different studies are shown in Table III. Results of the meta-analysis are shown in Fig 2. Patients undergoing LCBIs had a reduced risk of PTS (relative risk [RR], 0.84; 95% confidence interval [CI], 0.74-0.95, number needed to treat [NNT], 12), as well as a lower risk of developing moderate to severe PTS (RR, 0.75; 95% CI, 0.58-0.97; NNT, 18).
Table III.
Rate of post-thrombotic syndrome (PTS) and moderate to severe PTS
| Study name, author | Year | Rate of PTS-LCBI | Rate of PTS- anticoagulation only | Rate of moderate to severe PTS- LCBI | Rate of moderate to severe PTS- anticoagulation only |
|---|---|---|---|---|---|
| CaVenT, Haig | 2016 | 42.5 | 70.8 | 6.9 | 15.7 |
| ATTRACT, Vedantham | 2017 | 46.7 | 48.2 | 17.9 | 23.7 |
| ATTRACT, Comerotaa | 2019 | 49.0 | 51.3 | 18.4 | 28.2 |
| CAVA, Notten | 2021 | 46.8 | 69.0 | 27.4 | 27.6 |
Values are percent.
Subgroup analysis of the ATTRACT trial on iliofemoral deep vein thromboses only.
Fig 2.
Forest plot illustrating relative risk (RR) of developing (A) post-thrombotic syndrome (PTS) and (B) moderate to severe PTS for lytic catheter-based interventions (LCBI) in comparison with anticoagulation alone. CI, confidence interval; df, degrees of freedom.
Risk of bleeding
Trials used a similar definition of what constitutes a major bleed.19 All three trials showed an increased risk of major bleeding with LCBIs.
The ATTRACT trial reported 19 (5.7%) major bleeding events in the LCBI arm compared with 13 (3.7%) in the group treated with anticoagulation alone. The CaVenT and CAVA trials had three (3.3%) and four (5.2%) major bleeding events, respectively, in their LCBI arms compared with none in the control arms. In the pooled analysis (Fig 3), LCBIs increases the risk of a major bleeding event (RR, 2.03; 95% CI, 1.08-3.82; number needed to harm, 37). None of the bleeding events were fatal.
Fig 3.
Forest plot illustrating relative risk (RR) of developing major bleeding for lytic catheter-based interventions (LCBI) in comparison to anticoagulation alone. CI, confidence interval; df, degrees of freedom.
Subgroup analysis in iliofemoral DVTs
A subgroup analysis was undertaken including patients with iliofemoral DVT, pooling the CAVA trial and the ATTRACT subgroup analyses (Fig 4, Fig 5, Fig 6). This analysis was not possible for the CaVenT study because there were no separate data available.
Fig 4.
Subgroup analysis of iliofemoral deep vein thromboses (DVTs). Forest plot illustrating relative risk (RR) of developing (A) post-thrombotic syndrome (PTS) and (B) moderate to severe PTS for lytic catheter-based interventions (LCBI) in comparison with anticoagulation alone. CI, confidence interval; df, degrees of freedom.
Fig 5.
Subgroup analysis of iliofemoral deep vein thromboses (DVTs). Forest plot illustrating relative risk (RR) of developing major bleeding for lytic catheter-based interventions (LCBI) in comparison to anticoagulation alone. CI, confidence interval; df, degrees of freedom.
Fig 6.
Subgroup Analysis of iliofemoral deep vein thromboses (DVTs). Forest plot illustrating mean difference in the Venous Insufficiency Epidemiological and Economic Study - Quality of Life/Symptoms score for lytic catheter-based interventions (LCBI) in comparison with anticoagulation alone. CI, confidence interval; df, degrees of freedom.
With respect to iliofemoral DVT, the ATTRACT trial had 391 participants (53% male) compared with 120 in the CAVA trial (48% male). The median age was 52 years (interquartile range, 39-62 years) in ATTRACT and 49 years (interquartile range, 37-64 years) in CAVA. ATTRACT excluded patients >75 years of age, whereas CAVA had a higher exclusion criterion of 85 years. The majority of DVTs in both studies were left sided (Table IV). Both trials had a median of 6 days duration from start of DVT symptoms to inclusion and randomization. Of the patients in the ATTRACT subgroup, 36% underwent stenting compared with 45% in CAVA (Table II).
Table IV.
