NIHR Signal Thrombolysis may reduce complications of deep vein thrombosis

Published on 18 April 2017

Blood clots are cleared quickly for people who develop them in the deep leg veins if they receive thrombolysis drugs alongside other treatments directly into their veins. The chance of successful break down of the clot was compared with the chance following standard anti-clotting drugs alone, such as heparin and warfarin.

This Cochrane review found that over twice as many deep clots were completely broken down in the thrombolysis group compared with usual treatments. Thrombolysis also reduced the risk of long-term problems such as pain, swelling and skin damage, known as post-thrombotic syndrome, by a third.

However, bleeding was twice as common in people given thrombolysis (10%) than anticoagulants alone (4%). The specific drug, dose or method of administration used made no difference to the rate of this adverse effect.

This highlights the need for treatment to be targeted at people who are likely to gain most benefit, such as those with clots in the pelvis and thigh which carry higher risk of complications.

Why was this study needed?

Around one person in every 1,000 in the UK develops deep vein thrombosis (DVT) each year. It is usually treated with anticoagulant drugs to stop blood clots forming and reduce risk of the clot travelling to the heart and lungs and causing pulmonary embolism.

Despite anticoagulation, between 20 and 40% of people develop post-thrombotic syndrome, including long term swelling, aching and skin changes, which can have a long-term impact on quality of life.

Thrombolysis is an add on treatment option where drugs are injected into the veins to dissolve the clot. This could reduce risk of permanent damage to the veins and subsequent post-thrombotic syndrome. However, thrombolysis may also increase bleeding risk so isn’t used routinely. There were only 192 instances of thrombolysis recorded in England in 2014-15.

This study is the third update to previous Cochrane reviews, the first published in 2004. The authors were interested in quantifying the relative benefits and harms of thrombolysis treatments. No new trials were found, but additional follow-up results from one of the trials were included in this version.

What did this study do?

This systematic review included 17 randomised controlled trials comparing thrombolysis and anticoagulant drugs with anticoagulant drugs alone in 1,103 adults with confirmed DVT.

Participants were mostly older adults and treated within 21 days of symptom onset. The trials used different doses and types of thrombolytic drugs. Streptokinase and tissue plasminogen activator were most used. These were injected either into the arm veins (systemic), injected locally into the leg, or delivered via catheter. Trials were carried out in the USA, Scandinavia, Germany and the UK.

Fourteen studies were rated as low risk of bias while three were flagged as high risk. Common areas of potential bias related to method of treatment allocation. Overall, the evidence was graded as moderate quality for the main outcomes, which improves the reliability of the review.

What did it find?

  • Thrombolysis increased the chance that the blood clot was completely broken down. In the thrombolysis group 51% had complete clot breakdown at six months to five years after treatment versus 33% of the anticoagulation group (relative risk [RR] 2.44, 95% confidence interval [CI] 1.4 to 4.27; seven trials, 630 participants).
  • Fewer people developed post-thrombotic syndrome when assessed both before and after five years after thrombolysis. For example three trials with 306 people reported post-thrombotic syndrome at between six months and five years follow-up in 45% of the thrombolysis group versus 66% of the anticoagulant group (RR 0.66, 95% CI 0.53 to 0.81). Similar proportions were found in the two trials including that followed people beyond five years.
  • Bleeding complications were more common in people receiving thrombolysis, reported in 10% versus 4% of those receiving anticoagulation (RR 2.23, 95% CI 1.41 to 3.52; 17 trials, 1103 people).
  • Method of drug delivery (systemic injection or catheter) did not influence outcomes.
  • There was insufficient data to give reliable assessment of effects on stroke, death pulmonary embolism or mortality outcomes.

What does current guidance say on this issue?

The NICE guideline on diagnosis and management of venous thromboembolic diseases says that catheter-directed thrombolytic therapy should be considered only in certain circumstances. Patients should have a DVT above calf level, have had symptoms for less than 14 days, have good functional status and a life expectancy of a year or more, and have a low risk of bleeding.

NICE have also published guidance on a type of catheter-directed thrombolysis that uses ultrasound. There isn’t yet enough evidence to recommend routine use of this enhanced procedure.

What are the implications?

Thrombolysis improves the chance of successful clot breakdown and may prevent longer-term complications such as post-thrombotic syndrome. However, patient factors such as duration and location of the clot seem key to a successful balance of risk and benefit.

The strict eligibility criteria of more recent studies improved safety in terms of bleeding. This suggests that thrombolysis should only be considered for patients who meet select criteria. Individuals with clots in the pelvis and thigh, which carry higher risk of complications, may be likely to gain most benefit.

The review is not able to determine which drug, dose or method of delivery is most effective.

