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NIHR Signal Prolonging anticoagulant treatment after abdominal cancer surgery reduces clot risk

Published on 26 February 2019

doi: 10.3310/signal-000740

People who have low molecular weight heparin (LMWH) for between two to four weeks after abdominal or pelvic surgery, especially for cancer, have fewer blood clots in their large veins or lungs. In this review of seven trials, five per cent of people receiving extended treatment experienced a clot compared with 13% who received LMWH only while in hospital. There was no difference in bleeding complications.

The optimal duration of treatment following abdominal surgery is uncertain, balancing bleeding against clot risk. NICE recommends using LMWH (or alternative drug) for at least seven days, extending up to 28 days for people who have had major cancer surgery.

Extended treatment with LMWH may benefit a broader group of patients, but further exploration may be needed to look at whether those with non-cancer surgery might benefit to the same extent.

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Why was this study needed?

Every year about 1 in 1,000 people in the UK develop a venous thromboembolism (VTE). Either a blood clot in the deep veins (deep vein thrombosis) or in the lungs (pulmonary embolism). VTE is more common in people with cancer and following major surgery. Over half of all cases follow recent hospitalisation. VTE used to be a leading cause of preventable death in hospital.

It is now routine practice to give drug treatment to prevent blood clots while people recover in hospital after abdominal or pelvic surgery. But observational studies indicate that patients may remain at increased risk for up to four or six weeks after surgery.

The Cochrane review aimed to resolve the uncertainty by combining data from recent high-quality studies to see whether there is a place for a longer course of anticoagulation after abdominal or pelvic surgery.

What did this study do?

This Cochrane review includes seven randomised controlled trials of extended LMWH treatment, given for at least 14 days after abdominal or pelvic surgery compared with shorter treatment as an inpatient only. The 1,728 patients had either open or keyhole surgery. Five trials recruited patients specifically with cancer and two included surgery for either cancer or benign conditions.

Venous thromboembolism was confirmed by an objective test (such as venography). Most studies were of LMWH for around 28 days, with only one study treating for 14 days only. Studies using other anticoagulants or mechanical measures (e.g. compression stockings) were excluded.

Overall the evidence was rated as moderate quality. Sources of bias included lack of detail about randomisation methods, whether participants and assessors were blinded to group assignment and incomplete reporting of outcomes. Nevertheless, the results were similar across studies, and this increases confidence in the conclusions.

What did it find?

  • Extended LMWH reduced the risk of VTE up to 30 days after surgery, which occurred in 5.3% of the intervention group compared with 13.2% of the control group (odds ratio [OR] 0.38, 95% confidence interval [CI] 0.26 to 0.54; seven studies, 1,728 patients).
  • The findings were similar in the subgroup of patients who received open surgery: 6% experienced VTE after extended treatment vs 13.8% of the control group (OR 0.42, 95% CI 0.29 to 0.60; six studies).
  • Extended LMWH also reduced the risk of deep vein thrombosis in general (13% vs 5%; OR 0.39, 95% CI 0.27 to 0.55), and specifically thrombosis in the upper thigh or pelvic veins (4% vs 9%; OR 0.22, 95% CI 0.10 to 0.47; seven studies).
  • Extended treatment did not affect the risk of minor or major bleeds up to three months after surgery (3.4% in the intervention group vs 2.8% in the control group; OR 1.10, 95% CI 0.67 to 1.81; seven studies).

What does current guidance say on this issue?

The NICE guideline on reducing risk of hospital-acquired venous thromboembolism (published 2018) recommends using LMWH (or an alternative drug, fondaparinux sodium) for a minimum of seven days for people undergoing abdominal surgery, taking into account individual patient factors and according to clinical judgement. 

NICE recommends considering extending VTE prophylaxis to 28 days postoperatively for people who have had major cancer surgery in the abdomen. 

What are the implications?

These results suggest that extended VTE prophylaxis after abdominal or pelvic surgery is beneficial, especially in cancer surgery.  This is in agreement with evidence in orthopaedic surgery and with current NICE guidance in cancer surgery.

It is difficult to be certain whether the findings apply to patients following non-cancer surgery as two trials that included these patient groups didn’t separate their results.

Newer oral anticoagulant drugs may provide similar benefits, but these were not tested in the studies included.  

Citation and Funding

Felder S, Rasmussen MS, King R et al. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev. 2018;11:CD004318.

The review was carried out by the Cochrane Colorectal Cancer Group which is funded by the Danish Government.

Bibliography

NICE. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NG89. London National Institute for Health and Care Excellence; 2018.

Thrombosis UK. Thrombosis statistics. Llanwrda: Thrombosis UK; accessed 2019.

Why was this study needed?

Every year about 1 in 1,000 people in the UK develop a venous thromboembolism (VTE). Either a blood clot in the deep veins (deep vein thrombosis) or in the lungs (pulmonary embolism). VTE is more common in people with cancer and following major surgery. Over half of all cases follow recent hospitalisation. VTE used to be a leading cause of preventable death in hospital.

