Thrombolytic strategies versus standard anticoagulation for acute deep vein thrombosis of the lower limb

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 the review first published in 2004.
Objectives
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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 methods
The Cochrane Vascular Information Specialist searched the Cochrane Vascular
Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED databases
and World Health Organization International Clinical Trials Registry Platform and
ClinicalTrials.gov trials registers to 21 April 2020. We also undertook reference
checking to identify additional studies.
Selection criteria
Randomised controlled trials (RCTs) examining thrombolysis (with or without
adjunctive clot removal strategies) and anticoagulation versus anticoagulation alone
for acute DVT were considered.
Data collection and analysis
For this update, CB screened the references identified by the search by title and
abstract. Articles selected for full text assessment were independently assessed by
two of three review authors or editorial support (CB, LW, MA, MS). Data were
extracted and checked by two of three authors or editorial support (CB, LW, MA, MS).
We assessed study quality with the Cochrane 'Risk of bias' tool. For dichotomous
outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence
interval (CI). The primary outcomes of interest were clot lysis, bleeding and post
thrombotic syndrome. Data were pooled using a fixed-effect model unless
heterogeneity was identified in which case a random-effects model was used. We
used GRADE to assess the overall certainty of the evidence supporting the outcomes
assessed in this review.
Main results
Two new studies were added for this update, therefore a total of 19 RCTs with 1943
participants are now included. These studies differed in the thrombolytic agent, doses
of agent and in the technique used to deliver it. Systemic, loco-regional and catheterdirected
thrombolysis (CDT) 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 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, 8 studies) and at
intermediate follow-up (RR 2.42; 95% CI 1.42 to 4.12, 654 participants, 7 studies;
moderate-certainty evidence). Two studies reported on clot lysis at late follow-up with
no benefit from thrombolysis seen at this time point (RR 3.25, 95% CI 0.17 to 62.63,
2 studies). No differences between strategies were detected by subgroup analysis at
any of these time points (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-
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certainty evidence). No differences between strategies were detected by subgroup
analysis (P = 0.25).
Up to five years after treatment slightly less 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, 6 studies; moderate-certainty evidence). This
reduction in PTS 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 investigated if the level of DVT (iliofemoral, femoropopliteal or non-specified) had
an effect on the incidence of PTS by subgroup analysis. No benefit of thrombolysis
was seen for either iliofemoral or femoropopliteal DVT (6 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.
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. Evidence suggests that systemic
administration of thrombolytics and CDT have similar effectiveness. Using GRADE
assessment, the evidence was judged to be of moderate-certainty due to many trials
having low numbers of participants. 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.