RecommendationOffer combined VTE prophylaxis with mechanical and pharmacological methods to patients undergoing elective knee replacement surgery. * Dabigatran etexilate, within its marketing authorisation, is recommended as an option for the primary prevention of venous thromboembolic events in adults who have undergone elective total hip replacement surgery or elective total knee replacement surgery. NICE technology appraisal guidance 157 (2008).476
$ Rivaroxaban, within its marketing authorisation, is recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery. NICE technology appraisal guidance 170 (2009).479
Relative values of different outcomesThe orthopaedic subgroup noted that although all cause mortality is the most important outcome for this population the studies were not powered to detect a difference in mortality for any of the interventions under consideration. The next most important outcome was thought to be the risk of symptomatic venous thromboembolism balanced against the risk of major bleeding. The relative risk reduction for all DVT events was used as a surrogate for symptomatic VTE events as the orthopaedic subgroup accepted that there was a relationship between the risk reduction in DVT and PE.
Trade off between clinical benefit and harmsThe benefit of reducing VTE events was balanced with the potential harms of bleeding. The economic model includes consideration of long term sequelae such as the cost of reoperation due to bleeding, post thrombotic syndrome, chronic thromboembolic pulmonary hypertension and stroke.
Our decision model indicated that the QALYs lost due to major bleeding were outweighed by the QALYs gained from drug prophylaxis.
Economic considerationsAn economic model was developed for this population which found that fondaparinux, dabigatran, LMWH and rivaroxaban were the most cost-effective strategies.
AspirinHD_plus_IPCD-FID also came out as relatively cost-effective in the base case analysis but this was on the basis that aspirin does not increase the risk of major bleeding. When an increased risk of bleeding similar to LMW H was assumed then aspirin was no longer cost-effective. The GDG felt that the base case assumption was not plausible and therefore concluded that AspirinHD_plus_IPCD-FID was not sufficiently cost-effective.
Quality of evidenceAll included RCTs were either individually critically appraised to be of a high quality (level 1+ or level 1++) or came from systematic reviews of RCTs which had been critically appraised to be of a high quality (level 1+ or level 1++).
The clinical evidence consisted of 23 RCTs in knee replacement surgery of which 18 were included in the network meta-analysis for DVT. The studies tended to be relatively large and only 17% (4/23) had less than 100 patients. Additionally they were relatively recent studies with only9% (2/23) published before 1990 and 52% (11/23) published since 2000.
Other considerationsPharmacological prophylaxis: The orthopaedic subgroup were mindful of the increase in bleeding risk in the period immediately after knee surgery and agreed that prophylaxis should be started only after the immediate bleeding risk had reduced.
Only one RCT compared pre op start times with post-op start for LMWH and this showed no significant difference in major bleeding.
The summary of product characteristics states a postoperative start time for dabigatran, rivaroxaban and fondaparinux, and a preoperative start time for most LMWHs although the actual start times vary depending on the specific LMWH. In this guideline it is recommended that LMWH is started postoperatively which is off-label because concerns about the risk of bleeding into the joint. Patients would be protected preoperatively against VTE by mechanical prophylaxis. Some of the LMWH studies included in our analyses also started LMWH postoperatively. Further information should be sought from the summary of product characteristics for each anticoagulant.
The LMWH dose used in the comparison of LMWH with rivaroxaban is higher than that recommended for use in the UK. This was taken into account when considering which pharmacological agents to use.
Mechanical prophylaxis:
There was no evidence in knee replacement patients for the use of stockings alone. Because there were no trials which used stockings they could not be included in the network meta-analysis for knee replacement patients, and were not included in the cost-effectiveness model. There was a discussion within the orthopaedic subgroup about the practicality of using anti-embolism stockings after knee replacement surgery. Patients are likely to have swollen legs after surgery and so it was felt important to ensure that patient’s legs are re-measured after surgery to ensure stockings remained correctly fitted correctly.
The evidence demonstrates that IPCD/FID devices were effective at reducing DVT and were a more practical solution in these patients. The orthopaedic subgroup therefore recommended that IPCD/FID were available as an alternative to anti-embolism stockings. The orthopaedic subgroup were aware of potential patient compliance issues with the use of IPCD and difficulty of their use when patients regained mobility but agreed that either anti-embolism stockings or IPCD devices should be continued until the patient was discharged or no longer had significantly reduced mobility.
Mechanical prophylaxis was felt to be particularly important in the period around the operation where patients were not protected by chemical prophylaxis. The orthopaedic subgroup agreed that by providing mechanical methods from admission the risk of developing DVT in the peri-operative period was reduced.
Duration of prophylaxis: The duration of pharmacological prophylaxis from the trials and on which the cost-effectiveness model was based was between 7–14 days. The orthopaedic subgroup noted that the length of stay for knee replacement patients is likely to be around 5–7 days. The orthopaedic subgroup decided that the duration of prophylaxis should be for 10–14 days (as per licensing conditions), in order to reflect the evidence from trials. This may require prophylaxis outside the hospital period. If the patient is discharged with prophylaxis, their GP should be notified to ensure that appropriate after care is provided. A suitable regime might be LMWH whilst in hospital followed by oral agents once discharged home.

From: 11, Elective knee replacement

Cover of Venous Thromboembolism
Venous Thromboembolism: Reducing the Risk of Venous Thromboembolism (Deep Vein Thrombosis and Pulmonary Embolism) in Patients Admitted to Hospital.
NICE Clinical Guidelines, No. 92.
National Clinical Guideline Centre – Acute and Chronic Conditions (UK).
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