It is now routine practice to give drug treatment to prevent blood clots while people recover in hospital after abdominal or pelvic surgery. But observational studies indicate that patients may remain at increased risk for up to four or six weeks after surgery.

The Cochrane review aimed to resolve the uncertainty by combining data from recent high-quality studies to see whether there is a place for a longer course of anticoagulation after abdominal or pelvic surgery.

What did this study do?

This Cochrane review includes seven randomised controlled trials of extended LMWH treatment, given for at least 14 days after abdominal or pelvic surgery compared with shorter treatment as an inpatient only. The 1,728 patients had either open or keyhole surgery. Five trials recruited patients specifically with cancer and two included surgery for either cancer or benign conditions.

Venous thromboembolism was confirmed by an objective test (such as venography). Most studies were of LMWH for around 28 days, with only one study treating for 14 days only. Studies using other anticoagulants or mechanical measures (e.g. compression stockings) were excluded.

Overall the evidence was rated as moderate quality. Sources of bias included lack of detail about randomisation methods, whether participants and assessors were blinded to group assignment and incomplete reporting of outcomes. Nevertheless, the results were similar across studies, and this increases confidence in the conclusions.

What did it find?

  • Extended LMWH reduced the risk of VTE up to 30 days after surgery, which occurred in 5.3% of the intervention group compared with 13.2% of the control group (odds ratio [OR] 0.38, 95% confidence interval [CI] 0.26 to 0.54; seven studies, 1,728 patients).
  • The findings were similar in the subgroup of patients who received open surgery: 6% experienced VTE after extended treatment vs 13.8% of the control group (OR 0.42, 95% CI 0.29 to 0.60; six studies).
  • Extended LMWH also reduced the risk of deep vein thrombosis in general (13% vs 5%; OR 0.39, 95% CI 0.27 to 0.55), and specifically thrombosis in the upper thigh or pelvic veins (4% vs 9%; OR 0.22, 95% CI 0.10 to 0.47; seven studies).
  • Extended treatment did not affect the risk of minor or major bleeds up to three months after surgery (3.4% in the intervention group vs 2.8% in the control group; OR 1.10, 95% CI 0.67 to 1.81; seven studies).

What does current guidance say on this issue?

The NICE guideline on reducing risk of hospital-acquired venous thromboembolism (published 2018) recommends using LMWH (or an alternative drug, fondaparinux sodium) for a minimum of seven days for people undergoing abdominal surgery, taking into account individual patient factors and according to clinical judgement. 

NICE recommends considering extending VTE prophylaxis to 28 days postoperatively for people who have had major cancer surgery in the abdomen. 

What are the implications?

These results suggest that extended VTE prophylaxis after abdominal or pelvic surgery is beneficial, especially in cancer surgery.  This is in agreement with evidence in orthopaedic surgery and with current NICE guidance in cancer surgery.

It is difficult to be certain whether the findings apply to patients following non-cancer surgery as two trials that included these patient groups didn’t separate their results.

Newer oral anticoagulant drugs may provide similar benefits, but these were not tested in the studies included.  

Citation and Funding

Felder S, Rasmussen MS, King R et al. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev. 2018;11:CD004318.

The review was carried out by the Cochrane Colorectal Cancer Group which is funded by the Danish Government.

Bibliography

NICE. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NG89. London National Institute for Health and Care Excellence; 2018.

Thrombosis UK. Thrombosis statistics. Llanwrda: Thrombosis UK; accessed 2019.

Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery

Published on 28 November 2018

Felder, S.,Rasmussen, M. S.,King, R.,Sklow, B.,Kwaan, M.,Madoff, R.,Jensen, C.