Citation and Funding

Watson L, Broderick C, Armon MP. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev. 2016;(11):CD002783.

Bibliography

NHS Choices. Complications of deep vein thrombosis. London: Department of Health; 2016.

NHS Digital. Hospital Episode Statistics, Admitted Patient Care – England, 2014-15. London: NHS Digital; 2015.

NICE. Ultrasound-enhanced, catheter-directed thrombolysis for deep vein thrombosis. IPG523. London: National Institute for Health and Care Excellence; 2015.

NICE. Venous thromboembolic diseases: diagnosis, management and thrombophilia. CG144. London: National Institute for Health and Care Excellence; updated 2015.

Why was this study needed?

Around one person in every 1,000 in the UK develops deep vein thrombosis (DVT) each year. It is usually treated with anticoagulant drugs to stop blood clots forming and reduce risk of the clot travelling to the heart and lungs and causing pulmonary embolism.

Despite anticoagulation, between 20 and 40% of people develop post-thrombotic syndrome, including long term swelling, aching and skin changes, which can have a long-term impact on quality of life.

Thrombolysis is an add on treatment option where drugs are injected into the veins to dissolve the clot. This could reduce risk of permanent damage to the veins and subsequent post-thrombotic syndrome. However, thrombolysis may also increase bleeding risk so isn’t used routinely. There were only 192 instances of thrombolysis recorded in England in 2014-15.

This study is the third update to previous Cochrane reviews, the first published in 2004. The authors were interested in quantifying the relative benefits and harms of thrombolysis treatments. No new trials were found, but additional follow-up results from one of the trials were included in this version.

What did this study do?

This systematic review included 17 randomised controlled trials comparing thrombolysis and anticoagulant drugs with anticoagulant drugs alone in 1,103 adults with confirmed DVT.

Participants were mostly older adults and treated within 21 days of symptom onset. The trials used different doses and types of thrombolytic drugs. Streptokinase and tissue plasminogen activator were most used. These were injected either into the arm veins (systemic), injected locally into the leg, or delivered via catheter. Trials were carried out in the USA, Scandinavia, Germany and the UK.

Fourteen studies were rated as low risk of bias while three were flagged as high risk. Common areas of potential bias related to method of treatment allocation. Overall, the evidence was graded as moderate quality for the main outcomes, which improves the reliability of the review.

What did it find?

  • Thrombolysis increased the chance that the blood clot was completely broken down. In the thrombolysis group 51% had complete clot breakdown at six months to five years after treatment versus 33% of the anticoagulation group (relative risk [RR] 2.44, 95% confidence interval [CI] 1.4 to 4.27; seven trials, 630 participants).
  • Fewer people developed post-thrombotic syndrome when assessed both before and after five years after thrombolysis. For example three trials with 306 people reported post-thrombotic syndrome at between six months and five years follow-up in 45% of the thrombolysis group versus 66% of the anticoagulant group (RR 0.66, 95% CI 0.53 to 0.81). Similar proportions were found in the two trials including that followed people beyond five years.
  • Bleeding complications were more common in people receiving thrombolysis, reported in 10% versus 4% of those receiving anticoagulation (RR 2.23, 95% CI 1.41 to 3.52; 17 trials, 1103 people).
  • Method of drug delivery (systemic injection or catheter) did not influence outcomes.
  • There was insufficient data to give reliable assessment of effects on stroke, death pulmonary embolism or mortality outcomes.

What does current guidance say on this issue?

The NICE guideline on diagnosis and management of venous thromboembolic diseases says that catheter-directed thrombolytic therapy should be considered only in certain circumstances. Patients should have a DVT above calf level, have had symptoms for less than 14 days, have good functional status and a life expectancy of a year or more, and have a low risk of bleeding.

NICE have also published guidance on a type of catheter-directed thrombolysis that uses ultrasound. There isn’t yet enough evidence to recommend routine use of this enhanced procedure.

What are the implications?

Thrombolysis improves the chance of successful clot breakdown and may prevent longer-term complications such as post-thrombotic syndrome. However, patient factors such as duration and location of the clot seem key to a successful balance of risk and benefit.

The strict eligibility criteria of more recent studies improved safety in terms of bleeding. This suggests that thrombolysis should only be considered for patients who meet select criteria. Individuals with clots in the pelvis and thigh, which carry higher risk of complications, may be likely to gain most benefit.

The review is not able to determine which drug, dose or method of delivery is most effective.

Citation and Funding

Watson L, Broderick C, Armon MP. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev. 2016;(11):CD002783.

Bibliography

NHS Choices. Complications of deep vein thrombosis. London: Department of Health; 2016.

