Thrombolysis for treatment of acute deep vein thrombosis

Background

Deep vein thrombosis (DVT) occurs when a blood clot forms in a leg vein. The clot can break up and move to the lungs, leading to a potentially serious blockage in blood flow (pulmonary embolism or PE). Because of the damage to the leg vein, post-thrombotic syndrome (PTS) may develop any time over the next couple of years. Symptoms include leg pain, swelling, skin pigmentation and leg ulcers, leading to loss of mobility. Anticoagulants are the standard treatment for DVT or a clot in a leg vein. These medications thin the blood to reduce further clots from forming and prevent PE; yet PTS can still develop. Another way of treating DVT is by thrombolysis. Thrombolysis breaks down the blood clot, and drugs such as streptokinase, urokinase and tissue plasminogen activator are infused into a vein in the arm or foot. In some cases, these drugs may be directly delivered to the site of the clot, using a catheter and X-ray control. Additional surgical techniques can also be used to help remove the clot. Possible harmful side effects that can happen after both anticoagulation and thrombolysis include bleeding complications, stroke or intracerebral haemorrhage.

To find out whether thrombolytic clot removal strategies and anticoagulation might be better than anticoagulation alone for the management of people with acute DVT of the leg, we reviewed the evidence from research studies.

How did we identify and evaluate the evidence?

First, we searched the medical literature for randomised controlled trials (RCTs), clinical studies where people are randomly put into one of two or more treatment groups. This type of study provides the most robust evidence about the effects of a treatment. We then compared the results, and summarised the evidence from all the studies. Finally, we assessed how certain the evidence was. To do this, we considered factors such as the way studies were conducted, study sizes, and consistency of findings across studies. Based on our assessments, we categorised the evidence as being of very low, low, moderate or high certainty.

What did we find?

We found 19 RCTs that included a total of 1943 people with acute DVT to receive either thrombolysis or anticoagulant treatment. Trials were conducted in Belgium, Canada, Denmark, Egypt, France, Germany, the Netherlands, Norway, South Africa, Sweden, Switzerland, Turkey, the UK and the USA. All trials included men and women ranging in age from 18 to 75 years, with more older adults.

Our review found moderate-certainty evidence that thrombolysis effectively dissolved the clot so that complete clot breakdown occurred more often with thrombolysis than with standard anticoagulant therapy. Those receiving thrombolysis had more bleeding complications than with standard anticoagulation (6.7% versus 2.2%). Most bleeding episodes occurred in the older studies. Six trials (1393 participants) continued for over six months and found that slightly fewer people developed PTS when treated with thrombolysis; 50% compared with 53% in the standard anticoagulation treatment group. Two trials (211 participants) that continued for over five years showed that fewer people developed PTS when treated with thrombolysis. Use of strict eligibility criteria appears to have improved the safety of this treatment, which is effective delivered directly to the clot by catheter or via the bloodstream from another vein. We did not find any evidence that the position of the clot within the leg made it more or less likely for people to get PTS. Future studies are needed to investigate what clot removal method is most beneficial to patient important outcomes including PTS, bleeding and quality of life.

How up-to date is this review?

The evidence in this Cochrane Review is current to 21 April 2020.

Authors' conclusions: 

Complete clot lysis occurred more frequently after thrombolysis (with or without additional clot removal strategies) and PTS incidence was slightly reduced. Bleeding complications also increased with thrombolysis, but this risk has decreased over time with the use of stricter exclusion criteria of studies. Evidence suggests that systemic administration of thrombolytics and CDT have similar effectiveness. Using GRADE, we judged the evidence to be of moderate-certainty, due to many trials having small numbers of participants or events, or both. Future studies are needed to investigate treatment regimes in terms of agent, dose and adjunctive clot removal methods; prioritising patient-important outcomes, including PTS and quality of life, to aid clinical decision making.

Read the full abstract...
Background: 

Standard treatment for deep vein thrombosis (DVT) aims to reduce immediate complications. Use of thrombolytic clot removal strategies (i.e. thrombolysis (clot dissolving drugs), with or without additional endovascular techniques), could reduce the long-term complications of post-thrombotic syndrome (PTS) including pain, swelling, skin discolouration, or venous ulceration in the affected leg. This is the fourth update of a Cochrane Review first published in 2004.

Objectives: 

To assess the effects of thrombolytic clot removal strategies and anticoagulation compared to anticoagulation alone for the management of people with acute deep vein thrombosis (DVT) of the lower limb.

Search strategy: 

The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries to 21 April 2020. We also checked the references of relevant articles to identify additional studies.

Selection criteria: 

We considered randomised controlled trials (RCTs) examining thrombolysis (with or without adjunctive clot removal strategies) and anticoagulation versus anticoagulation alone for acute DVT.

Data collection and analysis: 

We used standard methodological procedures as recommended by Cochrane. We assessed the risk of bias in included trials with the Cochrane 'Risk of bias' tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we calculated the risk ratio (RR) with the corresponding 95% confidence interval (CI). We pooled data using a fixed-effect model, unless we identified heterogeneity, in which case we used a random-effects model. The primary outcomes of interest were clot lysis, bleeding and post thrombotic syndrome.

Main results: 

Two new studies were added for this update. Therefore, the review now includes a total of 19 RCTs, with 1943 participants. These studies differed with respect to the thrombolytic agent, the doses of the agent and the techniques used to deliver the agent. Systemic, loco-regional and catheter-directed thrombolysis (CDT) strategies were all included. For this update, CDT interventions also included those involving pharmacomechanical thrombolysis. Three of the 19 included studies reported one or more domain at high risk of bias. We combined the results as any (all) thrombolysis interventions compared to standard anticoagulation.

Complete clot lysis occurred more frequently in the thrombolysis group at early follow-up (RR 4.75; 95% CI 1.83 to 12.33; 592 participants; eight studies) and at intermediate follow-up (RR 2.42; 95% CI 1.42 to 4.12; 654 participants; seven studies; moderate-certainty evidence). Two studies reported on clot lysis at late follow-up with no clear benefit from thrombolysis seen at this time point (RR 3.25, 95% CI 0.17 to 62.63; two studies). No differences between strategies (e.g. systemic, loco-regional and CDT) were detected by subgroup analysis at any of these time points (tests for subgroup differences: P = 0.41, P = 0.37 and P = 0.06 respectively).

Those receiving thrombolysis had increased bleeding complications (6.7% versus 2.2%) (RR 2.45, 95% CI 1.58 to 3.78; 1943 participants, 19 studies; moderate-certainty evidence). No differences between strategies were detected by subgroup analysis (P = 0.25).

Up to five years after treatment, slightly fewer cases of PTS occurred in those receiving thrombolysis; 50% compared with 53% in the standard anticoagulation (RR 0.78, 95% CI 0.66 to 0.93; 1393 participants, six studies; moderate-certainty evidence). This was still observed at late follow-up (beyond five years) in two studies (RR 0.56, 95% CI 0.43 to 0.73; 211 participants; moderate-certainty evidence).

We used subgroup analysis to investigate if the level of DVT (iliofemoral, femoropopliteal or non-specified) had an effect on the incidence of PTS. No benefit of thrombolysis was seen for either iliofemoral or femoropopliteal DVT (six studies; test for subgroup differences: P = 0.29). Systemic thrombolysis and CDT had similar levels of effectiveness. Studies of CDT included four trials in femoral and iliofemoral DVT, and results from these are consistent with those from trials of systemic thrombolysis in DVT at other levels of occlusion.

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