Cochrane Database Syst Rev Volume 11 , 2018

BACKGROUND: This an update of the review first published in 2009.Major abdominal and pelvic surgery carries a high risk of venous thromboembolism (VTE). The efficacy of thromboprophylaxis with low molecular weight heparin (LMWH) administered during the in-hospital period is well-documented, but the optimal duration of prophylaxis after surgery remains controversial. Some studies suggest that patients undergoing major abdominopelvic surgery benefit from prolongation of the prophylaxis up to 28 days after surgery. OBJECTIVES: To evaluate the efficacy and safety of prolonged thromboprophylaxis with LMWH for at least 14 days after abdominal or pelvic surgery compared with thromboprophylaxis administered during the in-hospital period only in preventing late onset VTE. SEARCH METHODS: We performed electronic searches on 28 October 2017 in the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, LILACS and registered trials (Clinicaltrials.gov October 28, 2017 and World Health Organization International Clinical Trials Registry Platform (ICTRP) 28 October 2017). Abstract books from major congresses addressing thromboembolism were handsearched from 1976 to 28 October 2017, as were reference lists from relevant studies. SELECTION CRITERIA: We assessed randomized controlled clinical trials (RCTs) comparing prolonged thromboprophylaxis (>/= fourteen days) with any LMWH agent with placebo, or other methods, or both to thromboprophylaxis during the admission period only. The population consisted of persons undergoing abdominal or pelvic surgery for both benign and malignant pathology. The outcome measures included VTE (deep venous thrombosis (DVT) or pulmonary embolism (PE)) as assessed by objective means (venography, ultrasonography, pulmonary ventilation/perfusion scintigraphy, spiral computed tomography (CT) scan or autopsy). We excluded studies exclusively reporting on clinical diagnosis of VTE without objective confirmation. DATA COLLECTION AND ANALYSIS: Review authors identified studies and extracted data. Outcomes were VTE (DVT or PE) assessed by objective means. Safety outcomes were defined as bleeding complications within three months after surgery. Sensitivity analyses were also performed with unpublished studies excluded, and with study participants limited to those undergoing solely open and not laparoscopic surgery. We used a fixed-effect model for analysis. MAIN RESULTS: We identified seven RCTs (1728 participants) evaluating prolonged thromboprophylaxis with LMWH compared with control or placebo. The searches resulted in 1632 studies, of which we excluded 1528. One hundred and four abstracts, eligible for inclusion, were assessed of which seven studies met the inclusion criteria.For the primary outcome, the incidence of overall VTE after major abdominal or pelvic surgery was 13.2% in the control group compared to 5.3% in the patients receiving out-of-hospital LMWH (Mantel Haentzel (M-H) odds ratio (OR) 0.38, 95% confidence interval (CI) 0.26 to 0.54; I(2) = 28%; seven studies, n = 1728; moderate-quality evidence).For the secondary outcome of all DVT, seven studies, n = 1728, showed prolonged thromboprophylaxis with LMWH to be associated with a statistically significant reduction in the incidence of all DVT (M-H OR 0.39, 95% CI 0.27 to 0.55; I(2) = 28%; moderate-quality evidence).We found a similar reduction when analysis was limited to incidence in proximal DVT (M-H OR 0.22, 95% CI 0.10 to 0.47; I(2) = 0%; moderate-quality evidence).The incidence of symptomatic VTE was also reduced from 1.0% in the control group to 0.1% in patients receiving prolonged thromboprophylaxis (M-H OR 0.30, 95% CI 0.08 to 1.11; I(2) = 0%; moderate-quality evidence).No difference in the incidence of bleeding between the control and LMWH group was found, 2.8% and 3.4%, respectively (HM-H OR 1.10, 95% CI 0.67 to 1.81; I(2) = 0%; seven studies, n = 2239; moderate-quality evidence).Estimates of heterogeneity ranged between 0% and 28% depending on the analysis, suggesting low or unimportant heterogeneity. AUTHORS' CONCLUSIONS: Prolonged thromboprophylaxis with LMWH significantly reduces the risk of VTE compared to thromboprophylaxis during hospital admittance only, without increasing bleeding complications after major abdominal or pelvic surgery. This finding also holds true for DVT alone, and for both proximal and symptomatic DVT. The quality of the evidence is moderate and provides moderate support for routine use of prolonged thromboprophylaxis. Given the low heterogeneity between studies and the consistent and moderate evidence of a decrease in risk for VTE, our findings suggest that additional studies may help refine the degree of risk reduction but would be unlikely to significantly influence these findings. This updated review provides additional evidence and supports the previous results reported in the 2009 review.

Expert commentary

Abdominal and pelvic surgery carries a risk of postoperative venous thromboembolism (VTE). Current practice recommends mechanical and chemical VTE prophylaxis during hospital stay. NICE guidelines would only consider extended prophylaxis (28 days) for these patients.

This new meta-analysis adds sufficient evidence (although moderate) that 14 days extended VTE prophylaxis is effective in preventing VTE after discharge for these patients. The review assessed low molecular weight heparin (LMWH) only for extended prophylaxis. In order to update the NICE guidelines and influence the national practice, a cost-effectiveness analysis would be required. 

Furthermore, with emerging of new oral anticoagulation agents, future trials will be needed to show if these agents can be used instead of daily LMWH injections.

Zaed Z Hamady, PhD Senior Clinical Lecturer, University of Southampton; Consultant Hepatobiliary, Pancreatic and Laparoscopic Surgeon, University Hospital Southampton NHS Foundation Trust

The commentator declares no conflicting interests

Expert commentary

Up to two-thirds of hospital-associated venous thromboembolism (VTE) occurs after discharge from hospital. Post-discharge thromboprophylaxis is recommended after elective knee and hip replacement surgery and for hip fractures.

For other surgical procedures, prophylaxis after discharge is not routine though NICE recommend such an approach be considered after major abdominal cancer surgery. This review supports the case for prolonged thromboprophylaxis with low molecular weight heparin for at least 14 days after major abdominal or pelvic surgery, whether for benign or malignant disease. 

If implemented, this practice has the potential to reduce post-discharge VTE though resource implications would be significant.

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

The commentator declares previous support from the manufacturers of enoxaparin and dalteparin