Study characteristics of included studies in subgroup analysis
| Study name, author | Year | Type of study | Location | Participant number | Male, % | Age, median | BMI | Left sided DVT, % | Duration of symptoms at inclusion | Follow-up, months |
|---|---|---|---|---|---|---|---|---|---|---|
| ATTRACT, Comerotaa | 2019 | RCT | USA | 391 | 53 | 52 | 31 | 64 | 6 | 24 |
| CAVA, Notten | 2021 | RCT | Netherlands | 120 | 48 | 49 | 27.6 | 72 | 6 | 39b |
Subgroup analysis of the ATTRACT trial focusing on iliofemoral deep vein thromboses only.
Median follow-up .
The rate of PTS development in the ATTRACT subgroup analysis between the LCBI and anticoagulation only groups was similar (49% vs 51%; P = .59). The CAVA trial, in contrast, showed a decrease in PTS development in the LCBI group (47% vs 69%; odds ratio, 0.4; P = .01). The pooled meta-analysis showed a nonsignificantly reduced rate of PTS in the LCBI group (RR, 0.87; 95% CI, 0.74-1.03; P = .12). Conversely, the rate of moderate to severe PTS was reduced in the LCBI arm of the ATTRACT subgroup trial (18% vs 28%; RR, 0.65; P = .021) but not in the CAVA trial (27% vs 27%). The pooled meta-analysis was borderline for significance (RR, 0.73; 95% CI, 0.53-1.00; P = .05) (Fig 4).
Across the subgroup analysis, there were 7 major bleeds in the LCBI arm out of a combined total of 273 participants compared with 1 in 270 participants in the anticoagulation arm (RR, 4.93; 95% CI, 0.86-28.26; P = .07) (Fig 5). None of the bleeding events were fatal. Using the Venous Insufficiency Epidemiological and Economic Study - Quality of Life/Symptoms, there was no significant difference in QOL score between the two groups (Fig 6).
Risk of bias
Fig 7 shows the risk of bias using the Cochrane Risk of Bias assessment. The risk of bias for each study was similar for all the outcomes measured. The CaVenT trial had a low risk of overall bias. There was a higher drop-out rate in the control group (19 patients vs 6 patients) in the 5-year follow-up; however, a post hoc sensitivity analysis assuming the worst case scenario did not yield a different result. There were some concerns in the ATTRACT trial owing to deviations from intended interventions and missing outcome data. Five patients in the control group received LCBIs and 11 patients in the LCBI arm did not receive the intervention. There were no reasons given for these deviations. The per-protocol analysis revealed similar results to the intention-to-treat analysis, so this deviation is unlikely to be significant. Thirty-two percent of patients in the control arm and 23% of patients in the LCBI arm were not followed for the full 24 months, with the majority of these lost to follow-up (86 patients vs 62 patients). The CAVA trial also had an overall unclear risk of bias of attrition and deviations from the intended intervention. Owing to a combination of screening failures and withdrawals, 17% of patients enrolled did not start treatment and were not included in the intention-to-treat analysis. Only 79% of the patients participated in the long-term follow-up study; however, the numbers were similar between both groups and this factor is unlikely to have caused a significant impact.
Fig 7.
Risk of bias assessment.
There was a moderate certainty of evidence across all outcomes in the main analysis using the online assessment platform GradePro. The certainty of evidence was downgraded owing to the imprecision of the results obtained. Owing to the imprecision and inconsistency of the results, there was a low degree of certainty across outcomes in the subgroup analyses.
Discussion
The results of this meta-analysis show a significant reduction in the rate of PTS and moderate to severe PTS (NNT of 12 and 18, respectively) for those undergoing LCBIs for acute proximal DVT. However, LCBIs increases the risk of a major bleeding event. In the iliofemoral subgroup analysis, rates of both PTS and moderate to severe PTS were lower in the LCBI arm, but these results did not reach statistical significance.
These findings demonstrate that the efficacy of LCBIs in preventing PTS was less than anticipated. A meta-analysis of six studies published in 2014 found that LCBIs reduced the risk of PTS compared with anticoagulation alone (odds ratio, 0.4; 95% CI, 0.19-0.96).20 Correspondingly, in their sample size calculations, all three trials had an estimated a greater treatment effect size. In the CaVenT trial, PTS rates were expected to be 25% in the control arm and <10% in the LCBI arm at the 2-year follow-up, a RR reduction of 60%.11 The ATTRACT and CAVA trials calculated that the intervention arm would result in a reduction in PTS development by one-third (30% in control arm and <20% in the LCBI arm) and 68% (25% in control arm and <8% in the LCBI arm), respectively.13,15 Despite the pooled PTS rates in both the LCBI and control arms being higher than predicted (46% and 55%, respectively), the effect size was relatively modest with a risk reduction of 16%.
