Different strategies for pharmacological thromboprophylaxis for lower-limb immobilisation after injury: systematic review and economic evaluation

Abstract

Background Thromboprophylaxis can reduce the risk of venous thromboembolism (VTE) during lower-limb immobilisation, but it is unclear whether or not this translates into meaningful health benefit, justifies the risk of bleeding or is cost-effective. Risk assessment models (RAMs) could select higher-risk individuals for thromboprophylaxis. Objectives To determine the clinical effectiveness and cost-effectiveness of different strategies for providing thromboprophylaxis to people with lower-limb immobilisation caused by injury and to identify priorities for future research. Data sources Ten electronic databases and research registers (MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Review of Effects, the Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluation Database, Science Citation Index Expanded, ClinicalTrials.gov and the International Clinical Trials Registry Platform) were searched from inception to May 2017, and this was supplemented by hand-searching reference lists and contacting experts in the field. Review methods Systematic reviews were undertaken to determine the effectiveness of pharmacological thromboprophylaxis in lower-limb immobilisation and to identify any study of risk factors or RAMs for VTE in lower-limb immobilisation. Study quality was assessed using appropriate tools. A network meta-analysis was undertaken for each outcome in the effectiveness review and the results of risk-prediction studies were presented descriptively. A modified Delphi survey was undertaken to identify risk predictors supported by expert consensus. Decision-analytic modelling was used to estimate the incremental cost per quality-adjusted life-year (QALY) gained of different thromboprophylaxis strategies from the perspectives of the NHS and Personal Social Services. Results Data from 6857 participants across 13 trials were included in the meta-analysis. Thromboprophylaxis with low-molecular-weight heparin reduced the risk of any VTE [odds ratio (OR) 0.52, 95% credible interval (CrI) 0.37 to 0.71], clinically detected deep-vein thrombosis (DVT) (OR 0.40, 95% CrI 0.12 to 0.99) and pulmonary embolism (PE) (OR 0.17, 95% CrI 0.01 to 0.88). Thromboprophylaxis with fondaparinux (Arixtra®, Aspen Pharma Trading Ltd, Dublin, Ireland) reduced the risk of any VTE (OR 0.13, 95% CrI 0.05 to 0.30) and clinically detected DVT (OR 0.10, 95% CrI 0.01 to 0.94), but the effect on PE was inconclusive (OR 0.47, 95% CrI 0.01 to 9.54). Estimates of the risk of major bleeding with thromboprophylaxis were inconclusive owing to the small numbers of events. Fifteen studies of risk factors were identified, but only age (ORs 1.05 to 3.48), and injury type were consistently associated with VTE. Six studies of RAMs were identified, but only two reported prognostic accuracy data for VTE, based on small numbers of patients. Expert consensus was achieved for 13 risk predictors in lower-limb immobilisation due to injury. Modelling showed that thromboprophylaxis for all is effective (0.015 QALY gain, 95% CrI 0.004 to 0.029 QALYs) with a cost-effectiveness of £13,524 per QALY, compared with thromboprophylaxis for none. If risk-based strategies are included, it is potentially more cost-effective to limit thromboprophylaxis to patients with a Leiden thrombosis risk in plaster (cast) [L-TRiP(cast)] score of ≥ 9 (£20,000 per QALY threshold) or ≥ 8 (£30,000 per QALY threshold). An optimal threshold on the L-TRiP(cast) receiver operating characteristic curve would have sensitivity of 84–89% and specificity of 46–55%. Limitations Estimates of RAM prognostic accuracy are based on weak evidence. People at risk of bleeding were excluded from trials and, by implication, from modelling. Conclusions Thromboprophylaxis for lower-limb immobilisation due to injury is clinically effective and cost-effective compared with no thromboprophylaxis. Risk-based thromboprophylaxis is potentially optimal but the prognostic accuracy of existing RAMs is uncertain. Future work Research is required to determine whether or not an appropriate RAM can accurately select higher-risk patients for thromboprophylaxis. Study registration This study is registered as PROSPERO CRD42017058688. Funding The National Institute for Health Research Health Technology Assessment programme.

Pharmacological thromboprophylaxis to prevent venous thromboembolism in patients with temporary lower limb immobilization after injury: systematic review and network meta‐analysis

“…Several risk assessment models (RAM) have already been derived for use in this patient population, aiming to tailor thromboprophylaxis strategies at presumed high risk and limit financial costs, opportunity costs, and side effects . The current evidence base for RAMs is very limited, and estimates of sensitivity and specificity are subject to substantial uncertainty . Improving the evidence base for RAMs is a key research priority and external validation studies are urgently needed.…”

“…The systematic review was undertaken in accordance with the general principles recommended in the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement . This review was part of a larger project on thromboprophylaxis for lower limb immobilization that was registered on the PROSPERO international prospective register of systematic reviews (CRD42017058688) . The full protocol is available here (https://www.journalslibrary.nihr.ac.uk/programmes/hta/1518706/#/).…”

Thromboprophylaxis in lower limb immobilisation after injury (TiLLI)

“…We found that both LMWH and fondaparinux significantly reduced the odds of clinically detected DVT, PE and any VTE. Intervention appeared to halve the risk of VTE across all classifications 23…”

“…Can pharmacological thromboprophylaxis reduce this morbidity burden and, if so, by what margin? We performed a recently updated systematic review and network meta-analysis to compare any pharmacological intervention against control for this defined population 22 23. This review included the Prevention of Thrombosis after Lower Leg Plaster Cast (POT-CAST) trial,21 which has reignited debate on this important topic, and other recent randomised studies assessing the novel use of fondaparinux for this indication.…”

“…Although this may represent a potentially high number needed to treat, this value would depend primarily on baseline risk (which is likely to vary within the population) and also would be considered in the context of prevalence. Approximately 70 000 patients are immobilised and discharged from EDs in the UK alone every year 23. Even a 1% absolute risk reduction in the VTE event rate in this cohort would therefore represent prevention of 700 clinically relevant VTE events.…”