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Meta-Analysis
. 2021 Jan 19;1(1):CD002783.
doi: 10.1002/14651858.CD002783.pub5.

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

Cathryn Broderick  1 , Lorna Watson  2 , Matthew P Armon  3
Affiliations
Meta-Analysis

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

Cathryn Broderick et al. Cochrane Database Syst Rev. .

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 methods: 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.

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.

Trial registration: ClinicalTrials.gov NCT00251771 NCT01482273.

PubMed Disclaimer

Conflict of interest statement

CB is a member of Cochrane Vascular's editorial base staff. Where appropriate, editorial tasks were carried out by other group members. LW has declared that she received travel and accomodation fees from the European Society of Angiology for speaking at the 2012 meeting on this topic. LW is an editor for Cochrane Vascular but had no editor role for this review. MPA: none known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel plot of comparison: 1 Thrombolysis versus standard anticoagulation, outcome: 1.4 Bleeding (early, subgrouped by thrombolysis strategy).
1.1
1.1. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 1: Complete clot lysis (early, subgrouped by thrombolysis strategy)
1.2
1.2. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 2: Complete clot lysis (intermediate, subgrouped by thrombolysis strategy)
1.3
1.3. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 3: Complete clot lysis (late, subgrouped by thrombolysis strategy)
1.4
1.4. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 4: Bleeding (early, subgrouped by thrombolysis strategy)
1.5
1.5. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 5: PTS (intermediate, subgrouped by thrombolysis strategy)
1.6
1.6. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 6: PTS by iliofemoral/fempop (intermediate, subgrouped by location)
1.7
1.7. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 7: PTS (late, subgrouped by thrombolysis strategy)
1.8
1.8. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 8: Any improvement in venous patency (early)
1.9
1.9. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 9: Stroke (early, subgrouped by thrombolysis strategy)
1.10
1.10. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 10: Leg ulceration (intermediate, subgrouped by thrombolysis strategy)
1.11
1.11. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 11: Leg ulceration (late)
1.12
1.12. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 12: Mortality (early, subgrouped by thrombolysis strategy)
1.13
1.13. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 13: Mortality (intermediate, subgrouped by thrombolysis strategy)
1.14
1.14. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 14: Mortality (late, subgrouped by thrombolysis strategy)
1.15
1.15. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 15: Recurrent DVT (intermediate, subgrouped by thrombolysis strategy)
1.16
1.16. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 16: Recurrent DVT (late, subgrouped by thrombolysis strategy)
1.17
1.17. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 17: Pulmonary embolism (early, subgrouped by thrombolysis strategy)
1.18
1.18. Analysis
Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 18: Venous function (intermediate, subgrouped by thrombolysis strategy)
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References to studies awaiting assessment

Gong 2018 {published data only}
    1. Gong M, Gu J, Chen G, He X, Lou W, Chen L, et al. Interventional treatment by catheter-directed thrombolysis for subacute iliofemoral venous thrombosis: comparison of instant efficacy between recombinant human tissue plasminogen activator and urokinase. Chinese Journal of Radiology 2018;52(1):51-7.
Su 2017 {published data only}
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References to ongoing studies

ChiCTR‐INR‐16009090 {published data only}
    1. ChiCTR-INR-16009090. Combined pharmacomechanical thrombectomy and catheter-directed thrombolysis for acute lower extremity deep venous thrombosis: a multicenter prospective control study. chictr.org.cn/showprojen.aspx?proj=15097 (first posted 25 August 2016).
IRCT201108035625N3 {published data only}
    1. IRCT201108035625N3. Comparing the effect of conventional therapy (heparin followed by warfarin) with interventional therapy (thrombolysis with or without angioplasty and stenting) on venous patency in patients who admitted with acute iliofemoral DVT in Tehran Heart Center Emergency Department. en.irct.ir/trial/6154 (first received 13 August 2011).
NCT02959801 {published data only}
    1. NCT02959801. Outcome of percutaneous mechanical thrombectomy to treat acute deep venous thrombosis. clinicaltrials.gov/show/NCT02959801 (first posted 9 November 2016).

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References to other published versions of this review

Armon 2000
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Watson 2004
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