An interesting outcome of both the CaVenT and CAVA trials has been the increase in benefit that LCBIs confer over time. Between the 2- and 5-year follow-up in the CaVenT trial, the NNT to prevent PTS decreased from seven to four.11,12 Between the 12-month and the 39-month follow-up in the CAVA study, the NNT to prevent PTS decreased from 27 to 5, with the latter result reaching the threshold of significance.15,16 A longer follow-up study was not conducted for the ATTRACT trial. In the CaVenT trial, this change in PTS development between the two time points was associated with increased patency and decreased reflux in the LCBI arm.12 Future studies should include follow-up of >12 to 24 months to investigate the long-term benefit of LCBIs in preventing PTS.
Definitions of successful early thrombus removal differed across trials, and there is currently no consensus or accepted definition of what constitutes successful thrombolysis. The ATTRACT trial classified individuals into groups with complete lysis, light residual thrombus (score of ≤6) and those with substantial residual thrombus (score of >6) based on the Marder scale evaluated after lysis.21 Successful thrombolysis was defined by the CAVA study as an achieved patency of >90% with acceptable inflow and outflow in all afflicted vein segments as determined by venous angiography after the intervention.22 CaVenT assessed the thrombus score before and after lysis, with a lysis removal of >50% deemed successful.23
Importantly, CAVA noted a decrease in symptom severity in patients with successful thrombolysis (3.50 vs 4.88 on the Venous Clinical Severity Score severity scale; P = .02). Similarly, the ATTRACT trial reported reduced severity of PTS in patients with no residual thrombus after lysis.21,22 However, none of the trials could determine a link between successful thrombolysis and the long-term development of PTS (as a dichotomous outcome). CaVenT could not establish a link between the lysis grade or postlysis score and the emergence of PTS at 2 years.23 Only one-half of the patients undergoing thrombolysis in the CAVA trial were judged to have successful thrombolysis and there was no significant difference in the development of PTS between these patients and those with unsuccessful thrombolysis (37% vs 44%; P = .44).22 Patients with complete thrombolysis, small residual thrombus, and substantial residual thrombus all experienced similar PTS rates in the ATTRACT trial (46%, 47%, and 53%, respectively).21 In a separate study, however, an analysis of 71 individuals with iliofemoral DVTs revealed a direct link between post-thrombotic morbidity and residual thrombus after lysis.24 More research on the relationship between successful lysis and the development of PTS is needed. However, doing so is challenging given the lack of an international agreed definition of successful treatment.
Across the three RCTs, a variety of techniques for early thrombus removal were investigated. The thrombolytic agent differed between the trials, with the CaVenT and ATTRACT trial using alteplase whilst the CAVA trial used urokinase (Table II). CaVenT used thrombolysis alone, without any mechanical element. In the ATTRACT trial, two different devices were used, either pharmacomechanical therapy using either AngioJet (a rheolytic device) or Trellis (an aspiration device). The CAVA trial used neither of these, deploying the ultrasound-based Ekos Endowave system.
Since the publication of the trials, there has been a change in the techniques used in clinical practice, with some centers using mechanical thrombectomy alone without lytic therapy.25 Hence, these trials may no longer reflect contemporary venous practice; however, high-quality evidence is required to support this novel practice.
Our meta-analysis on PTS rates in the overall group had an I2 result of 81%. This is likely an overestimate of the actual heterogeneity, because all three trial populations were similar and the direction of change is consistent between them. The high value of the I2 is likely biased owing to the small number of studies in our analysis. I2 can be imprecise and biased with the heterogeneity overestimated in meta-analysis with fewer than seven studies.26
According to our study's subgroup analysis, LCBIs seems to be less effective for treating iliofemoral DVTs. This comparison lacked statistical significance and contradicted previous evidence in the literature. The result is likely explained by the poor outcomes in the CAVA trial and the exclusion of the CaVenT trial, which had the greatest favorable impact in the main analysis. Considering the signal of efficacy demonstrated here, future work using contemporary techniques, with adequate records of technical success, addressing the severity of disease in place of a dichotomous outcome, is required.
Conclusions
LCBIs in acute lower limb DVTs are likely to reduce the development of PTS and moderate to severe PTS as measured by the Vilalta score; however, the magnitudes of risk reduction are not as large as previously thought. The decreases in PTS development are accompanied by a small but significant increase in major bleeding complications. Hence, in light of the modest risk reduction, patient selection is paramount. Further trials using contemporary devices and techniques to address if early thrombus removal with a lower risk of major bleeding can be achieved are required.