NHS Digital. Hospital Episode Statistics, Admitted Patient Care – England, 2014-15. London: NHS Digital; 2015.

NICE. Ultrasound-enhanced, catheter-directed thrombolysis for deep vein thrombosis. IPG523. London: National Institute for Health and Care Excellence; 2015.

NICE. Venous thromboembolic diseases: diagnosis, management and thrombophilia. CG144. London: National Institute for Health and Care Excellence; updated 2015.

Thrombolysis for acute deep vein thrombosis

Published on 11 November 2016

Watson, L.,Broderick, C.,Armon, M. P.

Cochrane Database Syst Rev Volume 11 , 2016

BACKGROUND: Standard treatment for deep vein thrombosis aims to reduce immediate complications. Use of thrombolysis or clot dissolving drugs 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 third update of a review first published in 2004. OBJECTIVES: To assess the effects of thrombolytic therapy and anticoagulation compared to anticoagulation alone for the management of people with acute deep vein thrombosis (DVT) of the lower limb as determined by the effects on pulmonary embolism, recurrent venous thromboembolism, major bleeding, post-thrombotic complications, venous patency and venous function. SEARCH METHODS: For this update the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (February 2016). In addition the CIS searched the Cochrane Register of Studies (CENTRAL (2016, Issue 1)). Trial registries were searched for details of ongoing or unpublished studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) examining thrombolysis and anticoagulation versus anticoagulation for acute DVT were considered. DATA COLLECTION AND ANALYSIS: For this update (2016), LW and CB selected trials, extracted data independently, and sought advice from MPA where necessary. 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). Data were pooled using a fixed-effect model unless significant heterogeneity was identified in which case a random-effects model was used. GRADE was used to assess the overall quality of the evidence supporting the outcomes assessed in this review. MAIN RESULTS: Seventeen RCTs with 1103 participants were included. These studies differed in the both thrombolytic agent used and in the technique used to deliver it. Systemic, loco-regional and catheter-directed thrombolysis (CDT) were all included. Fourteen studies were rated as low risk of bias and three studies were rated as high risk of bias. We combined the results as any (all) thrombolysis compared to standard anticoagulation. Complete clot lysis occurred significantly more often in the treatment group at early follow-up (RR 4.91; 95% CI 1.66 to 14.53, P = 0.004) and at intermediate follow-up (RR 2.44; 95% CI 1.40 to 4.27, P = 0.002; moderate quality evidence). A similar effect was seen for any degree of improvement in venous patency. Up to five years after treatment significantly less PTS occurred in those receiving thrombolysis (RR 0.66, 95% CI 0.53 to 0.81; P < 0.0001; moderate quality evidence). This reduction in PTS was still observed at late follow-up (beyond five years), in two studies (RR 0.58, 95% CI 0.45 to 0.77; P < 0.0001; moderate quality evidence). Leg ulceration was reduced although the data were limited by small numbers (RR 0.87; 95% CI 0.16 to 4.73, P = 0.87). Those receiving thrombolysis had increased bleeding complications (RR 2.23; 95% CI 1.41 to 3.52, P = 0.0006; moderate quality evidence). Three strokes occurred in the treatment group, all in trials conducted pre-1990, and none in the control group. There was no significant effect on mortality detected at either early or intermediate follow-up. Data on the occurrence of pulmonary embolism (PE) and recurrent DVT were inconclusive. Systemic thrombolysis and CDT had similar levels of effectiveness. Studies of CDT included two 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: Thrombolysis increases the patency of veins and reduces the incidence of PTS following proximal DVT by a third. Evidence suggests that systemic administration and CDT have similar effectiveness. Strict eligibility criteria appears to improve safety in recent studies and may be necessary to reduce the risk of bleeding complications. This may limit the applicability of this treatment. In those who are treated there is a small increased risk of bleeding. Using GRADE assessment, the evidence was judged to be of moderate quality due to many trials having low numbers of participants. However, the results across studies were consistent and we have reasonable confidence in these results.

Expert commentary

Post-thrombotic syndrome is a serious long-term complication of deep vein thrombosis (DVT). Patients with this syndrome may present with pain, swelling or even leg ulcers. The standard therapy for DVT is the use of anticoagulants or blood thinners. Up to half of patients develop post-thrombotic syndrome. Compression stockings were claimed to prevent post-thrombotic syndrome but recent studies do not support their use. The use of thrombolysis or clot dissolving drugs provides a further option in selected patients. This approach might reduce this syndrome but at the cost of increased bleeding. The role of thrombolysis in treatment of acute deep vein thrombosis requires clarification.

Roopen Arya, Professor of Thrombosis and Haemostasis, King’s College Hospital

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