Author Contributions
Conception and design: AJ, MM, AG, BT, SO, JS, AD
Analysis and interpretation: AJ, MM, AG, BT, SO, JS, AD
Data collection: AJ, MM, AG, BT
Writing the article: AJ, MM, AG, BT
Critical revision of the article: AJ, MM, AG, BT, SO, JS, AD
Final approval of the article: AJ, MM, AG, BT, SO, JS, AD
Statistical analysis: AJ, MM, AG, AD
Obtained funding: Not applicable
Overall responsibility: AD
Footnotes
The infrastructure for this work was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC). The funder had no role in this analysis.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.
Additional material for this article may be found online at www.jvsvenous.org.
Appendix
Additional material for this article may be found online at www.jvsvenous.org.
Appendix (online only)
Supplementary Table (online only).
Search terms
| DVT∗ OR Deep Vein Thromb∗ OR Femoral Vein thromb∗ OR Femoral thomb∗ OR Iliofemoral thromb∗ OR Iliac vein thromb∗ OR iliac thromb∗ OR superficial femoral thromb∗ OR vein∗adj4 thromb∗ |
| AND |
| (Thrombolysis OR Thrombolys∗ OR PCDT OR Stent∗ OR Thrombolytic therapy) |
| AND |
| (Post thrombotic syndrome OR Post-thrombotic syndrome OR Postthrombotic syndrome OR Postphlebitic syndrome OR Chronic venous insufficiency OR Chronic venous disease OR Venous Ulcer∗ OR Venous Claudication OR Venous Ulceration OR PTS OR Post-phlebtiic syndrome) |
| AND |
| (Randomised-controlled trial OR Randomized-controlled trial OR Randomized controlled trial OR Randomised controlled trial OR RCT) |
References
- 1.Kahn S.R., Comerota A.J., Cushman M., et al. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014;130:1636–1661. doi: 10.1161/CIR.0000000000000130. [DOI] [PubMed] [Google Scholar]
- 2.Ashrani A.A., Heit J.A. Incidence and cost burden of post-thrombotic syndrome. J Thromb Thrombolysis. 2009;28:465–476. doi: 10.1007/s11239-009-0309-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Eklof B., Perrin M., Delis K., Rutherford R., Gloviczki P. Updated terminology of chronic venous disorders: the VEIN-TERM transatlantic interdisciplinary consensus document. J Vasc Surg. 2009;49:498–501. doi: 10.1016/j.jvs.2008.09.014. [DOI] [PubMed] [Google Scholar]
- 4.Kahn S.R., Ducruet T., Lamping D.L., et al. Prospective evaluation of health-related quality of life in patients with deep venous thrombosis. Arch Intern Med. 2005;165:1173–1178. doi: 10.1001/archinte.165.10.1173. [DOI] [PubMed] [Google Scholar]
- 5.Kahn S.R., Shbaklo H., Lamping D.L., et al. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost. 2008;6:1105–1112. doi: 10.1111/j.1538-7836.2008.03002.x. [DOI] [PubMed] [Google Scholar]
- 6.Cosmi B., Palareti G. “Early thrombus removal” in iliac-femoral deep vein thrombosis for prevention of post-thrombotic syndrome. Ann Transl Med. 2019;7:S343. doi: 10.21037/atm.2019.09.102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Go C., Chaer R.A., Avgerinos E.D. Catheter interventions for acute deep venous thrombosis: Who, when and how. Vasc Endovasc Rev. 2020;3 [Google Scholar]
- 8.Benarroch-Gampel J., Pujari A., Aizpuru M., Rajani R.R., Jordan W.D., Crawford R. Technical success and short-term outcomes after treatment of lower extremity deep vein thrombosis with the ClotTriever system, a preliminary experience. J Vasc Surg Venous Lymphat Disord. 2020;8:174–181. doi: 10.1016/j.jvsv.2019.10.024. [DOI] [PubMed] [Google Scholar]
- 9.Fleck D., Albadawi H., Shamoun F., Knuttinen G., Naidu S., Oklu R. Catheter-directed thrombolysis of deep vein thrombosis: literature review and practice considerations. Cardiovasc Diagn Ther. 2017;7:S228. doi: 10.21037/cdt.2017.09.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Page M.J., McKenzie J.E., Bossuyt P.M., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10:1. doi: 10.1186/s13643-021-01626-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Enden T., Haig Y., Kløw N.E., et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet. 2012;379:31–38. doi: 10.1016/S0140-6736(11)61753-4. [DOI] [PubMed] [Google Scholar]
- 12.Haig Y., Enden T., Grøtta O., et al. Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial. Lancet Haematol. 2016;3:e64–e71. doi: 10.1016/S2352-3026(15)00248-3. [DOI] [PubMed] [Google Scholar]
- 13.Vedantham S., Goldhaber S.Z., Julian J.A., et al. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med. 2017;377:2240–2252. doi: 10.1056/NEJMoa1615066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Comerota A.J., Kearon C., Gu C.S., et al. Endovascular thrombus removal for acute iliofemoral deep vein thrombosis: analysis from a stratified multicenter randomized trial. Circulation. 2019;139:1162–1173. doi: 10.1161/CIRCULATIONAHA.118.037425. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Notten P., ten Cate-Hoek A.J., Arnoldussen C.W., et al. Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial. Lancet Haematol. 2020;7:e40–e49. doi: 10.1016/S2352-3026(19)30209-1. [DOI] [PubMed] [Google Scholar]
- 16.Notten P., de Smet A.A., Tick L.W., et al. CAVA (ultrasound-accelerated catheter-directed thrombolysis on preventing post-thrombotic syndrome) trial: long-term follow-up results. J Am Heart Assoc. 2021;10 doi: 10.1161/JAHA.120.018973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Kahn S.R., Partsch H., Vedantham S., Prandoni P., Kearon C. Subcommittee on control of anticoagulation of the scientific and Standardization Committee of the international Society on thrombosis and Haemostasis. Definition of post-thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization. J Thromb Haemost. 2009;7:879–883. doi: 10.1111/j.1538-7836.2009.03294.x. [DOI] [PubMed] [Google Scholar]
- 18.Villalta S.B., Bagatella P., Piccioli A., Lensing A., Prins M.H., Prandoni P. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis. 1994;24:158a. [Google Scholar]
- 19.Schulman S., Kearon C. Subcommittee on control of anticoagulation of the scientific and standardization Committee of the international Society on thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–694. doi: 10.1111/j.1538-7836.2005.01204.x. [DOI] [PubMed] [Google Scholar]
- 20.Du G.C., Zhang M.C., Zhao J.C. Catheter-directed thrombolysis plus anticoagulation versus anticoagulation alone in the treatment of proximal deep vein thrombosis-a meta-analysis. Vasa. 2015;44:195–202. doi: 10.1024/0301-1526/a000430. [DOI] [PubMed] [Google Scholar]
- 21.Razavi M.K., Salter A., Goldhaber S.Z., et al. Correlation between post-procedure residual thrombus and clinical outcome in deep vein thrombosis patients receiving pharmacomechanical thrombolysis in a multicenter randomized trial. J Vasc Interv Radiol. 2020;31:1517–1528. doi: 10.1016/j.jvir.2020.07.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Notten P., Arnoldussen C.W., Brans R., et al. Association of successful ultrasound-accelerated catheter-directed thrombolysis with postthrombotic syndrome: a post hoc analysis of the CAVA trial. Thromb Haemost. 2020;120:1188–1199. doi: 10.1055/s-0040-1713171. [DOI] [PubMed] [Google Scholar]
- 23.Haig Y., Enden T., Slagsvold C.E., Sandvik L., Sandset P.M., Kløw N.E. Determinants of early and long-term efficacy of catheter-directed thrombolysis in proximal deep vein thrombosis. J Vasc Interv Radiol. 2013;24:17–24. doi: 10.1016/j.jvir.2012.09.023. [DOI] [PubMed] [Google Scholar]
- 24.Comerota A.J., Grewal N., Martinez J.T., et al. Postthrombotic morbidity correlates with residual thrombus following catheter-directed thrombolysis for iliofemoral deep vein thrombosis. J Vasc Surg. 2012;55:768–773. doi: 10.1016/j.jvs.2011.10.032. [DOI] [PubMed] [Google Scholar]
- 25.Wong P.C., Chan Y.C., Law Y., Cheng S.W. Percutaneous mechanical thrombectomy in the treatment of acute iliofemoral deep vein thrombosis: a systematic review. Hong Kong Med J. 2019;25:48. doi: 10.12809/hkmj187491. [DOI] [PubMed] [Google Scholar]
- 26.von Hippel P.T. The heterogeneity statistic I2 can be biased in small meta-analyses. BMC Med Res Methodol. 2015;15:1–8. doi: 10.1186/s12874-015-0024-z. [DOI] [PMC free article] [PubMed] [Google Scholar]